Cold weather can affect your body in different ways. You can get frostbite, which is an injury to the body that is caused by freezing. Your body can also lose heat faster than you can produce it. That can cause hypothermia, or abnormally low body temperature. It can make you sleepy, confused, and clumsy. Because it happens gradually and affects your thinking, you may not realize you need help. That makes it especially dangerous. A body temperature below 95 °F (35 °C) is a medical emergency and can lead to death if not treated promptly.
Anyone who spends much time outdoors in cold weather can get hypothermia. You can also get it from being cold and wet, or under cold water for too long. Babies and old people are especially at risk. Babies can get it from sleeping in a cold room.
Centers for Disease Control and Prevention
. mitochondrial defined as following: The distribution of mitochondria, including the mitochondrial genome, into daughter cells after mitosis or meiosis, mediated by interactions between mitochondria and the cytoskeleton. [GOC:mcc, PMID:10873824, PMID:11389764]. brown fat cells defined as following: Fat cells with dark coloration due to the densely packed MITOCHONDRIA. They contain numerous small lipid droplets or vacuoles. Their stored lipids can be converted directly to energy as heat by the mitochondria..", "label": "yes"} {"id": "converted_2454", "sentence1": "Does the human lncRNA LINC-PINT promote tumorigenesis?", "sentence2": "The human lncRNA LINC-PINT inhibits tumor cell invasion through a highly conserved sequence element., Here we characterize the function of the p53-regulated human lncRNA LINC-PINT in cancer. We find that LINC-PINT is downregulated in multiple types of cancer and acts as a tumor suppressor lncRNA by reducing the invasive phenotype of cancer cells. A cross-species analysis identifies a highly conserved sequence element in LINC-PINT that is essential for its function. This sequence mediates a specific interaction with PRC2, necessary for the LINC-PINT-dependent repression of a pro-invasion signature of genes regulated by the transcription factor EGR1., We find that LINC-PINT is downregulated in multiple types of cancer and acts as a tumor suppressor lncRNA by reducing the invasive phenotype of cancer cells., These results thus indicate that low plasma Linc-pint expression could serve as a minimally invasive biomarker for early PCa detection, and that low Linc-pint levels in PCa tumors could be used for predicting patient prognosis., Our data demonstrate that Linc-pint expression is lower in plasma samples from PCa patients than from healthy individuals, and indicate that plasma Linc-pint levels are more sensitive than CA19-9 for detecting PCa., Low plasma Linc-pint levels correlate with tumor recurrence, while low tumor Linc-pint levels correlate with poor prognosis for PCa patients after pancreatectomy., We find that LINC-PINT is downregulated in multiple types of cancer and acts as a tumor suppressor lncRNA by reducing the invasive phenotype of cancer cells., We find that LINC-PINT is downregulated in multiple types of cancer and acts as a tumor suppressor lncRNA by reducing the invasive phenotype of cancer cells., These results thus indicate that low plasma Linc-pint expression could serve as a minimally invasive biomarker for early PCa detection, and that low Linc-pint levels in PCa tumors could be used for predicting patient prognosis.Chickens raised for egg production
. topoisomerase I defined as following: DNA TOPOISOMERASES that catalyze ATP-independent breakage of one of the two strands of DNA, passage of the unbroken strand through the break, and rejoining of the broken strand. DNA Topoisomerases, Type I enzymes reduce the topological stress in the DNA structure by relaxing the superhelical turns and knotted rings in the DNA helix.. camptothecin defined as following: An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA TOPOISOMERASES, TYPE I. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity.. DNA-binding protein defined as following: Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.. Chromatin defined as following: The ordered and organized complex of DNA, protein, and sometimes RNA, that forms the chromosome. [GOC:elh, PMID:20404130]. pre-mRNA defined as following: A primary RNA transcript synthesized from a DNA template in eukaryotic nuclei which is post-transcriptionally modified and spliced to produce a mature mRNA.. transcription factors defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.. mammalian defined as following: Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young..", "label": "yes"} {"id": "converted_2626", "sentence1": "Can nanoparticles be used for afterglow imaging?", "sentence2": "Ultralong Phosphorescence of Water-Soluble Organic Nanoparticles for In Vivo Afterglow Imaging, Afterglow or persistent luminescence eliminates the need for light excitation and thus circumvents the issue of autofluorescence, holding promise for molecular imaging. However, current persistent luminescence agents are rare and limited to inorganic nanoparticles. This study reports the design principle, synthesis, and proof-of-concept application of organic semiconducting nanoparticles (OSNs) with ultralong phosphorescence for in vivo afterglow imaging. , This study not only introduces the first category of water-soluble ultralong phosphorescence organic nanoparticles but also reveals a universal design principle to prolong the lifetime of phosphorescent molecules to the level that can be effective for molecular imaging.[SEP]Definitions: inorganic defined as following: Relating or belonging to the class of compounds not having a carbon basis.. nanoparticles defined as following: Nanometer-sized particles that are nanoscale in three dimensions. They include nanocrystaline materials; NANOCAPSULES; METAL NANOPARTICLES; DENDRIMERS, and QUANTUM DOTS. The uses of nanoparticles include DRUG DELIVERY SYSTEMS and cancer targeting and imaging..", "label": "yes"} {"id": "converted_1237", "sentence1": "Has the protein GFP been used in transgenesis for live protein imaging?", "sentence2": "we review recent advancement in the functional studies of the three different GnRH neuron systems, mainly focusing on the electrophysiological analysis of the GnRH-green fluorescent protein (GFP) transgenic animals., founders were found to be transgenic for GFP., GFP expression was detected in a wide range of murine tissues, Transgenic Xenopus laevis for live imaging in cell and developmental biology., The stable transgenesis of genes encoding functional or spatially localized proteins, fused to fluorescent proteins such as green fluorescent protein (GFP) or red fluorescent protein (RFP), is an extremely important research tool in cell and developmental biology., GFP-transgenic animals for in vivo imaging: rats, rabbits, and pigs., We have further extended the techniques of genetic engineering to rats, rabbits, and pigs, and have created corresponding GFP-transgenic animals., The results revealed that the 3.6-GFP transgenic animals provide a unique model for direct analysis of cellular and molecular mechanisms of pulp repair and tertiary dentinogenesis in vivo., Long-term effects of PERV-specific RNA interference in transgenic pigs., green fluorescent protein (GFP) as reporter of the vector system were consistently expressed in transgenic animals., The ability to specify the expression levels of exogenous genes inserted in the genomes of transgenic animals is critical for the success of a wide variety of experimental manipulations. , Welfare assessment in transgenic pigs expressing green fluorescent protein (GFP)., transgenic animals expressing GFP with wildtype animals along various stages of post natal development, Production of transgenic chickens expressing a tetracycline-inducible GFP gene., transgenic animals can be readily created to express fluorescently tagged proteins or reporters, These findings suggest that mhc2dab:GFP and cd45:DsRed transgenic lines will be instrumental in elucidating the immune response in the zebrafish., f 33 mice born, 28 (81%) carried the transgene DNA and 15 (55.5%) were GFP-positive., Lentiviral vectors containing the green fluorescent protein gene have been successfully used to select transgenic embryos before transfer to a surrogate mother, Typically transgenes are generated by placing a promoter upstream of a GFP reporter gene or cDNA of interest, and this often produces a representative expression pattern., Survival and immunogenicity of mesenchymal stem cells from the green fluorescent protein transgenic rat in the adult rat brain., This problem has been lessened by the availability of transgenic animals that express \"reporter\" genes, such as green fluorescent protein (GFP), full-length GFP fusion proteins was examined, in transgenic animals, , Two stable transgenic lines express GFP prior to hair-bundle formation, we generated two transgenic pigs by somatic cell nuclear transfer (SCNT) that express green fluorescent protein (GFP) driven by cytomegalovirus (CMV)., Fluorescent proteins such as the green fluorescent protein (GFP) have widely been used in transgenic animals as reporter genes. , Green Fluorescent Protein (GFP) is used extensively as a reporter for transgene expression in Drosophila and other organisms.[SEP]Definitions: mesenchymal stem cells defined as following: An undifferentiated stromal cell with the ability to develop into the cells that form distinct mesenchymal tissues; such as bone, muscle, connective tissue, blood vessels, and lymphatic tissue.. transgenic animals defined as following: Experimental organism whose genome has been altered by the transfer of a gene or genes from another species or breed.. pulp defined as following: A richly vascularized and innervated connective tissue of mesodermal origin, contained in the central cavity of a tooth and delimited by the dentin, and having formative, nutritive, sensory, and protective functions. (Jablonski, Dictionary of Dentistry, 1992). rabbits defined as following: Taxonomic family which includes rabbits and hares.. rat defined as following: The common rat, Rattus norvegicus, often used as an experimental organism.. green fluorescent protein defined as following: Protein analogs and derivatives of the Aequorea victoria green fluorescent protein that emit light (FLUORESCENCE) when excited with ULTRAVIOLET RAYS. They are used in REPORTER GENES in doing GENETIC TECHNIQUES. Numerous mutants have been made to emit other colors or be sensitive to pH.. cDNA defined as following: Single-stranded complementary DNA synthesized from an RNA template by the action of RNA-dependent DNA polymerase. cDNA (i.e., complementary DNA, not circular DNA, not C-DNA) is used in a variety of molecular cloning experiments as well as serving as a specific hybridization probe.. zebrafish defined as following: An exotic species of the family CYPRINIDAE, originally from Asia, that has been introduced in North America. Zebrafish is a model organism for drug assay and cancer research.. cellular defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. transgenes defined as following: Genes that are introduced into an organism using GENE TRANSFER TECHNIQUES.. genomes defined as following: The genetic complement of an organism, including all of its GENES, as represented in its DNA, or in some cases, its RNA.. RFP defined as following: Zinc finger protein RFP (513 aa, ~58 kDa) is encoded by the human TRIM27 gene. This protein is involved in the modulation of both gene transcription and apoptosis.. reporter genes defined as following: Genes whose expression is easily detectable and therefore used to study promoter activity at many positions in a target genome. In recombinant DNA technology, these genes may be attached to a promoter region of interest.. murine defined as following: Any of numerous species of small rodents belonging to the genus Mus and various related genera of the family Muridae.. organisms defined as following: A living entity.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. GFP defined as following: Protein analogs and derivatives of the Aequorea victoria green fluorescent protein that emit light (FLUORESCENCE) when excited with ULTRAVIOLET RAYS. They are used in REPORTER GENES in doing GENETIC TECHNIQUES. Numerous mutants have been made to emit other colors or be sensitive to pH.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species..", "label": "yes"} {"id": "converted_3871", "sentence1": "Is Olaparib effective for prostate cancer?", "sentence2": "We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. , CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. , In addition, phase III trials in breast, gastric and pancreatic cancer are underway/planned, and phase I/II investigation is being conducted in other malignancies, including prostate cancer, non-small cell lung cancer, Ewing's sarcoma and advanced cancer. , In a phase II study, researchers found that the PARP inhibitor olaparib led to stable disease or tumor regressions in patients with advanced breast, ovarian, pancreatic, and prostate cancers who had germline mutations in BRCA1 or BRCA2., Eligibility included ovarian cancer resistant to prior platinum; breast cancer with ≥ three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy. , The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers, respectively. Stable disease ≥ 8 weeks was observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreatic, or prostate cancer, respectively. , It is increasingly clear that there are molecularly distinct subtypes of various common cancers, with different therapeutic approaches required for each subtype, for example, the use of the monoclonal antibodies (trastuzumab and cetuximab) in HER2-positive breast cancer and wild-type KRAS colorectal cancer; tyrosine kinase inhibitors (imatinib, gefitinib, erlotinib and crizotinib) in chronic myeloid leukaemia, gastrointestinal stromal tumours and non-small-cell lung cancer and intracellular agents (vemurafenib and olaparib) in metastatic malignant melanoma and ovarian, breast and prostate cancer., Olaparib, one of the most studied PARPis, has demonstrated activity in BRCA1/2(MUT+) and BRCA-like sporadic ovarian and breast cancers, and looks promising in prostate and pancreatic cancers., Prostate cancer cells cotreated with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) and the PARPi, olaparib, demonstrated a synergistic decrease in cell viability compared with single-agent treatment (combination index<0.9), whereas normal prostatic cells did not., CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate., Olaparib, one of the most studied PARPis, has demonstrated activity in BRCA1/2(MUT+) and BRCA-like sporadic ovarian and breast cancers, and looks promising in prostate and pancreatic cancers. , DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer., Prostate cancer cells cotreated with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) and the PARPi, olaparib, demonstrated a synergistic decrease in cell viability compared with single-agent treatment (combination index < 0.9), whereas normal prostatic cells did not., We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib., A phase II study of the PARP inhibitor olaparib (AstraZeneca) for cancer patients with inherited BRCA1 and BRCA2 gene mutations confirmed earlier results showing clinical benefit for advanced breast and ovarian cancers, and demonstrated evidence of effectiveness against pancreatic and prostate cancers., BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. , Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib., Silencing RAD51 sensitized prostate cancer cells to SAHA and olaparib alone. Collectively, cotreatment with HDACi and PARPi downregulated HR-related protein expression and concomitantly increased DNA damage, resulting in prostate cancer cell death., Prostate cancer cells cotreated with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) and the PARPi, olaparib, demonstrated a synergistic decrease in cell viability compared with single-agent treatment (combination index<0.9), whereas normal prostatic cells did not. , The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. , Prostate cancer cells cotreated with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) and the PARPi, olaparib, demonstrated a synergistic decrease in cell viability compared with single-agent treatment (combination index < 0.9), whereas normal prostatic cells did not., In addition, phase III trials in breast, gastric and pancreatic cancer are underway/planned, and phase I/II investigation is being conducted in other malignancies, including prostate cancer, non-small cell lung cancer, Ewing's sarcoma and advanced cancer. , INTERPRETATION: Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice., CONCLUSIONS: In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone., Olaparib is an additional option for second- and third-line treatment in those with alterations in BRCA1, BRCA2, and ATM. , In this review, we describe current therapies for mCRPC, the rationale for anti-PARP therapies, the pharmacology of olaparib for prostate cancer, clinical trials of olaparib for mCRPC, our clinical experience with olaparib for prostate cancer at a comprehensive cancer center, and future directions of olaparib for the treatment of mCRPC., Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC)., Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations., BACKGROUND: Patients with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations have a better response to treatment with the poly(ADP-ribose) polymerase inhibitor olaparib than patients without HRR mutations., The TOPARP-A clinical trial demonstrated that the PARP inhibitor olaparib may be an effective strategy for treating prostate cancer., MMARY: The poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib are now approved by the Food and Drug Administration for the treatment of advanced prostate cancer. Here, we , BACKGROUND: We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent., Recent clinical studies show favorable results for the PARP inhibitor olaparib used as single agent for treatment of metastatic castration-resistant PCa., The PROFOUND phase III trial, comparing olaparib with enzalutamide/abiraterone therapy, revealed increased radiological progression-free survival (rPFS) and overall survival (OS) among patients with metastatic castration-resistant prostate cancer (mCRPC) with BRCA1, BRCA2 or ATM mutations., Olaparib Targets Some Advanced Prostate Cancers., The PARP inhibitor (PARPi) olaparib received FDA breakthrough designation for treatment of metastatic castration-resistant prostate cancers (CRPC) carrying mutations in BRCA1/2 or ATM genes., In prostate cancer, two PARPi, rucaparib and olaparib, have been FDA approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC)., Olaparib is an FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use, Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer, RECENT FINDINGS: The approval of several PARPi (olaparib, rucaparib, and niraparib) has driven the focus of anticancer treatment on synthetic lethality in prostate cancer too. , PATIENT SUMMARY: A large clinical study concluded that treatment with the PARP inhibitor olaparib benefits men with metastatic castration-resistant prostate cancer whose tumors harbor alterations in 15 different DNA repair genes., Among them, olaparib and rucaparib have breakthrough designations for BRCA1/2-mutated mCRPC., In phase II clinical trials, including patients with advanced castration-resistant PC, olaparib seems to be efficacious and well tolerated. , Of note is the recent U.S. Food and Drug Administration breakthrough therapy designation of olaparib for the treatment of BRCA1/2- or ATM-mutated metastatic castration-resistant prostate cancer. [SEP]Definitions: castration-resistant prostate cancer defined as following: Prostate carcinoma that grows and continues to spread despite the surgical removal of the testes or medical intervention to block androgen production.. rucaparib defined as following: An orally bioavailable tricyclic indole and inhibitor of poly(ADP-ribose) polymerases (PARPs) 1 (PARP1), 2 (PARP2) and 3 (PARP3), with potential chemo/radiosensitizing and antineoplastic activities. Upon administration, rucaparib selectively binds to PARP1, 2 and 3 and inhibits PARP-mediated DNA repair. This enhances the accumulation of DNA strand breaks, promotes genomic instability and induces cell cycle arrest and apoptosis. This may enhance the cytotoxicity of DNA-damaging agents and reverse tumor cell resistance to chemotherapy and radiation therapy. PARPs are enzymes activated by single-strand DNA breaks that catalyze the post-translational ADP-ribosylation of nuclear proteins, which induces signaling and the recruitment of other proteins to repair damaged DNA. The PARP-mediated repair pathway plays a key role in DNA repair and is dysregulated in a variety of cancer cell types.. prostate cancer defined as following: A primary or metastatic malignant tumor involving the prostate gland. The vast majority are carcinomas.. pancreatic cancer defined as following: A primary or metastatic malignant tumor involving the pancreas. Representative examples include carcinoma and lymphoma.. PARP defined as following: Human PARP1 wild-type allele is located within 1q41-q42 and is approximately 47 kb in length. This allele, which encodes poly [ADP-ribose] polymerase 1 protein, plays a critical role in DNA repair.. niraparib defined as following: An orally bioavailable inhibitor of poly (ADP-ribose) polymerase (PARP) types 1 and 2 (PARP-1 and -2), with antineoplastic activity. Upon administration, niraparib binds to and inhibits the activity of PARP-1 and -2, thereby inhibiting PARP-1 and -2-mediated DNA repair, enhancing the accumulation of DNA strand breaks, promoting genomic instability and resulting in apoptosis. The PARP family of proteins catalyzes post-translational ADP-ribosylation of nuclear proteins and is activated by single-strand DNA (ssDNA) breaks.. BRCA2 defined as following: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human chromosome 13 at locus 13q12.3. Mutations in this gene predispose humans to breast and ovarian cancer. It encodes a large, nuclear protein that is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (from Genes Dev 2000;14(11):1400-6). erlotinib defined as following: A quinazoline derivative with antineoplastic properties. Competing with adenosine triphosphate, erlotinib reversibly binds to the intracellular catalytic domain of epidermal growth factor receptor (EGFR) tyrosine kinase, thereby reversibly inhibiting EGFR phosphorylation and blocking the signal transduction events and tumorigenic effects associated with EGFR activation.. breast cancers defined as following: A primary or metastatic malignant neoplasm involving the breast. The vast majority of cases are carcinomas arising from the breast parenchyma or the nipple. Malignant breast neoplasms occur more frequently in females than in males.. breast defined as following: In humans, one of the paired regions in the anterior portion of the THORAX. The breasts consist of the MAMMARY GLANDS, the SKIN, the MUSCLES, the ADIPOSE TISSUE, and the CONNECTIVE TISSUES.. non-small cell lung cancer defined as following: A heterogeneous aggregate of at least three distinct histological types of lung cancer, including SQUAMOUS CELL CARCINOMA; ADENOCARCINOMA; and LARGE CELL CARCINOMA. They are dealt with collectively because of their shared treatment strategy.. pancreatic defined as following: Peptide hormones secreted into the blood by cells in the ISLETS OF LANGERHANS of the pancreas. The alpha cells secrete glucagon; the beta cells secrete insulin; the delta cells secrete somatostatin; and the PP cells secrete pancreatic polypeptide.. ovarian cancer defined as following: A primary or metastatic malignant neoplasm involving the ovary. Most primary malignant ovarian neoplasms are either carcinomas (serous, mucinous, or endometrioid adenocarcinomas) or malignant germ cell tumors. Metastatic malignant neoplasms to the ovary include carcinomas, lymphomas, and melanomas.. abiraterone defined as following: A steroidal compound with antiandrogen activity. Abiraterone inhibits the enzymatic activity of steroid 17alpha-monooxygenase (17alpha-hydrolase/C17,20 lyase complex; CYP17A1), a member of the cytochrome p450 family that catalyzes the 17alpha-hydroxylation of steroid intermediates involved in testosterone synthesis. Administration of this agent may suppress testosterone production by both the testes and the adrenals to castrate-range levels.. gefitinib defined as following: A selective tyrosine kinase inhibitor for the EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) that is used for the treatment of locally advanced or metastatic NON-SMALL CELL LUNG CANCER.. crizotinib defined as following: An orally available aminopyridine-based inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) and the c-Met/hepatocyte growth factor receptor (HGFR) with antineoplastic activity. Crizotinib, in an ATP-competitive manner, binds to and inhibits ALK kinase and ALK fusion proteins. In addition, crizotinib inhibits c-Met kinase, and disrupts the c-Met signaling pathway. Altogether, this agent inhibits tumor cell growth. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development. ALK dysregulation and gene rearrangements are associated with a series of tumors.. AstraZeneca defined as following: A global, science-led biopharmaceutical company headquartered in Cambridge, United Kingdom. The company focuses on the discovery, development and commercialization of prescription medicines.. chronic myeloid leukaemia defined as following: chronic leukemia in which myeloid progenitor cells predominate; the hallmark of CML, the Philadelphia chromosome, is a reciprocal translocation between chromosomes 9 and 22 which activates the proto- oncogene c-abl.. disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. cetuximab defined as following: A chimeric monoclonal antibody that functions as an ANTINEOPLASTIC AGENT through its binding to the EPIDERMAL GROWTH FACTOR RECEPTOR, where it prevents the binding and signaling action of cell growth and survival factors.. cancers defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. enzalutamide defined as following: An orally bioavailable, organic, non-steroidal small molecule targeting the androgen receptor (AR) with potential antineoplastic activity. Through a mechanism that is reported to be different from other approved AR antagonists, enzalutamide inhibits the activity of prostate cancer cell ARs, which may result in a reduction in prostate cancer cell proliferation and, correspondingly, a reduction in the serum prostate specific antigen (PSA) level. AR over-expression in prostate cancer represents a key mechanism associated with prostate cancer hormone resistance.. genomic defined as following: The genetic complement of an organism, including all of its GENES, as represented in its DNA, or in some cases, its RNA.. suberoylanilide hydroxamic acid defined as following: A synthetic hydroxamic acid derivative with antineoplastic activity. Vorinostat, a second generation polar-planar compound, binds to the catalytic domain of the histone deacetylases (HDACs). This allows the hydroxamic moiety to chelate zinc ion located in the catalytic pockets of HDAC, thereby inhibiting deacetylation and leading to an accumulation of both hyperacetylated histones and transcription factors. Hyperacetylation of histone proteins results in the upregulation of the cyclin-dependant kinase p21, followed by G1 arrest. Hyperacetylation of non-histone proteins such as tumor suppressor p53, alpha tubulin, and heat-shock protein 90 produces additional anti-proliferative effects. This agent also induces apoptosis and sensitizes tumor cells to cell death processes. Vorinostat crosses the blood-brain barrier.. gastrointestinal stromal tumours defined as following: All tumors in the GASTROINTESTINAL TRACT arising from mesenchymal cells (MESODERM) except those of smooth muscle cells (LEIOMYOMA) or Schwann cells (SCHWANNOMA).. BRCA1 defined as following: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human CHROMOSOME 17 at locus 17q21. Mutations of this gene are associated with the formation of HEREDITARY BREAST AND OVARIAN CANCER SYNDROME. It encodes a large nuclear protein that is a component of DNA repair pathways.. HRR defined as following: The error-free repair of a double-strand break in DNA in which the broken DNA molecule is repaired using homologous sequences. A strand in the broken DNA searches for a homologous region in an intact chromosome to serve as the template for DNA synthesis. The restoration of two intact DNA molecules results in the exchange, reciprocal or nonreciprocal, of genetic material between the intact DNA molecule and the broken DNA molecule. [GOC:elh, PMID:10357855]. Olaparib defined as following: A small molecule inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential chemosensitizing, radiosensitizing, and antineoplastic activities. Olaparib selectively binds to and inhibits PARP, inhibiting PARP-mediated repair of single strand DNA breaks; PARP inhibition may enhance the cytotoxicity of DNA-damaging agents and may reverse tumor cell chemoresistance and radioresistance. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins and can be activated by single-stranded DNA breaks.. trastuzumab defined as following: A humanized monoclonal antibody against the ERBB-2 RECEPTOR (HER2). As an ANTINEOPLASTIC AGENT, it is used to treat BREAST CANCER where HER2 is overexpressed.. tyrosine kinase inhibitors defined as following: Protein kinase inhibitors that inhibit TYROSINE PROTEIN KINASES.. fatigue defined as following: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli.. vemurafenib defined as following: An orally bioavailable, ATP-competitive, small-molecule inhibitor of BRAF(V600E) kinase with potential antineoplastic activity. Vemurafenib selectively binds to the ATP-binding site of BRAF(V600E) kinase and inhibits its activity, which may result in an inhibition of an over-activated MAPK signaling pathway downstream in BRAF(V600E) kinase-expressing tumor cells and a reduction in tumor cell proliferation. Approximately 90% of BRAF gene mutations involve a valine-to-glutamic acid mutation at residue 600 (V600E); the oncogene protein product, BRAF(V600E) kinase, exhibits a markedly elevated activity that over-activates the MAPK signaling pathway. The BRAF(V600E) gene mutation has been found to occur in approximately 60% of melanomas, and in about 8% of all solid tumors, including melanoma, colorectal, thyroid and other cancers.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. imatinib defined as following: An antineoplastic agent that inhibits the Bcr-Abl fusion protein tyrosine kinase, an abnormal enzyme produced by chronic myeloid leukemia cells that contain the Philadelphia chromosome. Imatinib also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF)/c-kit; the SCF/c-kit receptor tyrosine kinase is activated in gastrointestinal stromal tumor (GIST). This agent inhibits proliferation and induces apoptosis in cells that overexpress these oncoproteins.. Ewing's sarcoma defined as following: A small round cell bone tumor that lacks morphologic, immunohistochemical, and electron microscopic evidence of neuroectodermal differentiation. It represents one of the two ends of the spectrum called Ewing sarcoma/peripheral neuroectodermal tumor. It often affects the diaphysis or metaphyseal-diaphyseal portion of long bones. Clinical findings include pain and a mass in the involved area. Fever, anemia, leukocytosis, and an increased sedimentation rate are often seen. X-ray examination reveals osteolytic lesions. The prognosis depends on the stage, anatomic location, and size of the tumor.. monoclonal antibodies defined as following: Antibodies produced by a single clone of cells.. tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. gastric defined as following: Relating to the stomach.. HER2-positive breast cancer defined as following: A biologic subset of breast carcinoma defined by high expression of HER2, GRB7, and TRAP100, and by lack of expression of estrogen receptor (ER).. RAD51 defined as following: DNA repair protein RAD51 homolog 1 (339 aa, ~37 kDa) is encoded by the human RAD51 gene. This protein is involved in both homologous recombination and DNA repair.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. Plk1 defined as following: This gene plays a role in mitotic regulation.. molecular defined as following: Relating to or produced by or consisting of molecules..", "label": "yes"} {"id": "converted_747", "sentence1": "Is Hirschsprung disease one of the characteristics of the Mowat-Wilson syndrome?", "sentence2": "Mowat-Wilson syndrome is a genetic disease caused by heterozygous mutations or deletions of the zinc finger E-box-binding homeobox 2 (ZEB2) gene. The syndrome is characterized by typical facial features, moderate-to-severe mental retardation, epilepsy and variable congenital malformations, including Hirschsprung disease, genital anomalies, congenital heart disease, agenesis of the corpus callosum, and eye defects, Mowat-Wilson syndrome (MWS) is a rare genetic condition where variable and multiple congenital anomalies including Hirschsprung's disease, intellectual disability, and prominent facial features are present, Individuals with Mowat-Wilson syndrome (MWS; OMIM#235730) have characteristic facial features, a variety of congenital anomalies such as Hirschsprung disease, and intellectual disabilities caused by mutation or deletion of ZEB2 gene, Mowat-Wilson syndrome is a genetic disease characterized by typical facial features, Hirschsprung disease and multiple congenital abnormalities, Mowat-Wilson syndrome (MWS) is a severe intellectual disability (ID)-distinctive facial gestalt-multiple congenital anomaly syndrome, commonly associating microcephaly, epilepsy, corpus callosum agenesis, conotruncal heart defects, urogenital malformations and Hirschsprung disease (HSCR), The prevalence of Mowat-Wilson syndrome is currently unknown, but it seems that Mowat-Wilson syndrome is underdiagnosed, particularly in patients without Hirschsprung disease., Mowat-Wilson syndrome is a mental retardation-multiple congenital anomaly syndrome characterized by a typical facies, developmental delay, epilepsy, and variable congenital malformations, including Hirschsprung disease, urogenital anomalies, congenital heart disease, and agenesis of the corpus callosum., \"Mowat-Wilson\" syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene., Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation; a multiple congenital anomaly syndrome characterised by a typical facial gestalt, Hirschsprung disease or severe constipation, genitourinary anomaly, congenital heart defects, agenesis of corpus callosum and eye defects., We report a girl who had Hirschsprung disease in association with distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation (Mowat-Wilson syndrome)., Mowat-Wilson syndrome (MWS) is characterized by severe mental retardation with seizures, specific facial dysmorphism, Hirschsprung disease, anomalies of the corpus callosum, and genitourinary and cardiac malformations., BACKGROUND/PURPOSE: Patients with zinc finger homeo box 1B (ZFHX1B) mutations or deletions develop multiple congenital anomalies including Hirschsprung disease, known as Mowat-Wilson syndrome (MWS)., Severe clinical course of Hirschsprung disease in a Mowat-Wilson syndrome patient., Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype (high forehead, frontal bossing, large eyebrows, medially flaring and sparse in the middle part, hypertelorism, deep set but large eyes, large and uplifted ear lobes, with a central depression, saddle nose with prominent rounded nasal tip, prominent columella, open mouth, with M-shaped upper lip, frequent smiling, and a prominent but narrow and triangular pointed chin), moderate-to-severe intellectual deficiency, epilepsy and variable congenital malformations including Hirschsprung disease (HSCR), genitourinary anomalies (in particular hypospadias in males), congenital heart defects, agenesis of the corpus callosum and eye anomalies., Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype, Hirschsprung disease, microcephaly and mental retardation., Mowat-Wilson syndrome is a genetic disease characterized by typical facial features, Hirschsprung disease and multiple congenital abnormalities., Supernumerary intestinal muscle coat in a patient with Hirschsprung disease/Mowat-Wilson syndrome., We present the 1st case report of an additional enteric smooth muscle layer in a patient with Mowat-Wilson syndrome and Hirschsprung disease., Mowat-Wilson\" syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene., Mowat-Wilson syndrome (MWS) is an autosomal dominant intellectual disability syndrome characterised by unique facial features and congenital anomalies such as Hirschsprung disease, congenital heart defects, corpus callosum agenesis and urinary tract anomalies., Mowat-Wilson syndrome (MWS) is a mental retardation syndrome associated with distinctive facial features, microcephaly, epilepsy, and a variable spectrum of congenital anomalies, including Hirschsprung disease (HSCR), agenesis of the corpus callosum, genitourinary abnormalities, and congenital heart disease., Mowat-Wilson syndrome is a mental retardation-multiple congenital anomaly syndrome characterized by a typical facies, developmental delay, epilepsy, and variable congenital malformations, including Hirschsprung disease, urogenital anomalies, congenital heart disease, and agenesis of the corpus callosum, Mowat-Wilson syndrome is a genetic disorder characterized by a distinct facial appearance, moderate-to-severe mental retardation, microcephaly, agenesis of the corpus callosum, Hirschsprung disease, congenital heart disease, and genital anomalies, We present the 1st case report of an additional enteric smooth muscle layer in a patient with Mowat-Wilson syndrome and Hirschsprung disease, Mowat-Wilson syndrome (MWS) is an autosomal dominant intellectual disability syndrome characterised by unique facial features and congenital anomalies such as Hirschsprung disease, congenital heart defects, corpus callosum agenesis and urinary tract anomalies, Mowat-Wilson syndrome (MWS) is characterized by severe mental retardation with seizures, specific facial dysmorphism, Hirschsprung disease, anomalies of the corpus callosum, and genitourinary and cardiac malformations, zfhz1b is the causative gene for Mowat-Wilson syndrome, in which patients demonstrate developmental delay and Hirschsprung disease, as well as other anomalies., Mowat-Wilson syndrome (MWS) is a mental retardation syndrome associated with distinctive facial features, microcephaly, epilepsy, and a variable spectrum of congenital anomalies, including Hirschsprung disease (HSCR), agenesis of the corpus callosum, genitourinary abnormalities, and congenital heart disease, Outcomes of Hirschsprung's disease associated with Mowat-Wilson syndrome., Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype, Hirschsprung disease, microcephaly and mental retardation[SEP]Definitions: genitourinary anomaly defined as following: Congenital structural abnormalities of the UROGENITAL SYSTEM in either the male or the female.. congenital heart defects defined as following: Developmental abnormalities involving structures of the heart. These defects are present at birth but may be discovered later in life.. frontal bossing defined as following: A skeletal deformity characterized by an unusually prominent forehead. Causes include acromegaly, Hurler syndrome, Silver-Russell syndrome, and thalassemia major.. ZFHX1B defined as following: Human ZEB2 wild-type allele is located in the vicinity of 2q22 and is approximately 132 kb in length. This allele, which encodes zinc finger E-box-binding homeobox 2 protein, is involved in regulation of transcription. Mutations in this gene are associated with Mowat-Wilson syndrome.. hypospadias defined as following: Location of the urethral opening on the inferior aspect of the penis. [HPO:curators]. epilepsy defined as following: A disorder characterized by recurrent episodes of paroxysmal brain dysfunction due to a sudden, disorderly, and excessive neuronal discharge. Epilepsy classification systems are generally based upon: (1) clinical features of the seizure episodes (e.g., motor seizure), (2) etiology (e.g., post-traumatic), (3) anatomic site of seizure origin (e.g., frontal lobe seizure), (4) tendency to spread to other structures in the brain, and (5) temporal patterns (e.g., nocturnal epilepsy). (From Adams et al., Principles of Neurology, 6th ed, p313). ZEB2 defined as following: This gene is involved in regulation of transcription.. congenital malformations defined as following: Malformations of organs or body parts during development in utero.. microcephaly defined as following: Head circumference below 2 standard deviations below the mean for age and gender. [PMID:15806441, PMID:19125436, PMID:25465325, PMID:9683597]. intellectual disability defined as following: Subnormal intellectual functioning which originates during the developmental period. This has multiple potential etiologies, including genetic defects and perinatal insults. Intelligence quotient (IQ) scores are commonly used to determine whether an individual has an intellectual disability. IQ scores between 70 and 79 are in the borderline range. Scores below 67 are in the disabled range. (from Joynt, Clinical Neurology, 1992, Ch55, p28). conotruncal heart defects defined as following: A congenital malformation of the outflow tract of the heart. Conotruncal defects are thought to result from a disturbance of the outflow tract of the embryonic heart, and comprise truncus arteriosus, tetralogy of Fallot, interrupted aortic arch, transposition of the great arteries, and double outlet right ventricle. [HPO:probinson]. ear lobes defined as following: The soft fleshy portion of the lower external ear composed of areolar and adipose connective tissues.. Hirschsprung's disease defined as following: Congenital MEGACOLON resulting from the absence of ganglion cells (aganglionosis) in a distal segment of the LARGE INTESTINE. The aganglionic segment is permanently contracted thus causing dilatation proximal to it. In most cases, the aganglionic segment is within the RECTUM and SIGMOID COLON.. deletions defined as following: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus.. MWS defined as following: An autoinflammatory disease caused by mutations in the NLRP3 gene which encodes cryopyrin. It is characterized by recurrent episodes of urticaria and fever which develop in infancy. It may lead to sensorineural hearing loss and/or amyloidosis.. facial defined as following: Of, or related to, or in the direction of the face.. Mowat-Wilson syndrome defined as following: A rare autosomal dominant syndrome caused by mutations in the ZEB2 gene. It is characterized by mental retardation, and a distinctive facial appearance (wide set eyes, uplifted earlobes, broad nasal bridge, prominent chin, and a smiling expression). The majority of patients have Hirschsprung disease (colonic enlargement and constipation due to intestinal blockage).. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. genital anomalies defined as following: An abnormality of the genital system. [HPO:probinson]. hypertelorism defined as following: Abnormal increase in the interorbital distance due to overdevelopment of the lesser wings of the sphenoid.. eyes defined as following: The organ of sight constituting a pair of globular organs made up of a three-layered roughly spherical structure specialized for receiving and responding to light.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. seizures defined as following: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or \"seizure disorder.\". urinary tract anomalies defined as following: An abnormality of the urinary system. [HPO:probinson]. eyebrows defined as following: Curved rows of HAIR located on the upper edges of the eye sockets..", "label": "yes"} {"id": "converted_1444", "sentence1": "Is arimoclomol a co-inducer of the heat shock response?", "sentence2": "Arimoclomol is a hydroxylamine derivative, a group of compounds which have unique properties as co-inducers of heat shock protein expression, but only under conditions of cellular stress. , In this review we summarize the evidence for the neuroprotective effects of enhanced heat shock protein expression by Arimoclomol and other inducers of the Heat Shock Response. , arimoclomol, a co-inducer of the heat shock stress response,, The heat-shock response (HSR) was activated in P23H retinae, and this was enhanced with arimoclomol treatment. , We also assessed these functions in mice treated with a known heat shock protein inducer, arimoclomol., Under conditions of excessive stress, arimoclomol induces amplification of the cytoprotective heat shock response in order to protect motor neurons from death. , Although both arimoclomol and celastrol induced the expression of Hsp70, Arimoclomol, an amplifier of heat shock protein expression involved in cellular stress response, has emerged as a potential therapeutic candidate in amyotrophic lateral sclerosis (ALS) in recent years., The mechanism of action of arimoclomol involves potentiation of the heat shock response, and treatment with arimoclomol increased Hsp70 expression. , Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress., Arimoclomol, a coinducer of heat shock proteins, delayed progression of amyotrophic lateral sclerosis (ALS) in a mouse model in which motor neurons in the spinal cord and motor cortex degenerate.[SEP]Definitions: death defined as following: Irreversible cessation of all bodily functions, manifested by absence of spontaneous breathing and total loss of cardiovascular and cerebral functions.. drug defined as following: Any natural, endogenously-derived, synthetic or semi-synthetic compound with pharmacologic activity. A pharmacologic substance has one or more specific mechanism of action(s) through which it exerts one or more effect(s) on the human or animal body. They can be used to potentially prevent, diagnose, treat or relieve symptoms of a disease. Formulation specific agents and some combination agents are also classified as pharmacologic substances.. amyotrophic lateral sclerosis defined as following: A degenerative disorder affecting upper MOTOR NEURONS in the brain and lower motor neurons in the brain stem and SPINAL CORD. Disease onset is usually after the age of 50 and the process is usually fatal within 3 to 6 years. Clinical manifestations include progressive weakness, atrophy, FASCICULATION, hyperreflexia, DYSARTHRIA, dysphagia, and eventual paralysis of respiratory function. Pathologic features include the replacement of motor neurons with fibrous ASTROCYTES and atrophy of anterior SPINAL NERVE ROOTS and corticospinal tracts. (From Adams et al., Principles of Neurology, 6th ed, pp1089-94). Hsp70 defined as following: A family of structurally related proteins that are involved in both protein folding and cellular stress responses. The members of this family are approximately 70 kDa.. heat shock proteins defined as following: Proteins which are synthesized in eukaryotic organisms and bacteria in response to hyperthermia and other environmental stresses. They increase thermal tolerance and perform functions essential to cell survival under these conditions.. heat shock protein defined as following: 78 kDa glucose-regulated protein (654 aa, ~72kDa) is encoded by HSPA5 gene. The protein is intracellularly localized in the endoplasmic reticulum lumen, and plays a role in the assembly of multimeric protein complexes inside the organelle. In addition, the protein is thought to function as a pro-survival protein, or an inhibitor of apoptosis.. HSR defined as following: The integration of epidemiologic, sociological, economic, and other analytic sciences in the study of health services. Health services research is usually concerned with relationships between need, demand, supply, use, and outcome of health services. The aim of the research is evaluation, particularly in terms of structure, process, output, and outcome. (From Last, Dictionary of Epidemiology, 2d ed). motor neurons defined as following: Neurons which send impulses peripherally to activate muscles or secretory cells.. spinal cord defined as following: A cylindrical column of tissue that lies within the vertebral canal. It is composed of WHITE MATTER and GRAY MATTER..", "label": "yes"} {"id": "converted_218", "sentence1": "Has vitamin D has been shown to reduce incidence of falls in older people in clinical trials?", "sentence2": "However, apart from the beneficial effects of 800 IU/d of vitamin D3 for reduction of falls in the elderly, causality remains yet unproven in randomized controlled trials (RCTs). , The rate of falls and the number of fallers was significantly reduced in two studies evaluating the effect of medication on preventing falls; one study (85 participants) compared vitamin D versus placebo in institutionalised women after stroke with low vitamin D levels, and the other study (79 participants) evaluated alendronate versus alphacalcidol in hospitalised people after stroke., Two studies testing vitamin D versus placebo and alendronate versus alphacalcidol found a significant reduction in falls and the number of people falling, .Overall, vitamin D supplementation does not appear to reduce falls but may be effective in people who have lower vitamin D levels before treatment., Overall, vitamin D did not reduce rate of falls (RaR 1.00, 95% CI 0.90 to 1.11; seven trials; 9324 participants) or risk of falling (RR 0.96, 95% CI 0.89 to 1.03; 13 trials; 26,747 participants), but may do so in people with lower vitamin D levels before treatment., Vitamin D affects bone and muscle health and likely reduces the risk of falls in the elderly., We found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96), This effect was more prominent in patients who were vitamin D deficient at baseline and in studies in which calcium was coadministered with vitamin D., Vitamin D combined with calcium reduces the risk of falls., The majority of the evidence is derived from trials enrolling elderly women., Studies of vitamin D and calcium for fracture prevention have produced inconsistent results, as a result of different vitamin D status and calcium intake at baseline, different doses and poor to adequate compliance., Despite significant increases in the provision of hip protectors and use of vitamin D supplementation in both intervention and control facilities, there was no difference in the number of falls or falls injuries between the intervention and control groups, nor a reduction in falls overall., Beyond fall and fracture prevention, vitamin D may also reduce overall morbidity by multiple mechanisms. , There is evidence to suggest that these agents may reduce the incidence of nonvertebral fractures and falls; however, their benefit on vertebral fracture reduction may depend on the type of active vitamin D. [SEP]Definitions: vitamin D defined as following: Vitamin D2, a fat-soluble vitamin important for many biochemical processes including the absorption and metabolism of calcium and phosphorus. In vivo, ergocalciferol is formed after sun (ultraviolet) irradiation of plant-derived ergosterol, another form of vitamin D. Ergocalciferol is the form of vitamin D usually found in vitamin supplements. (NCI04). calcium defined as following: A dietary supplement containing the mineral calcium.. vitamin D3 defined as following: Derivative of 7-dehydroxycholesterol formed by ULTRAVIOLET RAYS breaking of the C9-C10 bond. It differs from ERGOCALCIFEROL in having a single bond between C22 and C23 and lacking a methyl group at C24.. alendronate defined as following: A nonhormonal medication for the treatment of postmenopausal osteoporosis in women. This drug builds healthy bone, restoring some of the bone loss as a result of osteoporosis.. hip protectors defined as following: Mechanical shields worn over the hip area to prevent against hip fractures in the event of a patient fall. These shields are designed to transfer energy from the impact to the soft tissue and muscles anterior and posterior to the femoral bone, thus diverting the force of the impact away from the greater trochanter.. stroke defined as following: A group of pathological conditions characterized by sudden, non-convulsive loss of neurological function due to BRAIN ISCHEMIA or INTRACRANIAL HEMORRHAGES. Stroke is classified by the type of tissue NECROSIS, such as the anatomic location, vasculature involved, etiology, age of the affected individual, and hemorrhagic vs. non-hemorrhagic nature. (From Adams et al., Principles of Neurology, 6th ed, pp777-810).", "label": "yes"} {"id": "converted_4344", "sentence1": "Does trimetazidine protect from myocardial injury after percutaneous coronary intervention?", "sentence2": "After a median follow-up of 47·5 months (IQR 42·3-53·3), incidence of primary endpoint events was not significantly different between the trimetazidine group (700 [23·3%] patients) and the placebo group (714 [23·7%]; hazard ratio 0·98 [95% CI 0·88-1·09], p=0·73). When analysed individually, there were no significant differences in the incidence of the components of the primary endpoint between the treatment groups. , INTERPRETATION: Our results show that the routine use of oral trimetazidine 35 mg twice daily over several years in patients receiving optimal medical therapy, after successful PCI, does not influence the recurrence of angina or the outcome; these findings should be taken into account when considering the place of trimetazidine in clinical practice. [SEP]Definitions: trimetazidine defined as following: A vasodilator used in angina of effort or ischemic heart disease..", "label": "no"} {"id": "converted_2210", "sentence1": "Is dupilumab an antibody targeting the IL-1 receptor?", "sentence2": "Atopic dermatitis (AD) is characterized by type 2 helper T (Th2) cell-driven inflammation. Dupilumab is a fully human monoclonal antibody directed against the IL-4 receptor α subunit that blocks the signaling of IL-4 and IL-13, both key cytokines in Th2-mediated pathways., Dupilumab, a humanized monoclonal antibody to the interteukin-4R is the first antibody (i.e. 'biological') with published efficacy shown in controlled prospective studies in atopic dermatitis. , Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis., Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti-IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players., Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. , Dupilumab was also introduced as a possible treatment for patients with severe pemphigus. It can directly inhibit IL-4 by targeting IL-4 α-chain receptor., We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor[SEP]Definitions: IL-4 defined as following: A recombinant therapeutic agent which is chemically identical to or similar to the endogenous cytokine interleukin-4 (IL-4). Produced primarily by activated T-cells, IL-4 binds to and activates its cell-surface receptor, stimulating the proliferation and differentiation of activated B-cells and enhancing their ability to present antigens to T-cells. As a potential immunotherapeutic agent, recombinant IL-4 also augments the effects of other cytokines on dendritic cells (DC), cytotoxic T lymphocytes (CTL), and tumor-infiltrating lymphocytes (TIL). Check for \"https://www.cancer.gov/about-cancer/treatment/clinical-trials/intervention/C589\" active clinical trials using this agent. (\"http://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI%20Thesaurus&code=C589\" NCI Thesaurus). interleukin-4 receptor defined as following: Receptors present on a wide variety of hematopoietic and non-hematopoietic cell types that are specific for INTERLEUKIN-4. They are involved in signaling a variety of immunological responses related to allergic INFLAMMATION including the differentiation of TH2 CELLS and the regulation of IMMUNOGLOBULIN E production. Two subtypes of receptors exist and are referred to as the TYPE I INTERLEUKIN-4 RECEPTOR and the TYPE II INTERLEUKIN-4 RECEPTOR. Each receptor subtype is defined by its unique subunit composition.. alpha subunit defined as following: The alpha chain of pituitary glycoprotein hormones (THYROTROPIN; FOLLICLE STIMULATING HORMONE; LUTEINIZING HORMONE) and the placental CHORIONIC GONADOTROPIN. Within a species, the alpha subunits of these four hormones are identical; the distinct functional characteristics of these glycoprotein hormones are determined by the unique beta subunits. Both subunits, the non-covalently bound heterodimers, are required for full biologic activity.. interleukin-13 defined as following: Interleukin-13 (146 aa, ~16 kDa) is encoded by the human IL13 gene. This protein plays a role in the negative regulation of cytokine production and the positive regulation of B-cell proliferation.. human defined as following: Members of the species Homo sapiens.. interleukin-4 receptor alpha defined as following: Interleukin-4 receptor subunit alpha (825 aa, ~90 kDa) is encoded by the human IL4R gene. This protein plays a role in both interleukin-4 signaling and immunoglobulin E production.. Dupilumab defined as following: A recombinant human monoclonal immunoglobulin G4 (IgG4) antibody directed against the alpha chain of the interleukin-4 receptor (IL-4R alpha) with potential immunomodulatory activities. Upon injection, dupilumab selectively binds to the IL-4R alpha chain. This disrupts IL-4/IL-13 signaling and prevents the activation of downstream pathways that mediate type 2 inflammation and may potentially inhibit tumor cell proliferation, survival, and metastasis. IL-4 and IL-13 receptors are present on the surface of numerous cells involved in the pathophysiology of type-2 helper T-cell (Th2) allergic responses, including B-lymphocytes, eosinophils, dendritic cells (DCs), monocytes, macrophages, basophils, keratinocytes, bronchial epithelial cells, endothelial cells, fibroblasts, and airway smooth muscle cells. Additionally, both IL-4 and IL-13 receptors are overexpressed in a variety of cancers and IL-4 and IL-13 and may serve as biomarkers for cancer aggressiveness. IL-4 and IL-13 are thought to be key regulatory cytokines in the tumor microenvironment (TME) and may play a role in the activation of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) that mediate tumor cell survival.. antibody defined as following: An immunoglobulin complex that is secreted into extracellular space and found in mucosal areas or other tissues or circulating in the blood or lymph. In its canonical form, a circulating immunoglobulin complex is composed of two identical heavy chains and two identical light chains, held together by disulfide bonds. Some forms of are polymers of the basic structure and contain additional components such as J-chain and the secretory component. [GOC:add, ISBN:0781735149]. Atopic dermatitis defined as following: A pruritic papulovesicular dermatitis occurring as a reaction to many endogenous and exogenous agents (Dorland, 27th ed).. atopic dermatitis defined as following: A chronic inflammatory genetically determined disease of the skin marked by increased ability to form reagin (IgE), with increased susceptibility to allergic rhinitis and asthma, and hereditary disposition to a lowered threshold for pruritus. It is manifested by lichenification, excoriation, and crusting, mainly on the flexural surfaces of the elbow and knee. In infants it is known as infantile eczema.. monoclonal antibody defined as following: A humanized monoclonal antibody directed against parathyroid hormone-related protein (PTH-rP). As a poly-hormone with diverse biological roles, PTH-rP is expressed by normal tissues, acting in local tissue environments in a variety of ways; it is commonly overexpressed by breast, prostate, and other cancers, acting systemically by promoting bone resorption, inhibiting calcium excretion from the kidney, inducing hypercalcemia, and possibly playing a role in the formation of bony metastases. By blocking the effects of PTH-rP on calcium metabolism, monoclonal antibody CAL may inhibit cancer-related hypercalcemia. (NCI04). IL-1 receptor defined as following: Cell surface receptors that are specific for INTERLEUKIN-1. Included under this heading are signaling receptors, non-signaling receptors and accessory proteins required for receptor signaling. Signaling from interleukin-1 receptors occurs via interaction with SIGNAL TRANSDUCING ADAPTOR PROTEINS such as MYELOID DIFFERENTIATION FACTOR 88..", "label": "no"} {"id": "converted_4634", "sentence1": "Is HDAC1 required for GATA-1 transcriptional activity?", "sentence2": "HDAC1 is required for GATA-1 transcription activity, global chromatin occupancy and hematopoiesis., GATA-12RA knock-in (KI) mice suffer mild anemia and thrombocytopenia with accumulation of immature erythrocytes and megakaryocytes in bone marrow and spleen. Single cell RNA-seq analysis of Lin- cKit+ (LK) cells further reveal a profound change in cell subpopulations and signature gene expression patterns in HSC, myeloid progenitors, and erythroid/megakaryocyte clusters in KI mice. Thus, GATA-1 deacetylation and its interaction with HDAC1 modulates GATA-1 chromatin binding and transcriptional activity that control erythroid/megakaryocyte commitment and differentiation.[SEP]Definitions: megakaryocytes defined as following: Very large BONE MARROW CELLS which release mature BLOOD PLATELETS.. HDAC1 defined as following: This gene plays a role in chromatin remodeling and the repression of gene expression.. GATA-1 defined as following: Human GATA1 wild-type allele is located in the vicinity of Xp11.23 and is approximately 8 kb in length. This allele, which encodes erythroid transcription factor protein, is involved in the regulation of both transcription by RNA polymerase II and erythroid development.. HSC defined as following: Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood.. thrombocytopenia defined as following: An autosomal dominant disorder caused by mutation(s) in the ANKRD26 gene, encoding ANKRD26 protein. Additionally, in one family, a mutation(s) has been identified in the MASTL gene, encoding serine/threonine-protein kinase greatwall. The condition is characterized by mild to moderate bruisability..", "label": "yes"} {"id": "converted_1544", "sentence1": "Could Hyperthermic intraperitoneal chemotherapy (HIPEC) be effective for the treatment of recurrent ovarian cancer?", "sentence2": "The use of HIPEC after aggressive cytoreductive surgery in patients with ovarian cancer with peritoneal dissemination can be performed with acceptable postoperative morbidity rates. Knowledge of the factors associated with the onset of these postoperative adverse events allows better management of the same and offers the patient a safe procedure, These results showed that the association of HIPEC with a complete cytoreduction for recurrent ovarian cancer presents acceptable morbidity and survival, There is level-one evidence suggesting the benefit of postoperative adjuvant intraperitoneal chemotherapy for patients with advanced ovarian cancer after cytoreductive surgery, albeit catheter-related complications resulted after treatment discontinuation. Studies report the use of HIPEC predominantly in the setting of recurrent disease and have demonstrated encouraging results, which merits further investigation in future clinical trials, The combination of SCR and HIPEC seems to improve survival rate in patients suffering from platinum-sensitive EOC recurrence with respect to no-HIPEC treatments. This result further supports the need of a randomized trial, Cautious extrapolation of data from standard normothermic, nonintraoperative, intraperitoneal chemotherapy and data from Phase II and nonrandomized comparative studies suggest that HIPEC delivered at the time of surgery for ovarian cancer has definite potential, The available evidence suggests that a potential survival benefit of adding HIPEC may be largest in the settings of secondary CRS for stage III ovarian cancer and salvage CRS for recurrent ovarian cancer, two time-points representing failure of initial standard therapy. There is much less evidence for a potential benefit of HIPEC for less advanced stages (I-II) and for earlier time-points in the treatment of ovarian cancer (upfront, interval and consolidation), Survival benefit of adding Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) at the different time-points of treatment of ovarian cancer, Patients suffering from peritoneal recurrence of ovarian cancer should be considered for radical reoperation with HIPEC in a center with expertise in multimodal therapeutic options. Organ-preserving cytoreductive surgery allows complete cytoreduction with the goal of decreasing morbidity, In recurrent platinum-sensitive ovarian cancer patients, the use of CRS plus HIPEC represents a safe treatment, able to significantly influence the survival rates compared to chemotherapy alone or surgery plus standard chemotherapy, The results of our study indicate the feasibility and the potential benefit of a protocol including systemic chemotherapy, surgical cytoreduction and HIPEC in patients with peritoneal carcinomatosis from ovarian cancer. A phase III trial to compare this approach with conventional treatment is needed, In selected patients with heavily pretreated recurrent ovarian cancer, cytoreduction combined with HIPEC may provide a meaningful OS with acceptable morbidity. Optimal results are achieved in patients with a macroscopically complete resection and biologically favorable disease, HIPEC is a complement to radical surgery/ peritonectomy, which has been shown to be a surgical procedure with high tolerability, low morbimortality, enhanced survival and prolonged disease-free interval in patients with peritoneal carcinomatosis for recurrent ovarian cancer, Despite the heterogeneity of the studies reviewed, current evidence suggest that complete CRS and HIPEC may be a feasible option with potential benefits that are comparable with the current standard of care. A randomized trial is required to establish the role of HIPEC in ovarian cancer, in the majority of patients with primary and recurrent advanced ovarian cancer, cytoreductive surgery combined with HIPEC can lead to a substantial increase in subsequent rates of disease-free and overall survival, Peritonectomy procedures combined with HIPEC offer promising long-term survival in patients with diffuse peritoneal ovarian carcinomatosis. They achieve high adequate primary and secondary surgical cytoreduction rates with acceptable morbidity and mortality, Cytoreduction surgery with hyperthermic intraperitoneal chemotherapy in recurrent ovarian cancer improves progression-free survival, especially in BRCA-positive patients- a case-control study., Survival benefit of adding Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) at the different time-points of treatment of ovarian cancer: review of evidence., Some encouraging results have been reported by the treatment of peritoneal carcinomatosis (PC) from ovarian cancer by complete surgical cytoreduction, peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC)., Although standard treatment for advanced epithelial ovarian cancer (EOC) consists of surgical debulking and intravenous platinum- and taxane-based chemotherapy, favorable oncological outcomes have been recently reported with the use of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)., Trabectedin, Hyperthermic intraperitoneal chemotherapy (HIPEC) and chemo-immunotherapy may be become a promising therapy for the treatment of ovarian cancer., Hyperthermic intraperitoneal chemotherapy (HIPEC) represents a new treatment strategy aimed to improve outcome of patients with advanced ovarian cancer., Favorable oncological outcomes have been reported in several trials with the introduction of Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in the treatment of Advanced Epithelial Ovarian Cancer (EOC)., Based on theoretical and experimental basis, HIPEC should stand as an effective treatment for ovarian cancer., Some encouraging results have been reported by the treatment of peritoneal carcinomatosis (PC) from ovarian cancer by complete surgical cytoreduction, peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC), Based on theoretical and experimental basis, HIPEC should stand as an effective treatment for ovarian cancer, Hyperthermic intraperitoneal chemotherapy (HIPEC) represents a new treatment strategy aimed to improve outcome of patients with advanced ovarian cancer, [Importance of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer].[SEP]Definitions: Trabectedin defined as following: A tetrahydroisoquinoline alkaloid isolated from the marine tunicate Ecteinascidia turbinata with potential antineoplastic activity. Binding to the minor groove of DNA, trabectedin interferes with the transcription-coupled nucleotide excision repair machinery to induce lethal DNA strand breaks and blocks the cell cycle in the G2 phase.. HIPEC defined as following: A procedure performed in combination with abdominal surgery for cancer that has spread to the abdomen. It involves the infusion of a heated chemotherapy solution that circulates into the abdominal cavity.. ovarian cancer defined as following: A primary or metastatic malignant neoplasm involving the ovary. Most primary malignant ovarian neoplasms are either carcinomas (serous, mucinous, or endometrioid adenocarcinomas) or malignant germ cell tumors. Metastatic malignant neoplasms to the ovary include carcinomas, lymphomas, and melanomas.. CRS defined as following: Transplacental infection of the fetus with rubella usually in the first trimester of pregnancy, as a consequence of maternal infection, resulting in various developmental abnormalities in the newborn infant. They include cardiac and ocular lesions, deafness, microcephaly, mental retardation, and generalized growth retardation. (From Dorland, 27th ed). SCR defined as following: The confirmed disappearance of all signs of cancer, and absence of molecular or cytogenetic marker of disease, in response to treatment with additional biochemical, immunological and histopathological analyses to verify the CR.. platinum-sensitive ovarian cancer defined as following: Ovarian carcinoma that has a documented response to platinum-based chemotherapy.. PC defined as following: A group of inherited ectodermal dysplasias whose most prominent clinical feature is hypertrophic nail dystrophy resulting in PACHYONYCHIA. Several specific subtypes of pachyonychia congenita have been associated with mutations in genes that encode KERATINS..", "label": "yes"} {"id": "converted_4696", "sentence1": "Do Afamin bind Vitamin E?", "sentence2": "The plasma glycoprotein afamin has been previously identified as an alternative carrier protein for vitamin E in extravascular fluids such as plasma and cerebrospinal, ovarian follicular, and seminal fluids., afamin, a vitamin E-binding protein in human plasma, the human vitamin E-binding protein afamin, Afamin is a plasma vitamin E-binding glycoprotein, The human vitamin E-binding glycoprotein afamin is primarily expressed in the liver and has been associated with prevalent and incident metabolic syndrome[SEP]Definitions: human defined as following: Members of the species Homo sapiens.. metabolic syndrome defined as following: A combination of medical conditions that when present, increase the risk of heart attack, stroke, and diabetes mellitus. It includes the following medical conditions: increased blood pressure, central obesity, dyslipidemia, impaired glucose tolerance, and insulin resistance..", "label": "yes"} {"id": "converted_4100", "sentence1": "Are synonymous sites in primates and rodents functionally constrained?", "sentence2": "To resolve this contradiction between expectations and observations, we used processed pseudogenes as a model for strict neutral evolution, and estimated selective constraint on synonymous sites using the rate of substitution at pseudosynonymous and pseudononsynonymous sites in pseudogenes as the neutral expectation. After controlling for the effects of GC content, our results were similar to those from previous studies, i.e., synonymous sites in primates exhibited evidence for higher selective constraint that those in rodents. Specifically, our results indicated that in primates up to 24% of synonymous sites could be under purifying selection, while in rodents synonymous sites evolved neutrally. [SEP]Definitions: rodents defined as following: A mammalian order which consists of 29 families and many genera.. pseudogenes defined as following: Genes bearing close resemblance to known genes at different loci, but rendered non-functional by additions or deletions in structure that prevent normal transcription or translation. When lacking introns and containing a poly-A segment near the downstream end (as a result of reverse copying from processed nuclear RNA into double-stranded DNA), they are called processed genes.. substitution defined as following:Definition: Indicates that the subject Act has undergone or should undergo substitution of a type indicated by Act.code.
Rationale: Used to specify \"allowed\" substitution when creating orders, \"actual\" susbstitution when sending events, as well as the reason for the substitution and who was responsible for it.
. primates defined as following: An order of mammals consisting of more than 300 species that include LEMURS; LORISIDAE; TARSIERS; MONKEYS; and HOMINIDS. They are characterized by a relatively large brain when compared with other terrestrial mammals, forward-facing eyes, the presence of a CALCARINE SULCUS, and specialized MECHANORECEPTORS in the hands and feet which allow the perception of light touch..", "label": "no"} {"id": "converted_529", "sentence1": "Is TALEN being used on stem cells?", "sentence2": "Precise correction of the dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9., Genetic correction of patient-derived induced pluripotent stem cells (iPSCs) by TALENs or CRISPR-Cas9 holds promise for DMD gene therapy; however, the safety of such nuclease treatment must be determined., We generated helper-dependent, capsid-modified adenovirus (HD-Ad5/35) vectors for zinc-finger nuclease (ZFN)- or transcription activator-like effector nuclease (TALEN)-mediated genome editing in human CD34+ hematopoietic stem cells (HSCs) from mobilized adult donors. , We used transcription activator-like effector nuclease (TALEN)-mediated gene editing in mouse embryonic stem cells (mESCs) to produce mice with targeted gene disruptions and insertions in two Y-linked genes--Sry and Uty., Transcription activator-like effector nuclease (TALEN)-mediated gene correction in integration-free β-thalassemia induced pluripotent stem cells., A TALEN genome-editing system for generating human stem cell-based disease models., Low incidence of off-target mutations in individual CRISPR-Cas9 and TALEN targeted human stem cell clones detected by whole-genome sequencing., Using CRISPR-Cas9 and TALEN targeted human pluripotent stem cell clones, we performed whole-genome sequencing at high coverage in order to assess the degree of mutagenesis across the entire genome., A modified TALEN-based system for robust generation of knock-out human pluripotent stem cell lines and disease models., In this study, we utilized a cell-penetrating peptide-based system for ZFN and TALEN delivery., At all loci tested we obtained human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) clones carrying transgenic cassettes solely at the TALEN-specified location., We report here the use of TALENs to rapidly and efficiently generate mutant alleles of 15 genes in cultured somatic cells or human pluripotent stem cells, the latter for which we differentiated both the targeted lines and isogenic control lines into various metabolic cell types., Zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) have been successfully used to knock out endogenous genes in stem cell research., Here we report different methods to efficiently perform TALEN-mediated gene integration and inactivation in different mammalian cell systems including induced pluripotent stem cells and delineate experimental examples associated with these approaches, Together, our results demonstrate that TALE-based transcriptional repressor and TALENs are two promising approaches for loss-of-function studies of microRNA clusters in somatic cells and pluripotent stem cells, We report here the use of TALENs to rapidly and efficiently generate mutant alleles of 15 genes in cultured somatic cells or human pluripotent stem cells, the latter for which we differentiated both the targeted lines and isogenic control lines into various metabolic cell types, TALEN-mediated generation and genetic correction of disease-specific human induced pluripotent stem cells., Baculoviral transduction facilitates TALEN-mediated targeted transgene integration and Cre/LoxP cassette exchange in human-induced pluripotent stem cells., We used transcription activator-like effector nuclease (TALEN)-mediated gene editing in mouse embryonic stem cells (mESCs) to produce mice with targeted gene disruptions and insertions in two Y-linked genes--Sry and Uty. , Using CRISPR-Cas9 and TALEN targeted human pluripotent stem cell clones, we performed whole-genome sequencing at high coverage in order to assess the degree of mutagenesis across the entire genome. , A 5% modification rate was observed in human induced pluripotent stem cells (hiPSCs) treated with TAT-TALEN as measured by the Surveyor assay. TAT-TALEN protein-mediated gene disruption was applicable in hiPSCs and represents a promising technique for gene knockout in stem cells., Here we engineered transcription activator-like effector nucleases (TALENs) for five distinct genomic loci. At all loci tested we obtained human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) clones carrying transgenic cassettes solely at the TALEN-specified location., Seamless correction of the sickle cell disease mutation of the HBB gene in human induced pluripotent stem cells using TALENs., At all loci tested we obtained human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) clones carrying transgenic cassettes solely at the TALEN-specified location. Our data suggest that TALENs employing the specific architectures described here mediate site-specific genome modification in human pluripotent cells with similar efficiency and precision as do zinc-finger nucleases (ZFNs).[SEP]Definitions: TALENs defined as following: Artificial nucleases that cleave DNA at a defined distance from specific DNA sequences recognized by TRANSCRIPTION ACTIVATOR-LIKE EFFECTORS. They are composed of an endodeoxyribonuclease fused to DNA-binding domains of the transcription activator-like effectors.. genome defined as following: Anatomical set of genes in all the chromosomes.. HSCs defined as following: Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood.. human embryonic stem cell defined as following: A type of PLURIPOTENT STEM CELLS derived from early stage human embryos, up to and including the BLASTOCYST stage.. stem cells defined as following: Relatively undifferentiated cells that retain the ability to divide and proliferate throughout postnatal life to provide progenitor cells that can differentiate into specialized cells.. mutagenesis defined as following: Production of genetic alterations by any technique, including chemicals, radiation, recombination, or other molecular biology methods.. zinc-finger nucleases defined as following: Genetically engineered nucleases that cleave DNA at a defined distance from specific DNA sequences recognized by ZINC FINGER DNA-BINDING DOMAINS. They are composed of a DNA cleaving domain adapted from DNA endonucleases fused to a zinc finger DNA-binding domain.. Sry defined as following: Sex-determining region Y protein (204 aa, ~24 kDa) is encoded by the human SRY gene. This protein is involved in sex determination and transcriptional regulation.. clones defined as following: A group of genetically identical cells all descended from a single common ancestral cell by mitosis in eukaryotes or by binary fission in prokaryotes. Clone cells also include populations of recombinant DNA molecules all carrying the same inserted sequence. (From King & Stansfield, Dictionary of Genetics, 4th ed). modified defined as following: The act of alteration or modification; changed or altered in form or character.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. pluripotent stem cells defined as following: Cells that can give rise to cells of the three different GERM LAYERS.. insertions defined as following: The act of putting one thing into another.. modification defined as following:Respond with exceptions, completions and modifications or revisions done before completion
. mouse embryonic stem cells defined as following: PLURIPOTENT STEM CELLS derived from the BLASTOCYST INNER CELL MASS of day 3.5 mouse embryos.. Y-linked genes defined as following: Genes that are located on the Y CHROMOSOME.. HBB gene defined as following: This gene plays a role in the transport of oxygen to tissues of the adult body.. human defined as following: Members of the species Homo sapiens.. somatic cells defined as following: Nucleated cell which has one or more diploid sets (46 pairs) of chromosomes.. TALEN defined as following: Artificial nucleases that cleave DNA at a defined distance from specific DNA sequences recognized by TRANSCRIPTION ACTIVATOR-LIKE EFFECTORS. They are composed of an endodeoxyribonuclease fused to DNA-binding domains of the transcription activator-like effectors..", "label": "yes"} {"id": "converted_3471", "sentence1": "Are the members of the KRAB-ZNF gene family promoting gene repression?", "sentence2": " The proteins encoded by these genes, whose expression is often tissue-specific, act as epigenetic suppressors contributing to the addition of repressive chromatin marks and DNA methylation., Here, using a reporter system, we show that TRIM28/KRAB-ZNFs alter DNA methylation patterns in addition to H3K9me3 to cause stable gene repression during reprogramming. Using several expression datasets, we identified KRAB-ZNFs (ZNF114, ZNF483, ZNF589) in the human genome that maintain pluripotency., Further analyses of our data sets link GABPa to cognitive disorders, diabetes, KRAB zinc finger (KRAB-ZNF), and human-specific genes., The stem cell zinc finger 1 (SZF1)/ZNF589 protein belongs to the large family of Krüppel-associated box domain-zinc finger (KRAB-ZNF) transcription factors, which are present only in higher vertebrates and epigenetically repress transcription by recruiting chromatin-modifying complexes to the promoter regions of their respective target genes, Because KAP1 is recruited to the DNA via interaction with KRAB-ZNF proteins, we suggest that expression of KRAB-ZNF genes may be controlled via an auto-regulatory mechanism involving KAP1., Interestingly, although most KAP1 binding sites were within core promoter regions, the binding sites near ZNF genes were greatly enriched within transcribed regions of the target gene[SEP]Definitions: gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. KAP1 defined as following: Human TRIM28 wild-type allele is located in the vicinity of 19q13.43 and is approximately 7 kb in length. This allele, which encodes transcription intermediary factor 1-beta protein, plays a role in protein modification, chromatin remodeling, inhibition of herpesvirus 8-mediated lysis and transcriptional regulation. Mutation of the gene may be associated with familial Wilms tumor.. binding sites defined as following: The parts of a macromolecule that directly participate in its specific combination with another molecule.. H3K9me3 defined as following: A post-translationally modified form of histone H3 where the lysine residue at position 9 is trimethylated. This modification is associated with heterochromatin formation and plays a role in embryonic stem cell lineage commitment and maintenance of lineage fidelity.. promoter regions defined as following: DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes.. DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. diabetes defined as following: A heterogeneous group of disorders characterized by HYPERGLYCEMIA and GLUCOSE INTOLERANCE.. vertebrates defined as following: Animals having a vertebral column, members of the phylum Chordata, subphylum Craniata comprising mammals, birds, reptiles, amphibians, and fishes.. stem cell defined as following: Relatively undifferentiated cells that retain the ability to divide and proliferate throughout postnatal life to provide progenitor cells that can differentiate into specialized cells..", "label": "yes"} {"id": "converted_1655", "sentence1": "Are ultraconserved elements depleted among copy number variants (CNVs)?", "sentence2": "We have demonstrated that nonexonic UCEs are depleted among segmental duplications (SDs) and copy number variants (CNVs) and proposed that their ultraconservation may reflect a mechanism of copy counting via comparison. Here, we report that nonexonic UCEs are also depleted among 10 of 11 recent genomewide data sets of human CNVs, including 3 obtained with strategies permitting greater precision in determining the extents of CNVs, Interestingly, human UCEs have been reported to be strongly depleted among segmental duplications and benign copy number variants (CNVs), We propose that these elements may be interpreted as hallmarks for dose-sensitive genes, particularly for those genes whose gain or loss may be directly implied in neurodevelopmental disorders. Therefore, their presence in genomic imbalances of unknown effect might be suggestive of a clinically relevant condition, Mammalian ultraconserved elements are strongly depleted among segmental duplications and copy number variants., Ultraconserved elements (UCEs) are strongly depleted from segmental duplications and copy number variations (CNVs) in the human genome, suggesting that deletion or duplication of a UCE can be deleterious to the mammalian cell., Interestingly, human UCEs have been reported to be strongly depleted among segmental duplications and benign copy number variants (CNVs)., We have demonstrated that nonexonic UCEs are depleted among segmental duplications (SDs) and copy number variants (CNVs) and proposed that their ultraconservation may reflect a mechanism of copy counting via comparison., We have demonstrated that nonexonic UCEs are depleted among segmental duplications (SDs) and copy number variants (CNVs) and proposed that their ultraconservation may reflect a mechanism of copy counting via comparison, Interestingly, human UCEs have been reported to be strongly depleted among segmental duplications and benign copy number variants (CNVs), Here, we show that UCEs are significantly depleted among segmental duplications and copy number variants, The depletion of UCEs among copy number variation as well as the significant under-representation of single-nucleotide polymorphisms (SNPs) within UCEs have also revealed their evolutional and functional importance indicating their potential impact on disease, such as cancer[SEP]Definitions: SNPs defined as following: A single nucleotide variation in a genetic sequence that occurs at appreciable frequency in the population.. neurodevelopmental disorders defined as following: A childhood disorder that has a neurological basis and manifests as a developmental disability.. cancer defined as following: A malignant tumor at the original site of growth.. mammalian cell defined as following: A cell originating from or isolated from an animal of class Mammalia.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "yes"} {"id": "converted_1717", "sentence1": "Is marijuana use associated with increased risk for stroke?", "sentence2": "The illicit drugs more commonly associated with stroke are psychomotor stimulants, such as amphetamine and cocaine. Less commonly implicated are opioids and psychotomimetic drugs, including cannabis., Among 326 patients (184 males), the most frequent stroke risk factors overall were dyslipidaemia (187), smoking (161), hypertension (105) and obesity (92). Fifty-one patients used illicit drugs, mostly comprising marijuana and amphetamines., Patients in Adelaide are more likely to be obese, to be misusing marijuana and amphetamines, to suffer a cardioembolic event and to have a stroke that concurrently affects both the anterior and posterior cerebral circulation., RCVS was spontaneous in 37% of patients and secondary in the 63% others, to postpartum in 5 and to exposure to various vasoactive substances in 37, mainly cannabis, selective serotonin-recapture inhibitors and nasal decongestants., We reported two cases of young stroke associated with drug misuse. Case 1 used amphetamine, cocaine, marijuana and LSD for few yaers, and developed occlusion of a middle cerebral artery. Case 2 presented aphasia shortly after marijuana smoking., Marijuana may have accelerated stroke onset, but essential cause of stroke in this case must be protein S mutation., Cannabis is the most widely consumed among the illicit drugs worldwide, but it has only exceptionally been associated to cerebrovascular disease., We here describe 2 young patients (26 and 29 years, respectively) who suffered from ischemic stroke in temporal relation with cannabis consumption., The review of the literature on this topic reveals another 18 patients with stroke in association to cannabis use., Although a causal relationship is difficult to establish due to the widespread use of cannabis, this drug may play an etiologic role in ischemic stroke., Marijuana may trigger a myocardial infarction and have a vasospastic effect., Despite the fact that cannabis is the most widely used illicit drug, there are only a few reports associating its use with cerebrovascular disease., We describe a patient who suffered three ischaemic strokes immediately after cannabis consumption., Cannabis use may be associated with ischaemic stroke in young patients, but its mechanism is unclear., A right occipital ischemic stroke occurred in a 37-year-old Albanese man with a previously uneventful medical history, 15 min after having smoked a cigarette with approximately 250 mg of marijuana., Therefore, as the family history for cerebrovascular events, blood pressure, clotting tests, examinations for thrombophilia, vasculitis, extracranial and intracranial arteries and cardiac investigations were normal or respectively negative, the stroke was attributed to the chronic cannabis consumption., Three adolescent males had similar presentations of headache, fluctuating level of consciousness or lethargy, visual disturbance, and variable ataxia after self-administration of marijuana., Episodic marijuana use may represent a risk factor for stroke in childhood, particularly in the posterior circulation., Although several mechanisms exist by which marijuana use might contribute to the development of chronic cardiovascular conditions or acutely trigger cardiovascular events, there are few data regarding marijuana/THC use and cardiovascular disease outcomes., Reported here is the case of a previously healthy young man who smoked marijuana on a daily basis and had an occipital lobe stroke; he was found to be heterozygous for factor V Leiden., This case suggests that marijuana smoking may increase the risk of arterial thrombosis in otherwise healthy individuals who are heterozygous for factor V Leiden., Thus, chronic abuse of marijuana might be a risk factor for stroke., A 22-year-old man with a five-year history of drug and alcohol abuse presented with a left hemiparesis preceded by three transient ischaemic attacks, two of which occurred whilst smoking cannabis. Substance abuse was the only identifiable risk factor for cerebrovascular disease., Chronic marijuana smoking, however, seems to reduce CBF., Research directions might include more studies of cardiovascular disease outcomes and relationships of marijuana with cardiovascular risk factors, studies of metabolic and physiologic effects of chronic marijuana use that may affect cardiovascular disease risk, increased understanding of the role of the cannabinoid receptor system in cardiovascular regulation, and studies to determine if there is a therapeutic role for cannabinoids in blood pressure control or for neuroprotection after stroke.[SEP]Definitions: amphetamines defined as following: Analogs or derivatives of AMPHETAMINE. Many are sympathomimetics and central nervous system stimulators causing excitation, vasopressin, bronchodilation, and to varying degrees, anorexia, analepsis, nasal decongestion, and some smooth muscle relaxation.. drug defined as following: Any natural, endogenously-derived, synthetic or semi-synthetic compound with pharmacologic activity. A pharmacologic substance has one or more specific mechanism of action(s) through which it exerts one or more effect(s) on the human or animal body. They can be used to potentially prevent, diagnose, treat or relieve symptoms of a disease. Formulation specific agents and some combination agents are also classified as pharmacologic substances.. opioids defined as following: Compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS.. visual disturbance defined as following: An interference to normal eyesight.. RCVS defined as following: Syndrome is characterized by severe headaches, with or without other acute neurological symptoms, and diffuse segmental constriction of cerebral arteries that resolves spontaneously within 3 months.. marijuana defined as following: Use of marijuana associated with abnormal psychological, social, and or occupational functioning.. hypertension defined as following: Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more.. ataxia defined as following: Incoordination of voluntary movements that occur as a manifestation of CEREBELLAR DISEASES. Characteristic features include a tendency for limb movements to overshoot or undershoot a target (dysmetria), a tremor that occurs during attempted movements (intention TREMOR), impaired force and rhythm of diadochokinesis (rapidly alternating movements), and GAIT ATAXIA. (From Adams et al., Principles of Neurology, 6th ed, p90). LSD defined as following: Semisynthetic derivative of ergot (Claviceps purpurea). It has complex effects on serotonergic systems including antagonism at some peripheral serotonin receptors, both agonist and antagonist actions at central nervous system serotonin receptors, and possibly effects on serotonin turnover. It is a potent hallucinogen, but the mechanisms of that effect are not well understood.. man defined as following: Members of the species Homo sapiens.. ischaemic stroke defined as following: An acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of brain tissue.. cardiovascular disease defined as following: Pathological conditions involving the CARDIOVASCULAR SYSTEM including the HEART; the BLOOD VESSELS; or the PERICARDIUM.. cardiovascular defined as following: The HEART and the BLOOD VESSELS by which BLOOD is pumped and circulated through the body.. headache defined as following: The symptom of PAIN in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of HEADACHE DISORDERS.. vasculitis defined as following: Inflammation of any one of the blood vessels, including the ARTERIES; VEINS; and rest of the vasculature system in the body.. aphasia defined as following: A cognitive disorder marked by an impaired ability to comprehend or express language in its written or spoken form. This condition is caused by diseases which affect the language areas of the dominant hemisphere. Clinical features are used to classify the various subtypes of this condition. General categories include receptive, expressive, and mixed forms of aphasia.. cannabinoids defined as following: Compounds having the cannabinoid structure. They were originally extracted from Cannabis sativa L. The most pharmacologically active constituents are TETRAHYDROCANNABINOL; CANNABINOL; and CANNABIDIOL.. stroke defined as following: A group of pathological conditions characterized by sudden, non-convulsive loss of neurological function due to BRAIN ISCHEMIA or INTRACRANIAL HEMORRHAGES. Stroke is classified by the type of tissue NECROSIS, such as the anatomic location, vasculature involved, etiology, age of the affected individual, and hemorrhagic vs. non-hemorrhagic nature. (From Adams et al., Principles of Neurology, 6th ed, pp777-810). cerebrovascular disease defined as following: A spectrum of pathological conditions of impaired blood flow in the brain. They can involve vessels (ARTERIES or VEINS) in the CEREBRUM, the CEREBELLUM, and the BRAIN STEM. Major categories include INTRACRANIAL ARTERIOVENOUS MALFORMATIONS; BRAIN ISCHEMIA; CEREBRAL HEMORRHAGE; and others.. CBF defined as following: CBF is an alpha/beta heterodimeric transcription factor involved in the transcriptional regulation of several genes important in hematopoiesis. The CBFalpha subunit binds directly to the enhancer core DNA sequence on target genes, whereas the beta subunit does not bind the DNA directly but increases the affinity and stabilizes the binding of the alpha subunit to the DNA.. thrombophilia defined as following: A disorder of HEMOSTASIS in which there is a tendency for the occurrence of THROMBOSIS.. cocaine defined as following: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake.. Substance abuse defined as following: Any substance, including any illegal, prescription, over-the-counter agent or any other compound, used for the purpose other than indicated or used in quantities other than directed. Substances from various drug classes can be abused, such as opioids, amphetamines, analgesics, benzodiazepines, barbiturates, hallucinogens, steroids, tobacco products and alcoholic substances. A substance of abuse may act on the central nervous system (CNS) or can have an effect in other parts of the body and can lead to physical and/or physiological dependence.. dyslipidaemia defined as following: A lipoprotein metabolism disorder characterized by decreased levels of high-density lipoproteins, or elevated levels of plasma cholesterol, low-density lipoproteins and/or triglycerides.. cerebrovascular defined as following: Relating to the brain and the blood vessels that supply it..", "label": "yes"} {"id": "converted_1372", "sentence1": "Does nimotuzumab improve survival of glioblastoma patients?", "sentence2": "The survival times were similar to those seen in historical data of standard therapy., The survival time of a matched population treated at the same hospital with irradiation alone was decreased (median 8.0 and 12.2 mo for GBM and AA patients, respectively) compared with that of the patients who received nimotuzumab and curative-intent radiotherapy., This study, in a poor prognosis population, validates the previous data of survival gain after combining nimotuzumab and radiotherapy, in newly diagnosed high-grade glioma patients., The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. CONCLUSIONS: In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation., Nimotuzumab was well-tolerated and treatment with the antibody yielded a survival benefit: median survival time was 32.66 mo and the 2-y survival rate was 54.2%. This study demonstrated the feasibility of prolonged administration of nimotuzumab and showed preliminary evidence of clinical benefit in HGG patients with poor prognosis., Recent clinical studies show that patients with malignant gliomas could benefit from nimotuzumab treatment., CONCLUSIONS: Nimotuzumab in combination with chemotherapy has moderate activity in patients with malignant gliomas and the toxicities are well tolerable, therefore, worth further investigation., It has been evaluated in malignant brain tumors in adults and children, and shown to be therapeutically safe and effective in terms of increased survival and improved quality of life. , Conclusions As used in this study, nimotuzumab demonstrated a broad safety profile, making it acceptable for chronic use, and implied clinical benefits in terms of increased survival and improved functional status in these patients, compared to findings described in the literature. , Nimotuzumab prolongs survival in patients with malignant gliomas: A phase I/II clinical study of concomitant radiochemotherapy with or without nimotuzumab., Conclusions As used in this study, nimotuzumab demonstrated a broad safety profile, making it acceptable for chronic use, and implied clinical benefits in terms of increased survival and improved functional status in these patients, compared to findings described in the literature., This study, in a poor prognosis population, validates the previous data of survival gain after combining nimotuzumab and radiotherapy, in newly diagnosed high-grade glioma patients, Conclusions As used in this study, nimotuzumab demonstrated a broad safety profile, making it acceptable for chronic use, and implied clinical benefits in terms of increased survival and improved functional status in these patients, compared to findings described in the literature, A multicenter exploratory study combining nimotuzumab and radiotherapy showed disease control and an overall patient survival similar to previous experiences along with an improvement in the quality of patient survival and no severe side effects., Combining craniospinal irradiation (CSI) with concurrent temozolomide and nimotuzumab therapy may slightly improve tumor control and overall survival[SEP]Definitions: malignant gliomas defined as following: A grade 3 or grade 4 glioma arising from the central nervous system. This category includes glioblastoma, anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma.. GBM defined as following: A sheet of amorphous extracellular material upon which the basal surfaces of epithelial cells rest and is the covering surface of a glomerular capillary, interposed between the cellular elements and the underlying connective tissue.. nimotuzumab defined as following: A humanized monoclonal antibody directed against the epidermal growth factor receptor (EGFR) with potential antineoplastic activity. Nimotuzumab binds to and inhibits EGFR, resulting in growth inhibition of tumor cells that overexpress EGFR. This agent may act synergistically with radiation therapy.. AA defined as following: A rare autosomal dominant inherited chorioretinal degenerative disease presenting at birth or during infancy. The disease has characteristics of progressive bilateral retinal and choroidal atrophy which appears as lesions on the optic nerve and peripheral ocular fundus and leads to loss of central vision. Congenital anterior polar cataracts are sometimes associated with this disease. There is evidence this disease is caused by heterozygous mutation in the TEA domain family member-1 gene (TEAD1) on chromosome 11p15.. temozolomide defined as following: A dacarbazine derivative that is used as an alkylating antineoplastic agent for the treatment of MALIGNANT GLIOMA and MALIGNANT MELANOMA.. antibody defined as following: A protein complex that in its canonical form is composed of two identical immunoglobulin heavy chains and two identical immunoglobulin light chains, held together by disulfide bonds and sometimes complexed with additional proteins. An immunoglobulin complex may be embedded in the plasma membrane or present in the extracellular space, in mucosal areas or other tissues, or circulating in the blood or lymph. [GOC:add, GOC:jl, ISBN:0781765196]. toxicities defined as following: The finding of bodily harm due to the poisonous effects of something.. malignant brain tumors defined as following: A primary or metastatic malignant neoplasm affecting the brain.. glioblastoma defined as following: The most malignant astrocytic tumor (WHO grade 4). It is composed of poorly differentiated neoplastic astrocytes and is characterized by the presence of cellular polymorphism, nuclear atypia, brisk mitotic activity, vascular thrombosis, microvascular proliferation, and necrosis. It typically affects adults and is preferentially located in the cerebral hemispheres. (Adapted from WHO).", "label": "yes"} {"id": "converted_579", "sentence1": "Is there any link between the aurora B kinase and the polycomb protein ring1B?", "sentence2": "The aurora B kinase and the polycomb protein ring1B combine to regulate active promoters in quiescent lymphocytes., We show that the Aurora B kinase and the polycomb protein Ring1B have essential roles in regulating transcriptionally active genes in quiescent lymphocytes. Ring1B and Aurora B bind to a wide range of active promoters in resting B and T cells. Conditional knockout of either protein results in reduced transcription and binding of RNA Pol II to promoter regions and decreased cell viability. Aurora B phosphorylates histone H3S28 at active promoters in resting B cells as well as inhibiting Ring1B-mediated ubiquitination of histone H2A and enhancing binding and activity of the USP16 deubiquitinase at transcribed genes. Our results identify a mechanism for regulating transcription in quiescent cells that has implications for epigenetic regulation of the choice between proliferation and quiescence., We show that the Aurora B kinase and the polycomb protein Ring1B have essential roles in regulating transcriptionally active genes in quiescent lymphocytes., We show that the Aurora B kinase and the polycomb protein Ring1B have essential roles in regulating transcriptionally active genes in quiescent lymphocytes. Ring1B and Aurora B bind to a wide range of active promoters in resting B and T cells. Conditional knockout of either protein results in reduced transcription and binding of RNA Pol II to promoter regions and decreased cell viability. , We show that the Aurora B kinase and the polycomb protein Ring1B have essential roles in regulating transcriptionally active genes in quiescent lymphocytes. Ring1B and Aurora B bind to a wide range of active promoters in resting B and T cells.[SEP]Definitions: promoter regions defined as following: DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes.. histone H2A defined as following: Slightly lysine rich histone. One of four histones assembled into a nucleosomal core octamer. Various posttranslationally modified forms and variants exist. Combines with histone H2B in a heterodimer; two H2A/H2B dimers are incorporated in the nucleosomal octamer.. Aurora B defined as following: Aurora kinase B (344 aa, ~39 kDa) is encoded by the human AURKB gene. This protein plays a role in both the modulation of microtubule structure and facilitation of chromosome segregation during mitosis and meiosis.. aurora B kinase defined as following: An aurora kinase that is a component of the chromosomal passenger protein complex and is involved in the regulation of MITOSIS. It mediates proper CHROMOSOME SEGREGATION and contractile ring function during CYTOKINESIS.. Ring1B defined as following: Human RNF2 wild-type allele is located in the vicinity of 1q25.3 and is approximately 57 kb in length. This allele, which encodes E3 ubiquitin-protein ligase RING2 protein, plays a role in histone ubiquitination and the repression of gene transcription.. RNA Pol II defined as following: A DNA-dependent RNA polymerase present in bacterial, plant, and animal cells. It functions in the nucleoplasmic structure and transcribes DNA into RNA. It has different requirements for cations and salt than RNA polymerase I and is strongly inhibited by alpha-amanitin. EC 2.7.7.6..", "label": "yes"} {"id": "converted_3788", "sentence1": "Is Semagacestat effective for Alzheimer's Disease?", "sentence2": "However, a large phase 3 trial of semagacestat, a potential non-transition state analog (non-TSA) GSI, in patients with Alzheimer's disease (AD) was terminated due to unexpected aggravation of cognitive deficits and side effects. , BACKGROUND: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD)., CONCLUSION: In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. , INTRODUCTION: The negative efficacy study examining the γ-secretase inhibitor semagacestat in mild to moderate Alzheimer's disease (AD) included a number of biomarkers of the disease as well as safety outcomes., A clinical trial with the wide-spectrum γ-secretase inhibitor semagacestat has, however, demonstrated that global inhibition of all γ-secretases causes serious toxicity. , ESULTS: Semagacestat treatment was associated with increased reporting of suspected Notch-related adverse events (gastrointestinal, infection, and skin cancer related). Other relevant safety findings associated with semagacestat treatment included cognitive and functional worsening, skin-related TEAEs, renal and hepatic changes, increased QT interval, and weight loss. , CONCLUSIONS: As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability., RESULTS: The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board., The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, -9.0 points in the placebo group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). , Recently disclosed Phase III findings on semagacestat indicated that Alzheimer's disease (AD) patients on this drug showed significantly worsened cognitive function compared to those treated with placebo., The recent failure of semagacestat in two large Phase III studies questions the value of γ-secretase inhibitors in treating Alzheimer's disease., ntly disclosed Phase III findings on semagacestat indicated that Alzheimer's disease (AD) patients on this drug showed significantly worsened cognitive function compared to those treated with placebo. Since, ts from Phase III studies showed that semagacestat failed to slow disease progression, and it was associated with worsening of clinical measures of cognition and the ability to perform activities of daily living. Furthermore, sem, rge Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of a detrimental cognitive and functional effect of the drug. These detrimental ef, BACKGROUND: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's d, However, a large phase 3 trial of semagacestat, a potential non-transition state analog (non-TSA) GSI, in patients with Alzheimer's disease (AD) was terminated due to unexpected aggravation of cognitive deficits and side effects., However, the preliminary equivocal cognitive results obtained with bapineuzumab as well as the detrimental cognitive effects observed with semagacestat, a potent γ-secretase inhibitor, raise the possibility that targeting Aβ may not be clinically efficacious in AD.[SEP]Definitions: drug defined as following: Any natural, endogenously-derived, synthetic or semi-synthetic compound with pharmacologic activity. A pharmacologic substance has one or more specific mechanism of action(s) through which it exerts one or more effect(s) on the human or animal body. They can be used to potentially prevent, diagnose, treat or relieve symptoms of a disease. Formulation specific agents and some combination agents are also classified as pharmacologic substances.. renal defined as following: Body organ that filters blood for the secretion of URINE and that regulates ion concentrations.. NPS defined as following: A syndrome of multiple abnormalities characterized by the absence or hypoplasia of the PATELLA and congenital nail dystrophy. It is a genetically determined autosomal dominant trait.. skin cancer defined as following: A primary or metastatic malignant neoplasm involving the skin. Primary malignant skin neoplasms most often are carcinomas (either basal cell or squamous cell carcinomas) or melanomas. Metastatic malignant neoplasms to the skin include carcinomas and lymphomas.. toxicity defined as following: The finding of bodily harm due to the poisonous effects of something.. bapineuzumab defined as following: A humanized monoclonal antibody (IgG1) raised against amyloid beta peptides with Alzheimer disease treatment application. Bapineuzumab recognizes and binds the N-terminal amino acids 1-5 of the amyloid beta peptide, and may be used in a passive immunotherapy treatment.. Alzheimer's disease defined as following: Alzheimer's disease caused by mutation(s) in the APP gene, encoding amyloid-beta A4 protein. The onset of this condition typically occurs before age 65.. cognitive deficits defined as following: Disorders characterized by disturbances in mental processes related to learning, thinking, reasoning, and judgment.. disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. weight loss defined as following: The measured decrease in body weight over a specified period of time..", "label": "no"} {"id": "converted_3337", "sentence1": "Are Spinal Intradural Primary Malignant Peripheral Nerve Sheath Tumors(MPNST) rare in neurofibromatosis patients?", "sentence2": "Spinal intradural primary malignant peripheral nerve sheath tumors (MPNST) are rare in patients without neurofibromatosis., Primary malignant peripheral nerve sheath tumors (MPNSTs) are extremely rare in patients without a history of neurofibromatosis; only 18 cases have been reported in the English-language literature to this point.[SEP]Definitions: MPNST defined as following: A malignant neurilemmoma with nerve sheath differentiation. It is often associated with NEUROFIBROMATOSIS 1 and RHABDOMYOSARCOMA.. neurofibromatosis defined as following: Tumor suppressor genes located on the long arm of human chromosome 17 in the region 17q11.2. Mutation of these genes is thought to cause NEUROFIBROMATOSIS 1, Watson syndrome, and LEOPARD syndrome..", "label": "no"} {"id": "converted_1733", "sentence1": "Is mitofusin 2 a receptor for parkin?", "sentence2": "Recent work demonstrates that a phosphorylated form of the mitochondrial fusion protein Mitofusin 2 serves as a receptor for Parkin translocation to damaged mitochondria., We show that the mitochondrial outer membrane guanosine triphosphatase mitofusin (Mfn) 2 mediates Parkin recruitment to damaged mitochondria. , Mfn2 functions as a mitochondrial receptor for Parkin and is required for quality control of cardiac mitochondria., Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy[SEP]Definitions: mitochondria defined as following: Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed). mitofusin 2 defined as following: This gene is involved in mitochondrial fusion..", "label": "yes"} {"id": "converted_4655", "sentence1": "Is Erythropoietin effective for neuroprotection of Preterm Infants.", "sentence2": "BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established., There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events.CONCLUSIONS: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age., Based on existing evidence, it is still too early to recommend Epo as the standard treatment for preterm brain injury., Erythropoietin treatment of preterm infants did not result in neuroprotection at 2 years of age in two out of three published large randomized controlled trials; however, long-term follow-up of these infants is needed to come to definite conclusions.[SEP]Definitions: death defined as following: Irreversible cessation of all bodily functions, manifested by absence of spontaneous breathing and total loss of cardiovascular and cerebral functions.. Erythropoietin defined as following: A recombinant glycosylated form of erythropoietin which stimulates the differentiation and proliferation of erythroid precursors. It is used for the treatment of ANEMIA associated with CHRONIC RENAL FAILURE in dialysis and predialysis patients.. erythropoietin defined as following: This gene is involved in the regulation of red blood cell production and function.. Epo defined as following: Glycoprotein hormone, secreted chiefly by the KIDNEY in the adult and the LIVER in the FETUS, that acts on erythroid stem cells of the BONE MARROW to stimulate proliferation and differentiation.. bronchopulmonary dysplasia defined as following: A chronic lung disease developed after OXYGEN INHALATION THERAPY or mechanical ventilation (VENTILATION, MECHANICAL) usually occurring in certain premature infants (INFANT, PREMATURE) or newborn infants with respiratory distress syndrome (RESPIRATORY DISTRESS SYNDROME, NEWBORN). Histologically, it is characterized by the unusual abnormalities of the bronchioles, such as METAPLASIA, decrease in alveolar number, and formation of CYSTS.. intracranial hemorrhage defined as following: Bleeding within the cranium.. retinopathy defined as following: Diseases involving the RETINA.. brain injury defined as following: Acute and chronic (see also BRAIN INJURIES, CHRONIC) injuries to the brain, including the cerebral hemispheres, CEREBELLUM, and BRAIN STEM. Clinical manifestations depend on the nature of injury. Diffuse trauma to the brain is frequently associated with DIFFUSE AXONAL INJURY or COMA, POST-TRAUMATIC. Localized injuries may be associated with NEUROBEHAVIORAL MANIFESTATIONS; HEMIPARESIS, or other focal neurologic deficits.. prematurity defined as following: Birth when a fetus is less than 37 weeks and 0 days gestational age..", "label": "no"} {"id": "converted_865", "sentence1": "Have C12orf65 mutations been associated with axonal neuropathy and optic atrophy?", "sentence2": "Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy, Charcot-Marie Tooth disease (CMT) forms a clinically and genetically heterogeneous group of disorders. Although a number of disease genes have been identified for CMT, the gene discovery for some complex form of CMT has lagged behind. The association of neuropathy and optic atrophy (also known as CMT type 6) has been described with autosomaldominant, recessive and X-linked modes of inheritance. Mutations in Mitofusin 2 have been found to cause dominant forms of CMT6. Phosphoribosylpyrophosphate synthetase-I mutations cause X-linked CMT6, but until now, mutations in the recessive forms of disease have never been identified.METHODS: We here describe a family with three affected individuals who inherited in an autosomal recessive fashion a childhood onset neuropathy and optic atrophy. Using homozygosity mapping in the family and exome sequencing in two affected individuals we identified a novel protein-truncating mutation in the C12orf65 gene, which encodes for a protein involved in mitochondrial translation, Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy., Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features., C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families., A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55)., Optic atrophy and a Leigh-like syndrome due to mutations in the c12orf65 gene: report of a novel mutation and review of the literature., Recently, we identified the causative gene, C12orf65, that was reported the gene for Leigh syndrome, for autosomal recessive spastic paraplegia with optic atrophy and neuropathy (SPG55)., We describe 2 siblings with compound heterozygous mutations in the recently identified C12orf65 gene who presented with optic atrophy and mild developmental delays and subsequently developed bilateral, symmetric lesions in the brainstem reminiscent of Leigh syndrome., C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families, Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features, CONCLUSIONS: This work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy., C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families. , Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. , We described a large consanguineous family with neuropathy and optic atrophy carrying a loss of function mutation in the C12orf65 gene., In these patients, we identified a homozygous splice mutation, g.21043 T>A (c.282+2 T>A) which leads to skipping of exon 2. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features., This work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy., Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features., Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy., This work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy., A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55)., C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families.[SEP]Definitions: gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. CMT6 defined as following: A rare axonal hereditary motor and sensory neuropathy disease characterized by progressive, peripheral, axonal sensorimotor neuropathy (of variable severity), affecting predominantly the distal lower limbs, associated with progressive, variably severe, optic atrophy, which frequently leads to visual loss. Patients typically present distal limb muscle weakness and atrophy, hypo/areflexia, foot deformities, poor visual acuity (often with a central scotoma), nystagmus, and reduced peripheral and nocturnal vision. Additional reported manifestations include sensorineural hearing loss, major joint contractures, anosmia, scoliosis/lumbar hyperlordosis, cognitive impairment and vocal cord paresis.. Mitofusin 2 defined as following: This gene is involved in mitochondrial fusion.. peripheral neuropathy defined as following: Diseases of the peripheral nerves external to the brain and spinal cord, which includes diseases of the nerve roots, ganglia, plexi, autonomic nerves, sensory nerves, and motor nerves.. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. axonal neuropathy defined as following: Any nerve disorder affecting the axon of a nerve.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. CMT defined as following: brand name of choline magnesium trisalicylate. Leigh syndrome defined as following: A group of metabolic disorders primarily of infancy characterized by the subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, dysphagia, and lactic acidosis. Pathological features include spongy degeneration of the neuropile of the basal ganglia, thalamus, brain stem, and spinal cord. Patterns of inheritance include X-linked recessive, autosomal recessive, and mitochondrial. Leigh disease has been associated with mutations in genes for the PYRUVATE DEHYDROGENASE COMPLEX; CYTOCHROME-C OXIDASE; ATP synthase subunit 6; and subunits of mitochondrial complex I. (From Menkes, Textbook of Child Neurology, 5th ed, p850).. optic atrophy defined as following: Dominant optic atrophy is a hereditary optic neuropathy causing decreased visual acuity, color vision deficits, a centrocecal scotoma, and optic nerve pallor (Hum. Genet. 1998; 102: 79-86). Mutations leading to this condition have been mapped to the OPA1 gene at chromosome 3q28-q29. OPA1 codes for a dynamin-related GTPase that localizes to mitochondria.. Mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. mitochondrial dysfunction defined as following: A functional anomaly of mitochondria. [ORCID:0000-0001-5208-3432]. spastic paraparesis defined as following: Mild or moderate loss of motor function accompanied by spasticity in the lower extremities. This condition is a manifestation of CENTRAL NERVOUS SYSTEM DISEASES that cause injury to the motor cortex or descending motor pathways.. neuropathy defined as following: A disorder affecting the cranial nerves or the peripheral nervous system. It manifests with pain, tingling, numbness, and muscle weakness. It may be the result of physical injury, toxic substances, viral diseases, diabetes, renal failure, cancer, and drugs.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA..", "label": "yes"} {"id": "converted_172", "sentence1": "Is cytisine superior to nicotine replacement therapy for smoking cessation?", "sentence2": "The effectiveness of cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week, 2 months, and 6 months. In a prespecified subgroup analysis of the primary outcome, cytisine was superior to nicotine-replacement therapy among women and noninferior among men., CONCLUSIONS: When combined with brief behavioral support, cytisine was found to be superior to nicotine-replacement therapy in helping smokers quit smoking, but it was associated with a higher frequency of self-reported adverse events.[SEP]", "label": "yes"} {"id": "converted_811", "sentence1": "Is myasthenia gravis associated with osteoporosis?", "sentence2": "We performed PVP in 4 patients with generalized MG associated with recent steroid-induced symptomatic VFs. , In this case report, we used tacrolimus to successfully treat a 13-year-old boy with ocular MG who had suffered from severe steroid complications, including a failure of thrive and osteoporosis., INTRODUCTION: Myasthenia gravis (MG) is a neuromuscular disease which has been associated with an increased falls risk and glucocorticoid-induced osteoporosis, recognized determinants of increased fracture risk. , RESULTS: Compared to the control cohort, there was no statistically significant increased risk observed in patients with MG for any fracture (adjusted hazard ratio [AHR] 1.11; 95 % confidence interval [CI], 0.84-1.47) or osteoporotic fractures (AHR 0.98 [95 % CI 0.67-1.41]). Further, use of oral glucocorticoids up to a cumulative dose exceeding 5 g prednisolone equivalents did not increase risk of osteoporotic fracture (AHR 0.99 [95 % CI, 0.31-3.14]) compared with MG patients without glucocorticoid exposure., The RANKL/OPG ratio and indices of bone metabolisms are also not affected by THX, although THX increases the levels of IL-7 and RANKL., Both disorders had been controlled for around 15 years by oral prednisolone and a cholinesterase inhibitor following surgical removal of invasive thymoma and radiotherapy, but muscular weakness due to myalgia and an increase in serum levels of myogenic enzymes, mainly ascribable to the recurrence of PM, reappeared immediately after cessation of these drugs, which was done because the patient had multiple bone fractures and severe osteoporosis due to the long-term corticosteroid therapy. , We measured bone density in 36 patients (26 females and 10 males) who had undergone long-term prednisolone administration, and found a decrease in bone density in 31% of female patients and osteoporosis in only 11.5% (three cases)., In conclusion, prednisolone-treated patients with myasthenia gravis have an acceptable risk of bone loss if prophylactic medication is administered., INTRODUCTION: Myasthenia gravis (MG) is a neuromuscular disease which has been associated with an increased falls risk and glucocorticoid-induced osteoporosis, recognized determinants of increased fracture risk., Alendronate should be used with caution in patients with myasthenia gravis who have corticosteroid-induced osteoporosis, In this paper we present two cases of young women who developed severe PAO with vertebral fractures: a 42-year-old woman with a family history of osteoporosis, and a 21-year-old woman affected with myasthenia gravis, Myasthenia gravis (MG) is a neuromuscular disease which has been associated with an increased falls risk and glucocorticoid-induced osteoporosis, recognized determinants of increased fracture risk[SEP]Definitions: RANKL defined as following: Human TNFSF11 wild-type allele is located within 13q14 and is approximately 45 kb in length. This allele, which encodes tumor necrosis factor ligand superfamily member 11 protein, plays a role in osteoclast differentiation and activation. This allele also is involved in apoptotic signal transduction and regulation.. osteoporotic fracture defined as following: A pathologic bone fracture due to osteoporosis. It is generally caused by a fall from a standing height or lower and usually involves the spine, hip, or wrist.. fracture defined as following: A traumatic injury to the bone in which the continuity of the bone is broken.. MG defined as following: A disorder of neuromuscular transmission characterized by fatigable weakness of cranial and skeletal muscles with elevated titers of ACETYLCHOLINE RECEPTORS or muscle-specific receptor tyrosine kinase (MuSK) autoantibodies. Clinical manifestations may include ocular muscle weakness (fluctuating, asymmetric, external ophthalmoplegia; diplopia; ptosis; and weakness of eye closure) and extraocular fatigable weakness of facial, bulbar, respiratory, and proximal limb muscles. The disease may remain limited to the ocular muscles (ocular myasthenia). THYMOMA is commonly associated with this condition.. neuromuscular disease defined as following: A general term encompassing lower MOTOR NEURON DISEASE; PERIPHERAL NERVOUS SYSTEM DISEASES; and certain MUSCULAR DISEASES. Manifestations include MUSCLE WEAKNESS; FASCICULATION; muscle ATROPHY; SPASM; MYOKYMIA; MUSCLE HYPERTONIA, myalgias, and MUSCLE HYPOTONIA.. steroid defined as following: A group of polycyclic compounds closely related biochemically to TERPENES. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (STEROLS), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. (From Hawley's Condensed Chemical Dictionary, 11th ed). vertebral fractures defined as following: Broken bones in the vertebral column.. Alendronate defined as following: A nonhormonal medication for the treatment of postmenopausal osteoporosis in women. This drug builds healthy bone, restoring some of the bone loss as a result of osteoporosis.. myalgia defined as following: Painful sensation in the muscles.. bone loss defined as following: Decreased calcification or density of bone tissue.. IL-7 defined as following: A recombinant protein which is chemically identical to or similar to endogenous interleukin-7 (IL-7) with hematopoietic and immunopotentiating properties. Produced by bone marrow, thymic stromal, and spleen cells, the cytokine interleukin-7 is a hematopoietic growth factor for progenitor B cells and T cells and stimulates proliferation and differentiation of mature T-cells and Natural Killer cells. (NCI05). muscular weakness defined as following: A vague complaint of debility, fatigue, or exhaustion attributable to weakness of various muscles. The weakness can be characterized as subacute or chronic, often progressive, and is a manifestation of many muscle and neuromuscular diseases. (From Wyngaarden et al., Cecil Textbook of Medicine, 19th ed, p2251). AHR defined as following: approximately 280kD soluble protein complex; binds and mediates carcinogenesis by polycyclic aromatic hydrocarbons, heterocyclic amines, and chlorinated aromatic compounds.. prednisolone defined as following: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states.. myasthenia gravis defined as following: A disorder of neuromuscular transmission characterized by fatigable weakness of cranial and skeletal muscles with elevated titers of ACETYLCHOLINE RECEPTORS or muscle-specific receptor tyrosine kinase (MuSK) autoantibodies. Clinical manifestations may include ocular muscle weakness (fluctuating, asymmetric, external ophthalmoplegia; diplopia; ptosis; and weakness of eye closure) and extraocular fatigable weakness of facial, bulbar, respiratory, and proximal limb muscles. The disease may remain limited to the ocular muscles (ocular myasthenia). THYMOMA is commonly associated with this condition..", "label": "yes"} {"id": "converted_2462", "sentence1": "Can radius fracture cause carpal tunnel syndrome?", "sentence2": "Carpal tunnel syndrome (CTS) after distal radius fractures can present in 3 forms: acute, transient, and delayed., Complications were categorized as carpal tunnel syndrome, other sensibility issues, tendon complications including irritation and rupture, deep infections, complex regional pain syndrome and unidentified DRUJ or scapholunar problems., The overall complication rate was 14.6% (95% CI 11.8-17.7) including carpal tunnel syndrome or change in sensibility in 5.2% and tendon complications in 4.7%. , BACKGROUND: Although median nerve neuropathy and carpal tunnel syndrome (CTS) are known complications of both untreated and acutely treated distal radius fracture, median neuropathy after correction of distal radius malunion is not commonly reported in hand surgery literature. , Complications were defined as malunion, carpal tunnel syndrome, complex regional pain syndrome (CRPS), persistent pain, and subjective cosmetic deformity of the wrist., Carpal tunnel syndrome is a common complication associated with distal radius fractures., The patient also had minor complications of little finger flexor tendon irritation and carpal tunnel syndrome. She underwent implant removal and carpal tunnel release at 8 months., Acute multiple flexor tendon injury and carpal tunnel syndrome after open distal radius fracture., Carpal tunnel syndrome is a common condition and is a well-recognized phenomenon following a distal radius fracture., We report the incidence of late onset post-operative carpal tunnel syndrome (late carpal tunnel syndrome) and late median nerve neuropathy after volar plating of distal radius fracture by conducting a retrospective study on volar plating for distal radius fracture performed during 2002 to 2006., Carpal tunnel syndrome after distal radius fracture., [Case-control study on transverse carpal ligament resection for the prevention of delayed carpal tunnel syndrome after distal radius fracture]., Hand numbness and carpal tunnel syndrome after volar plating of distal radius fracture., Delayed carpal tunnel syndrome presenting after a distal radius fracture has healed is best managed in standard fashion., Being well known and accepted techniques of carpal tunnel release, we believe that the techniques described in this paper provide a viable alternative for carpal tunnel release in the setting of distal radius fracture fixation; with the added advantages of the original minimally invasive techniques., Carpal tunnel syndrome after fracture of the distal radius is a well known complication in adults, but in small children carpal tunnel syndrome is extremely rare., Carpal Tunnel Syndrome and Distal Radius Fractures., Carpal tunnel syndrome after distal radius fracture., Hand numbness and carpal tunnel syndrome after volar plating of distal radius fracture.[SEP]Definitions: CTS defined as following: Entrapment of the MEDIAN NERVE in the carpal tunnel, which is formed by the flexor retinaculum and the CARPAL BONES. This syndrome may be associated with repetitive occupational trauma (CUMULATIVE TRAUMA DISORDERS); wrist injuries; AMYLOID NEUROPATHIES; rheumatoid arthritis (see ARTHRITIS, RHEUMATOID); ACROMEGALY; PREGNANCY; and other conditions. Symptoms include burning pain and paresthesias involving the ventral surface of the hand and fingers which may radiate proximally. Impairment of sensation in the distribution of the median nerve and thenar muscle atrophy may occur. (Joynt, Clinical Neurology, 1995, Ch51, p45). malunion defined as following: Faulty healing of bone, resulting in improper anatomical alignment.. fracture defined as following: A traumatic injury to the bone in which the continuity of the bone is broken.. CRPS defined as following: Conditions characterized by pain involving an extremity or other body region, HYPERESTHESIA, and localized autonomic dysfunction following injury to soft tissue or nerve. The pain is usually associated with ERYTHEMA; SKIN TEMPERATURE changes, abnormal sudomotor activity (i.e., changes in sweating due to altered sympathetic innervation) or edema. The degree of pain and other manifestations is out of proportion to that expected from the inciting event. Two subtypes of this condition have been described: type I; (REFLEX SYMPATHETIC DYSTROPHY) and type II; (CAUSALGIA). (From Pain 1995 Oct;63(1):127-33). tendon defined as following: Fibrous bands or cords of CONNECTIVE TISSUE at the ends of SKELETAL MUSCLE FIBERS that serve to attach the MUSCLES to bones and other structures.. neuropathy defined as following: A disorder affecting the cranial nerves or the peripheral nervous system. It manifests with pain, tingling, numbness, and muscle weakness. It may be the result of physical injury, toxic substances, viral diseases, diabetes, renal failure, cancer, and drugs.. rupture defined as following: Forcible or traumatic tear or break of an organ or other soft part of the body..", "label": "yes"} {"id": "converted_2947", "sentence1": "Are there tools for reviewing variant calls?", "sentence2": "VIPER: a web application for rapid expert review of variant calls., With the rapid development in next-generation sequencing, cost and time requirements for genomic sequencing are decreasing, enabling applications in many areas such as cancer research. Many tools have been developed to analyze genomic variation ranging from single nucleotide variants to whole chromosomal aberrations. As sequencing throughput increases, the number of variants called by such tools also grows. Often employed manual inspection of such calls is thus becoming a time-consuming procedure. We developed the Variant InsPector and Expert Rating tool (VIPER) to speed up this process by integrating the Integrative Genomics Viewer into a web application. Analysts can then quickly iterate through variants, apply filters and make decisions based on the generated images and variant metadata. VIPER was successfully employed in analyses with manual inspection of more than 10 000 calls.Availability and implementation: VIPER is implemented in Java and Javascript and is freely available at https://github.com/MarWoes/viper., Variant Review with the Integrative Genomics Viewer., VIPER: a web application for rapid expert review of variant calls.Supplementary data are available at Bioinformatics online., We developed the Variant InsPector and Expert Rating tool (VIPER) to speed up this process by integrating the Integrative Genomics Viewer into a web application.[SEP]Definitions: variants defined as following: An alteration or difference from a norm or standard..", "label": "yes"} {"id": "converted_2024", "sentence1": "Is the enzyme EPRS phosphorylated?", "sentence2": "Phosphorylation of glutamyl-prolyl tRNA synthetase (EPRS) has been investigated extensively in our laboratory for more than a decade, and has served as an archetype for studies of other AARSs., EPRS is dually phosphorylated by cyclin-dependent kinase 5 (Cdk5) at Ser(886) and then by a Cdk5-dependent-AGC kinase at Ser(999); , Diphosphorylated EPRS is released from its residence in the tRNA multisynthetase complex for immediate binding to NS1-associated protein and subsequent binding to ribosomal protein L13a and GAPDH. , Two-site phosphorylation of EPRS coordinates multimodal regulation of noncanonical translational control activity.[SEP]Definitions: GAPDH defined as following: Glyceraldehyde-3-phosphate dehydrogenase (335 aa, ~36 kDa) is encoded by the human GAPDH gene. This protein is involved in carbohydrate metabolism.. cyclin-dependent kinase 5 defined as following: Protein kinases that control cell cycle progression in all eukaryotes and require physical association with CYCLINS to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events.. Cdk5 defined as following: Cyclin-dependent kinase 5 (292 aa, ~33 kDa) is encoded by the human CDK5 gene. This protein plays a role in protein phosphorylation and may be involved in cell cycle regulation..", "label": "yes"} {"id": "converted_1392", "sentence1": "Do RNA:DNA hybrids preferentially form in high or low GC regions?", "sentence2": "Intrinsic termination signals for multisubunit bacterial RNA polymerases (RNAPs) encode a GC-rich stem-loop structure followed by a polyuridine [poly(U)] tract, and it has been proposed that steric clash of the stem-loop with the exit pore of the RNAP imposes a shearing force on the RNA in the downstream RNA:DNA hybrid, resulting in misalignment of the active site, We have observed that transcription through the GC-rich FMR1 5'UTR region favors R-loop formation, with the nascent (G-rich) RNA forming a stable RNA:DNA hybrid with the template DNA strand, thereby displacing the non-template DNA strand., Transcription termination by bacterial RNA polymerase (RNAP) occurs at sequences coding for a GC-rich RNA hairpin followed by a U-rich tract. We used single-molecule techniques to investigate the mechanism by which three representative terminators (his, t500, and tR2) destabilize the elongation complex (EC)., In the 5' flanking region, nucleotides -234 to -213 encompass a GC-rich region which exhibits high homology (greater than 70%) to the 5' flanking regions of the genes of all the apolipoproteins published to date, namely, apo-A-II (-497 to -471), apo-A-I (approximately -196 to -179), apo-E (-409 to -391), and apo-C-III (approximately -116 to -103)., Recently, we demonstrated that cotranscriptional RNA•DNA hybrids are preferentially formed at GC-rich trinucleotide and tetranucleotide repeat sequences in vitro as well as in human genomic DNA., Considering the extent of transcription through the human genome as well as the abundance of GC-rich and/or non-canonical DNA structure forming tandem repeats, RNA•DNA hybrids may represent a common mutagenic conformation., Recently, we demonstrated that cotranscriptional RNA•DNA hybrids are preferentially formed at GC-rich trinucleotide and tetranucleotide repeat sequences in vitro as well as in human genomic DNA. [SEP]Definitions: apo-E defined as following: A class of protein components which can be found in several lipoproteins including HIGH-DENSITY LIPOPROTEINS; VERY-LOW-DENSITY LIPOPROTEINS; and CHYLOMICRONS. Synthesized in most organs, Apo E is important in the global transport of lipids and cholesterol throughout the body. Apo E is also a ligand for LDL receptors (RECEPTORS, LDL) that mediates the binding, internalization, and catabolism of lipoprotein particles in cells. There are several allelic isoforms (such as E2, E3, and E4). Deficiency or defects in Apo E are causes of HYPERLIPOPROTEINEMIA TYPE III.. RNA defined as following: A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed). nucleotides defined as following: The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. (From King & Stansfield, A Dictionary of Genetics, 4th ed). apolipoproteins defined as following: Major structural proteins of triacylglycerol-rich LIPOPROTEINS. There are two forms, apolipoprotein B-100 and apolipoprotein B-48, both derived from a single gene. ApoB-100 expressed in the liver is found in low-density lipoproteins (LIPOPROTEINS, LDL; LIPOPROTEINS, VLDL). ApoB-48 expressed in the intestine is found in CHYLOMICRONS. They are important in the biosynthesis, transport, and metabolism of triacylglycerol-rich lipoproteins. Plasma Apo-B levels are high in atherosclerotic patients but non-detectable in ABETALIPOPROTEINEMIA.. FMR1 defined as following: This gene may be involved in the regulation of mRNA trafficking.. homology defined as following: A gene from one species which corresponds to a gene in another species and that is related via a common ancestral species. These genes retain a similar sequence and function.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "yes"} {"id": "converted_3173", "sentence1": "Can prevnar 13 be used in children?", "sentence2": "PCV13 is approved for routine vaccination of all infants as a 4-dose series at age 2, 4, 6, and 12-15 months for children who previously received 1 or more doses of the 7-valent pneumococcal conjugate vaccine (PCV7), and for children with underlying medical conditions that increase their risk for pneumococcal disease or its complications. , Based on published immunogenicity and safety data, as well as the recent recommendations by the ACIP for routine use in infants and indications for high-risk pediatric patients, PCV13 is a revised formulation of pneumococcal vaccine that should be included on pharmacy formularies., To review the immunogenicity, efficacy, and safety of the 13-valent pneumococcal conjugate vaccine (PCV13) for use in pediatric patients.[SEP]", "label": "yes"} {"id": "converted_3052", "sentence1": "Is Netrin-1 a secreted protein?", "sentence2": "The axon guidance cues netrin-1 is a secreted protein overexpressed in many different cancer tissues, Netrin-1 is a secreted protein that directs long-range axon guidance during early stages of neural circuit formation and continues to be expressed in the mammalian forebrain during the postnatal period of peak synapse formation. , Netrin-1, a laminin-related secreted protein, displays proto-oncogenic activity in cancers., Netrin-1, a multifunctional secreted protein, is up-regulated in cancer and inflammation., etrin-1 is a laminin-related secreted protein, is highly induced after tissue injury, and may serve as a marker of injury., Netrins are a family of secreted protein related to laminin and act as tropic cues directing axon growth and cell migration during neural development. [SEP]Definitions: cancer defined as following: A malignant tumor at the original site of growth.. laminin defined as following: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion.. inflammation defined as following: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.. Netrins defined as following: A family of extracellular proteins that are related structurally to LAMININ. They function as CHEMOTACTIC FACTORS for CELL MIGRATION and AXON GUIDANCE, acting as chemoattractants for some cell types, and as chemorepellents for others.. netrin-1 defined as following: This gene plays a role in neurogenesis. It may also be involved in cell migration during development.. cancers defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. Netrin-1 defined as following: This gene plays a role in neurogenesis. It may also be involved in cell migration during development.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species..", "label": "yes"} {"id": "converted_2007", "sentence1": "Is the mouse Sry gene locus free of repetitive sequences?", "sentence2": "We demonstrate that the presence of long inverted repeats (IR) flanking the mouse Sry gene leads to the formation of the Sry circular transcript in cultured cells, Circularization requires the presence of both IR. As few as 400 complementary nt are necessary for this process, The presence of the IR does not significantly stimulate intermolecular annealing and trans-splicing in vivo, We have found that in an in vitro assay, the SRY protein binds to several sites of the Sry gene and especially to a (CA)25 sequence and to a (CAG)30 repeat, The Q-rich domain of the mouse sex determining gene, Sry, is encoded by an in-frame insertion of a repetitive sequence composed of mostly CAG repeats., Inverted repeat structure of the Sry locus in mice., We performed separate amplifications of DXZ4 repetitive satellite sequences on the X chromosome, and SRY gene - testis determined factor on the Y chromosome, using nested PCR, Detailed analysis of the Sry genomic locus reveals a further difference in that the mouse Sry open reading frame lies within 2.8 kilobases of unique sequence at the center of a large inverted repeat. , Detailed analysis of the Sry genomic locus reveals a further difference in that the mouse Sry open reading frame lies within 2.8 kilobases of unique sequence at the center of a large inverted repeat., The mouse genomic Sry locus is characterized by two arms of a large inverted repeat, flanking a unique region that, between an acceptor and a donor splice site, contains a single exon encoding the Sry protein., Recombination involving the repeat region may have led to an 11-kilobase deletion, precisely excising Sry in a line of XY female mice., Repetitive element analysis revealed numerous LINE-L1 elements at regions where conservation is lost among the Sry copies., Inverted repeat structure of the Sry locus in mice.[SEP]Definitions: gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. Sry gene defined as following: The primary testis-determining gene in mammalians, located on the Y CHROMOSOME. It codes for a high mobility group box transcription factor (TRANSCRIPTION FACTORS) which initiates the development of the TESTES from the embryonic GONADS.. exon defined as following: The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA.. cultured cells defined as following: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.. repeat defined as following: Something occurring more than once.. conservation defined as following: The maintenance of certain characteristics in an unchanged condition.. Sry defined as following: Sex-determining region Y protein (204 aa, ~24 kDa) is encoded by the human SRY gene. This protein is involved in sex determination and transcriptional regulation.. IR defined as following: A lymphoma response that cannot be distinguished between flare/pseudo-progression and true progressive disease.. region defined as following: The continents and countries situated on those continents; the UNITED STATES and each of the constituent states arranged by region; CANADA and each of its provinces; AUSTRALIA and each of its states; the major bodies of water and major islands on both hemispheres; and selected major cities.. repetitive sequence defined as following: Nucleotide sequences present in multiple copies in the genome. There are several types of repeated sequences. Interspersed (or dispersed) DNA repeats (Interspersed Repetitive Sequences) are copies of transposable elements interspersed throughout the genome. Flanking (or terminal) repeats (Terminal Repeat Sequences) are sequences that are repeated on both ends of a sequence, for example, the long terminal repeats (LTRs) on retroviruses. Direct terminal repeats are in the same direction and inverted terminal repeats are opposite to each other in direction. Tandem repeats (Tandem Repeat Sequences) are repeated copies which lie adjacent to each other. These can also be direct or inverted. The ribosomal RNA and transfer RNA genes belong to the class of middle repetitive DNA.. Y chromosome defined as following: The male sex chromosome, being the differential sex chromosome carried by half the male gametes and none of the female gametes in humans and in some other male-heterogametic species in which the homologue of the X chromosome has been retained.. X chromosome defined as following: The female sex chromosome, being the differential sex chromosome carried by half the male gametes and all female gametes in human and other male-heterogametic species.. repetitive sequences defined as following: Nucleotide sequences present in multiple copies in the genome. There are several types of repeated sequences. Interspersed (or dispersed) DNA repeats (Interspersed Repetitive Sequences) are copies of transposable elements interspersed throughout the genome. Flanking (or terminal) repeats (Terminal Repeat Sequences) are sequences that are repeated on both ends of a sequence, for example, the long terminal repeats (LTRs) on retroviruses. Direct terminal repeats are in the same direction and inverted terminal repeats are opposite to each other in direction. Tandem repeats (Tandem Repeat Sequences) are repeated copies which lie adjacent to each other. These can also be direct or inverted. The ribosomal RNA and transfer RNA genes belong to the class of middle repetitive DNA..", "label": "no"} {"id": "converted_3710", "sentence1": "Has ORMD-0801 been tested in patients?", "sentence2": "Glucose-reducing effect of the ORMD-0801 oral insulin preparation in patients with uncontrolled type 1 diabetes: a pilot study., In efforts to provide patients with a more compliable treatment method, Oramed Pharmaceuticals tested the capacity of its oral insulin capsule (ORMD-0801, 8 mg insulin) in addressing this resistant clinical state.[SEP]Definitions: insulin defined as following: A synthetic or animal-derived form of insulin used in the treatment of diabetes mellitus. Therapeutic insulin is formulated to be short-, intermediate- and long-acting in order to individualize an insulin regimen according to individual differences in glucose and insulin metabolism. Therapeutic insulin may be derived from porcine, bovine or recombinant sources. Endogenous human insulin, a pancreatic hormone composed of two polypeptide chains, is important for the normal metabolism of carbohydrates, proteins and fats and has anabolic effects on many types of tissues.. Pharmaceuticals defined as following: Any natural, endogenously-derived, synthetic or semi-synthetic compound with pharmacologic activity. A pharmacologic substance has one or more specific mechanism of action(s) through which it exerts one or more effect(s) on the human or animal body. They can be used to potentially prevent, diagnose, treat or relieve symptoms of a disease. Formulation specific agents and some combination agents are also classified as pharmacologic substances..", "label": "yes"} {"id": "converted_1173", "sentence1": "Do Parkinson's disease patients experience stridor?", "sentence2": "The authors describe a patient experiencing stridor and dysphagia with confirmed pulmonary restriction and aspiration following subthalamic nucleus deep brain stimulator adjustment, with a resolution of symptoms and signs when the stimulator was switched off., Stridor was not noted during sleep at night. Endoscopic examination of the larynx revealed insufficient abduction of the bilateral vocal cords, although the glottis was not so small as to cause stridor during inspiration. , The stridor was specific to MSA. , Patients with MSA can present other clinical features, such as inspiratory stridor and rapid eye movement (REM) sleep behaviour disorder (RBD). We report a patient with pathologically confirmed MSA who presented with a longstanding history of stridor, RBD and autonomic disturbances but did not develop overt parkinsonism or cerebellar signs. This case illustrates that MSA may present clinically without its cardinal motor symptoms, and that stridor and RBD may be clues to recognise the disease in a patient with autonomic failure., Patients with PD did not display sleep hypoventilation, stridor and abnormal central sleep apnea. , DEVELOPMENT: Autonomic disorders such as seborrhoeic dermatitis and disorders involving sweating, fatigue, weight loss or respiratory problems (dyspnea, inspiratory stridor) are highly prevalent and very disabling symptoms. In addition, they may be the main problem in a particular phase of PD (fatigue, stridor) and condition the quality of life of patients with Parkinson. , . Her dyspneic attacks consisting of inspiratory stridor and cyanosis occurred mainly during the wearing-off time and continued for less than 30 min, The most commonly reported sleep disorders were sleep fragmentation (52.5%), vocalisation (60%), REM sleep behaviour disorder (47.5%), and nocturnal stridor (19%). Except for sleep fragmentation, the incidence of these disorders was significantly higher than in PD, Six days after admission, dyspnea and inspiratory stridor were noted, and the respiratory distress worsened. , A patient is described with idiopathic Parkinson's disease and severe laryngeal stridor., The laryngeal stridor responded to levodopa therapy, and we are not aware that this has been reported previously., The subsequent clinical course of the former eight patients has been typical of idiopathic Parkinson's disease, whilst the ninth patient has developed postural hypotension, urinary incontinence and respiratory stridor typical of multiple system atrophy. , Although each of five autonomic domains was affected in variable numbers of IPD patients, AD in MSA generally involved more autonomic domains than in IPD, and to a more severe degree, in particular with regard to inspiratory stridor., However, the presence of severe AD, of AD preceding parkinsonism, or of inspiratory stridor, are all individually suggestive of MSA., Apart from dysautonomia, the principal discriminant clinical features that distinguished SND from PD were the early appearance of the following symptoms and signs: (a) severe and atypical progressive parkinsonism characterized by bilateral bradykinesia and rigidity, slowness of gait, postural instability, and falls, and poor or absent response to adequate levodopa treatment; (b) increased tendon reflexes associated or not with frank pyramidal signs, severe dysarthria, and less consistently, dysphagia, stridor, antecollis, and stimulus-sensitive myoclonus, which, when present, are highly suggestive of the disease., OBJECTIVES: (1) To present a rare case of stridor secondary to prolonged laryngospasm in a patient with Parkinson's disease, and (2) to review the literature on stridor in Parkinson's disease. METHODS: We report a 73-year-old Parkinson's disease patient who developed acute stridor due to prolonged laryngospasm triggered by overspill of excessive secretions. , RESULT: Only 12 previously reported cases of stridor in Parkinson's disease patients were identified. , This case emphasises the importance of recognising different causes of stridor in Parkinson's disease patients, as this affects management., RESULT: Only 12 previously reported cases of stridor in Parkinsons disease patients were identified., This case emphasises the importance of recognising different causes of stridor in Parkinsons disease patients, as this affects management., OBJECTIVES: (1) To present a rare case of stridor secondary to prolonged laryngospasm in a patient with Parkinsons disease, and (2) to review the literature on stridor in Parkinsons disease., METHODS: We report a 73-year-old Parkinsons disease patient who developed acute stridor due to prolonged laryngospasm triggered by overspill of excessive secretions., (1) To present a rare case of stridor secondary to prolonged laryngospasm in a patient with Parkinson's disease, and (2) to review the literature on stridor in Parkinson's disease.[SEP]Definitions: SND defined as following: An Indo-Aryan language spoken by the Sindhi people of the Pakistani province of Sindh.. PD defined as following: A score of 4 or 5 on a 5-point PET scale with an increase in intensity of uptake from baseline and/or new FDG-avid foci consistent with lymphoma at interim or end of treatment assessment.. sleep disorders defined as following: Conditions characterized by disturbances of usual sleep patterns or behaviors. SLEEP WAKE DISORDERS may be divided into three major categories: DYSSOMNIAS (i.e. disorders characterized by insomnia or hypersomnia), PARASOMNIAS (abnormal sleep behaviors), and SLEEP WAKE DISORDERS secondary to medical or psychiatric disorders. (From Thorpy, Sleep Disorders Medicine, 1994, p187). RBD defined as following: An approximately 80 amino acid RNA binding motif that consists of four anti-parallel surface beta sheets and two alpha helices arranged in a beta-alpha-beta-beta-alpha-beta configuration. One of the surface beta sheets interacts with two or three specific RNA bases. Interactions between additional sequences and the RNA, as well as within the RNA recognition motif increase the affinity and specificity of the protein-RNA interaction.. dysautonomia defined as following: An acute or chronic disorder, affecting the sympathetic or parasympathetic nervous system. It can be primary, the result of central nervous system degeneration, or secondary due to diabetes or alcoholism. Patients with the chronic form of this disorder usually have a progressive clinical course and a poor prognosis.. rigidity defined as following: Continuous involuntary sustained muscle contraction which is often a manifestation of BASAL GANGLIA DISEASES. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from MUSCLE SPASTICITY. (From Adams et al., Principles of Neurology, 6th ed, p73). stridor defined as following: A symptom resulting from laryngeal obstruction. It is characterized by a high pitched breathing sound.. Parkinsons disease defined as following: A progressive, degenerative neurologic disease characterized by a TREMOR that is maximal at rest, retropulsion (i.e. a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression. Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem. LEWY BODIES are present in the substantia nigra and locus coeruleus but may also be found in a related condition (LEWY BODY DISEASE, DIFFUSE) characterized by dementia in combination with varying degrees of parkinsonism. (Adams et al., Principles of Neurology, 6th ed, p1059, pp1067-75). MSA defined as following: A syndrome complex composed of three conditions which represent clinical variants of the same disease process: STRIATONIGRAL DEGENERATION; SHY-DRAGER SYNDROME; and the sporadic form of OLIVOPONTOCEREBELLAR ATROPHIES. Clinical features include autonomic, cerebellar, and basal ganglia dysfunction. Pathologic examination reveals atrophy of the basal ganglia, cerebellum, pons, and medulla, with prominent loss of autonomic neurons in the brain stem and spinal cord. (From Adams et al., Principles of Neurology, 6th ed, p1076; Baillieres Clin Neurol 1997 Apr;6(1):187-204; Med Clin North Am 1999 Mar;83(2):381-92). glottis defined as following: The vocal apparatus of the larynx, situated in the middle section of the larynx. Glottis consists of the VOCAL FOLDS and an opening (rima glottidis) between the folds.. urinary incontinence defined as following: Involuntary loss of URINE, such as leaking of urine. It is a symptom of various underlying pathological processes. Major types of incontinence include URINARY URGE INCONTINENCE and URINARY STRESS INCONTINENCE.. autonomic failure defined as following: A degenerative disease of the AUTONOMIC NERVOUS SYSTEM that is characterized by idiopathic ORTHOSTATIC HYPOTENSION and a greatly reduced level of CATECHOLAMINES. No other neurological deficits are present.. fatigue defined as following: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli.. cyanosis defined as following: A bluish or purplish discoloration of the skin and mucous membranes due to an increase in the amount of deoxygenated hemoglobin in the blood or a structural defect in the hemoglobin molecule.. inspiratory stridor defined as following: Inspiratory stridor is a high pitched sound upon inspiration that is generally related to laryngeal abnormalities. [HPO:curators]. laryngeal stridor defined as following: A disorder in which the adductor muscles of the VOCAL CORDS exhibit increased activity leading to laryngeal spasm. Laryngismus causes closure of the VOCAL FOLDS and airflow obstruction during inspiration.. parkinsonism defined as following: A group of disorders which feature impaired motor control characterized by bradykinesia, MUSCLE RIGIDITY; TREMOR; and postural instability. Parkinsonian diseases are generally divided into primary parkinsonism (see PARKINSON DISEASE), secondary parkinsonism (see PARKINSON DISEASE, SECONDARY) and inherited forms. These conditions are associated with dysfunction of dopaminergic or closely related motor integration neuronal pathways in the BASAL GANGLIA.. levodopa defined as following: The naturally occurring form of DIHYDROXYPHENYLALANINE and the immediate precursor of DOPAMINE. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to DOPAMINE. It is used for the treatment of PARKINSONIAN DISORDERS and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system.. disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. dysphagia defined as following: Difficulty in SWALLOWING which may result from neuromuscular disorder or mechanical obstruction. Dysphagia is classified into two distinct types: oropharyngeal dysphagia due to malfunction of the PHARYNX and UPPER ESOPHAGEAL SPHINCTER; and esophageal dysphagia due to malfunction of the ESOPHAGUS.. dyspnea defined as following: Difficult or labored breathing.. larynx defined as following: A tubular organ of VOICE production. It is located in the anterior neck, superior to the TRACHEA and inferior to the tongue and HYOID BONE.. IPD defined as following: An autosomal recessive condition caused by mutation(s) in the SLC6A3 gene, encoding sodium-dependent dopamine transporter. It is characterized by Parkinsonian features and has an onset in early infancy.. weight loss defined as following: The measured decrease in body weight over a specified period of time.. Parkinson's disease defined as following: A progressive, degenerative neurologic disease characterized by a TREMOR that is maximal at rest, retropulsion (i.e. a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression. Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem. LEWY BODIES are present in the substantia nigra and locus coeruleus but may also be found in a related condition (LEWY BODY DISEASE, DIFFUSE) characterized by dementia in combination with varying degrees of parkinsonism. (Adams et al., Principles of Neurology, 6th ed, p1059, pp1067-75).", "label": "yes"} {"id": "converted_1691", "sentence1": "Is STAT3 transcription factor regulated by mTORC1?", "sentence2": "Mechanistically, mTORC1 mediated IL-6-induced Stat3 activation in intestinal epithelial cells to stimulate the expression of downstream targets essential for cell proliferation and tissue regeneration. Therefore, mTORC1 signaling critically protects against inflammatory bowel disease through modulation of inflammation-induced Stat3 activity., we demonstrated that STAT3 is directly phosphorylated by mTORC1 on Ser727 during hypoxia, promoting HIF-1α mRNA transcription, Mechanistically, mTORC1 signaling was activated by excess amino acids, which then positively regulated Notch1 expression through the activation of the signal transducer and activator of transcription 3 (STAT3)., Here we present evidence for the involvement of STAT3, a known mTORC1 regulated transcription factor, in this process, Furthermore, we demonstrated that STAT3 is directly phosphorylated by mTORC1 on Ser727 during hypoxia, promoting HIF-1α mRNA transcription. mTORC1 also regulates HIF-1α synthesis on a translational level via co-operative regulation of both initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase-1 (S6K1), whereas HIF-1α degradation remains unaffected, Here we present evidence for the involvement of STAT3, a known mTORC1 regulated transcription factor, in this process. , TSC1/TSC2 inactivation inhibits AKT through mTORC1-dependent up-regulation of STAT3-PTEN cascade., Mechanistically, mTORC1 signaling was activated by excess amino acids, which then positively regulated Notch1 expression through the activation of the signal transducer and activator of transcription 3 (STAT3). , Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids., Here, we review the connections between mTORC1 and gene transcription by focusing on its impact in regulating the activation of specific transcription factors including including STAT3, SREBPs, PPARγ, PPARα, HIF1α, YY1–PGC1α and TFEB. We also discuss the importance of these transcription factors in mediating the effects of mTORC1 on various cellular processes in physiological and pathological contexts.[SEP]Definitions: TFEB defined as following: Transcription factor EB (476 aa, ~53 kDa) is encoded by the human TFEB gene. This protein plays a role in transcriptional regulation.. S6K1 defined as following: Human RPS6KB1 wild-type allele is located in the vicinity of 17q23.1 and is approximately 57 kb in length. This allele, which encodes ribosomal protein S6 kinase beta-1 protein, plays a role in the regulation of protein phosphorylation.. epithelial cells defined as following: Cells that line the inner and outer surfaces of the body by forming cellular layers (EPITHELIUM) or masses. Epithelial cells lining the SKIN; the MOUTH; the NOSE; and the ANAL CANAL derive from ectoderm; those lining the RESPIRATORY SYSTEM and the DIGESTIVE SYSTEM derive from endoderm; others (CARDIOVASCULAR SYSTEM and LYMPHATIC SYSTEM) derive from mesoderm. Epithelial cells can be classified mainly by cell shape and function into squamous, glandular and transitional epithelial cells.. 4E-BP1 defined as following: Eukaryotic translation initiation factor 4E-binding protein 1 (118 aa, ~13 kDa) is encoded by the human EIF4EBP1 gene. This protein is involved in the modulation of translation and the sequestration of eukaryotic translation initiation factor 4E.. STAT3 defined as following: Signal transducer and activator of transcription 3 (770 aa, ~88 kDa) is encoded by the human STAT3 gene. This protein plays a role in cytokine signaling and gene expression.. AKT defined as following: Expressed in diverse tissues, Protein Kinase B (AKT/RAC Family) is a group (Alpha, Beta and Gamma) of cytoplasmic serine/threonine enzymes that covalently transfer the terminal, gamma phosphate group from ATP to a variety of substrate proteins and regulate cell signaling responses to insulin, PDGF, and IGF1 (through PI3K) involved in cell survival, cell proliferation, differentiation, apoptosis, glycogen synthesis, and glucose uptake.. mTORC1 defined as following: A protein complex that is involved in the both serine/threonine phosphorylation and the regulation of protein synthesis in response to cellular stress.. AMPK defined as following: Intracellular signaling protein kinases that play a signaling role in the regulation of cellular energy metabolism. Their activity largely depends upon the concentration of cellular AMP which is increased under conditions of low energy or metabolic stress. AMP-activated protein kinases modify enzymes involved in LIPID METABOLISM, which in turn provide substrates needed to convert AMP into ATP.. hypoxia defined as following: A disorder characterized by a decrease in the level of oxygen in the body.. transcription factors defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process..", "label": "yes"} {"id": "converted_4357", "sentence1": "Is MEDI2228 a bispecific antibody?", "sentence2": "We here delineated the molecular and cellular mechanisms underlying novel immunomodulatory effects triggered by BCMA pyrrolobenzodiazepine (PBD) antibody drug conjugate (ADC) MEDI2228 which can augment efficacy of these immunotherapies.[SEP]Definitions: molecular defined as following: Relating to or produced by or consisting of molecules.. bispecific antibody defined as following: Antibodies, often monoclonal, in which the two antigen-binding sites are specific for separate ANTIGENIC DETERMINANTS. They are artificial antibodies produced by chemical crosslinking, fusion of HYBRIDOMA cells, or by molecular genetic techniques. They function as the main mediators of targeted cellular cytotoxicity and have been shown to be efficient in the targeting of drugs, toxins, radiolabeled haptens, and effector cells to diseased tissue, primarily tumors..", "label": "no"} {"id": "converted_1828", "sentence1": "Is Migalastat used for treatment of Fabry Disease?", "sentence2": "Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study., BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking., CONCLUSIONS: Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations., Migalastat (Galafold™)-a small molecule drug developed by Amicus Therapeutics that restores the activity of specific mutant forms of α-galactosidase-has been approved for the treatment of Fabry disease in the EU in patients with amenable mutations., This article summarizes the milestones in the development of migalastat leading to this first approval in the EU for the long-term treatment of adults and adolescents aged ≥16 years with a confirmed diagnosis of Fabry disease., Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat., BACKGROUND: Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes., Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase., UNLABELLED: Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. , Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients., migalastat for Fabry disease) and inhibitors of glucosylceramide synthesis (e.g., A Phase 2 study of migalastat hydrochloride in females with Fabry disease: selection of population, safety and pharmacodynamic effects., Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder, Migalastat HCl is an investigational, oral treatment for Fabry disease, an X-linked lysosomal storage disorder, Oral administration of migalastat HCl reduces tissue GL-3 in Fabry transgenic mice, and in urine and kidneys of some FD patients. , Migalastat HCl is an investigational, oral treatment for Fabry disease, an X-linked lysosomal storage disorder., Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder., Molecular chaperones (e.g. migalastat for Fabry disease) and inhibitors of glucosylceramide synthesis (e.g. eliglustat tartrate for Gaucher disease) are currently under investigation in various clinical trials.Mandibular left third molar prosthesis
. Profilin defined as following: This gene plays a role in the regulation of actin polymerization.. 4p16.3 defined as following: A chromosome band present on 4p. neuronal migration disorder defined as following: A diverse group of congenital brain developmental disorders characterized by defects in neuronal migration in the brain during early fetal development. The neuronal migration defects result in brain abnormalities that are usually manifested with mental retardation and epilepsy.. Angelman syndrome defined as following: A syndrome characterized by multiple abnormalities, MENTAL RETARDATION, and movement disorders. Present usually are skull and other abnormalities, frequent infantile spasms (SPASMS, INFANTILE); easily provoked and prolonged paroxysms of laughter (hence \"happy\"); jerky puppetlike movements (hence \"puppet\"); continuous tongue protrusion; motor retardation; ATAXIA; MUSCLE HYPOTONIA; and a peculiar facies. It is associated with maternal deletions of chromosome 15q11-13 and other genetic abnormalities. (From Am J Med Genet 1998 Dec 4;80(4):385-90; Hum Mol Genet 1999 Jan;8(1):129-35). deletions defined as following: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus.. Y chromosome defined as following: The male sex chromosome, being the differential sex chromosome carried by half the male gametes and none of the female gametes in humans and in some other male-heterogametic species in which the homologue of the X chromosome has been retained.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. Prader-Willi syndrome defined as following: An autosomal dominant disorder caused by deletion of the proximal long arm of the paternal chromosome 15 (15q11-q13) or by inheritance of both of the pair of chromosomes 15 from the mother (UNIPARENTAL DISOMY) which are imprinted (GENETIC IMPRINTING) and hence silenced. Clinical manifestations include MENTAL RETARDATION; MUSCULAR HYPOTONIA; HYPERPHAGIA; OBESITY; short stature; HYPOGONADISM; STRABISMUS; and HYPERSOMNOLENCE. (Menkes, Textbook of Child Neurology, 5th ed, p229). death defined as following: Irreversible cessation of all bodily functions, manifested by absence of spontaneous breathing and total loss of cardiovascular and cerebral functions.. trisomy 5p defined as following: Duplication of the short arm of chromosome 5 most frequently associated with craniofacial, cardiac, renal, and limb abnormalities, and moderate to severe mental retardation. Dandy-Walker malformation (agenesis of the cerebellar vermis, hydrocephalus, and posterior fossa cyst continuous with the fourth ventricle) occurs in some cases. The phenotype is related to the amount of genetic material duplicated and the specific duplicated segment.. tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. Wolf-Hirschhorn syndrome defined as following: A syndrome caused by large deletions of the telomereic end of the short arm of CHROMOSOME 4 (4p) in Wolf-Hirchhorn syndrome critial regions (WHSCRs). Several candidate genes have been identified including WHSC1 and WHSCH2 which appear to be responsible for the core phenotype and in combination with other linked and unlinked genes determine the severity and inclusion of rarer phenotypes. Most cases have a characteristic cranio-facial defect often referred to as \"Greek helmet face\" - a combined result of MICROCEPHALY, broad forehead, prominent glabella, HYPERTELORISM, high arched eyebrows, short philtrum and micrognathia. In addition there is mental retardation, growth delays, EPILEPSY, and frequently a wide range of midline and skeletal defects, including HYPOSPADIAS; CONGENITAL HEART DEFECTS; CLEFT LIP; CLEFT PALATE; colobomata; CLUBFOOT; clinodactyly; SCOLIOSIS; and KYPHOSIS.. lissencephaly defined as following: A lissencephaly syndrome characterized by smoothness of the surface of the brain (lissencephaly type I) with thickening of the cerebral cortex (pachygyria), absence of gyri and sulci (agyria), microcephaly, mental retardation, low sloping forehead, and prominent nasal bridge.. eukaryotes defined as following: Organism or cells with a nucleus separated from the cytoplasm by a two membrance nuclear envelope and compartmentalization of function into distinct cytoplasmic organelles.. ring chromosome 20 defined as following: A rare condition in which the two arms of chromosome 20 are fused resulting in a ring chromosome. It is characterized by recurrent seizures with an onset in childhood. Additional features my include microcephaly and short stature.. chromosome 17 defined as following: A specific pair of GROUP E CHROMOSOMES of the human chromosome classification.. human defined as following: Members of the species Homo sapiens.. chromosome 17p defined as following: Proximal (short) arm of chromosome 17. MDS defined as following: A rare syndrome caused by deletion of genetic material in the short arm of chromosome 17. It is characterized by an abnormally smooth brain with fewer folds and grooves. It results in intellectual disability, developmental delay, seizures, spasticity, hypotonia, and feeding difficulties. Affected individuals have distinctive facial features that include a prominent forehead, midface hypoplasia, small, upturned nose, low-set ears, small jaw, and thick upper lip.. congenital disorder defined as following: existing at, and usually before, birth; referring to conditions that are present at birth, regardless of their causation; inborn metabolism disorders are generally not treed here.. Miller-Dieker syndrome defined as following: A rare syndrome caused by deletion of genetic material in the short arm of chromosome 17. It is characterized by an abnormally smooth brain with fewer folds and grooves. It results in intellectual disability, developmental delay, seizures, spasticity, hypotonia, and feeding difficulties. Affected individuals have distinctive facial features that include a prominent forehead, midface hypoplasia, small, upturned nose, low-set ears, small jaw, and thick upper lip.. chromosome 1 defined as following: A specific pair of human chromosomes in group A (CHROMOSOMES, HUMAN, 1-3) of the human chromosome classification..", "label": "no"} {"id": "converted_4238", "sentence1": "Does daily atemoya juice intake change the pharmacokinetics of CYP1A2 substrates?", "sentence2": "Atemoya juice significantly inhibited CYP1A2 activity in human liver microsomes, but not the activities of CYP2C9 and CYP3A. In spite of this inhibition, preadministration of atemoya had no effect on the pharmacokinetics of phenacetin, a CYP1A2 substrate, in rats. , The results indicate that a daily intake of atemoya would not change the pharmacokinetics of CYP1A2 substrates such as phenacetin as well as CYP2C9- and CYP3A-substrate drugs.[SEP]Definitions: CYP2C9 defined as following: A cytochrome P-450 subtype that has specificity for acidic XENOBIOTICS. It oxidizes a broad range of important clinical drugs that fall under the categories of NONSTEROIDAL ANTI-INFLAMMATORY AGENTS; HYPOGLYCEMIC AGENTS; ANTCOAGULANTS; and DIURETICS.. phenacetin defined as following: A phenylacetamide that was formerly used in ANALGESICS but nephropathy and METHEMOGLOBINEMIA led to its withdrawal from the market. (From Smith and Reynard, Textbook of Pharmacology,1991, p431). rats defined as following: The common rat, Rattus norvegicus, often used as an experimental organism.. CYP3A defined as following: A cytochrome P-450 suptype that has specificity for a broad variety of lipophilic compounds, including STEROIDS; FATTY ACIDS; and XENOBIOTICS. This enzyme has clinical significance due to its ability to metabolize a diverse array of clinically important drugs such as CYCLOSPORINE; VERAPAMIL; and MIDAZOLAM. This enzyme also catalyzes the N-demethylation of ERYTHROMYCIN.. human defined as following: Members of the species Homo sapiens.. CYP1A2 substrates defined as following: Any substance acted upon by cytochrome P450 1A2..", "label": "no"} {"id": "converted_1551", "sentence1": "Can we use platelet biomarkers to study Alzheimer's disease?", "sentence2": "Platelet biomarkers in Alzheimer's disease., platelets are the most important source of circulating forms of the amyloid precursor protein and other important proteins such as Tau and glycogen synthase kinase-3B., Alternative plasma and platelet measures are described,, The success of these studies led to the application of platelet proteomics to the study of several pathologies where platelets play a fundamental role. Those include platelet-related disorders, such as storage pool disease, gray platelet syndrome, and Quebec platelet disorder; diseases where unwanted platelet activation is highly relevant, such as thrombosis and cardiovascular disease; and other diseases, such as cystic fibrosis, uremia, or Alzheimer's disease. [SEP]Definitions: platelets defined as following: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. Tau defined as following: A synthetic uridine pro-drug that is converted to uridine in vivo. Uridine, a pyrimidine nucleotide, has been used in a variety of diseases including depressive disorders and inherited myopathies. (NCI04). thrombosis defined as following: Formation and development of a thrombus or blood clot in the blood vessel.. uremia defined as following: A laboratory test result indicating abnormally high concentration of non-protein nitrogen in the blood.. cardiovascular disease defined as following: Pathological conditions involving the CARDIOVASCULAR SYSTEM including the HEART; the BLOOD VESSELS; or the PERICARDIUM.. amyloid precursor protein defined as following: Serum amyloid A-1 protein (122 aa, ~14 kDa) is encoded by the human SAA1 gene. This protein plays a role in heparin binding and acute phase inflammatory responses.. Alzheimer's disease defined as following: Alzheimer's disease caused by mutation(s) in the APP gene, encoding amyloid-beta A4 protein. The onset of this condition typically occurs before age 65..", "label": "yes"} {"id": "converted_159", "sentence1": "Is glycyl-tRNA synthetase gene involved in the development of Charcot-Marie-Tooth disease?", "sentence2": "Charcot-Marie-Tooth disease type 2D (CMT2D) is an autosomal-dominant axonal peripheral neuropathy characterized by impaired motor and sensory function in the distal extremities. Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D, Dominant mutations in GARS cause rare forms of Charcot-Marie-Tooth disease and distal spinal muscular atrophy, Using exome sequencing she was found to harbor compound heterozygous mutations within the glycyl-tRNA synthetase (GARS) gene, mutations of human GlyRS (hGlyRS) were also found to be associated with Charcot-Marie-Tooth disease, Dominant mutations in GARS, encoding the essential enzyme glycyl-tRNA synthetase (GlyRS), result in a form of Charcot-Marie-Tooth disease, type 2D (CMT2D), predominantly characterized by lower motor nerve degeneration, A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease type 2D with facial and respiratory muscle involvement, Here we describe a 45-year-old woman with a long course of motor-dominant neuropathy. Distal weakness appeared in childhood and became worse with age. After a diagnosis of CMT type 2, the symptoms progressed, and in her fourth decade, facial and respiratory muscle weakness appeared, ultimately requiring non-invasive mechanical ventilation. There was no family history of CMT. Comprehensive analysis of known CMT-related genes revealed a novel heterozygous c.815T>A, p.L218Q mutation in glycyl-tRNA synthetase (GARS), a causative gene for both CMT type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V), Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS)., Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase., Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V., [A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease type 2D with facial and respiratory muscle involvement]., Glycyl-tRNA synthetase (GARS), which encodes the enzyme responsible for charging tRNA(Gly) with glycine in both the cytoplasm and mitochondria, is implicated to Charcot-Marie-Tooth disease 2D (CMT2D) and distal hereditary motor neuropathy type V (dHMN-V)., These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease, the most common heritable disease of the peripheral nervous system., Here, we report the identification of four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V., Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D., Of the many inherited Charcot-Marie-Tooth peripheral neuropathies, type 2D (CMT2D) is caused by dominant point mutations in the gene GARS, encoding glycyl tRNA synthetase (GlyRS)., Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS), Charcot-Marie-Tooth disease type 2D is a hereditary axonal and glycyl-tRNA synthetase (GARS)-associated neuropathy that is caused by a mutation in GARS, Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase, These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease, the most common heritable disease of the peripheral nervous system, A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease type 2D with facial and respiratory muscle involvement., Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS). , Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D. , An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy., We previously implicated mutations in the gene encoding glycyl-tRNA synthetase (GARS) as the cause of CMT2D and dSMA-V. , An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model., Charcot-Marie-Tooth disease type 2D is a hereditary axonal and glycyl-tRNA synthetase (GARS)-associated neuropathy that is caused by a mutation in GARS. , Dominant mutations in GARS, encoding the essential enzyme glycyl-tRNA synthetase (GlyRS), result in a form of Charcot-Marie-Tooth disease, type 2D (CMT2D), predominantly characterized by lower motor nerve degeneration. , Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS). In addition to GARS, mutations in three other tRNA synthetase genes cause similar neuropathies, although the underlying mechanisms are not fully understood., These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease,, Charcot-Marie-Tooth disease type 2D (CMT2D) is an autosomal-dominant axonal peripheral neuropathy characterized by impaired motor and sensory function in the distal extremities. Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D., Of the many inherited Charcot-Marie-Tooth peripheral neuropathies, type 2D (CMT2D) is caused by dominant point mutations in the gene GARS, encoding glycyl tRNA synthetase (GlyRS)., Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS)., Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase., Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V., These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease, the most common heritable disease of the peripheral nervous system., A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease type 2D with facial and respiratory muscle involvement., An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model., Glycyl-tRNA synthetase (GARS), which encodes the enzyme responsible for charging tRNA(Gly) with glycine in both the cytoplasm and mitochondria, is implicated to Charcot-Marie-Tooth disease 2D (CMT2D) and distal hereditary motor neuropathy type V (dHMN-V).[SEP]Definitions: glycyl tRNA synthetase defined as following: An enzyme that activates glycine with its specific transfer RNA. EC 6.1.1.14.. mitochondria defined as following: Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed). Charcot-Marie-Tooth disease type 2D defined as following: Charcot-Marie-Tooth disease inherited in an autosomal dominant pattern. It is caused by mutations in the GARS gene. It results in axonal peripheral neuropathy.. Mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. neuropathy defined as following: A disorder affecting the cranial nerves or the peripheral nervous system. It manifests with pain, tingling, numbness, and muscle weakness. It may be the result of physical injury, toxic substances, viral diseases, diabetes, renal failure, cancer, and drugs.. Charcot-Marie-Tooth disease defined as following: A hereditary motor and sensory neuropathy transmitted most often as an autosomal dominant trait and characterized by progressive distal wasting and loss of reflexes in the muscles of the legs (and occasionally involving the arms). Onset is usually in the second to fourth decade of life. This condition has been divided into two subtypes, hereditary motor and sensory neuropathy (HMSN) types I and II. HMSN I is associated with abnormal nerve conduction velocities and nerve hypertrophy, features not seen in HMSN II. (Adams et al., Principles of Neurology, 6th ed, p1343). distal hereditary motor neuropathy type V defined as following: A rare autosomal dominant distal hereditary motor neuropathy disease characterized by muscle weakness and wasting predominantly affecting the hands, in particular the thenar and first dorsal interosseus muscles, and/or marked foot deformity and gait disturbance. Sensation is normal, although reduced response to vibration has been described. The disease is slowly progressive with an age of onset within the first few decades of life.. cytoplasm defined as following: The part of a cell that contains the CYTOSOL and small structures excluding the CELL NUCLEUS; MITOCHONDRIA; and large VACUOLES. (Glick, Glossary of Biochemistry and Molecular Biology, 1990). CMT defined as following: brand name of choline magnesium trisalicylate. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. point mutations defined as following: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair.. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. glycyl-tRNA synthetase gene defined as following: Human GARS1 wild-type allele is located in the vicinity of 7p14.3 and is approximately 39 kb in length. This allele, which encodes glycine-tRNA ligase protein, is involved in the synthesis of glycyl-tRNA. Mutation of the gene is associated with type 2D Charcot-Marie-Tooth disease and distal hereditary motor neuropathy, type Va..", "label": "yes"} {"id": "converted_4399", "sentence1": "Is gabapentin effective for chronic pelvic pain?", "sentence2": "There were no significant between-group differences in both worst and average numerical rating scale (NRS) pain scores at 13-16 weeks after randomisation. The mean worst NRS pain score was 7·1 (standard deviation [SD] 2·6) in the gabapentin group and 7·4 (SD 2·2) in the placebo group. Mean change from baseline was -1·4 (SD 2·3) in the gabapentin group and -1·2 (SD 2·1) in the placebo group (adjusted mean difference -0·20 [97·5% CI -0·81 to 0·42]; p=0·47). The mean average NRS pain score was 4·3 (SD 2·3) in the gabapentin group and 4·5 (SD 2·2) in the placebo group. Mean change from baseline was -1·1 (SD 2·0) in the gabapentin group and -0·9 (SD 1·8) in the placebo group (adjusted mean difference -0·18 [97·5% CI -0·71 to 0·35]; p=0·45)., INTERPRETATION: This study was adequately powered, but treatment with gabapentin did not result in significantly lower pain scores in women with chronic pelvic pain, and was associated with higher rates of side-effects than placebo. Given the increasing reports of abuse and evidence of potential harms associated with gabapentin use, it is important that clinicians consider alternative treatment options to off-label gabapentin for the management of chronic pelvic pain and no obvious pelvic pathology., Gabapentin not effective for chronic pelvic pain in women., Gabapentin not effective for chronic pelvic pain in women[SEP]Definitions: gabapentin defined as following: A cyclohexane-gamma-aminobutyric acid derivative that is used for the treatment of PARTIAL SEIZURES; NEURALGIA; and RESTLESS LEGS SYNDROME..", "label": "no"} {"id": "converted_3054", "sentence1": "Is the yeast (Saccharomyces cerevisiae) genome organized into topologically associated domains (TADs)?", "sentence2": "Recent advances in our understanding of the three-dimensional organization of the eukaryotic nucleus have rendered the spatial distribution of genes increasingly relevant. In a recent work (Tsochatzidou et al., Nucleic Acids Res 45:5818-5828, 2017), we proposed the existence of a functional compartmentalization of the yeast genome according to which, genes occupying the chromosomal regions at the nuclear periphery have distinct structural, functional and evolutionary characteristics compared to their centromeric-proximal counterparts. Around the same time, it was also shown that the genome of Saccharomyces cerevisiae is organized in topologically associated domains (TADs), which are largely associated with the replication timing., Form and function of topologically associating genomic domains in budding yeast., Although similar structures appear to be conserved in fission yeast, computational modeling and analysis of high-throughput chromosome conformation capture (Hi-C) data have been used to argue that the small, highly constrained budding yeast chromosomes could not have these structures. In contrast, herein we analyze Hi-C data for budding yeast and identify 200-kb scale TADs, whose boundaries are enriched for transcriptional activity. Furthermore, these boundaries separate regions of similarly timed replication origins connecting the long-known effect of genomic context on replication timing to genome architecture. To investigate the molecular basis of TAD formation, we performed Hi-C experiments on cells depleted for the Forkhead transcription factors, Fkh1 and Fkh2, previously associated with replication timing. Forkhead factors do not regulate TAD formation, but do promote longer-range genomic interactions and control interactions between origins near the centromere. Thus, our work defines spatial organization within the budding yeast nucleus, demonstrates the conserved role of genome architecture in regulating DNA replication, and identifies a molecular mechanism specifically regulating interactions between pericentric origins., Around the same time, it was also shown that the genome of Saccharomyces cerevisiae is organized in topologically associated domains (TADs), which are largely associated with the replication timing., Around the same time, it was also shown that the genome of Saccharomyces cerevisiae is organized in topologically associated domains (TADs), which are largely associated with the replication timing. , In contrast, herein we analyze Hi-C data for budding yeast and identify 200-kb scale TADs, whose boundaries are enriched for transcriptional activity.[SEP]Definitions: Fkh1 defined as following: Human FOXO1 wild-type allele is located in the vicinity of 13q14.1 and is approximately 111 kb in length. This allele, which encodes forkhead box protein O1A, is involved in the modulation of transcription by RNA polymerase II.. TADs defined as following: Tietz syndrome is a genetic hypopigmentation and deafness syndrome characterized by congenital profound bilateral sensorineural hearing loss and generalized albino-like hypopigmentation of skin, eyes and hair.. genome defined as following: Anatomical set of genes in all the chromosomes.. Fkh2 defined as following: Human FOXG1 wild-type allele is located within 14q12-q13 and is approximately 4 kb in length. This allele, which encodes forkhead box protein G1, is involved in both the modulation of transcription by RNA polymerase II and in the regional development of the brain.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. Forkhead transcription factors defined as following: A subclass of winged helix DNA-binding proteins that share homology with their founding member fork head protein, Drosophila.. yeast defined as following: A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as \"baker's\" or \"brewer's\" yeast. The dried form is used as a dietary supplement..", "label": "yes"} {"id": "converted_1505", "sentence1": "Is it possible to visualize subtahalamic nucleus by using transcranial ultrasound?", "sentence2": "After measuring thermal effects of TCS and imaging artefact sizes of DBS lead using a skull phantom, we prospectively enrolled 34 patients with DBS of globus pallidus internus, ventro-intermediate thalamic or subthalamic nucleus. TCS had no influence on lead temperature, electrical parameters of DBS device or clinical state of patients. TCS measures of lead coordinates agreed with MRI measures in anterior-posterior and medial-lateral axis. Lead dislocation requiring reinsertion was reliably detected., TCS may therefore become a first-choice modality to monitor lead location., Two pilot studies have demonstrated that the intraoperative visualization with TCS and the TCS-assisted insertion of deep-brain stimulation (DBS) electrodes into the subthalamic nucleus and the globus pallidus interna are feasible and safe provided there is exact knowledge on the extent of electrode TCS imaging artifacts. , Peroperative transcranial sonography for electrode placement into the targeted subthalamic nucleus of patients with Parkinson disease: technical note, The correct anatomic position of the electrode tip could be indirectly assessed thanks to the topographic relationship of the STN with the hyperechogenic substantia nigra and the nucleus ruber., CONCLUSIONS: Transcranial sonography is easily feasible during stereotactic surgery. In combination with the clinical effects of electrostimulation on the symptoms of Parkinson's disease and with stereotactic x-ray images, it enables the assessment and the documentation of the correct position of implanted STN electrodes in real time., After measuring thermal effects of TCS and imaging artefact sizes of DBS lead using a skull phantom, we prospectively enrolled 34 patients with DBS of globus pallidus internus, ventro-intermediate thalamic or subthalamic nucleus, Two pilot studies have demonstrated that the intraoperative visualization with TCS and the TCS-assisted insertion of deep-brain stimulation (DBS) electrodes into the subthalamic nucleus and the globus pallidus interna are feasible and safe provided there is exact knowledge on the extent of electrode TCS imaging artifacts[SEP]Definitions: TCS defined as following: A hereditary disorder occurring in two forms: the complete form (Franceschetti's syndrome) is characterized by antimongoloid slant of the palpebral fissures, COLOBOMA of the lower lid, MICROGNATHIA and hypoplasia of the ZYGOMATIC ARCHES, and CONGENITAL MICROTIA. It is transmitted as an autosomal trait. The incomplete form (Treacher Collins syndrome) is characterized by the same anomalies in less pronounced degree. It occurs sporadically, but an autosomal dominant mode of transmission is suspected. (Dorland, 27th ed). STN defined as following: Human EEF1A2 wild-type allele is located in the vicinity of 20q13.3 and is approximately 11 kb in length. This allele, which encodes elongation factor 1-alpha 2 protein, is involved in the promotion of protein elongation. The gene is expressed aberrantly at elevated levels in many ovarian cancers.. position defined as following: A reference to the alignment of an object, a particular situation or view of a situation, or the location of an object.. insertion defined as following: Something inserted or to be inserted.. Parkinson's disease defined as following: A progressive, degenerative neurologic disease characterized by a TREMOR that is maximal at rest, retropulsion (i.e. a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression. Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem. LEWY BODIES are present in the substantia nigra and locus coeruleus but may also be found in a related condition (LEWY BODY DISEASE, DIFFUSE) characterized by dementia in combination with varying degrees of parkinsonism. (Adams et al., Principles of Neurology, 6th ed, p1059, pp1067-75). subthalamic nucleus defined as following: Lens-shaped structure on the inner aspect of the INTERNAL CAPSULE. The SUBTHALAMIC NUCLEUS and pathways traversing this region are concerned with the integration of somatic motor function.. globus defined as following: A feeling of a lump in the throat that occurs between meals in the absence of other gastrointestinal and motility disorders (e.g., DYSPHAGIA; GASTROESOPHAGEAL REFLUX)..", "label": "yes"} {"id": "converted_2136", "sentence1": "Is Cri Du Chat associated with an expansion of a repeat with in the gene found on chromosome 5?", "sentence2": "Cri-du-chat syndrome is a chromosomal disorder caused by a deletion of the short arm of chromosome 5, The typical cri du chat syndrome, due to 5p15.2 deletion, includes severe intellectual disability, facial dysmorphisms, neonatal hypotonia and pre- and post-natal growth retardation, whereas more distal deletions in 5p15.3 lead to cat-like cry and speech delay and produce the clinical picture of the atypical cri du chat syndrome, with minimal or absent intellectual impairment., Cri-du-chat is a human contiguous gene deletion syndrome resulting from hemizygous deletions of chromosome 5p., Cri-du-chat is a chromosomal deletion syndrome characterized by partial deletion of the short arm of chromosome 5., The karyotype showed a terminal deletion of the short arm of chromosome 5 including the critical region 5p15 for cri du chat syndrome., Fewer than 1 in 200 of cri du chat syndrome cases are due to recombination aneusomy arising from a parental inversion of chromosome 5., Molecular approach to analyzing the human 5p deletion syndrome, cri du chat., Cri-du-chat is a human contiguous gene deletion syndrome resulting from hemizygous deletions of chromosome 5p, The cri du chat syndrome (CdCS) is a chromosomal deletion syndrome associated with a partial deletion of the short (p) arm of chromosome 5, The cri-du-chat syndrome is a contiguous gene syndrome that results from a deletion of the short arm of chromosome 5 (5p)., Cri-du-chat syndrome is associated with a deletion of the short arm of chromosome 5., The deletion of the short arm of chromosome 5 is associated with the cri-du-chat syndrome., The Cri du Chat syndrome (CdCS) is a genetic disease resulting from a deletion of variable size occurring on the short arm of chromosome 5 (5p-)., Cri-du-chat is a well described partial aneusomy resulting from deletion of the short arm of chromosome 5., Cri-du-chat syndrome is caused by haploinsufficiency of the genes on the distal part of the short arm of chromosome 5, and characteristic features include microcephaly, developmental delays, and a distinctive high-pitched mewing cry., The pathological condition of cri du chat syndrome is due to the cytogenetic deletion of band p15.2 of chromosome 5. , Karyotype analysis indicated that the patient has carried a terminal deletion in 5p. FISH with Cri du Chat syndrome region probe confirmed that D5S23 and D5S721 loci are deleted. [SEP]Definitions: chromosome 5 defined as following: One of the two pairs of human chromosomes in the group B class (CHROMOSOMES, HUMAN, 4-5).. human defined as following: Members of the species Homo sapiens.. cri-du-chat syndrome defined as following: An infantile syndrome characterized by a cat-like cry, failure to thrive, microcephaly, MENTAL RETARDATION, spastic quadriparesis, micro- and retrognathia, glossoptosis, bilateral epicanthus, hypertelorism, and tiny external genitalia. It is caused by a deletion of the short arm of chromosome 5 (5p-).. chromosomal disorder defined as following: Clinical conditions caused by an abnormal chromosome constitution in which there is extra or missing chromosome material (either a whole chromosome or a chromosome segment). (from Thompson et al., Genetics in Medicine, 5th ed, p429). 5p15 defined as following: A chromosome band present on 5p.. deletions defined as following: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus.. hypotonia defined as following: A diminution of the skeletal muscle tone marked by a diminished resistance to passive stretching.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. microcephaly defined as following: Head circumference below 2 standard deviations below the mean for age and gender. [PMID:15806441, PMID:19125436, PMID:25465325, PMID:9683597]. intellectual disability defined as following: Subnormal intellectual functioning which originates during the developmental period. This has multiple potential etiologies, including genetic defects and perinatal insults. Intelligence quotient (IQ) scores are commonly used to determine whether an individual has an intellectual disability. IQ scores between 70 and 79 are in the borderline range. Scores below 67 are in the disabled range. (from Joynt, Clinical Neurology, 1992, Ch55, p28). gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "no"} {"id": "converted_1122", "sentence1": "Is there evidence for somatic mosaicism in Tuberous Sclerosis?", "sentence2": "There are several case reports of solitary SEGA without any other manifestations of TSC. Usually these cases are thought to be forme fruste of TSC due to somatic mosaicism., Female germline mosaicism in tuberous sclerosis confirmed by molecular genetic analysis, This is the first case of germline mosaicism in tuberous sclerosis proven by molecular genetic analysis and also the first example of female germline mosaicism for a characterized autosomal dominant gene mutation apparently not associated with somatic mosaicism., Mutation screening by RT-PCR and direct sequencing of the TSC2 gene identified a 4 bp insertion TACT following nucleotide 2077 in exon 18 which was present in the three affected children but not in five unaffected siblings or the parents. This mutation would cause a frameshift and premature termination at codon 703. Absence of the mutation in lymphocyte DNA from the parents was consistent with germline mosaicism and this was confirmed by our finding of identical chromosome 16 haplotypes in affected and unaffected siblings, providing unequivocal evidence of two different cell lines in the gametes. Molecular analysis of the TSC2 alleles present in the affected subjects showed that the mutation had been inherited from the mother.[SEP]Definitions: TSC2 defined as following: Tuberous sclerosis mapped to chromosome 16p13.3 (TSC2 gene).. TSC defined as following: Autosomal dominant neurocutaneous syndrome classically characterized by MENTAL RETARDATION; EPILEPSY; and skin lesions (e.g., adenoma sebaceum and hypomelanotic macules). There is, however, considerable heterogeneity in the neurologic manifestations. It is also associated with cortical tuber and HAMARTOMAS formation throughout the body, especially the heart, kidneys, and eyes. Mutations in two loci TSC1 and TSC2 that encode hamartin and tuberin, respectively, are associated with the disease.. TSC2 gene defined as following: This gene plays a role in signal transduction and cell cycle control. It is involved in cell adhesion, differentiation, growth and migration.. gene mutation defined as following: A change in the nucleotide sequence of the TAF1 gene.. cell lines defined as following: Established cell cultures that have the potential to propagate indefinitely.. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. haplotypes defined as following: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the MAJOR HISTOCOMPATIBILITY COMPLEX.. nucleotide defined as following: The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. (From King & Stansfield, A Dictionary of Genetics, 4th ed). frameshift defined as following: A type of mutation in which a number of NUCLEOTIDES deleted from or inserted into a protein coding sequence is not divisible by three, thereby causing an alteration in the READING FRAMES of the entire coding sequence downstream of the mutation. These mutations may be induced by certain types of MUTAGENS or may occur spontaneously.. autosomal defined as following: Any chromosome other than a sex chromosome. [GOC:mah]. Tuberous Sclerosis defined as following: This gene is involved in cell cycle regulation and the loss of cellular adhesion.. somatic mosaicism defined as following: The presence of genetically distinct populations of somatic cells in a given organism caused by DNA mutations, epigenetic alterations of DNA, chromosomal abnormalities or the spontaneous reversion of inherited mutations. [HPO:probinson, PMID:12360233].", "label": "yes"} {"id": "converted_3468", "sentence1": "Can Patient-derived organoids (PDOs) recapitulate patient responses in the clinic?", "sentence2": "Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living biobank of PDOs from metastatic, heavily pretreated colorectal and gastroesophageal cancer patients recruited in phase 1/2 clinical trials. Phenotypic and genotypic profiling of PDOs showed a high degree of similarity to the original patient tumors. Molecular profiling of tumor organoids was matched to drug-screening results, suggesting that PDOs could complement existing approaches in defining cancer vulnerabilities and improving treatment responses. We compared responses to anticancer agents ex vivo in organoids and PDO-based orthotopic mouse tumor xenograft models with the responses of the patients in clinical trials. Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs., Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs., Molecular profiling of tumor organoids was matched to drug-screening results, suggesting that PDOs could complement existing approaches in defining cancer vulnerabilities and improving treatment responses., Phenotypic and genotypic profiling of PDOs showed a high degree of similarity to the original patient tumors., Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC., Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs, Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs, Molecular profiling of tumor organoids was matched to drug-screening results , suggesting that PDOs could complement existing approaches in defining cancer vulnerabilities and improving treatment responses, Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs.[SEP]Definitions: cancer defined as following: A malignant tumor at the original site of growth.. PDX defined as following: A mouse model for human cancer studies in which a human-derived tumor sample is transplanted into an immunodeficient mouse.. colorectal defined as following: Relating to the colon and rectum, or to the entire large bowel.. organoids defined as following: An organization of cells into an organ-like structure. Organoids can be generated in culture, e.g., self-organized three-dimensional tissue structures derived from STEM CELLS (see MICROPHYSIOLOGICAL SYSTEMS). They are also found in certain NEOPLASMS.. PDAC defined as following: A rare clinical entity including as main characteristics anophthalmia or severe microphthalmia, and pulmonary hypoplasia or aplasia. Only five cases have been reported so far, two of who were siblings. In the three nonfamilial cases, unilateral pulmonary agenesis and microphthalmia were associated with diaphragmatic hernia and pulmonary vessel agenesis. It has been suggested that two different entities can be distinguished: on one hand, the association of anophthalmia-pulmonary hypoplasia with/without anomalies of the face, heart, spleen and uterus, which may be due to a putative autosomal recessive gene with pleiotropic effects; on the other hand, a sporadic association including pulmonary hypoplasia, anophthalmia, unilateral diaphragmatic defect and agenesis of the pulmonary trunk, which may represent the expression of a developmental field defect. There is evidence that syndromic microphthalmia- is caused by homozygous or compound heterozygous mutation in the STRA6 gene on chromosome 15q24..", "label": "yes"} {"id": "converted_4619", "sentence1": "Do we find bacteriophages in the gut?", "sentence2": "a multitude of symbiotic bacteria and bacteriophages are decreased in abundance in patients with COVID-19, Bacterial viruses (bacteriophages, phages) of the gut have increasingly become a focus in microbiome studies, with an understanding that they are likely key players in health and disease., Already without exogenous intervention, a multitude of phage-bacterial interactions occur within the human gut, some of which might play a direct role in disease progression, We are surrounded by microbes, mostly bacteria and their viruses or phages, on the inside and outside of our bodies. , crAssphages are a broad group of diverse bacteriophages in the order Caudovirales that have been found to be highly abundant in the human gastrointestinal tract. Despite their high prevalence, we have an incomplete understanding of how crAssphages shape and respond to ecological and evolutionary dynamics in the gut.[SEP]Definitions: Bacterial viruses defined as following: Viruses whose hosts are bacterial cells.. viruses defined as following: Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells.. bacteria defined as following: One of the three domains of life (the others being Eukarya and ARCHAEA), also called Eubacteria. They are unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. Bacteria can be classified by their response to OXYGEN: aerobic, anaerobic, or facultatively anaerobic; by the mode by which they obtain their energy: chemotrophy (via chemical reaction) or PHOTOTROPHY (via light reaction); for chemotrophs by their source of chemical energy: CHEMOLITHOTROPHY (from inorganic compounds) or chemoorganotrophy (from organic compounds); and by their source for CARBON; NITROGEN; etc.; HETEROTROPHY (from organic sources) or AUTOTROPHY (from CARBON DIOXIDE). They can also be classified by whether or not they stain (based on the structure of their CELL WALLS) with CRYSTAL VIOLET dye: gram-negative or gram-positive..", "label": "yes"} {"id": "converted_3561", "sentence1": "Is Niraparib effective for ovarian cancer?", "sentence2": "Niraparib and olaparib have been approved by the US FDA for maintenance therapy after partial or complete remission in recurrent ovarian cancer., PURPOSE OF REVIEW: The recent United States Food and Drug Administration approvals of niraparib and olaparib as maintenance monotherapy for platinum-sensitive, high-grade ovarian cancers independent of BRCA status reflect a willingness to seek indications for poly-ADP-ribose polymerase (PARP) inhibitors beyond cancers with deleterious breast cancer 1 and breast cancer 2 mutations., PURPOSE: Niraparib is a highly selective inhibitor of PARP-1 and PARP-2 approved in the United States for maintenance treatment of adult patients with recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy., Indeed, three PARP1 inhibitors (Olaparib, Rucaparib, and Niraparib) have recently been approved by the Food and Drug Administration for the treatment of ovarian cancer., Niraparib is an oral poly(ADP ribose) polymerase (PARP) inhibitor that is currently approved by the United States Food and Drug Administration (US FDA) as well as recently approved by the European Medicines Agency (EMA) for the maintenance treatment of women with recurrent ovarian cancer who are in complete or partial response to platinum-based chemotherapy. , Niraparib is a poly adenosine diphosphate ribose polymerase inhibitor that has shown to be clinically effective as maintenance therapy in patients with platinum sensitive, recurrent ovarian cancer., Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer., Niraparib for the treatment of ovarian cancer., BACKGROUND\n\nNiraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer., Niraparib Slows Ovarian Cancer Progression., Niraparib for the treatment of ovarian cancer., INTRODUCTION\n\nNiraparib, an orally available selective inhibitor of poly(adenosine diphosphate-ribose) polymerase (PARP), is the first PARP inhibitor approved for use in patients with ovarian cancer who do not harbor a germ-line or somatic mutation in the breast cancer gene (BRCA)., The role of niraparib as maintenance following frontline platinum-based chemotherapy as well as in the treatment of recurrent high-grade serous ovarian cancer is an active area of investigation., Niraparib in ovarian cancer: results to date and clinical potential., Niraparib , an orally available selective inhibitor of poly(adenosine diphosphate-ribose ) polymerase ( PARP) , is the first PARP inhibitor approved for use in patients with ovarian cancer who do not harbor a germ-line or somatic mutation in the breast cancer gene ( BRCA) . , Results from a phase III trial indicate that maintenance therapy with the PARP inhibitor niraparib is more effective than placebo in slowing the progression of recurrent platinum-sensitive ovarian cancer . , Niraparib (Zejula®), a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for the maintenance treatment of recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in complete or partial response to platinum-based chemotherapy., Niraparib, an orally available selective inhibitor of poly(adenosine diphosphate-ribose) polymerase (PARP), is the first PARP inhibitor approved for use in patients with ovarian cancer who do not harbor a germ-line or somatic mutation in the breast cancer gene (BRCA)., Current evidence suggests that niraparib is an effective new option with a manageable tolerability profile for the maintenance treatment of recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer in adults, with or without BRCA1/2 mutation or HRD., Oral niraparib, a highly-selective, potent poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 inhibitor, is approved in the USA for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy., This article summarizes the milestones in the development of niraparib leading to its first global approval for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer., Niraparib (Zejula ), a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for the maintenance treatment of recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in complete or partial response to platinum-based chemotherapy., INTRODUCTION: Niraparib, an orally available selective inhibitor of poly(adenosine diphosphate-ribose) polymerase (PARP), is the first PARP inhibitor approved for use in patients with ovarian cancer who do not harbor a germ-line or somatic mutation in the breast cancer gene (BRCA).[SEP]Definitions: Rucaparib defined as following: An orally bioavailable tricyclic indole and inhibitor of poly(ADP-ribose) polymerases (PARPs) 1 (PARP1), 2 (PARP2) and 3 (PARP3), with potential chemo/radiosensitizing and antineoplastic activities. Upon administration, rucaparib selectively binds to PARP1, 2 and 3 and inhibits PARP-mediated DNA repair. This enhances the accumulation of DNA strand breaks, promotes genomic instability and induces cell cycle arrest and apoptosis. This may enhance the cytotoxicity of DNA-damaging agents and reverse tumor cell resistance to chemotherapy and radiation therapy. PARPs are enzymes activated by single-strand DNA breaks that catalyze the post-translational ADP-ribosylation of nuclear proteins, which induces signaling and the recruitment of other proteins to repair damaged DNA. The PARP-mediated repair pathway plays a key role in DNA repair and is dysregulated in a variety of cancer cell types.. PARP defined as following: Human PARP1 wild-type allele is located within 1q41-q42 and is approximately 47 kb in length. This allele, which encodes poly [ADP-ribose] polymerase 1 protein, plays a critical role in DNA repair.. niraparib defined as following: An orally bioavailable inhibitor of poly (ADP-ribose) polymerase (PARP) types 1 and 2 (PARP-1 and -2), with antineoplastic activity. Upon administration, niraparib binds to and inhibits the activity of PARP-1 and -2, thereby inhibiting PARP-1 and -2-mediated DNA repair, enhancing the accumulation of DNA strand breaks, promoting genomic instability and resulting in apoptosis. The PARP family of proteins catalyzes post-translational ADP-ribosylation of nuclear proteins and is activated by single-strand DNA (ssDNA) breaks.. ovarian cancer defined as following: A primary or metastatic malignant neoplasm involving the ovary. Most primary malignant ovarian neoplasms are either carcinomas (serous, mucinous, or endometrioid adenocarcinomas) or malignant germ cell tumors. Metastatic malignant neoplasms to the ovary include carcinomas, lymphomas, and melanomas.. breast cancer gene defined as following: Human BRCA2 wild-type allele is located in the vicinity of 13q12.3 and is approximately 84 kb in length. This allele, which encodes breast cancer type 2 susceptibility protein, is involved in double-stranded DNA break repair, homologous recombination and transcriptional regulation. Certain allelic variants of the BRCA2 gene are associated with early-onset breast cancer, prostate cancer and Fanconi anemia.. PARP1 defined as following: Poly [ADP-ribose] polymerase 1 (1013aa, ~113 kDa) is encoded by the human PARP1 gene. This protein is involved in poly ADP-ribosylation and in the regulation of various cellular processes such as differentiation, proliferation, tumor transformation, and recovery from DNA damage.. cancers defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. platinum-sensitive ovarian cancer defined as following: Ovarian carcinoma that has a documented response to platinum-based chemotherapy.. platinum-sensitive defined as following: A finding indicating that a cancer responds to platinum therapy initially, but it comes back after a certain period. For ovarian cancer, it refers to cancer relapse at least six months after the end of platinum therapy.. Olaparib defined as following: A small molecule inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential chemosensitizing, radiosensitizing, and antineoplastic activities. Olaparib selectively binds to and inhibits PARP, inhibiting PARP-mediated repair of single strand DNA breaks; PARP inhibition may enhance the cytotoxicity of DNA-damaging agents and may reverse tumor cell chemoresistance and radioresistance. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins and can be activated by single-stranded DNA breaks.. peritoneal cancer defined as following: A primary or metastatic malignant neoplasm involving the peritoneum. Representative examples include carcinoma and malignant mesothelioma.. PARP-2 defined as following: Human PARP2 wild-type allele is located within 14q11.2-q12 and is approximately 14 kb in length. This allele, which encodes poly [ADP-ribose] polymerase 2 protein, plays a role in DNA repair through base excision.. PARP-1 defined as following: This gene is involved in ADP-ribosylation of proteins.. breast cancer 2 defined as following: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human chromosome 13 at locus 13q12.3. Mutations in this gene predispose humans to breast and ovarian cancer. It encodes a large, nuclear protein that is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (from Genes Dev 2000;14(11):1400-6). EMA defined as following: An autosomal recessive disorder of fatty acid oxidation, and branched chain amino acids (AMINO ACIDS, BRANCHED-CHAIN); LYSINE; and CHOLINE catabolism, that is due to defects in either subunit of ELECTRON TRANSFER FLAVOPROTEIN or its dehydrogenase, electron transfer flavoprotein-ubiquinone oxidoreductase (EC 1.5.5.1)..", "label": "yes"} {"id": "converted_2562", "sentence1": "Is subacute sclerosing panencephalitis caused by the Measles vaccine?", "sentence2": "Subacute sclerosing panencephalitis (SSPE) is a potentially fatal complication of measles. , Subacute sclerosing panencephalitis (SSPE) is a fatal complication of measles. We reviewed California cases from 1998-2015 to understand risk f, Subacute sclerosing panencephalitis should be eliminated by measles vaccination, The mean interval between measles infection and onset of subacute sclerosing panencephalitis was 6.5 years (range = 3-11 years)., Active surveillance of subacute sclerosing panencephalitis for those with measles infection during the 1988 outbreak is necessary to conduct multicenter drug trials for this devastating disease.Respond with exceptions, completions and modifications or revisions done before completion
. Mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. p21 defined as following: A cyclin-dependent kinase inhibitor that mediates TUMOR SUPPRESSOR PROTEIN P53-dependent CELL CYCLE arrest. p21 interacts with a range of CYCLIN-DEPENDENT KINASES and associates with PROLIFERATING CELL NUCLEAR ANTIGEN and CASPASE 3.. regulatory gene defined as following: Genes which regulate or circumscribe the activity of other genes; specifically, genes which code for PROTEINS or RNAs which have GENE EXPRESSION REGULATION functions..", "label": "yes"} {"id": "converted_3248", "sentence1": "Is endotrophin derived from collagen?", "sentence2": "endotrophin production from type IV collagen, High levels of COL6A3 and its cleaved product, endotrophin (ETP), Endotrophin is released from COL VI[SEP]Definitions: COL6A3 defined as following: Collagen alpha-3(VI) chain (3177 aa, ~344 kDa) is encoded by the human COL6A3 gene. This protein plays a role in extracellular matrix formation and cell-matrix adhesion in connective tissues.. endotrophin defined as following: Endotrophin is encoded by the human COL6A3 gene. This protein is involved in macrophage infiltration, fibrosis and epithelial-mesenchymal transition.. type IV collagen defined as following: A non-fibrillar collagen found in the structure of BASEMENT MEMBRANE. Collagen type IV molecules assemble to form a sheet-like network which is involved in maintaining the structural integrity of basement membranes. The predominant form of the protein is comprised of two alpha1(IV) subunits and one alpha2(IV) subunit, however, at least six different alpha subunits can be incorporated into the heterotrimer.. collagen defined as following: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of SKIN; CONNECTIVE TISSUE; and the organic substance of bones (BONE AND BONES) and teeth (TOOTH)..", "label": "yes"} {"id": "converted_792", "sentence1": "Is protein CXCR4 used as a prognostic marker of cancer?", "sentence2": "Aberrant overexpression of CXCR4 is associated with worse overall survival, adenocarcinoma histology, distant metastasis, lymph node involvement in NSCLC., CXCR4 belongs to a family of G protein-coupled cell surface receptors and has been proved to a prognostic marker in a various tumors, including esophageal squamous cell cancer. , The chemokine C-X-C motif receptor 4 (CXCR4) has been found to be a prognostic marker in various types of cancer, being involved in chemotaxis, stemness and drug resistance. , The chemokine receptor CXCR4 that has been shown to be implicated in PDAC tumorigenicity and aggressiveness could serve as a prognostic marker for survival after a curative-intent surgery and was associated with the pattern of tumour recurrence (distant versus local relapse)., XCR4 promotes tumor growth, angiogenesis and metastasis, and is a prognostic marker in a number of different types of tumors., CXCR4 has been identified as a prognostic marker for acute myeloid leukemia (AML) and other malignancies. , The chemokine receptor CXCR4 has been found to be a prognostic marker in various types of cancer, including breast cancer. , Upregulated expression of C-X-C chemokine receptor 4 is an independent prognostic predictor for patients with gastric cancer., detection of CXCR4 expression will be helpful for predicting prognosis for patients with gastric cancer., The chemokine receptor CXCR4 is a marker of metastatic disease., High CXCR4 level in cancer specimens independently predicts a poor outcome for patients with node-positive breast cancer., Univariate and multivariate analyses demonstrated that the high levels of nuclear CXCR4 and CXCL12 expression in hepatocytes were significantly better prognostic factors for overall and hepatic disease-free survival in patients with CLM., The chemokine receptor CXCR4 has been implicated in sarcoma development and has been found to be a prognostic marker for poor clinical outcome. , high CXCR4 expression is correlated to shorter DFS and could be used as a prognostic marker in order to stratify melanoma patients at higher progression risk.[SEP]Definitions: esophageal squamous cell cancer defined as following: A carcinoma that originates usually from cells on the surface of the middle and lower third of the ESOPHAGUS. Tumor cells exhibit typical squamous morphology and form large polypoid lesions. Mutations in RNF6, LZTS1, TGFBR2, DEC1, and WWOX1 genes are associated with this cancer.. melanoma defined as following: A benign or malignant, primary or metastatic neoplasm affecting the melanocytes.. CXCL12 defined as following: A CXC chemokine that is chemotactic for T-LYMPHOCYTES and MONOCYTES. It has specificity for CXCR4 RECEPTORS. Two isoforms of CXCL12 are produced by alternative mRNA splicing.. cancer defined as following: A malignant tumor at the original site of growth.. acute myeloid leukemia defined as following: Clonal expansion of myeloid blasts in bone marrow, blood, and other tissue. Myeloid leukemias develop from changes in cells that normally produce NEUTROPHILS; BASOPHILS; EOSINOPHILS; and MONOCYTES.. chemokine C-X-C motif receptor 4 defined as following: This gene plays a role in immune cell chemotaxis and trafficking.. tumour defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. CXCR4 defined as following: Combining with the C-X-C motif chemokine 12 (CXCL12) and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity. [GOC:bf, PMID:22204316]. breast cancer defined as following: A primary or metastatic malignant neoplasm involving the breast. The vast majority of cases are carcinomas arising from the breast parenchyma or the nipple. Malignant breast neoplasms occur more frequently in females than in males.. aggressiveness defined as following: Behavior which may be manifested by destructive and attacking action which is verbal or physical, by covert attitudes of hostility or by obstructionism.. sarcoma defined as following: A malignant neoplasm arising exclusively from the soft tissues.. gastric cancer defined as following: A primary or metastatic malignant neoplasm involving the stomach.. hepatocytes defined as following: The main structural component of the LIVER. They are specialized EPITHELIAL CELLS that are organized into interconnected plates called lobules.. NSCLC defined as following: A heterogeneous aggregate of at least three distinct histological types of lung cancer, including SQUAMOUS CELL CARCINOMA; ADENOCARCINOMA; and LARGE CELL CARCINOMA. They are dealt with collectively because of their shared treatment strategy.. malignancies defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. PDAC defined as following: A rare clinical entity including as main characteristics anophthalmia or severe microphthalmia, and pulmonary hypoplasia or aplasia. Only five cases have been reported so far, two of who were siblings. In the three nonfamilial cases, unilateral pulmonary agenesis and microphthalmia were associated with diaphragmatic hernia and pulmonary vessel agenesis. It has been suggested that two different entities can be distinguished: on one hand, the association of anophthalmia-pulmonary hypoplasia with/without anomalies of the face, heart, spleen and uterus, which may be due to a putative autosomal recessive gene with pleiotropic effects; on the other hand, a sporadic association including pulmonary hypoplasia, anophthalmia, unilateral diaphragmatic defect and agenesis of the pulmonary trunk, which may represent the expression of a developmental field defect. There is evidence that syndromic microphthalmia- is caused by homozygous or compound heterozygous mutation in the STRA6 gene on chromosome 15q24..", "label": "yes"} {"id": "converted_353", "sentence1": "Are there any functional differences between Mfd and its human Cocaine syndrome protein B (CSB) homolog?", "sentence2": "In humans, the TCR coupling factor, CSB, plays a critical role in restoring transcription following both UV-induced and oxidative DNA damage. It also contributes indirectly to the global repair of some forms of oxidative DNA damage. The Escherichia coli homolog, Mfd, is similarly required for TCR of UV-induced lesions., Mfd may be functionally distinct from its human CSB homolog in that it does not detectably contribute to the recovery of gene expression or global repair following oxidative damage., CSB has an ATPase activity that is stimulated strongly by DNA; however, it neither acts as a helicase nor does it dissociate stalled RNA polymerase II, suggesting a coupling mechanism in humans different from that in prokaryotes. , In addition, these findings imply that Mfd may be functionally distinct from its human CSB homolog in that it does not detectably contribute to the recovery of gene expression or global repair following oxidative damage., In addition, these findings imply that Mfd may be functionally distinct from its human CSB homolog in that it does not detectably contribute to the recovery of gene expression or global repair following oxidative damage., In contrast, no difference was detected in the rate of transcription recovery in mfd, uvrA, fpg, nth, or polB dinB umuDC mutants relative to wild-type cells following oxidative damage[SEP]Definitions: ATPase defined as following: A group of enzymes which catalyze the hydrolysis of ATP. The hydrolysis reaction is usually coupled with another function such as transporting Ca(2+) across a membrane. These enzymes may be dependent on Ca(2+), Mg(2+), anions, H+, or DNA.. CSB defined as following: A form of syndromic craniosynostosis with characteristics of highly variable craniosynostosis with frontal bossing, turribrachycephaly and cloverleaf skull anomaly. Hypoplasia of the supraorbital ridges, cleft palate, extra teeth and limb anomalies has also been described. Associated problems include headache, poor vision, and seizures. Intelligence is normal.. TCR defined as following: The nucleotide-excision repair process that carries out preferential repair of DNA lesions on the actively transcribed strand of the DNA duplex. In addition, the transcription-coupled nucleotide-excision repair pathway is required for the recognition and repair of a small subset of lesions that are not recognized by the global genome nucleotide excision repair pathway. [PMID:10197977, PMID:11900249]. RNA polymerase II defined as following: A DNA-dependent RNA polymerase present in bacterial, plant, and animal cells. It functions in the nucleoplasmic structure and transcribes DNA into RNA. It has different requirements for cations and salt than RNA polymerase I and is strongly inhibited by alpha-amanitin. EC 2.7.7.6.. humans defined as following: Members of the species Homo sapiens.. DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. mutants defined as following: An altered form of an individual, organism, population, or genetic character that differs from the corresponding wild type due to one or more alterations (mutations)..", "label": "yes"} {"id": "converted_2784", "sentence1": "Is there any association between the human gut microbiome and depression?", "sentence2": "Moreover, recent findings are suggestive of the possibility that dysregulation of the enteric microbiota (i.e., dysbiosis) and associated bacterial translocation across the intestinal epithelium may be involved in the pathophysiology of stress-related psychiatric disorders, particularly depression.[SEP]Definitions: human defined as following: Members of the species Homo sapiens..", "label": "yes"} {"id": "converted_2565", "sentence1": "Does armodafinil improve fatigue of glioma patients?", "sentence2": "CONCLUSIONS: While treatment was well-tolerated, an 8-week course of armodafinil did not improve fatigue or QOL in glioma patients undergoing RT in this pilot study. , We evaluated whether armodafinil, a wakefulness-promoting medication, improves fatigue in glioma patients undergoing RT., Armodafinil did not significantly improve fatigue or QOL based on the 42-day change in FACIT-F fatigue subscale, FACT-G, CFS, or BFI. Further analysis suggests no difference between the arms even after accounting for the potential bias of missing data. , Treatment was well tolerated with few grade 3 or 4 toxicities.Respond with exceptions, completions and modifications or revisions done before completion
. liver cirrhosis defined as following: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules..", "label": "yes"} {"id": "converted_1052", "sentence1": "Is Propofol used for short-term sedation?", "sentence2": "The current study explores the incidence and content of dreaming during short-term sedation with sevoflurane or propofo, Propofol is the sedative most frequently used for short-term sedation and the weaning phase, whereas benzodiazepines are the preferred substances for medium- and long-term sedation., Performance of the A-line Autoregressive Index (AAI) and of the Bispectral Index (BIS) at assessing depth of short-term sedation following cardiac surgery., All patients received sedation with propofol according to the study protocol., Short-term sedation with either sevoflurane using ACD or propofol did not negatively affect renal function postoperatively., Assessing feasibility and physiological effects of sedation with sevoflurane, administered with the anesthetic conserving device (AnaConDa), in comparison with propofol and remifentanil., Sevoflurane can be effectively and safely used for short-term sedation of ICU patients with stable hemodynamic conditions., Propofol was used for most of the patients during short-term sedation (57%) and during weaning (48%)., Effects of short-term propofol administration on pancreatic enzymes and triglyceride levels in children., This prospective, clinical trial evaluated the effects of short-term propofol administration on triglyceride levels and serum pancreatic enzymes in children undergoing sedation for magnetic resonance imaging., Dexmedetomidine vs. propofol for short-term sedation of postoperative mechanically ventilated patients., The aim of this study was to compare the efficacy and endocrine response of propofol vs. the new alpha2-agonist dexmedetomidine for sedation in surgical intensive care patients who need postoperative short-term ventilation., A total of 89 adult, nonemergent, coronary artery bypass graft patients with an expected length of intubation of <24 hrs. METHODS: Patients were randomized to either DEX or propofol, The majority of practitioners (82%) use propofol infusion in children in PICU, the main indication being for short-term sedation in children requiring procedures., Pharmacokinetics and effects of propofol 6% for short-term sedation in paediatric patients following cardiac surgery., This paper describes the pharmacokinetics and effects of propofol in short-term sedated paediatric patients., Twenty patients who were expected to require 8 h of post-operative sedation and ventilation were allocated randomly to receive either an infusion of dexmedetomidine 0.2-2.5 microg kg(-1) h(-1) or propofol 1-3 mg kg(-1) h(-1), Pharmacokinetics and pharmacodynamics of propofol 6% SAZN versus propofol 1% SAZN and Diprivan-10 for short-term sedation following coronary artery bypass surgery., The pharmacokinetics, pharmacodynamics and safety characteristics of propofol 6% SAZN were investigated during a short-term infusion and compared with the commercially available product propofol 1% in Intralipid 10% (Diprivan-10) and propofol 1% in Lipofundin MCT/LCT 10% (propofol 1% SAZN). METHODS: In a randomised double-blind study, 24 male patients received a 5-h infusion of propofol at the rate of 1 mg/kg/h for sedation in the immediate postoperative period following coronary artery bypass surgery, Propofol infusion and oxycodone-thiopental bolus dosages, titrated to the same sedation end point, resulted in similar time from admission to extubation, although the weaning period was shorter in the propofol group. In terms of breathing pattern, gas exchange, blood gases and haemodynamics, the methods were similar. Propofol, despite its attractive pharmacological profile, may offer no clinical benefit in short-term sedation after a moderate dose fentanyl anaesthesia in cardiac surgery., Postoperative short-term sedation with propofol in cardiac surgery., We conducted a randomized double-blind study to assess the safety and effectiveness of short-term sedation with propofol in adult patients immediately after cardiac surgery., The use of propofol for short-term sedation in ICUs has allowed the maintenance of sedation to continue until just a few hours before extubation but the benefits of propofol for longer-term indications are more debatable., Midazolam and propofol are available as hypnotics for short-term sedation during the post-operative period., The use of midazolam versus propofol for short-term sedation following coronary artery bypass grafting., Midazolam and propofol were compared in an open randomized study for postoperative sedation during 12 h of mechanical ventilation in 40 patients following coronary artery bypass grafting, Propofol is a known anesthetic agent, widely used for short-term anesthesia and for longer-term sedation., Propofol was the most commonly used agent overall during the observational period (primarily for short-term and intermediate-length sedation); midazolam was the most commonly used for long-term sedation.[SEP]Definitions: Propofol defined as following: An intravenous anesthetic agent which has the advantage of a very rapid onset after infusion or bolus injection plus a very short recovery period of a couple of minutes. (From Smith and Reynard, Textbook of Pharmacology, 1992, 1st ed, p206). Propofol has been used as ANTICONVULSANTS and ANTIEMETICS.. sevoflurane defined as following: A fluorinated isopropyl ether with general anesthetic property. Although the mechanism of action has not been fully elucidated, sevoflurane may act by interfering with the release and re-uptake of neurotransmitters at post-synaptic terminals, and/or alter ionic conductance following receptor activation by a neurotransmitter. Sevoflurane may also interact directly with lipid matrix of neuronal membranes, thereby affecting gating properties of ion channels. In addition, this agent may activate gamma-aminobutyric acid (GABA) receptors hyperpolarizing cell membranes. This results in a general anesthetic effect, a decrease in myocardial contractility and mean arterial pressure as well as an increased respiratory rate.. remifentanil defined as following: A piperidine-propionate derivative and opioid analgesic structurally related to FENTANYL. It functions as a short-acting MU OPIOID RECEPTOR agonist, and is used as an analgesic during induction or maintenance of general anesthesia, following surgery, during childbirth, and in mechanically ventilated patients under intensive care.. midazolam defined as following: A short-acting hypnotic-sedative drug with anxiolytic and amnestic properties. It is used in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. The short duration and cardiorespiratory stability makes it useful in poor-risk, elderly, and cardiac patients. It is water-soluble at pH less than 4 and lipid-soluble at physiological pH.. Dexmedetomidine defined as following: An imidazole derivate and active d-isomer of medetomidine with analgesic, anxiolytic and sedative properties. Dexmedetomidine selectively binds to presynaptic alpha-2 adrenoceptors located in the brain, thereby inhibiting the release of norepinephrine from synaptic vesicles. This leads to an inhibition of postsynaptic activation of adrenoceptors, which inhibit sympathetic activity, thereby leading to sedation and anxiolysis. The analgesic effect of this agent is mediated by binding to alpha-2 adrenoceptors in the spinal cord.. benzodiazepines defined as following: A group of two-ring heterocyclic compounds consisting of a benzene ring fused to a diazepine ring.. pancreatic enzymes defined as following: Pancreatic enzymes are comprised primarily of proteases, lipase and amylase that catalyze the breakdown of fats, carbohydrates and proteins during the digestion of food. However, the pancreas also produces many other digestive enzymes such as ribonuclease, deoxyribonuclease, gelatinase and elastase.. substances defined as following: Any matter of defined composition that has discrete existence, whose origin may be biological, mineral or chemical..", "label": "yes"} {"id": "converted_3031", "sentence1": "Is cabozantinib effective for Hepatocellular Carcinoma?", "sentence2": "However, clinical trials of nonselective kinase inhibitors with c-Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. , Rationale for use, clinical trial data, and current recommendations for cabozantinib in renal cell cancer, thyroid cancer, prostate cancer, hepatocellular cancer, and lung cancer are detailed in this article., More recently, promising outcomes have also been reported with new agents, such as nivolumab and cabozantinib., Positive results in recent phase III clinical trials have confirmed the high value of anti-angiogenic therapies for HCC in both first (sorafenib and lenvatinib) and second line (regorafenib and cabozantinib) treatment modalities. , More recently, regorafenib and nivolumab have received approval in the second-line setting after sorafenib, with further positive phase 3 studies emerging in the first line (lenvatinib non-inferior to sorafenib) and second line versus placebo (cabozantinib and ramucirumab). , The rapidly changing treatment landscape due to the emergence of new treatment options (sorafenib and lenvatinib equally effective in first line; regorafenib, cabozantinib, and ramucirumab showing OS benefit in second line with nivolumab approved by the FDA based on response rate) underscores the importance of re-assessing the role of the first approved systemic agent in HCC, sorafenib., Positive phase III-study data have been published for lenvatinib as first-line and cabozantinib as second-line therapy. , Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma., BACKGROUND: Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. , CONCLUSIONS: Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo., Expert opinion: Based on favorable phase III clinical trial data, sorafenib and lenvatinib are considered promising agents for HCC as first-line systemic chemotherapy. Moreover, regorafenib and cabozantinib are useful second-line therapies after the failure of sorafenib., CONCLUSIONS: Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. , Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma.Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. , Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo., Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the objective response rates were 4% and less than 1%, respectively (P=0.009)., The most common high-grade events were palmar-plantar erythrodysesthesia (17% with cabozantinib vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%).Your liver is the largest organ inside your body. It helps your body digest food, store energy, and remove poisons. Primary liver cancer starts in the liver. Metastatic liver cancer starts somewhere else and spreads to your liver.
Risk factors for primary liver cancer include
Symptoms can include a lump or pain on the right side of your abdomen and yellowing of the skin. However, you may not have symptoms until the cancer is advanced. This makes it harder to treat. Doctors use tests that examine the liver and the blood to diagnose liver cancer. Treatment options include surgery, radiation, chemotherapy, or liver transplantation.
NIH: National Cancer Institute
. renal cell cancer defined as following: Primary or metastatic malignant neoplasm involving the kidney.. hypertension defined as following: Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more.. Hepatocellular Carcinoma defined as following: A primary malignant neoplasm of epithelial liver cells. It ranges from a well-differentiated tumor with EPITHELIAL CELLS indistinguishable from normal HEPATOCYTES to a poorly differentiated neoplasm. The cells may be uniform or markedly pleomorphic, or form GIANT CELLS. Several classification schemes have been suggested.. sorafenib defined as following: A synthetic compound targeting growth signaling and angiogenesis. Sorafenib blocks the enzyme RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation; in addition, sorafenib inhibits the VEGFR-2/PDGFR-beta signaling cascade, thereby blocking tumor angiogenesis.. regorafenib defined as following: The anhydrous form of regorafenib, an orally bioavailable small molecule with potential antiangiogenic and antineoplastic activities. Regorafenib binds to and inhibits vascular endothelial growth factor receptors (VEGFRs) 2 and 3, and Ret, Kit, PDGFR and Raf kinases, which may result in the inhibition of tumor angiogenesis and tumor cell proliferation. VEGFRs are receptor tyrosine kinases that play important roles in tumor angiogenesis; the receptor tyrosine kinases RET, KIT, and PDGFR, and the serine/threonine-specific Raf kinase are involved in tumor cell signaling.. AXL defined as following: Tyrosine-protein kinase receptor UFO (894 aa, ~98 kDa) is encoded by the human AXL gene. This protein plays a role in ligand binding, signaling and cellular growth and differentiation.. thyroid cancer defined as following: A primary or metastatic malignant neoplasm affecting the thyroid gland.. palmar-plantar erythrodysesthesia defined as following: Chemotherapy-induced dermal side effects that are associated with the use of various CYTOSTATIC AGENTS. Symptoms range from mild ERYTHEMA and/or PARESTHESIA to severe ulcerative dermatitis with debilitating pain involving typically palmoplantar and intertriginous areas. These cutaneous manifestations are sometimes accompanied by nail anomalies.. diarrhea defined as following: An increased liquidity or decreased consistency of FECES, such as running stool. Fecal consistency is related to the ratio of water-holding capacity of insoluble solids to total water, rather than the amount of water present. Diarrhea is not hyperdefecation or increased fecal weight.. nivolumab defined as following: A fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1, PCD-1) with immune checkpoint inhibitory and antineoplastic activities. Upon administration, nivolumab binds to and blocks the activation of PD-1, an immunoglobulin superfamily (IgSF) transmembrane protein, by its ligands programmed cell death ligand 1 (PD-L1), which is overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on antigen-presenting cells (APCs). This results in the activation of T-cells and cell-mediated immune responses against tumor cells. Activated PD-1 negatively regulates T-cell activation and plays a key role in tumor evasion from host immunity.. fatigue defined as following: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli.. advanced hepatocellular carcinoma defined as following: Hepatocellular carcinoma that has spread extensively to other anatomic sites or is no longer responding to treatment.. lenvatinib defined as following: A synthetic, orally available inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2, also known as KDR/FLK-1) tyrosine kinase with potential antineoplastic activity. Lenvatinib blocks VEGFR2 activation by VEGF, resulting in inhibition of the VEGF receptor signal transduction pathway, decreased vascular endothelial cell migration and proliferation, and vascular endothelial cell apoptosis.. tivantinib defined as following: An orally bioavailable small molecule inhibitor of c-Met with potential antineoplastic activity. c-Met inhibitor ARQ 197 binds to the c-Met protein and disrupts c-Met signal transduction pathways, which may induce cell death in tumor cells overexpressing c-Met protein or expressing constitutively activated c-Met protein. c-Met protein, the product of the proto-oncogene c-Met, is a receptor tyrosine kinase also known as hepatocyte growth factor receptor (HGFR); this protein is overexpressed or mutated in many tumor cell types and plays key roles in tumor cell proliferation, survival, invasion, and metastasis, and tumor angiogenesis.. foretinib defined as following: An orally bioavailable small molecule with potential antineoplastic activity. Foretinib binds to and selectively inhibits hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor 2 (VEGFR2), which may result in the inhibition of tumor angiogenesis, tumor cell proliferation and metastasis. The proto-oncogene c-MET has been found to be over-expressed in a variety of cancers. VEGFR2 is found on endothelial and hematopoietic cells and mediates the development of the vasculature and hematopoietic cells through VEGF signaling.. MET defined as following: Human MET wild-type allele is located within 7q31 and is approximately 126 kb in length. This allele, which encodes hepatocyte growth factor receptor protein, plays a role in the regulation of cellular tyrosine-kinase activity. Mutations in the MET gene are associated with papillary renal carcinoma.. cabozantinib defined as following: An orally bioavailable, small molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Cabozantinib strongly binds to and inhibits several RTKs, which are often overexpressed in a variety of cancer cell types, including hepatocyte growth factor receptor (MET), RET (rearranged during transfection), vascular endothelial growth factor receptor types 1 (VEGFR-1), 2 (VEGFR-2), and 3 (VEGFR-3), mast/stem cell growth factor (KIT), FMS-like tyrosine kinase 3 (FLT-3), TIE-2 (TEK tyrosine kinase, endothelial), tropomyosin-related kinase B (TRKB) and AXL. This may result in an inhibition of both tumor growth and angiogenesis, and eventually lead to tumor regression..", "label": "yes"} {"id": "converted_1971", "sentence1": "Is golimumab effective for ulcerative colitis?", "sentence2": "Initial experience with golimumab in clinical practice for ulcerative colitis., BACKGROUND: Golimumab is a TNF-blocking agent indicated as a second-line therapy in ulcerative colitis., CONCLUSIONS: In this short study, golimumab seems to be an alternative treatment in naive and non-naive anti-TNF ulcerative colitis patients., Cost-Effectiveness Analysis of 1-Year Treatment with Golimumab/Standard Care and Standard Care Alone for Ulcerative Colitis in Poland., OBJECTIVE: The objective of this study was to assess the cost-effectiveness of induction and maintenance treatment up to 1 year of ulcerative colitis with golimumab/standard care and standard care alone in Poland., CONCLUSIONS: The biologic treatment of ulcerative colitis patients with golimumab/standard care is more effective but also more costly compared with standard care alone., Currently, infliximab, adalimumab, and golimumab are available in the East Asian medical market, and these agents have been shown to be effective for inducing and maintaining long-term remission of IBD., Furthermore, upcoming treatments are introduced, such as golimumab, vedolizumab, AJM300, tofacitinib., CONCLUSIONS: No significant differences in efficacy in the maintenance phase between infliximab and golimumab or adalimumab were revealed. Infliximab proved to be more effective than adalimumab but of similar efficacy to that of golimumab in the induction phase., In this review, we will provide a detailed discussion of the three tumor necrosis factor-alpha (TNF-α) inhibitors currently approved for treatment of ulcerative colitis: infliximab, adalimumab, and golimumab., Golimumab, a human anti-TNF antibody, is effective in patients with ulcerative colitis, according to new findings from an international phase III double-blind trial., Golimumab for moderately to severely active ulcerative colitis., Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis., Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis., Subcutaneous golimumab, a fully human monoclonal antibody to tumor necrosis factor-α (TNFα), was evaluated as maintenance therapy in TNFα antagonist-naive adults with moderate-to-severe active ulcerative colitis, despite conventional therapy, who responded to golimumab induction therapy.We performed a phase 3, double-blind trial of patients who completed golimumab induction trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment, eg, PURSUIT), Golimumab, a human anti-TNF antibody, is effective in patients with ulcerative colitis, according to new findings from an international phase III double-blind trial, The purpose of this review was to describe the management of ulcerative colitis with emphasis on the use of anti-tumor necrosis factor (TNF) agents.Recent research has shown that new anti-TNF agents, adalimumab (ADA) and golimumab, are effective in induction of remission and maintenance of remission in patients with extensive ulcerative colitis, Vedolizumab and golimumab occurred more effective, and comparably as safe as placebo in patients with active moderate to severe ulcerative colitis increasing the number of available therapeutic options, The required sample sizes for direct head-to-head trials between infliximab and adalimumab for induction and maintenance are 174 and 204 subjects respectively.This study demonstrates that, compared to placebo, infliximab, adalimumab and golimumab are all effective for the induction and maintenance of remission in ulcerative colitis, The biosimilar of infliximab is as effective and as safe as its originator in rheumatologic conditions, while a new anti-TNF agent, namely golimumab, has been recently approved for refractory ulcerative colitis, We evaluated subcutaneous golimumab induction therapy in TNF-α antagonist-naïve patients with moderate-to-severe UC despite conventional treatment. , Vedolizumab and golimumab occurred more effective, and comparably as safe as placebo in patients with active moderate to severe ulcerative colitis increasing the number of available therapeutic options., The purpose of this review was to describe the management of ulcerative colitis with emphasis on the use of anti-tumor necrosis factor (TNF) agents.Recent research has shown that new anti-TNF agents, adalimumab (ADA) and golimumab, are effective in induction of remission and maintenance of remission in patients with extensive ulcerative colitis., Vedolizumab and golimumab occurred more effective, and comparably as safe as placebo in patients with active moderate to severe ulcerative colitis increasing the number of available therapeutic options., The biosimilar of infliximab is as effective and as safe as its originator in rheumatologic conditions, while a new anti-TNF agent, namely golimumab, has been recently approved for refractory ulcerative colitis., The incremental cost-utility ratio of golimumab/standard care compared to the standard care alone is estimated to be 391,252 PLN/QALY gained (93,155 €/QALYG) from public payer perspective and 374,377 PLN/QALY gained (89,137 €/QALYG) from social perspective.The biologic treatment of ulcerative colitis patients with golimumab/standard care is more effective but also more costly compared with standard care alone., The required sample sizes for direct head-to-head trials between infliximab and adalimumab for induction and maintenance are 174 and 204 subjects respectively.This study demonstrates that, compared to placebo, infliximab, adalimumab and golimumab are all effective for the induction and maintenance of remission in ulcerative colitis., Recently, 2 new antibodies have been approved: golimumab is a new option for ulcerative colitis and with another more selective mechanism of action; vedolizumab could be useful for ulcerative colitis as well as Crohn's disease., The present review summarizes the literature on the role of golimumab, a new anti TNF agent, in ulcerative colitis.Literature search was done on PubMed using the search terms 'golimumab' AND 'ulcerative colitis' from inception till March 2016., The aim of this systematic review was to evaluate the efficacy and safety of biological agents (vedolizumab, abatacept, visilizumab, golimumab) in patients with active moderate to severe ulcerative colitis.This paper was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines., Vedolizumab and golimumab occurred more effective, and comparably as safe as placebo in patients with active moderate to severe ulcerative colitis increasing the number of available therapeutic options., BACKGROUND & AIMS: Subcutaneous golimumab, a fully human monoclonal antibody to tumor necrosis factor-á (TNFá), was evaluated as maintenance therapy in TNFá antagonist-naive adults with moderate-to-severe active ulcerative colitis, despite conventional therapy, who responded to golimumab induction therapy.METHODS: We performed a phase 3, double-blind trial of patients who completed golimumab induction trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment, eg, PURSUIT)., BACKGROUND & AIMS: Little is known about the efficacy of golimumab, a fully human monoclonal antibody to tumor necrosis factor (TNF) -á, for treatment of ulcerative colitis (UC)., This study demonstrates that, compared to placebo, infliximab, adalimumab and golimumab are all effective for the induction and maintenance of remission in ulcerative colitis., Vedolizumab and golimumab occurred more effective, and comparably as safe as placebo in patients with active moderate to severe ulcerative colitis increasing the number of available therapeutic options.., Recent research has shown that new anti-TNF agents, adalimumab (ADA) and golimumab, are effective in induction of remission and maintenance of remission in patients with extensive ulcerative colitis., Golimumab for moderately to severely active ulcerative colitis., Initial experience with golimumab in clinical practice for ulcerative colitis., Golimumab was found to be effective and safe in inducing and maintaining clinical remission, clinical response and mucosal healing in patients with UC in the two registration trials., [Golimumab Therapy in Ulcerative Colitis]., Golimumab: clinical update on its use for ulcerative colitis., This review will focus on golimumab therapy in ulcerative colitis., To assess golimumab pharmacokinetics [PK] and exposure-response [ER] in adults with moderate-to-severe ulcerative colitis [UC] from the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment [PURSUIT] studies.[SEP]Definitions: Ulcerative Colitis defined as following: Inflammation of the COLON that is predominantly confined to the MUCOSA. Its major symptoms include DIARRHEA, rectal BLEEDING, the passage of MUCUS, and ABDOMINAL PAIN.. visilizumab defined as following: A humanized, non-Fc receptor (FcR)-binding IgG2 monoclonal antibody (MoAb) directed against CD3 with potential immunosuppressive activity. Visilizumab binds to invariant CD3 epsilon, one of the non-covalently-associated subunits of T-cell receptors (TCRs) on activated T-cells. Upon binding to the TCR/CD3 complex, visilizumab induces apoptosis, which may result in the selective clonal deletion of activated pathogenic T-cells. This MoAb is engineered with a substitution at amino acid residues 234 and 237 (Val3Ala) within the IgG2 Fc arm, rendering it unable to bind to type II FcRs; accordingly, this agent is less likely to activate type II FcR-expressing resting T-cells.. ADA defined as following: Catalysis of the reaction: acetaldehyde + CoA + NAD+ = acetyl-CoA + NADH + H+. [EC:1.2.1.10]. ER defined as following: A system of cisternae in the CYTOPLASM of many cells. In places the endoplasmic reticulum is continuous with the plasma membrane (CELL MEMBRANE) or outer membrane of the nuclear envelope. If the outer surfaces of the endoplasmic reticulum membranes are coated with ribosomes, the endoplasmic reticulum is said to be rough-surfaced (ENDOPLASMIC RETICULUM, ROUGH); otherwise it is said to be smooth-surfaced (ENDOPLASMIC RETICULUM, SMOOTH). (King & Stansfield, A Dictionary of Genetics, 4th ed). human defined as following: Members of the species Homo sapiens.. abatacept defined as following: A soluble fusion protein consisting of the extracellular domain of human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1) with immunosuppressive activity. Abatacept binds CD80 and CD86 on antigen presenting cells (APCs), blocking interaction with CD28 on T lymphocytes, which initiates a co-stimulatory signal required for full activation of T lymphocytes.. TNF defined as following: A recombinant therapeutic agent which is chemically identical to or similar to one of a number of endogenous tumor necrosis factor (TNF) proteins. TNF family cytokines bind to and activate specific cell-surface receptors, thereby mediating inflammatory processes, cell proliferation, immunity, angiogenesis, and tumor cell cytotoxicity. One primary antitumor effect of TNFs involves stimulation of T cell-mediated antitumor cytotoxicity.. Vedolizumab defined as following: A recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody directed against the human lymphocyte Peyer's patch adhesion molecule 1 (LPAM-1; alpha4beta7; a4b7), with immunomodulating, anti-inflammatory, and potential antineoplastic activities. Upon administration, vedolizumab selectively binds to integrin a4b7 and prevents the binding of a4b7, expressed on the surface of a subset of T-lymphocytes, to its natural ligand, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is mainly expressed on the surface of gut endothelial cells. This prevents a4b7-mediated signaling, adhesion of lymphocytes to the endothelium and the migration of T-lymphocytes across the endothelium into inflamed gastrointestinal (GI) tissue. By preventing this infiltration to the affected area, inflammation is reduced. The human lymphocyte a4b7 integrin, plays a key role in gastrointestinal (GI) inflammation; it is overexpressed in certain types of cancer cells. The alpha4beta7/MAdCAM-1 signaling pathway plays a critical role in the homing of T-lymphocytes to intestinal tissue.. tumor necrosis factor defined as following: Serum glycoprotein produced by activated MACROPHAGES and other mammalian MONONUCLEAR LEUKOCYTES. It has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. Also known as TNF-alpha, it is only 30% homologous to TNF-beta (LYMPHOTOXIN), but they share TNF RECEPTORS.. infliximab defined as following: A chimeric monoclonal antibody to TNF-ALPHA that is used in the treatment of RHEUMATOID ARTHRITIS; ANKYLOSING SPONDYLITIS; PSORIATIC ARTHRITIS and CROHN'S DISEASE.. PK defined as following: ATP:pyruvate 2-O-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (L, R, M1, and M2). Deficiency of the enzyme results in hemolytic anemia. EC 2.7.1.40.. adalimumab defined as following: A recombinant, human IgG1 monoclonal antibody directed against tumor necrosis factor-alpha (TNF-alpha), with immunomodulating activity. Upon administration, adalimumab binds to TNF-alpha, thereby preventing its binding to the p55 and p75 TNF cell surface receptors and inhibiting TNF-mediated immune responses. TNF-alpha, a pro-inflammatory cytokine, is upregulated in various autoimmune diseases.. IBD defined as following: Gastrointestinal symptoms characterized by chronic abdominal pain and altered bowel habits in the absence of any organic cause.. tofacitinib defined as following: An orally available inhibitor of Janus kinases (JAK), with immunomodulatory and anti-inflammatory activities. Upon administration, tofacitinib binds to JAK and prevents the activation of the JAK-signal transducers and activators of transcription (STAT) signaling pathway. This may decrease the production of pro-inflammatory cytokines, such as interleukin (IL)-6, -7, -15, -21, interferon-alpha and -beta, and may prevent both an inflammatory response and the inflammation-induced damage caused by certain immunological diseases. JAK kinases are intracellular enzymes involved in signaling pathways affecting hematopoiesis, immunity and inflammation.. Golimumab defined as following: A human monoclonal antibody directed against the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-a) with immunosuppressive activity. Golimumab binds to TNF-a, thereby preventing TNF-a-mediated immune responses. TNF-a production is dysregulated in various auto-immune diseases and in cancer.. golimumab defined as following: A human monoclonal antibody directed against the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-a) with immunosuppressive activity. Golimumab binds to TNF-a, thereby preventing TNF-a-mediated immune responses. TNF-a production is dysregulated in various auto-immune diseases and in cancer.. ulcerative colitis defined as following: Inflammation of the COLON that is predominantly confined to the MUCOSA. Its major symptoms include DIARRHEA, rectal BLEEDING, the passage of MUCUS, and ABDOMINAL PAIN..", "label": "yes"} {"id": "converted_1226", "sentence1": "Are there interactomes available for POU5F1 and SOX2?", "sentence2": "The interactomes of POU5F1 and SOX2 enhancers in human embryonic stem cells., We assayed long-range chromosomal interactions on putative enhancers of POU5F1 and SOX2 genes in human embryonic stem cells (hESCs) using 4C-Seq technique. We discovered that their frequent interacting regions mainly overlap with early DNA replication domains. The interactomes are associated with active histone marks and enriched with 5-hydroxymethylcytosine sites. In hESCs, genes within the interactomes have elevated expression. Additionally, some genes associated with the POU5F1 enhancer contribute to pluripotency. Binding sites for multiple DNA binding proteins, including ATF3, CTCF, GABPA, JUND, NANOG, RAD21 and YY1, are enriched in both interactomes.[SEP]Definitions: NANOG defined as following: This gene plays a role in the underlying pluripotency of inner cell mass and embryonic stem cells.. CTCF defined as following: CCN family member 2 (349 aa, ~38kDa) is encoded by the human CCN2 gene. This protein plays a role in the promotion of proliferation and differentiation of chondrocytes and also mediates heparin- and divalent cation-dependent cell adhesion in many different cell types.. POU5F1 defined as following: POU domain, class 5, transcription factor 1 protein (360 aa, ~39 kDa) is encoded by the human POU5F1 gene. This protein plays a role in the regulation of early embryonic development.. Binding sites defined as following: The parts of a macromolecule that directly participate in its specific combination with another molecule.. JUND defined as following: Human JUND wild-type allele is located in the vicinity of 19p13.2 and is approximately 2 kb in length. This allele, which encodes transcription factor jun-D protein, plays a role in the modulation of transcription by RNA polymerase II.. RAD21 defined as following: Double-strand-break repair protein rad21 homolog (631 aa, ~72 kDa) is encoded by the human RAD21 gene. This protein is involved in DNA repair, cell cycle-dependent chromosomal cohesion and apoptosis.. ATF3 defined as following: Cyclic AMP-dependent transcription factor ATF-3 (181 aa, ~21 kDa) is encoded by the human ATF3 gene. This protein plays a role in both DNA binding and the repression of gene expression.. YY1 defined as following: This gene is involved in the negative regulation of transcription.. SOX2 defined as following: Transcription factor SOX-2 protein (317 aa, ~34 kDa) is encoded by the human SOX2 gene. This protein is involved in neural cell progenitor differentiation and neurogenesis.. hESCs defined as following: A type of PLURIPOTENT STEM CELLS derived from early stage human embryos, up to and including the BLASTOCYST stage.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "yes"} {"id": "converted_381", "sentence1": "Is cadasil syndrome a hereditary disease?", "sentence2": " CADASIL is the most frequent hereditary small-vessel disease of the brain. The clinical impact of various MR imaging markers has been repeatedly studied in this disorder, but alterations of contrast between gray matter and normal-appearing white matter remain unknown. The aim of this study was to evaluate the contrast alterations between gray matter and normal-appearing white matter on T1-weighted images in patients with CADASIL compared with healthy subjects, (CADASIL) is the most common form of hereditary cerebral angiopathy, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease, clinically characterized by migraine, recurrent transient ischemic attacks or strokes, psychiatric disorders and cognitive decline. Strokes are typically ischemic, while hemorrhagic events have been only sporadically described, Mutations in the TREX1 and NOTCH3 genes cause retinal vasculopathy with cerebral leukodystrophy (RVCL) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), respectively, We used immunohistochemistry and immunogold electron microscopy (EM) to examine the distribution of GOM and NOTCH3 ectodomain (N3ECD) protein in microvasculature of brain gray matter and white matter in patients with CADASIL, non-CADASIL hereditary small-vessel disease and sporadic age-related degenerative disease, and comparable-age controls[SEP]Definitions: RVCL defined as following: An inherited group of small vessel diseases comprised of cerebroretinal vasculopathy (CRV), hereditary vascular retinopathy (HRV) and hereditary endotheliopathy with retinopathy, nephropathy and stroke all exhibiting progressive visual impairment as well as variable cerebral dysfunction. There is evidence the disease is caused by heterozygous mutation in the TREX1 gene on chromosome 3p21.. psychiatric disorders defined as following: Troublesome or disruptive behavioral displays.. CADASIL defined as following: A hereditary cerebrovascular disorder caused by mutations in the Notch 3 gene. It is characterized by alterations of the muscular wall of the small vessels in the brain, resulting in transient ischemic attacks. It may lead to cognitive problems and dementia.. Strokes defined as following: A group of pathological conditions characterized by sudden, non-convulsive loss of neurological function due to BRAIN ISCHEMIA or INTRACRANIAL HEMORRHAGES. Stroke is classified by the type of tissue NECROSIS, such as the anatomic location, vasculature involved, etiology, age of the affected individual, and hemorrhagic vs. non-hemorrhagic nature. (From Adams et al., Principles of Neurology, 6th ed, pp777-810). TREX1 defined as following: Three prime repair exonuclease 1 (369 aa, ~39 kDa) is encoded by the human TREX1 gene. This protein is involved in DNA mismatch repair.. migraine defined as following: A common, severe type of vascular headache often associated with increased sympathetic activity, resulting in nausea, vomiting, and light sensitivity.. cerebral small vessel disease defined as following: Pathological processes or diseases where cerebral MICROVESSELS show abnormalities. They are often associated with aging, hypertension and risk factors for lacunar infarcts (see LACUNAR INFARCTION); LEUKOARAIOSIS; and CEREBRAL HEMORRHAGE.. cognitive decline defined as following: Loss of previously present mental abilities, generally in adults. [HPO:probinson]. Mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. leukoencephalopathy defined as following: Any of various diseases affecting the white matter of the central nervous system.. cadasil syndrome defined as following: A hereditary cerebrovascular disorder caused by mutations in the Notch 3 gene. It is characterized by alterations of the muscular wall of the small vessels in the brain, resulting in transient ischemic attacks. It may lead to cognitive problems and dementia.. hereditary disease defined as following: Genetic diseases are diseases in which inherited genes predispose to increased risk. The genetic disorders associated with cancer often result from an alteration or mutation in a single gene. The diseases range from rare dominant cancer family syndrome to familial tendencies in which low-penetrance genes may interact with other genes or environmental factors to induce cancer. Research may involve clinical, epidemiologic, and laboratory studies of persons, families, and populations at high risk of these disorders..", "label": "yes"} {"id": "converted_409", "sentence1": "Does a linker histone exist in the yeast genome?", "sentence2": "Hho1p is a bona fide linker histone, In Saccharomyces cerevisiae, HHO1 encodes a putative linker histone with very significant homology to histone H1, HHO1p may play a similar role to linker histones, but at restricted locations in the chromatin, The putative linker histone in Saccharomyces cerevisiae, Hho1p, has two regions of sequence (GI and GII) that are homologous to the single globular domains of linker histones H1 and H5 in higher eukaryotes. , The Saccharomyces cerevisiae homologue of the linker histone H1, Hho1p, has two domains that are similar in sequence to the globular domain of H1 (and variants such as H5), Two homologous domains of similar structure but different stability in the yeast linker histone, Hho1p, Saccharomyces cerevisiae encodes a single linker histone, Hho1p, with two globular domains. , The Saccharomyces cerevisiae linker histone Hho1p, with two globular domains, can simultaneously bind to two four-way junction DNA molecules, Here, we show in yeast, that the presence of yeast linker histone Hho1p represses expression of a pol II transcribed gene (MET15) embedded in the rDNA., Yeast linker histone Hho1p is required for efficient RNA polymerase I processivity and transcriptional silencing at the ribosomal DNA, Saccharomyces cerevisiae linker histone Hho1p is not essential for cell viability, and very little is known about its function in vivo. , Saccharomyces cerevisiae linker histone Hho1p functionally interacts with core histone H4 and negatively regulates the establishment of transcriptionally silent chromatin, Unlike canonical linker histones in higher eukaryotes that have a single conserved globular domain, Hho1p possesses two globular domains. We show that the carboxyl-terminal globular domain of Hho1p is dispensable for its function, suggesting that the mode of Hho1p action is similar to that of canonical linker histones, To identify new proteins involved in spore nuclear organization, we purified chromatin from mature spores and discovered a significant enrichment of the linker histone (Hho1), Hho1 chromatin immunoprecipitation followed by sequencing (ChIP-seq) revealed increased genome-wide binding in mature spores and provides novel in vivo evidence of the linker histone binding to nucleosomal linker DNA, One of the peculiarities of S. cerevisiae cells is the unusual and less abundant linker histone, Hho1p., Hho1p, the linker histone of Saccharomyces cerevisiae, is important for the proper chromatin organization in vivo, Characteristically, linker histone depleted chromatin generally exhibited longer chromatin loops than the wild-type. , Saccharomyces cerevisiae linker histone-Hho1p maintains chromatin loop organization during ageing., Database homology searching against the complete yeast genome has identified a gene, HHO1, (or YPL127C, formerly LPI17) which encodes a protein that has two regions that show similarity to the pea histone H1 globular domain., Database homology searching against the complete yeast genome has identified a gene, HHO1, (or YPL127C, formerly LPI17) which encodes a protein that has two regions that show similarity to the pea histone H1 globular domain. , Biochemical studies to date have not been able to identify the linker histone H1 protein in the budding yeast Saccharomyces cerevisiae. Database homology searching against the complete yeast genome has identified a gene, HHO1, (or YPL127C, formerly LPI17) which encodes a protein that has two regions that show similarity to the pea histone H1 globular domain., Database homology searching against the complete yeast genome has identified a gene, HHO1, (or YPL127C, formerly LPI17) which encodes a protein that has two regions that show similarity to the pea histone H1 globular domain.[SEP]Definitions: yeast defined as following: A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as \"baker's\" or \"brewer's\" yeast. The dried form is used as a dietary supplement.. rDNA defined as following: DNA sequences encoding RIBOSOMAL RNA and the segments of DNA separating the individual ribosomal RNA genes, referred to as RIBOSOMAL SPACER DNA.. chromatin loop defined as following: A higher order chromatin structure above the level of the chromatin fiber. The organization of chromatin into loops permits the partitioning of chromatin into topologically independent domains, and is thought to facilitate its compartmentation into functionally independent regions.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. histones defined as following: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each.. histone H1 defined as following: Linker Histone H1 interacts with DNA between nucleosome units in mediating chromatin compaction into higher order structures. Histones are basic nuclear proteins responsible for the nucleosome structure of eukaryotic chromatin. Repeating nucleosome units contain two molecules each of core Histones H2A, H2B, H3, and H4 that form an octamer complex around which approximately 146 base pairs of DNA is wrapped. (NCI). protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. chromatin defined as following: The ordered and organized complex of DNA, protein, and sometimes RNA, that forms the chromosome. [GOC:elh, PMID:20404130]. RNA polymerase I defined as following: A DNA-dependent RNA polymerase present in bacterial, plant, and animal cells. The enzyme functions in the nucleolar structure and transcribes DNA into RNA. It has different requirements for cations and salts than RNA polymerase II and III and is not inhibited by alpha-amanitin.. eukaryotes defined as following: Organism or cells with a nucleus separated from the cytoplasm by a two membrance nuclear envelope and compartmentalization of function into distinct cytoplasmic organelles.. gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. H5 defined as following: This gene plays a role in mitogenesis and differentiation.. homology defined as following: A gene from one species which corresponds to a gene in another species and that is related via a common ancestral species. These genes retain a similar sequence and function..", "label": "yes"} {"id": "converted_2911", "sentence1": "Are there ultraconserved regions in the budding yeast (Saccharomyces cerevisiae)?", "sentence2": "The systematic analysis of ultraconserved genomic regions in the budding yeast., In the evolution of species, a kind of special sequences, termed ultraconserved sequences (UCSs), have been inherited without any change, which strongly suggests those sequences should be crucial for the species to survive or adapt to the environment. However, the UCSs are still regarded as mysterious genetic sequences so far. Here, we present a systematic study of ultraconserved genomic regions in the budding yeast based on the publicly available genome sequences, in order to reveal their relationship with the adaptability or fitness advantages of the budding yeast.Results: Our results indicate that, in addition to some fundamental biological functions, the UCSs play an important role in the adaptation of Saccharomyces cerevisiae to the acidic environment, which is backed up by the previous observation. Besides that, we also find the highly unchanged genes are enriched in some other pathways, such as the nutrient-sensitive signaling pathway. To facilitate the investigation of unique UCSs, the UCSC Genome Browser was utilized to visualize the chromosomal position and related annotations of UCSs in S.cerevisiae genome., Here, we present a systematic study of ultraconserved genomic regions in the budding yeast based on the publicly available genome sequences, in order to reveal their relationship with the adaptability or fitness advantages of the budding yeast., Motivation\nIn the evolution of species, a kind of special sequences, termed ultraconserved sequences (UCSs), have been inherited without any change, which strongly suggests those sequences should be crucial for the species to survive or adapt to the environment., The systematic analysis of ultraconserved genomic regions in the budding yeast.rotavirus vaccine, tetravalent, live, oral
. acid defined as following: Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. (Grant & Hackh's Chemical Dictionary, 5th ed). dehydration defined as following: The condition that results from excessive loss of water from a living organism.. infection defined as following: An illness caused by an infectious agent or its toxins that occurs through the direct or indirect transmission of the infectious agent or its products from an infected individual or via an animal, vector or the inanimate environment to a susceptible animal or human host.. gastroenteritis defined as following: INFLAMMATION of any segment of the GASTROINTESTINAL TRACT from ESOPHAGUS to RECTUM. Causes of gastroenteritis are many including genetic, infection, HYPERSENSITIVITY, drug effects, and CANCER.. human defined as following: Members of the species Homo sapiens.. rotavirus gastroenteritis defined as following: Enteritis attributed to the rotavirus.. rotavirus disease defined as following: Infection with any of the rotaviruses. Specific infections include human infantile diarrhea, neonatal calf diarrhea, and epidemic diarrhea of infant mice.. oral poliovirus vaccine defined as following: A live vaccine containing attenuated poliovirus, types I, II, and III, grown in monkey kidney cell tissue culture, used for routine immunization of children against polio. This vaccine induces long-lasting intestinal and humoral immunity. Killed vaccine induces only humoral immunity. Oral poliovirus vaccine should not be administered to immunocompromised individuals or their household contacts. (Dorland, 28th ed). diarrhoea defined as following: An increased liquidity or decreased consistency of FECES, such as running stool. Fecal consistency is related to the ratio of water-holding capacity of insoluble solids to total water, rather than the amount of water present. Diarrhea is not hyperdefecation or increased fecal weight.. intussusception defined as following: A form of intestinal obstruction caused by the PROLAPSE of a part of the intestine into the adjoining intestinal lumen. There are four types: colic, involving segments of the LARGE INTESTINE; enteric, involving only the SMALL INTESTINE; ileocecal, in which the ILEOCECAL VALVE prolapses into the CECUM, drawing the ILEUM along with it; and ileocolic, in which the ileum prolapses through the ileocecal valve into the COLON.. product defined as following:Participant material that is brought forth (produced) in the act (e.g., specimen in a specimen collection, access or drainage in a placement service, medication package in a dispense service). It does not matter whether the material produced had existence prior to the service, or whether it is created in the service (e.g., in supply services the product is taken from a stock).
. RIT defined as following: Human RIT1 wild-type allele is located in the vicinity of 1q22 and is approximately 14 kb in length. This allele, which encodes GTP-binding protein Rit1, is involved in signaling pathway regulation. Mutation of the gene is associated with Noonan syndrome type 8.. GSK defined as following: Catalysis of the reaction: ATP + tau-protein = ADP + O-phospho-tau-protein. [EC:2.7.11.26, MetaCyc:TAU-PROTEIN-KINASE-RXN].", "label": "yes"} {"id": "converted_555", "sentence1": "Could DNA (cytosine-5-)-methyltransferases serve as tumour markers?", "sentence2": "Here, we report evidence of the overexpression of DNA methyltransferases 3B (DNMT3B) in invasive cervical cancer and of the inhibition of metastasis by DNMT3B interference., This study was designed to determine the significance of DNA methyltransferases (DNMTs) in DNA hypermethylation in esophageal squamous cell carcinoma (ESCC) and to identify DNA methylation markers in serum for the early diagnosis of ESCC., DNA methyltransferase 1 as a predictive biomarker and potential therapeutic target for chemotherapy in gastric cancer., We examined the prognostic and predictive impact of DNA methyltransferase (DNMT) 1 and 3b expression in gastric carcinomas (GC) treated by neoadjuvant chemotherapy., High DNMT1 and DNMT3b expression was found in 105/127 (83%) and 79/127 (62%) carcinomas, respectively., Tumoral DNMT3b mRNA up-regulation was significantly correlated with hypermethylation of multiple tumor-related genes (P=0.021)., A regulator of de novo DNA methyltransferases DNMT3A and DNMT3B, DNMT3L promoter was found to have lost DNA methylation to varying levels in 14 out of 15 cancer cervix samples analysed. The present study highlights the importance of DNA methylation profile at DNMT3L promoter not only as a promising biomarker for cervical cancer, which is the second most common cancer among women worldwide, but also provides insight into the possible role of DNMT3L in cancer development., DNMT3L is a novel marker and is essential for the growth of human embryonal carcinoma., Among the DNMT genes, we found that mRNA for DNMT3L was specifically expressed in TGCTs, but neither in normal testicular tissues nor in cancer cells of somatic tissue origin. DNMT3L protein was strongly expressed in two EC cell lines, but not in the cell lines of somatic tissue origin., Positive nuclear labeling for DNMT3a was found only in few neoplasms: 1 pleomorphic adenoma (9.0%), 2 adenoid cystic carcinoma (16.6%) and 1 mucoepidermoid (9.0%) cases. CONCLUSIONS: Our results were not able to demonstrate a clear correlation between DNMT1 and DNMT3a immunoexpression and salivary gland neoplasms development., DNA methylation, mediated by the combined action of three DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B), is essential for mammalian development and is a major contributor to cellular transformation., The prevalence, the prognostic effect, and interaction with other molecular markers of DNMT3A mutations was studied in 415 patients with acute myeloid leukemia (AML) younger than 60 years., The recent identification of DNMT3A mutations in de novo acute myeloid leukemia prompted us to determine their frequency, patterns and clinical impact in a cohort of 98 patients with either therapy-related or secondary acute myeloid leukemia developing from an antecedent hematologic disorder., DNA methyltransferases (DNMT1 and DNMT3b) were also decreased in vorinostat-treated A549 cancer cells., To identify the mechanisms responsible for these genome-wide DNA methylation alterations, we measured the gene expression levels of several DNA methyltransferases (DNMTs) and their interacting proteins by TaqMan qPCR and observed increased expression of DNMT3A2, DNMT3B, and EZH2 in tumors., DNA methyltransferase 1 (DNMT1) is the primary enzyme that maintains DNA methylation., 5-Azactydine inhibits cell growth by direct cytotoxic action as well as by inhibition of DNA methyl transferase enzyme., Alterations in metabolism of methyl donors, disturbances in activity and/or expression of DNA methyltransferases, and presence of DNA single-strand breaks could contribute to the loss of cytosine methylation during carcinogenesis; however, the precise mechanisms of genomic hypomethylation induced by chemical carcinogens remain largely unknown., Recently, three single nucleotide polymorphisms (SNPs) of the DNMT3B promoter region, C46359T (-149C>T), -283T>C, and -579G>T have also been reported to be stratification markers that can predict an individual's susceptibility to cancers., Aberrant DNA methylation has been shown to play important roles during multistage carcinogenesis in various human organs., Thus, tumour subsets exist that display concurrent decreased BRCA1 expression, BRCA1 promoter methylation, cytoplasmic CTCF expression and with DNMT3b over-expression., DNA methylation patterns in genome are maintained during replication by a DNA methyltransferase Dnmt1., Aberrant DNA methylation has been shown to play an important role during multistage carcinogenesis in various human organs., To investigate the relationship between the expression of DNMT and clinical prognosis in adult patients with acute leukemia (AL), the mRNA expressions of DNMT, p15(INK4B), mdr1 were measured in 72 AL patients and 20 normal controls by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR); the ratio of p15 CpG land methylation was measured in 56 AL patients and 14 normal controls by methylation-specific PCR (MSP-PCR)., DNA methyltransferase Dnmt1 ensures clonal transmission of lineage-specific DNA methylation patterns in a mammalian genome during replication., Overexpression of the major DNA methyltransferase Dnmt1 is cytotoxic and has been hypothesized to result in aberrant hypermethylation of genes required for cell survival., DNA (cytosine-5-)-methyltransferase 1 (DNMT1) plays an important role in the maintenance of DNA methylation patterns via complicated networks including signaling pathways and transcriptional factors, relating to cell differentiation or carcinogenesis., We evaluated the significance of aberrant DNA methyltransferase 1 (DNMT1) protein expression during gastric carcinogenesis.[SEP]Definitions: EZH2 defined as following: Histone-lysine N-methyltransferase EZH2 (746 aa, ~85 kDa) is encoded by the human EZH2 gene. This protein is involved in the regulation of chromatin modification.. Dnmt1 defined as following: Human DNMT1 wt allele is located in the vicinity of 19p13.2 and is approximately 62 kb in length. This allele, which encodes DNA (Cytosine-5)-Methyltransferase 1, is involved in epigenetic modification of chromatin DNA and control of gene expression.. cancer defined as following: A malignant tumor at the original site of growth.. acute myeloid leukemia defined as following: Clonal expansion of myeloid blasts in bone marrow, blood, and other tissue. Myeloid leukemias develop from changes in cells that normally produce NEUTROPHILS; BASOPHILS; EOSINOPHILS; and MONOCYTES.. genome defined as following: Anatomical set of genes in all the chromosomes.. DNMT3L defined as following: DNA (cytosine-5)-methyltransferase 3-like (386 aa, ~44 kDa) is encoded by the human DNMT3L gene. This protein is involved in the modulation of DNA methyltransferase activity.. DNMT3b defined as following: DNA (cytosine-5)-methyltransferase 3B (853 aa, ~96 kDa) is encoded by the human DNMT3B gene. This protein is involved in DNA methylation.. cytosine defined as following: A pyrimidine base that is a fundamental unit of nucleic acids.. DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. cervical cancer defined as following: A primary or metastatic malignant neoplasm involving the cervix.. mdr1 defined as following: Human ABCB1 wild-type allele is located in the vicinity of 7q21.1 and is approximately 210 kb in length. This allele, which encodes multidrug resistance protein 1, is involved in transmembrane transport. Amplification of the ABCB1 gene is a major determinant in the development of multi-drug resistance, which decreases the effectiveness of many chemotherapeutic agents used in cancer treatment.. DNMT3B defined as following: This gene plays a role in embryonic development, imprinting, and X-chromosome inactivation.. DNMT3a defined as following: DNA (cytosine-5)-methyltransferase 3A protein (909 aa, ~102 kDa) is encoded by the human DNMT3A gene. This soluble, nuclear protein is involved in epigenetic modification of chromatin, catalyzing the methylation of C5 in CpG dinucleotides within DNA.. hematologic disorder defined as following: Disorders of the blood and blood forming tissues.. esophageal squamous cell carcinoma defined as following: A carcinoma that originates usually from cells on the surface of the middle and lower third of the ESOPHAGUS. Tumor cells exhibit typical squamous morphology and form large polypoid lesions. Mutations in RNF6, LZTS1, TGFBR2, DEC1, and WWOX1 genes are associated with this cancer.. gastric carcinomas defined as following: A malignant epithelial tumor of the stomach mucosa. The vast majority of gastric carcinomas are adenocarcinomas, arising from the gastric glandular epithelium.. transcriptional factors defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.. mammalian defined as following: Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young.. mRNA defined as following: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.. cancers defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. cancer cells defined as following: Cells of, or derived from, a malignant tumor.. DNA methyltransferase 1 defined as following: Enzymes that are part of the restriction-modification systems. They are responsible for producing a species-characteristic methylation pattern, on either adenine or cytosine residues, in a specific short base sequence in the host cell's own DNA. This methylated sequence will occur many times in the host-cell DNA and remain intact for the lifetime of the cell. Any DNA from another species which gains entry into a living cell and lacks the characteristic methylation pattern will be recognized by the restriction endonucleases of similar specificity and destroyed by cleavage. Most have been studied in bacterial systems, but a few have been found in eukaryotic organisms.. acute leukemia defined as following: A clonal (malignant) hematopoietic disorder with an acute onset, affecting the bone marrow and the peripheral blood. The malignant cells show minimal differentiation and are called blasts, either myeloid blasts (myeloblasts) or lymphoid blasts (lymphoblasts).. BRCA1 defined as following: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human CHROMOSOME 17 at locus 17q21. Mutations of this gene are associated with the formation of HEREDITARY BREAST AND OVARIAN CANCER SYNDROME. It encodes a large nuclear protein that is a component of DNA repair pathways.. gastric cancer defined as following: A primary or metastatic malignant neoplasm involving the stomach.. DNMT3A2 defined as following: Human DNMT3A wt allele is located in the vicinity of 2p23 and is approximately 110 kb in length. This allele, which encodes DNA (Cytosine-5)-Methyltransferase 3A, is involved in epigenetic modification of chromatin DNA and control of gene expression.. CTCF defined as following: CCN family member 2 (349 aa, ~38kDa) is encoded by the human CCN2 gene. This protein plays a role in the promotion of proliferation and differentiation of chondrocytes and also mediates heparin- and divalent cation-dependent cell adhesion in many different cell types.. adenoid cystic carcinoma defined as following: Carcinoma characterized by bands or cylinders of hyalinized or mucinous stroma separating or surrounded by nests or cords of small epithelial cells. When the cylinders occur within masses of epithelial cells, they give the tissue a perforated, sievelike, or cribriform appearance. Such tumors occur in the mammary glands, the mucous glands of the upper and lower respiratory tract, and the salivary glands. They are malignant but slow-growing, and tend to spread locally via the nerves. (Dorland, 27th ed). cell lines defined as following: Established cell cultures that have the potential to propagate indefinitely.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. clonal defined as following: Related by descent from a single progenitor cell.. carcinomas defined as following: A malignant neoplasm made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. It is a histological type of neoplasm and not a synonym for \"cancer.\". single nucleotide polymorphisms defined as following: A single nucleotide variation in a genetic sequence that occurs at appreciable frequency in the population.. pleomorphic adenoma defined as following: A benign, slow-growing tumor, most commonly of the salivary gland, occurring as a small, painless, firm nodule, usually of the parotid gland, but also found in any major or accessory salivary gland anywhere in the oral cavity. It is most often seen in women in the fifth decade. Histologically, the tumor presents a variety of cells: cuboidal, columnar, and squamous cells, showing all forms of epithelial growth. (Dorland, 27th ed). tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. p15 defined as following: Human CDKN2B wild-type allele is located within 9p21 and is approximately 27 kb in length. This allele, which encodes cyclin-dependent kinase 4 inhibitor B protein, plays roles in both the regulation of cell growth and tumor suppression.. human defined as following: Members of the species Homo sapiens.. embryonal carcinoma defined as following: A highly malignant, primitive form of carcinoma, probably of germinal cell or teratomatous derivation, usually arising in a gonad and rarely in other sites. It is rare in the female ovary, but in the male it accounts for 20% of all testicular tumors. (From Dorland, 27th ed & Holland et al., Cancer Medicine, 3d ed, p1595).", "label": "yes"} {"id": "converted_2005", "sentence1": "Is Doxorubicin cardiotoxic?", "sentence2": "Doxorubicin (DOXO) is widely used to treat solid tumors. However, its clinical use is limited by side effects including serious cardiotoxicity due to cardiomyocyte damage. , The results provide direct evidence for the role of catalase in doxorubicin cardiotoxic responses., These results do not support the possibility that mitomycin C potentiates the acute cardiotoxic effects produced by doxorubicin., The anthracycline chemotherapeutic agent doxorubicin is converted by the enzyme carbonyl reductase 1 (CBR1) into its cardiotoxic metabolite doxorubicinol, The clinical efficiency of the highly potent antitumor agent doxorubicin is limited by cardiotoxic effects, Doxorubicin (DOX), a highly active chemotherapeutic drug, faces limitations in clinical application due to severe cardiotoxic effects (mainly through increased oxidative stress), Clinical uses of doxorubicin (DOX), a highly active anticancer agent, are limited by its severe cardiotoxic side effects associated with increased oxidative stress and apoptosis, Doxorubicin (DOX) and trastuzumab (TRZ) are highly effective chemotherapeutic agents in the breast cancer setting, limited by their cardiotoxic side effects, Twisting and ironing: doxorubicin cardiotoxicity by mitochondrial DNA damage., Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin., On the other hand, pretreatment of rats with hesperidin protected cardiac tissues against the cardiotoxic effects of doxorubicin as evidenced from amelioration of histopathological changes and normalization of cardiac biochemical parameters.Hesperidin may have a protective effect against DOX-induced cardiotoxicity., However, with cumulative doses, doxorubicin also is known to have cardiotoxic effects, including cardiomyopathy and heart failure., Methods of reducing or preventing doxorubicin-induced cardiotoxicity have been suggested, including an investigational doxorubicin analog, mitoxantrone ( Novantrone )., The most cardiotoxic drug, doxorubicin, is the most potent inducer of superoxide generation, while epirubicin, which is less cardiotoxic, has a relatively limited effect on superoxide production., The mechanism of doxorubicin cardiotoxicity is likely multifactorial and most importantly, the genetic factors predisposing to doxorubicin cardiotoxicity are unknown., As doxorubicin cardiotoxicity is considered irreversible, early detection of cardiotoxicity and prevention of overt heart failure is essential., Although there are monitoring guidelines for cardiotoxicity, optimal timing for early detection of subclinical doxorubicin cardiotoxicity is still obscure., Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression., However, doxorubicin cardiotoxicity of the heart has largely limited its clinical use., Mitochondrial topoisomerase I (top1mt) is a novel limiting factor of doxorubicin cardiotoxicity., Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application., he clinical use of doxorubicin (DOX) and other anthracyclines is limited by a dosage-dependent cardiotoxicity, which can lead to cardiomyopathy. , Besides its cardiotoxic effect, doxorubicin also elicits inflammatory effects in vivo. 7-Monohydroxyethylrutoside (monoHER) has recently been used as a protector against doxorubicin-induced cardiotoxicity in vivo., Doxorubicin is an effective antineoplastic agent, but it frequently causes dose-related cardiotoxic effects. , Among these analogs, idarubicin (4-demethoxy-daunorubicin) was shown to be less cardiotoxic than doxorubicin i, Verapamil has also been suggested to potentiate the cardiotoxicity of doxorubicin. , Doxorubicin treatment is associated with both acute and chronic cardiotoxicity. , cardiac effects of diclofenac sodium on doxorubicin-induced cardiomyopathy in rats[SEP]Definitions: epirubicin defined as following: An anthracycline which is the 4'-epi-isomer of doxorubicin. The compound exerts its antitumor effects by interference with the synthesis and function of DNA.. Doxorubicin defined as following: Antineoplastic antibiotic obtained from Streptomyces peucetius. It is a hydroxy derivative of DAUNORUBICIN.. Verapamil defined as following: A calcium channel blocker that is a class IV anti-arrhythmia agent.. idarubicin defined as following: An orally administered anthracycline antineoplastic. The compound has shown activity against BREAST NEOPLASMS; LYMPHOMA; and LEUKEMIA.. heart failure defined as following: Heart failure accompanied by EDEMA, such as swelling of the legs and ankles and congestion in the lungs.. anthracycline defined as following: An antineoplastic antibiotic that is structurally similar to the benzoquinone ansamycin antibiotic geldanamycin. A geldanamycin analogue binds to HSP90, a chaperone protein that aids in the assembly, maturation, and folding of proteins. Subsequently, the function of HSP90 is inhibited, leading to the degradation and depletion of client proteins such as kinases and transcription factors involved with cell cycle regulation and signal transduction.. catalase defined as following: An oxidoreductase that catalyzes the conversion of HYDROGEN PEROXIDE to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in ACATALASIA.. Quercetin defined as following: A flavonol widely distributed in plants. It is an antioxidant, like many other phenolic heterocyclic compounds. Glycosylated forms include RUTIN and quercetrin.. cardiomyopathy defined as following: A group of diseases in which the dominant feature is the involvement of the CARDIAC MUSCLE itself. Cardiomyopathies are classified according to their predominant pathophysiological features (DILATED CARDIOMYOPATHY; HYPERTROPHIC CARDIOMYOPATHY; RESTRICTIVE CARDIOMYOPATHY) or their etiological/pathological factors (CARDIOMYOPATHY, ALCOHOLIC; ENDOCARDIAL FIBROELASTOSIS).. mitomycin C defined as following: An antineoplastic antibiotic produced by Streptomyces caespitosus. It is one of the bi- or tri-functional ALKYLATING AGENTS causing cross-linking of DNA and inhibition of DNA synthesis.. trastuzumab defined as following: A humanized monoclonal antibody against the ERBB-2 RECEPTOR (HER2). As an ANTINEOPLASTIC AGENT, it is used to treat BREAST CANCER where HER2 is overexpressed.. hesperidin defined as following: A flavanone glycoside found in CITRUS fruit peels.. mitoxantrone defined as following: An anthracenedione-derived antineoplastic agent.. CBR1 defined as following: Carbonyl reductase [NADPH] 1 (277 aa, ~30 kDa) is encoded by the human CBR1 gene. This protein plays a role in the reduction of carbonyl compounds.. superoxide defined as following: Highly reactive compounds produced when oxygen is reduced by a single electron. In biological systems, they may be generated during the normal catalytic function of a number of enzymes and during the oxidation of hemoglobin to METHEMOGLOBIN. In living organisms, SUPEROXIDE DISMUTASE protects the cell from the deleterious effects of superoxides.. rats defined as following: The common rat, Rattus norvegicus, often used as an experimental organism.. cardiotoxicity defined as following: Damage to the HEART or its function secondary to exposure to toxic substances such as drugs used in CHEMOTHERAPY; IMMUNOTHERAPY; or RADIATION.. cardiomyocyte defined as following: Striated muscle cells found in the heart. They are derived from cardiac myoblasts (MYOBLASTS, CARDIAC).. solid tumors defined as following: A benign or malignant neoplasm arising from tissues that do not include fluid areas. Representative examples include epithelial neoplasms (e.g. lung carcinoma, prostate carcinoma, breast carcinoma, colon carcinoma), and neoplasms arising from the soft tissues and bones (e.g. leiomyosarcoma, liposarcoma, chondrosarcoma, osteosarcoma). Neoplasms originating from the blood or bone marrow (leukemias and myeloproliferative disorders) are not considered solid tumors..", "label": "yes"} {"id": "converted_3799", "sentence1": "Can SMAD6 variants cause craniosynostosis?", "sentence2": "SMAD6 variants in craniosynostosis: genotype and phenotype evaluation., Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism nearBMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype.METHODS: We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants.RESULTS: We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P < 10-7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype.CONCLUSION: Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.[SEP]Definitions: variants defined as following: An alteration or difference from a norm or standard.. SMAD6 defined as following: Mothers against decapentaplegic homolog 6 (496 aa, ~53 kDa) is encoded by the human SMAD6 gene. This protein is involved in receptor signaling-dependent regulation of gene transcription.. craniosynostosis defined as following: This gene plays a role in regulation of transcription and the inhibition of apoptosis. It is also involved in the control of morphogenesis during embryonic development.. genotype defined as following: The determination of the DNA sequence of an individual.. metopic synostosis defined as following: Premature fusion of the metopic suture. [DDD:awilkie].", "label": "yes"} {"id": "converted_543", "sentence1": "Is the gene DUX4 epigenetically regulated in somatic cells?", "sentence2": "There are several genes on chromosome 4q35 region including DUX4 within D4Z4 repeats. Transcription of these genes is usually repressed by epigenetic modifications of this chromosomal region and also accumulation of transcriptional repressors to the repeat array., Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues. , The human double-homeodomain retrogene DUX4 is expressed in the testis and epigenetically repressed in somatic tissues., Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused by decreased epigenetic repression of the D4Z4 macrosatellite repeats and ectopic expression of DUX4, a retrogene encoding a germline transcription factor encoded in each repeat., These mice recapitulate important epigenetic and DUX4 expression attributes seen in patients and controls, respectively, including high DUX4 expression levels in the germline, (incomplete) epigenetic repression in somatic tissue, and FSHD-specific variegated DUX4 expression in sporadic muscle nuclei associated with D4Z4 chromatin relaxation., DUX4, a retrogene contained in the D4Z4 repeats, is normally epigenetically silenced in somatic cells., In contrast to control skeletal muscle and most other somatic tissues, full-length DUX4 transcript and protein is expressed at relatively abundant levels in human testis, most likely in the germ-line cells. Induced pluripotent (iPS) cells also express full-length DUX4 and differentiation of control iPS cells to embryoid bodies suppresses expression of full-length DUX4, whereas expression of full-length DUX4 persists in differentiated FSHD iPS cells. Together, these findings indicate that full-length DUX4 is normally expressed at specific developmental stages and is suppressed in most somatic tissues., Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues., DUX4, a retrogene contained in the D4Z4 repeats, is normally epigenetically silenced in somatic cells. , DUX4, a retrogene contained in the D4Z4 repeats, is normally epigenetically silenced in somatic cells., Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues., Normally expressed in the testis and epigenetically repressed in somatic tissues, DUX4 expression in skeletal muscle induces expression of many germline, stem cell, and other genes that might account for the pathophysiology of FSHD., Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues, The human double-homeodomain retrogene DUX4 is expressed in the testis and epigenetically repressed in somatic tissues, Normally expressed in the testis and epigenetically repressed in somatic tissues, DUX4 expression in skeletal muscle induces expression of many germline, stem cell, and other genes that might account for the pathophysiology of FSHD, DUX4, a retrogene contained in the D4Z4 repeats, is normally epigenetically silenced in somatic cells, Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues, The identification of the gene(s) and the exact epigenetic pathway underlining this disease will be mandatory to increase the rate of diagnosis for FSHD2 patients and to confirm the hypothesis of a common FSHD1 and FSHD2 pathophysiological pathway involving DUX4 gene, This deletion induces epigenetic modifications that affect the expression of several genes located in the vicinity. In each D4Z4 element, we identified the double homeobox 4 (DUX4) gene. DUX4 expresses a transcription factor that plays a major role in the development of FSHD through the initiation of a large gene dysregulation cascade that causes myogenic differentiation defects, atrophy and reduced response to oxidative stress. , decreased epigenetic repression and variegated expression of DUX4 in skeletal muscle, (incomplete) epigenetic repression in somatic tissue,, Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle., derepression of the DUX4 retrogene, The aim of our study was to identify relationships between epigenetic parameters correlating with a relaxed chromatin state of the DUX4 promoter region and clinical severity as measured by a clinical severity score or muscle pathologic changes in D4Z4 contraction-dependent (FSHD1) and -independent (FSHD2) facioscapulohumeral muscular dystrophy patients. , Specifically, abundance of RNA transcripts encoded by the DUX4 locus correlated to differential DNA methylation and H3K36me3 enrichment., Together, these findings indicate that full-length DUX4 is normally expressed at specific developmental stages and is suppressed in most somatic tissue[SEP]Definitions: DUX4 defined as following: Human DUX4L1 gene is located in the vicinity of 4q35 and is approximately 2 kb in length. The product is a processed pseudogene that produces an RNA transcript, but does not encode a protein product. This gene is within a D4Z4 repeat array; contraction of this macrosatellite repeat is associated with facioscapulohumeral muscular dystrophy (FSHD).. FSHD defined as following: An autosomal dominant degenerative muscle disease characterized by slowly progressive weakness of the muscles of the face, upper-arm, and shoulder girdle. The onset of symptoms usually occurs in the first or second decade of life. Affected individuals usually present with impairment of upper extremity elevation. This tends to be followed by facial weakness, primarily involving the orbicularis oris and orbicularis oculi muscles. (Neuromuscul Disord 1997;7(1):55-62; Adams et al., Principles of Neurology, 6th ed, p1420). chromosome 4 defined as following: A specific pair of GROUP B CHROMOSOMES of the human chromosome classification.. stem cell defined as following: Relatively undifferentiated cells that retain the ability to divide and proliferate throughout postnatal life to provide progenitor cells that can differentiate into specialized cells.. disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. transcription factor defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. muscular dystrophy defined as following: A heterogeneous group of inherited MYOPATHIES, characterized by wasting and weakness of the SKELETAL MUSCLE. They are categorized by the sites of MUSCLE WEAKNESS; AGE OF ONSET; and INHERITANCE PATTERNS.. DUX4 gene defined as following: This gene plays a role in transcriptional regulation.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. germ-line cells defined as following: The reproductive cells in multicellular organisms at various stages during GAMETOGENESIS.. FSHD1 defined as following: An autosomal dominant form of facioscapulohumeral muscular dystrophy associated with contraction of the D4Z4 macrosatellite repeat.. chromosomal region defined as following: Any subdivision of a chromosome along its length. [GOC:dos]. H3K36me3 defined as following: A post-translationally modified form of histone H3 where the lysine residue at position 36 is trimethylated. This modification may be involved in defining exon boundaries; it also may be a marker for genes targeted for transcriptional repression.. testis defined as following: The male gonad containing two functional parts: the SEMINIFEROUS TUBULES for the production and transport of male germ cells (SPERMATOGENESIS) and the interstitial compartment containing LEYDIG CELLS that produce ANDROGENS.. atrophy defined as following: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes.. repeat defined as following: Something occurring more than once.. human defined as following: Members of the species Homo sapiens.. iPS cells defined as following: Cells from adult organisms that have been reprogrammed into a pluripotential state similar to that of EMBRYONIC STEM CELLS.. somatic cells defined as following: Nucleated cell which has one or more diploid sets (46 pairs) of chromosomes.. repeats defined as following: Make or do or perform again..", "label": "yes"} {"id": "converted_1856", "sentence1": "Can beans induce apoptosis?", "sentence2": "A 60-kDa glucosamine binding lectin, white kidney bean lectin (WKBL), was purified from Phaseolus vulgaris cv. white kidney beans, by application of anion exchange chromatography on Q-Sepharose, affinity chromatography on Affi-gel blue gel, and FPLC-size exclusion on Superdex 75. The anti-proliferative activity of WKBL on HONE1 cells and HepG2 cells was stronger than the activity on MCF7 cells and WRL68 cells , Treatment of human stomach cancer KATO III cells with hot-water extracts from adzuki beans led to their growth inhibition as well as apoptosis induction., Stimulation of dendritic cell maturation and induction of apoptosis in leukemia cells by a heat-stable extract from azuki bean (Vigna angularis), a promising immunopotentiating food and dietary supplement for cancer prevention., Human gut flora-fermented nondigestible fraction from cooked bean ( Phaseolus vulgaris L.) modifies protein expression associated with apoptosis, cell cycle arrest, and proliferation in human adenocarcinoma colon cancer cells., This paper reports the effect of fermentation products (FP) by hgf (FP-hgf) from NDF of cooked beans on survival and protein expression associated with apoptosis, cell cycle arrest, and proliferation in human adenocarcinoma colon cancer cells., PHA-E is a natural product extracted from red kidney beans, and it has been reported to induce cell apoptosis by blocking EGFR in lung cancer cells, A Glucosamine-Specific Lectin from Green Dragon No. 8 Beans (Phaseolus vulgaris) Induced Apoptosis on Nasopharyngeal Carcinoma Cells, PHA-E is a natural product extracted from red kidney beans, and it has been reported to induce cell apoptosis by blocking EGFR in lung cancer cells., The anticancer activity of δ-tocotrienol, a bioactive vitamin E present in whole grain cereals, annatto beans and palm fruit, is strongly dependent on its effect on the induction of apoptosis. δ-Tocotrienol-induced apoptosis is associated with consistent induction in the expression of the proapoptotic protein Bcl-2-associated X protein (Bax)., NDF of cooked common beans inhibited colon carcinogenesis at an early stage by inducing cell cycle arrest of colon cells and morphological changes linked to apoptosis, thus confirming previous results obtained with gene expression studies., Azuki extract also inhibited the growth of human leukemia U937 cells, leading to induction of apoptosis., Fermentation product of soybean, black bean, and green bean mixture induces apoptosis in a wide variety of cancer cells., A non-digestible fraction of the common bean (Phaseolus vulgaris L.) induces cell cycle arrest and apoptosis during early carcinogenesis.[SEP]Definitions: MCF7 cells defined as following: An estrogen responsive cell line derived from a patient with metastatic human breast ADENOCARCINOMA (at the Michigan Cancer Foundation.). NDF defined as following: Human NRG1 wild-type allele is located within 8p21-p12 and is approximately 1,124 kb in length. This allele, which encodes pro-neuregulin-1, membrane-bound isoform protein, is involved in the compositional regulation of neurotransmitter receptors in maturing synapses in the brain, proliferation and differentiation.. HepG2 cells defined as following: A human liver tumor cell line used to study a variety of liver-specific metabolic functions.. Bax defined as following: Apoptosis regulator BAX (192 aa, ~21 kDa) is encoded by the human BAX gene. This protein plays a role in both apoptosis and protein-protein interactions.. hgf defined as following: Multifunctional growth factor which regulates both cell growth and cell motility. It exerts a strong mitogenic effect on hepatocytes and primary epithelial cells. Its receptor is PROTO-ONCOGENE PROTEINS C-MET.. cancer cells defined as following: Cells of, or derived from, a malignant tumor.. Nasopharyngeal Carcinoma defined as following: A carcinoma that originates in the EPITHELIUM of the NASOPHARYNX and includes four subtypes: keratinizing squamous cell, non-keratinizing, basaloid squamous cell, and PAPILLARY ADENOCARCINOMA. It is most prevalent in Southeast Asian populations and is associated with EPSTEIN-BARR VIRUS INFECTIONS. Somatic mutations associated with this cancer have been identified in NPCR, BAP1, UBAP1, ERBB2, ERBB3, MLL2, PIK3CA, KRAS, NRAS, and ARID1A genes.. Phaseolus vulgaris defined as following: The plant species that provides kidney beans..", "label": "yes"} {"id": "converted_1057", "sentence1": "Are there clinical trials on stem cells in multiple sclerosis", "sentence2": "Cells are generally given intravenously. Multiple sclerosis, rheumatoid arthritis and lupus have been successfully treated in human clinical trials, Human multipotent mesenchymal stem cell (MSC) therapies are currently being tested in clinical trials for Crohn's disease, multiple sclerosis, graft-versus-host disease, type 1 diabetes, bone fractures, cartilage damage, and cardiac diseases., Based on these results, several small pilot clinical trials in subjects with advanced MS have demonstrated that MSC administration is safe and provided an early signal of clinical effectiveness. The current aim of clinicians and scientists interested in the development of MSC-based strategies for the treatment of MS is to have the ultimate demonstration in large clinical trials that MSC can inhibit CNS inflammation and foster tissue repair, Mesenchymal stem cells (MSC) promote functional recovery in experimental models of central nervous system (CNS) pathology and are currently being tested in clinical trials for stroke, multiple sclerosis and CNS injury., Autologous bone marrow stromal cells (BMSCs) offer significant practical advantages for potential clinical applications in multiple sclerosis (MS). Based on recent experimental data, a number of clinical trials have been designed for the intravenous (IV) and/or intrathecal (ITH) administration of BMSCs in MS patients., Fingolimod is a S1P receptor modulator in MS clinical trials due to systemic anti-inflammatory properties, yet may impact cells within the CNS by crossing the blood-brain barrier., Their development in vitro and their use in vivo in animal models of degenerative neurological disease and recent first efforts in human clinical trials were the topics of a recent international meeting sponsored by the Multiple Sclerosis International Federation and the National Multiple Sclerosis Society on \"Stem Cells & MS: Prospects and Strategies\", Here we discuss key observations and questions emerging from clinical trials of hematopoietic stem cell transplantation for MS, Another possibility to achieve remyelination is the transplantation of myelinating cells into the central nervous system. Proof of principle and demonstration of the functionality were shown in numerous experiments, and a first clinical trial in patients with MS has started, This first trial will show if cell transplantation is a feasible concept in MS and whether the transplanted cells will survive and form new myelin.[SEP]Definitions: rheumatoid arthritis defined as following: A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated.. inflammation defined as following: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.. human defined as following: Members of the species Homo sapiens.. graft-versus-host disease defined as following: The clinical entity characterized by anorexia, diarrhea, loss of hair, leukopenia, thrombocytopenia, growth retardation, and eventual death brought about by the GRAFT VS HOST REACTION.. MSC defined as following: A naturally occurring organoselenium compound found in many plants, including garlic, onions, and broccoli, with potential antioxidant and chemopreventive activities. Se-Methyl-seleno-L-cysteine (MSC) is an amino acid analogue of cysteine in which a methylselenium moiety replaces the sulphur atom of cysteine. This agent acts as an antioxidant when incorporated into glutathione peroxidase and has been shown to exhibit potent chemopreventive activity in animal models.. multiple sclerosis defined as following: An autoimmune disorder mainly affecting young adults and characterized by destruction of myelin in the central nervous system. Pathologic findings include multiple sharply demarcated areas of demyelination throughout the white matter of the central nervous system. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia, and bladder dysfunction. The usual pattern is one of recurrent attacks followed by partial recovery (see MULTIPLE SCLEROSIS, RELAPSING-REMITTING), but acute fulminating and chronic progressive forms (see MULTIPLE SCLEROSIS, CHRONIC PROGRESSIVE) also occur. (Adams et al., Principles of Neurology, 6th ed, p903). Mesenchymal stem cells defined as following: An undifferentiated stromal cell with the ability to develop into the cells that form distinct mesenchymal tissues; such as bone, muscle, connective tissue, blood vessels, and lymphatic tissue.. Fingolimod defined as following: An orally available derivate of myriocin and sphingosine-1-phosphate receptor 1 (S1PR1, S1P1) modulator, with potential anti-inflammatory and immunomodulating activities. Upon oral administration, fingolimod, as a structural analogue of sphingosine, selectively targets and binds to S1PR1 on lymphocytes and causes transient receptor activation followed by S1PR1 internalization and degradation. This results in the sequestration of lymphocytes in lymph nodes. By preventing egress of lymphocytes. fingolimod reduces both the amount of circulating peripheral lymphocytes and the infiltration of lymphocytes into target tissues. This prevents a lymphocyte-mediated immune response and may reduce inflammation. S1PR1, a G-protein coupled receptor, plays a key role in lymphocyte migration from lymphoid tissues. Fingolimod also shifts macrophages to an anti-inflammatory M2 phenotype, and modulates their proliferation, morphology, and cytokine release via inhibition of the transient receptor potential cation channel, subfamily M, member 7 (TRPM7).. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. stroke defined as following: A group of pathological conditions characterized by sudden, non-convulsive loss of neurological function due to BRAIN ISCHEMIA or INTRACRANIAL HEMORRHAGES. Stroke is classified by the type of tissue NECROSIS, such as the anatomic location, vasculature involved, etiology, age of the affected individual, and hemorrhagic vs. non-hemorrhagic nature. (From Adams et al., Principles of Neurology, 6th ed, pp777-810). myelin defined as following: The lipid-rich sheath surrounding AXONS in both the CENTRAL NERVOUS SYSTEMS and PERIPHERAL NERVOUS SYSTEM. The myelin sheath is an electrical insulator and allows faster and more energetically efficient conduction of impulses. The sheath is formed by the cell membranes of glial cells (SCHWANN CELLS in the peripheral and OLIGODENDROGLIA in the central nervous system). Deterioration of the sheath in DEMYELINATING DISEASES is a serious clinical problem.. CNS defined as following: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges.. lupus defined as following: chronic form of cutaneous lupus erythematosus in which the skin lesions mimic those of the systemic form but in which systemic signs are rare; characterized by the presence of discoid skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy; lesions are surrounded by an elevated erythematous border; the condition typically involves the face and scalp, but widespread dissemination may occur.. cardiac diseases defined as following: Pathological conditions involving the HEART including its structural and functional abnormalities.. stem cells defined as following: Relatively undifferentiated cells that retain the ability to divide and proliferate throughout postnatal life to provide progenitor cells that can differentiate into specialized cells..", "label": "yes"} {"id": "converted_725", "sentence1": "Is acid alpha-glucosidase the enzyme that causes Pompe disease when mutant?", "sentence2": "Pompe disease is an autosomal recessive genetic disorder characterized by a deficiency of the enzyme responsible for degradation of lysosomal glycogen (acid α-glucosidase (GAA)), Pompe disease is a systemic metabolic disorder characterized by lack of acid-alpha glucosidase (GAA) resulting in ubiquitous lysosomal glycogen accumulation, Pompe disease is an autosomal recessive myopathic disorder caused by the deficiency of lysosomal acid α-glucosidase (GAA), Acid α-glucosidase deficiency, that is, Pompe disease, is a glycogenosis for which enzyme replacement therapy (ERT) is available, The analysis revealed that the amino acid substitutions causing a processing or transport defect responsible for Pompe disease were widely spread over all of the five domains comprising the acid alpha-glucosidase., Pompe disease is a lysosomal storage disease (LSD) caused by a deficiency in the lysosomal enzyme acid alpha-glucosidase., Glycogen storage disease type II (GSDII; Pompe disease or acid maltase deficiency) is an autosomal recessive disorder caused by lysosomal acid alpha-glucosidase (AalphaGlu) deficiency and manifests predominantly as skeletal muscle weakness., Structural study on a mutant acid alpha-glucosidase in silico combined with biochemical investigation is useful for understanding the molecular pathology of Pompe disease., The nature of mutant acid alpha-glucosidase (AAG) in muscle was studied in 6 patients with Pompe disease, consisting of 2 each of the infantile, childhood and adult types., Pompe disease (glycogen storage disease II) is caused by mutations in the acid alpha-glucosidase gene., Glycogen storage disease type II (Pompe disease) is inherited by autosomal recessive transmission and caused by a deficiency of acid alpha-glucosidase (GAA), resulting in impaired degradation and lysosomal accumulation of glycogen., Pompe disease is a lysosomal storage disorder (LSD) caused by mutations in the gene that encodes acid alpha-glucosidase (GAA)., Demonstration of acid alpha-glucosidase in different types of Pompe disease by use of an immunochemical method., Acid alpha-glucosidase (GAA) deficiency causes Pompe disease, a lethal lysosomal glycogen storage disease for which no effective treatment currently exists., Deficiency of acid alpha glucosidase (GAA) causes Pompe disease, which is usually fatal if onset occurs in infancy., Ambulatory electrocardiogram analysis in infants treated with recombinant human acid alpha-glucosidase enzyme replacement therapy for Pompe disease., Infantile Pompe disease is caused by deficiency of lysosomal acid alpha-glucosidase., Determination of acid alpha-glucosidase activity in blood spots as a diagnostic test for Pompe disease., The pharmacological chaperone AT2220 increases the specific activity and lysosomal delivery of mutant acid alpha-glucosidase, and promotes glycogen reduction in a transgenic mouse model of Pompe disease, Structural study on a mutant acid alpha-glucosidase in silico combined with biochemical investigation is useful for understanding the molecular pathology of Pompe disease, Glycogen stored in skeletal but not in cardiac muscle in acid alpha-glucosidase mutant (Pompe) mice is highly resistant to transgene-encoded human enzyme, Although many lysosomal disorders are corrected by a small amount of the missing enzyme, it has been generally accepted that 20-30% of normal acid alpha-glucosidase (GAA) activity, provided by gene or enzyme replacement therapy, would be required to reverse the myopathy and cardiomyopathy in Pompe disease, The nature of mutant acid alpha-glucosidase (AAG) in muscle was studied in 6 patients with Pompe disease, consisting of 2 each of the infantile, childhood and adult types, As in the severe human infantile disease (Pompe Syndrome), mice homozygous for disruption of the acid alpha-glucosidase gene (6(neo)/6(neo)) lack enzyme activity and begin to accumulate glycogen in cardiac and skeletal muscle lysosomes by 3 weeks of age, with a progressive increase thereafter, Glycogen-storage disease type II, Pompe disease, is caused by the deficiency of acid alpha-D-glucosidase in lysosome, Pompe disease (glycogen storage disease II) is caused by mutations in the acid alpha-glucosidase gene, Glycogen storage disease type II (Pompe disease) is inherited by autosomal recessive transmission and caused by a deficiency of acid alpha-glucosidase (GAA), resulting in impaired degradation and lysosomal accumulation of glycogen, Glycogen stored in skeletal but not in cardiac muscle in acid alpha-glucosidase mutant (Pompe) mice is highly resistant to transgene-encoded human enzyme., Structural modeling of mutant alpha-glucosidases resulting in a processing/transport defect in Pompe disease., Replacing acid alpha-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers., The pharmacological chaperone AT2220 increases the specific activity and lysosomal delivery of mutant acid alpha-glucosidase, and promotes glycogen reduction in a transgenic mouse model of Pompe disease., Pompe disease is an autosomal recessive muscle-wasting disorder caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase. , Structural study on a mutant acid alpha-glucosidase in silico combined with biochemical investigation is useful for understanding the molecular pathology of Pompe disease., We describe an improved method for detecting deficiency of the acid hydrolase, alpha-1,4-glucosidase in leukocytes, the enzyme defect in glycogen storage disease Type II (Pompe disease)., Acid alpha-glucosidase (GAA) deficiency causes Pompe disease,, Infantile Pompe disease is caused by deficiency of lysosomal acid alpha-glucosidase. Trials with recombinant human acid alpha-glucosidase enzyme replacement therapy (ERT) show a decrease in left ventricular mass and improved function., Pompe disease is an autosomal recessive muscle-wasting disorder caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase. Due to virtual absence of acid alpha-glucosidase, patients with classical infantile Pompe disease develop progressive cardiomyopathy, skeletal muscle weakness and respiratory insufficiency leading to death in early infancy., Pompe disease is caused by the congenital deficiency of the lysosomal enzyme acid alpha-glucosidase., The nature of mutant acid alpha-glucosidase (AAG) in muscle was studied in 6 patients with Pompe disease,, Pompe disease is a lysosomal storage disorder (LSD) caused by mutations in the gene that encodes acid alpha-glucosidase (GAA). Recently, small molecule pharmacological chaperones have been shown to increase protein stability and cellular levels for mutant lysosomal enzymes and have emerged as a new therapeutic strategy for the treatment of LSDs., Acid alpha-glucosidase (GAA) deficiency causes Pompe disease, a lethal lysosomal glycogen storage disease for which no effective treatment currently exists., Infantile Pompe disease is caused by deficiency of lysosomal acid alpha-glucosidase., Glycogen-storage disease type II, Pompe disease, is caused by the deficiency of acid alpha-D-glucosidase in lysosome., Structural modeling of mutant alpha-glucosidases resulting in a processing/transport defect in Pompe disease., Pompe disease is a lysosomal storage disorder (LSD) caused by mutations in the gene that encodes acid alpha-glucosidase (GAA)., Structural study on a mutant acid alpha-glucosidase in silico combined with biochemical investigation is useful for understanding the molecular pathology of Pompe disease., Ambulatory electrocardiogram analysis in infants treated with recombinant human acid alpha-glucosidase enzyme replacement therapy for Pompe disease., Mutations in alpha-glucosidase cause accumulation of glycogen in lysosomes, resulting in Pompe disease, a lysosomal storage disorder., Pompe disease is an autosomal recessive muscle-wasting disorder caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase., Infantile Pompe disease is a fatal genetic muscle disorder caused by a deficiency of acid alpha-glucosidase, a glycogen-degrading lysosomal enzyme.[SEP]Definitions: autosomal recessive disorder defined as following: An inherited disorder manifested only when two copies of a mutated gene are present.. alpha-glucosidase defined as following: Enzymes that catalyze the exohydrolysis of 1,4-alpha-glucosidic linkages with release of alpha-glucose. Deficiency of alpha-1,4-glucosidase may cause GLYCOGEN STORAGE DISEASE TYPE II.. LSD defined as following: Semisynthetic derivative of ergot (Claviceps purpurea). It has complex effects on serotonergic systems including antagonism at some peripheral serotonin receptors, both agonist and antagonist actions at central nervous system serotonin receptors, and possibly effects on serotonin turnover. It is a potent hallucinogen, but the mechanisms of that effect are not well understood.. glycogen defined as following: large branched polysaccharide consisting of glucose residues; the major carbohydrate reserve of animals, stored primarily in liver and muscle, synthesized and degraded for energy as demanded.. amino acid substitutions defined as following: The naturally occurring or experimentally induced replacement of one or more AMINO ACIDS in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish, enhance, or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties.. muscle defined as following: Contractile tissue that produces movement in animals.. alpha-1,4-glucosidase defined as following: An enzyme that catalyzes the hydrolysis of terminal 1,4-linked alpha-D-glucose residues successively from non-reducing ends of polysaccharide chains with the release of beta-glucose. It is also able to hydrolyze 1,6-alpha-glucosidic bonds when the next bond in sequence is 1,4.. glycogenosis defined as following: An autosomal recessive disease in which gene expression of glucose-6-phosphatase is absent, resulting in hypoglycemia due to lack of glucose production. Accumulation of glycogen in liver and kidney leads to organomegaly, particularly massive hepatomegaly. Increased concentrations of lactic acid and hyperlipidemia appear in the plasma. Clinical gout often appears in early childhood.. Mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. lysosome defined as following: A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes MEMBRANE FUSION. (From Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed).. ERT defined as following: The use of hormonal agents with estrogen-like activity in postmenopausal or other estrogen-deficient women to alleviate effects of hormone deficiency, such as vasomotor symptoms, DYSPAREUNIA, and progressive development of OSTEOPOROSIS. This may also include the use of progestational agents in combination therapy.. cardiomyopathy defined as following: A group of diseases in which the dominant feature is the involvement of the CARDIAC MUSCLE itself. Cardiomyopathies are classified according to their predominant pathophysiological features (DILATED CARDIOMYOPATHY; HYPERTROPHIC CARDIOMYOPATHY; RESTRICTIVE CARDIOMYOPATHY) or their etiological/pathological factors (CARDIOMYOPATHY, ALCOHOLIC; ENDOCARDIAL FIBROELASTOSIS).. Pompe disease defined as following: Glycogen storage disease due to acid maltase deficiency (AMD) is an autosomal recessive trait leading to metabolic myopathy that affects cardiac and respiratory muscles in addition to skeletal muscle and other tissues. AMD represents a wide spectrum of clinical presentations caused by an accumulation of glycogen in lysosomes.. mutant defined as following: An altered form of an individual, organism, population, or genetic character that differs from the corresponding wild type due to one or more alterations (mutations).. myopathy defined as following: Acquired, familial, and congenital disorders of SKELETAL MUSCLE and SMOOTH MUSCLE.. AAG defined as following: An antineoplastic antibiotic that is structurally similar to the benzoquinone ansamycin antibiotic geldanamycin. A geldanamycin analogue binds to HSP90, a chaperone protein that aids in the assembly, maturation, and folding of proteins. Subsequently, the function of HSP90 is inhibited, leading to the degradation and depletion of client proteins such as kinases and transcription factors involved with cell cycle regulation and signal transduction.. GAA defined as following: A Niger-Congo Kwa language spoken in the capital area of Ghana.. death defined as following: Irreversible cessation of all bodily functions, manifested by absence of spontaneous breathing and total loss of cardiovascular and cerebral functions.. respiratory insufficiency defined as following: Failure to adequately provide oxygen to cells of the body and to remove excess carbon dioxide from them. (Stedman, 25th ed). glycogen storage disease II defined as following: An autosomal recessive metabolic disorder due to deficient expression of amylo-1,6-glucosidase (one part of the glycogen debranching enzyme system). The clinical course of the disease is similar to that of glycogen storage disease type I, but milder. Massive hepatomegaly, which is present in young children, diminishes and occasionally disappears with age. Levels of glycogen with short outer branches are elevated in muscle, liver, and erythrocytes. Six subgroups have been identified, with subgroups Type IIIa and Type IIIb being the most prevalent.. gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. human defined as following: Members of the species Homo sapiens..", "label": "yes"} {"id": "converted_1055", "sentence1": "Does splicing occur co-transcriptionally?", "sentence2": "Researchers working in multiple model organisms - notably yeast, insects and mammalian cells - have shown that pre-mRNA can be spliced during the process of transcription (i.e. co-transcriptionally), as well as after transcription termination (i.e. post-transcriptionally), The consensus view, based on four organisms, is that the majority of splicing events take place co-transcriptionally in most cells and tissues., Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional, We show that in the human genome, splicing occurs predominantly during transcription., Consistent with co-transcriptional spliceosome assembly and splicing, we have found significant enrichment of spliceosomal snRNAs in chromatin-associated RNA compared with other cellular RNA fractions and other nonspliceosomal snRNAs. , The majority of introns in higher eukaryotes are excised prior to transcript release in a manner that is dependent on transcription through pol II, s a result of co-transcriptional splicing, variations in pol II elongation influence alternative splicing patterns, wherein a slower elongation rate is associated with increased inclusion of alternative exons within mature mRNA. , We show that the pattern of intronic sequence read coverage is explained by nascent transcription in combination with co-transcriptional splicing, Modelling reveals co-transcriptional splicing to be the most probable and most efficient splicing pathway for the reporter transcripts, due in part to a positive feedback mechanism for co-transcriptional second step splicing, RNA processing events that take place on the transcribed pre-mRNA include capping, splicing, editing, 3' processing, and polyadenylation. Most of these processes occur co-transcriptionally while the RNA polymerase II (Pol II) enzyme is engaged in transcriptional elongation, Abundant evidence indicates that splicing to excise introns occurs co-transcriptionally, prior to release of the nascent transcript from RNAP II, Together, our work establishes a system for co-transcriptional splicing in vitro, in which the spliceosome containing the 5' and 3' exons are tethered to RNAP II for splicing., Co-transcriptional splicing of constitutive and alternative exons, Current evidence supports co-transcriptional spliceosomal assembly, but there is little quantitative information on how much splicing is completed during RNA synthesis, Thus, we demonstrate that the decision to include or skip an alternative exon is made during transcription and not post-transcriptionally, Here, we demonstrated that the co-transcriptional splicing of the intron in vitro was blocked by antisense oligonucleotides (AONs) targeting the P3-P7 core of the intron, RNA editing and alternative splicing: the importance of co-transcriptional coordination, Co-transcriptional splicing of pre-messenger RNAs: considerations for the mechanism of alternative splicing, The realization that splicing occurs co-transcriptionally requires two important considerations[SEP]Definitions: pre-mRNA defined as following: A primary RNA transcript synthesized from a DNA template in eukaryotic nuclei which is post-transcriptionally modified and spliced to produce a mature mRNA.. RNA polymerase II defined as following: A DNA-dependent RNA polymerase present in bacterial, plant, and animal cells. It functions in the nucleoplasmic structure and transcribes DNA into RNA. It has different requirements for cations and salt than RNA polymerase I and is strongly inhibited by alpha-amanitin. EC 2.7.7.6.. yeast defined as following: A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as \"baker's\" or \"brewer's\" yeast. The dried form is used as a dietary supplement.. tissues defined as following: Collections of differentiated CELLS, such as EPITHELIUM; CONNECTIVE TISSUE; MUSCLES; and NERVE TISSUE. Tissues are cooperatively arranged to form organs with specialized functions such as RESPIRATION; DIGESTION; REPRODUCTION; MOVEMENT; and others.. eukaryotes defined as following: Organism or cells with a nucleus separated from the cytoplasm by a two membrance nuclear envelope and compartmentalization of function into distinct cytoplasmic organelles.. introns defined as following: Sequences of DNA in the genes that are located between the EXONS. They are transcribed along with the exons but are removed from the primary gene transcript by RNA SPLICING to leave mature RNA. Some introns code for separate genes.. antisense oligonucleotides defined as following: Short fragments of DNA or RNA that are used to alter the function of target RNAs or DNAs to which they hybridize.. RNA editing defined as following: A process that changes the nucleotide sequence of mRNA from that of the DNA template encoding it. Some major classes of RNA editing are as follows: 1, the conversion of cytosine to uracil in mRNA; 2, the addition of variable number of guanines at pre-determined sites; and 3, the addition and deletion of uracils, templated by guide-RNAs (RNA, GUIDE, KINETOPLASTIDA).. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. mRNA defined as following: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.. exons defined as following: The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA.. organisms defined as following: A living entity.. transcript defined as following: The initial RNA molecule produced by transcription..", "label": "yes"} {"id": "converted_3007", "sentence1": "Can mitochondria be inherited by both parents in humans?", "sentence2": "Biparental Inheritance of Mitochondrial DNA in Humans., Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. [SEP]Definitions: mitochondria defined as following: Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed). mtDNA defined as following: Double-stranded DNA of MITOCHONDRIA. In eukaryotes, the mitochondrial GENOME is circular and codes for ribosomal RNAs, transfer RNAs, and about 10 proteins.. heteroplasmy defined as following: The occurrence of more than one organellar GENOME in the organelle population of a cell, tissue, or individual organism. It is due to the accumulation of different mutations that occur within the population of individual organelles of a cell.. Humans defined as following: Members of the species Homo sapiens.. humans defined as following: Members of the species Homo sapiens..", "label": "yes"} {"id": "converted_3962", "sentence1": "Is MIS-C or Multisystem Inflammatory syndrome in children a complication of Covid-19?", "sentence2": "Much remains unknown about the risk factors, pathogenesis, prognosis, and specific therapy for this emerging manifestation of COVID-19 known as Multisystem Inflammatory Syndrome in Children (MIS-C)., Multisystem Inflammatory Syndrome in Children During the Coronavirus 2019 Pandemic: A Case Series, COVID-19 and Multisystem Inflammatory Syndrome in Latin American Children, This study aims to assess COVID-19 and Multisystem Inflammatory Syndrome (MIS-C) in Latin American children,, A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation., We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage., OBJECTIVE: Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease (COVID-19) is a rare and challenging diagnosis requiring early treatment., This syndrome is now known as either \"Pediatric Inflammatory Multisystem Syndrome temporally related with COVID-19\" (PIMS-TS) (1), or Multisystem Inflammatory Syndrome in Children (MIS-C) (2) and is currently considered a rare post-COVID-19 complication which, in a minority of cases, can lead to death., Multisystem Inflammatory Syndrome in Children (MIS-C) associated with Coronavirus Disease 2019 (COVID-19) is a newly recognized condition in which children with recent SARS-CoV-2 infection present with a constellation of symptoms including hypotension, multiorgan involvement, and elevated inflammatory markers. Thes, Background: Kawasaki-like syndrome occurring in children during the COVID-19 pandemic has been labelled multisystem inflammatory syndrome in children (MIS-C) by the CDC and paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS) by , em inflammatory syndrome in children (MIS-C), a possible complication of COVID-19, has been described as a hyperinflammatory condition with multiorgan involvement similar to that in Kawasaki disease or toxic shock syndrome in children with evidence of SARS-CoV-2 infection. This revie, BACKGROUND: A small subset of pediatric patients develop a rare syndrome associated with Coronavirus Disease 2019 (COVID-19) infection called multisystem inflammatory syndrome in childr, adults. However, the newly described multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) has been associated with cardiac complicat, BACKGROUND: Multisystem inflammatory syndrome temporally associated with COVID-19 (MIS-C) has been described as a novel and often severe presentation of SARS-CoV-2 infection i, OBJECTIVE: Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease (COVID-19) is a rare and challenging diagnosis requiring early tr, Background: Multisystem inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory multisystem syndrome, is a new dangerous childhood disease that is temporally associated with coronavirus disease 2019 (, Recent COVID-19 publications describe a variety of clinical presentations including an asymptomatic state, pneumonia, a hemophagocytic lymphohistiocytosis like syndrome, Multisystem Inflammatory Syndrome in Children (MIS-C) but, also called Pediatric Inflammatory Multisystem Syndrome-Toxic Shock (PIMS-TS), Kawasaki Disease, and myocarditis., We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission., Multisystem inflammatory syndrome in children (MIS-C), a possible complication of COVID-19, has been described as a hyperinflammatory condition with multiorgan involvement similar to that in Kawasaki disease or toxic shock syndrome in children with evidence of SARS-CoV-2 infection., It includes a discussion of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, as well as other aspects of the COVID-19 pandemic that are affecting children and families, such as poisonings, childhood immunizations, mental health, nonaccidental trauma, and neglect., Importance: To date, no study has characterized the mucocutaneous features seen in hospitalized children with multisystem inflammatory syndrome in children (MIS-C) or the temporal association of these findings with the onset of systemic symptoms.Objective: To describe the mucocutaneous findings seen in children with MIS-C during the height of the coronavirus disease 2019 (COVID-19) pandemic in New York City in 2020.Design, Setting, and Participants: A retrospective case series was conducted of 35 children admitted to 2 hospitals in New York City between April 1 and July 14, 2020, who met Centers for Disease Control and Prevention and/or epidemiologic criteria for MIS-C.Main Outcomes and Measures: Laboratory and clinical characteristics, with emphasis on mucocutaneous findings, of children who met criteria for MIS-C., This condition, since defined as the multisystem inflammatory syndrome in children (MIS-C), is assumed to be a delayed immune response to coronavirus disease 2019 (COVID-19), and there are frequently cardiac manifestations of ventricular dysfunction and/or coronary artery dilation.Methods: We surveyed the inpatient MIS-C management approaches of the members of the International Kawasaki Disease Registry across 38 institutions and 11 countries.Results: Among the respondents, 56% reported using immunomodulatory treatment for all MIS-C patients, regardless of presentation., DESIGN: Children ages 0-22 years with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presenting to urgent care clinics or being hospitalized for confirmed/suspected SARS-CoV-2 infection or multisystem inflammatory syndrome in children (MIS-C) at Massachusetts General Hospital were offered enrollment in the Massachusetts General Hospital Pediatric COVID-19 Biorepository., We recently discovered a superantigen-like motif, similar to Staphylococcal enterotoxin B (SEB), near the S1/S2 cleavage site of SARS-CoV-2 Spike protein, which might explain the multisystem-inflammatory syndrome (MIS-C) observed in children and cytokine storm in severe COVID-19 patients., METHODS: An extensive search strategy was conducted by combining the terms multisystem inflammatory syndrome in children and coronavirus infection or using the term multisystem inflammatory syndrome in children in bibliographic electronic databases (PubMed, EMBASE, and CINAHL) and in preprint servers (BioRxiv.org and MedRxiv.org) following the Preferred Reporting Items for Systematic Reviews and Metaanalyses guidelines to retrieve all articles published from January 1, 2020, to July 31, 2020., Here, we show that pediatric patients with multisystem inflammatory syndrome in children (MIS-C) possess higher SARS-CoV-2 spike IgG titers compared to those with severe coronavirus disease 2019 (COVID-19), likely reflecting a longer time since onset of infection in MIS-C patients., Here, we show that pediatric patients with multisystem inflammatory syndrome in children (MIS-C) possess higher SARS-CoV-2 spike IgG titers compared to those with severe coronavirus disease 2019 (COVID-19), likely reflecting a longer time since onset of infection in MIS-C patients., Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV2 infection in otherwise healthy children., Data on multisystem inflammatory syndrome in children (MIS-C) related to coronavirus disease-19 (COVID-19) is increasing in the current COVID-19 pandemic., Introduction Multisystem inflammatory syndrome in children (MIS-C) is a unique clinical complication of SARS-CoV-2 infection observed in pediatric patients., New onset diabetes with diabetic ketoacidosis in a child with multisystem inflammatory syndrome due to COVID-19., Case presentation An eight-year-old female presented with hyperglycemia, ketosis and metabolic acidosis consistent with diabetic ketoacidosis (DKA) in the setting of fever, rash, respiratory distress, hemodynamic instability, reduced systolic function with dilation of the left anterior descending artery, and positive SARS-CoV-2 antibodies suggestive of MIS-C., However, the newly described multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) has been associated with cardiac complications.M, Toxic shock-like syndrome and COVID-19: Multisystem inflammatory syndrome in children (MIS-C)., Many of these cases feature a toxic shock-like syndrome or Kawasaki-like syndrome in the setting of SARS-CoV-2 positive diagnostic testing and the CDC has termed this presentation Multisystem Inflammatory Syndrome (MIS-C)., We describe a case of MIS-C in a child who presented to our Emergency Department (ED) twice and on the second visit was found to have signs of distributive shock, multi-organ injury and systemic inflammation associated with COVID-19., PURPOSE OF REVIEW: Here we summarize current knowledge about multisystem inflammatory syndrome in children (MIS-C), a presumed postinfectious inflammatory condition that has emerged as an important COVID-19-associated complication, to help clinicians identify and manage cases.RECENT FINDINGS: Clinical presentation of MIS-C is do, MIS-C is a rare yet severe and highly critical complication of COVID-19 infection in pediatrics, leading to serious and life-threatening illnesses., BACKGROUND: A multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C) has recently been described.OBJECTIVE: To evaluate imaging findings of MIS-C associated with COVID-19.SUBJECTS AND METHODS: Imaging studies and medical records of sixteen patients (0-20 years) admit, BACKGROUND: Recently, cases of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 have been reporte, Recent reports have described a secondary Multisystem Inflammatory Syndrome in Children (MIS-C) after a prior COVID-19 infection that often has features of Kawasaki disease (KD)., discharged home (length of hospital stay 3-20 days). There were no mortalities.CONCLUSION: MIS-C associated with COVID-19 is characterized predominantly by cardiovascular abnormalities, though also solid visceral organ, gallbladder, and bowel abnormalities as well as ascites, reflecting a multisystemic inflammatory process.CLINICAL IMPACT: The constellation of imaging findings in the setting of COVID-19 may alert pediatr, Multisystem Inflammatory Syndrome in Children Temporally Related to COVID-19: A Case Report From Saudi Arabia., BACKGROUND: Multisystem inflammatory syndrome temporally associated with COVID-19 (MIS-C) has been described as a novel and often severe presentation of SARS-CoV-2 infection , ric patients. An association between COVID-19 and a Kawasaki-like inflammatory syndrome has recently presented in pediatric patients.CASE REPORT: We report a unique case of multisystem inflammatory syndrome in children presenting with characteristic findings in a child who later developed cardiogenic shock requiring venoarterial extracorporeal membrane oxygenation.CONCLUSION: Recognition of these early signs and symptoms facilitates screening and risk stratification of pediatric COVID-19 cas, Severe cardiac dysfunction in a patient with multisystem inflammatory syndrome in children associated with COVID-19: Retrospective diagnosis of a puzzling presentation. A case report.[SEP]Definitions: T cell subsets defined as following: A classification of T-lymphocytes, especially into helper/inducer, suppressor/effector, and cytotoxic subsets, based on structurally or functionally different populations of cells.. SEB defined as following: A bacterial enterotoxin with potential immunostimulatory activity. Staphylococcal enterotoxin B (SEB), a gram positive superantigen produced by Staphylococcus aureus, is a potent stimulator of T-cell activation. SEB binds directly to class II major histocompatibility complex (MHC) molecules and the V beta region of the T-cell receptor (TCR), leading to an amplified T-cell response. In response to SEB, both CD4+ and CD8+ cells proliferate, secrete cytokines and demonstrate enhanced cytotoxic activity against a broad range of antigens. Co-administration of SEB with interleukin-2 (IL-2) by direct injection into tumor cells, may induce clonal T-cell expansion and potentiate apoptosis of tumor cells, resulting in decreased tumor growth.. DKA defined as following: A life-threatening complication of diabetes mellitus, primarily of TYPE 1 DIABETES MELLITUS with severe INSULIN deficiency and extreme HYPERGLYCEMIA. It is characterized by KETOSIS; DEHYDRATION; and depressed consciousness leading to COMA.. cytokine defined as following: Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner.. inflammation defined as following: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.. pneumonia defined as following: Infection of the lung often accompanied by inflammation.. ketosis defined as following: A condition characterized by an abnormally elevated concentration of KETONE BODIES in the blood (acetonemia) or urine (acetonuria). It is a sign of DIABETES COMPLICATION, starvation, alcoholism or a mitochondrial metabolic disturbance (e.g., MAPLE SYRUP URINE DISEASE).. coronavirus defined as following: Virus diseases caused by the CORONAVIRUS genus. Some specifics include transmissible enteritis of turkeys (ENTERITIS, TRANSMISSIBLE, OF TURKEYS); FELINE INFECTIOUS PERITONITIS; and transmissible gastroenteritis of swine (GASTROENTERITIS, TRANSMISSIBLE, OF SWINE).. autoantibodies defined as following: Antibodies that react with self-antigens (AUTOANTIGENS) of the organism that produced them.. rash defined as following: Diseases in which skin eruptions or rashes are a prominent manifestation. Classically, six such diseases were described with similar rashes; they were numbered in the order in which they were reported. Only the fourth (Duke's disease), fifth (ERYTHEMA INFECTIOSUM), and sixth (EXANTHEMA SUBITUM) numeric designations survive as occasional synonyms in current terminology.. poisonings defined as following: A condition or physical state produced by the ingestion, injection, inhalation of or exposure to a deleterious agent.. cardiogenic shock defined as following: Shock resulting from diminution of cardiac output in heart disease.. SARS-CoV-2 infection defined as following: A viral disorder generally characterized by high FEVER; COUGH; DYSPNEA; CHILLS; PERSISTENT TREMOR; MUSCLE PAIN; HEADACHE; SORE THROAT; a new loss of taste and/or smell (see AGEUSIA and ANOSMIA) and other symptoms of a VIRAL PNEUMONIA. In severe cases, a myriad of coagulopathy associated symptoms often correlating with COVID-19 severity is seen (e.g., BLOOD COAGULATION; THROMBOSIS; ACUTE RESPIRATORY DISTRESS SYNDROME; SEIZURES; HEART ATTACK; STROKE; multiple CEREBRAL INFARCTIONS; KIDNEY FAILURE; catastrophic ANTIPHOSPHOLIPID ANTIBODY SYNDROME and/or DISSEMINATED INTRAVASCULAR COAGULATION). In younger patients, rare inflammatory syndromes are sometimes associated with COVID-19 (e.g., atypical KAWASAKI SYNDROME; TOXIC SHOCK SYNDROME; pediatric multisystem inflammatory disease; and CYTOKINE STORM SYNDROME). A coronavirus, SARS-CoV-2, in the genus BETACORONAVIRUS is the causative agent.. cardiovascular abnormalities defined as following: Congenital, inherited, or acquired anomalies of the CARDIOVASCULAR SYSTEM, including the HEART and BLOOD VESSELS.. death defined as following: Irreversible cessation of all bodily functions, manifested by absence of spontaneous breathing and total loss of cardiovascular and cerebral functions.. hypotension defined as following: Abnormally low BLOOD PRESSURE that can result in inadequate blood flow to the brain and other vital organs. Common symptom is DIZZINESS but greater negative impacts on the body occur when there is prolonged depravation of oxygen and nutrients.. ascites defined as following: Accumulation or retention of free fluid within the peritoneal cavity.. toxic shock syndrome defined as following: Staphylococcal toxic shock syndrome (staphylococcal TSS) is an acute disease mediated by the production of superantigenic toxins, characterized by high fever, skin rash followed by skin peeling, hypotension, vomiting, diarrhea and potentially leading to multisystem organ failure and caused by a <i>Staphylococcus aureus</i> bacterial infection.. infection defined as following: An illness caused by an infectious agent or its toxins that occurs through the direct or indirect transmission of the infectious agent or its products from an infected individual or via an animal, vector or the inanimate environment to a susceptible animal or human host.. respiratory distress defined as following: A pathological increase in the effort and frequency of breathing movements.. ventricular dysfunction defined as following: A condition in which HEART VENTRICLES exhibit impaired function.. toxic defined as following: The finding of bodily harm due to the poisonous effects of something.. myocarditis defined as following: Inflammatory processes of the muscular walls of the heart (MYOCARDIUM) which result in injury to the cardiac muscle cells (MYOCYTES, CARDIAC). Manifestations range from subclinical to sudden death (DEATH, SUDDEN). Myocarditis in association with cardiac dysfunction is classified as inflammatory CARDIOMYOPATHY usually caused by INFECTION, autoimmune diseases, or responses to toxic substances. Myocarditis is also a common cause of DILATED CARDIOMYOPATHY and other cardiomyopathies..", "label": "yes"} {"id": "converted_3256", "sentence1": "Is ACE2 expressed on cell surfaces?", "sentence2": " Recent studies reported that shedding of the enzymatically active ectodomain of ACE2 from the cell surface, ACE2 is a type 1 integral membrane protein and contains a catalytically active ectodomain that can be shed from the cell surface into the extracellular space,[SEP]Definitions: cell surface defined as following: The external part of the cell wall and/or plasma membrane. [GOC:jl, GOC:mtg_sensu, GOC:sm]. ACE2 defined as following: Angiotensin-converting enzyme 2 (805 aa, ~92 kDa) is encoded by the human ACE2 gene. This protein plays a role in both vasodilation and protein cleavage.. extracellular space defined as following: Interstitial space between cells, occupied by INTERSTITIAL FLUID as well as amorphous and fibrous substances. For organisms with a CELL WALL, the extracellular space includes everything outside of the CELL MEMBRANE including the PERIPLASM and the cell wall..", "label": "yes"} {"id": "converted_895", "sentence1": "Does the histidine-rich Ca-binding protein (HRC) interact with triadin?", "sentence2": "The HRC effects on RyR may be regulated by the Ca(2+)-sensitivity of its interaction with triadin., In rabbit skeletal and cardiac muscles, HRC binds to sarcoplasmic reticulum (SR) membranes via triadin, a junctional SR protein. , HRC may play a key role in the regulation of SR Ca cycling through its direct interactions with SERCA2 and triadin, mediating a fine cross talk between SR Ca uptake and release in the heart., Histidine-rich calcium binding protein (HRC) is located in the lumen of sarcoplasmic reticulum (SR) that binds to both triadin (TRN) and SERCA affecting Ca(2+) cycling in the SR., HRC is a SR luminal Ca(2+) binding protein known to associate with both triadin and the sarcoplasmic reticulum Ca(2+)-ATPase, and may thus mediate the crosstalk between SR Ca(2+) uptake and release., The histidine-rich Ca(2+) binding protein (HRC) is a high capacity Ca(2+) binding protein in the sarcoplasmic reticulum (SR). Because HRC appears to interact directly with triadin, HRC may play a role in the regulation of Ca(2+) release during excitation-contraction coupling., In the present study, we have performed co-immunoprecipitation experiments and show that HRC binds directly to triadin, which is an integral membrane protein of the sarcoplasmic reticulum., A direct binding of HRC (histidine-rich Ca(2+)-binding protein) to triadin, the main transmembrane protein of the junctional sarcoplasmic reticulum (SR) of skeletal muscle, seems well supported., The present study documents the binding interaction of skeletal muscle sarcoplasmic reticulum (SR) transmembrane protein triadin with peripheral histidine-rich, Ca(2+)-binding protein (HCP)., In addition, the intra-luminal histidine-rich calcium binding protein (HRC) has been shown to interact with both SERCA2a and triadin., Notably, there is physical and direct interaction between these protein players, mediating a fine-cross talk between SR Ca-uptake, storage and release., The histidine-rich calcium-binding protein (HRCBP) is expressed in the junctional SR, the site of calcium release from the SR. HRCBP is expressed exclusively in muscle tissues and binds calcium with low affinity and high capacity. In addition, HRCBP interacts with triadin, a protein associated with the ryanodine receptor and thought to be involved in calcium release. Its calcium binding properties, localization to the SR, and interaction with triadin suggest that HRCBP is involved in calcium handling by the SR., Using a fusion protein binding assay, we further identified the histidine-rich acidic repeats of HRC as responsible for the binding of HRC to triadin. , The HRC binding domain of triadin was also localized by fusion protein binding assay to the lumenal region containing the KEKE motif that was previously shown to be involved in the binding of triadin to calsequestrin. Notably, the interaction of HRC and triadin is Ca(2+)-sensitive. Our data suggest that HRC may play a role in the regulation of Ca(2+) release from the sarcoplasmic reticulum by interaction with triadin., Further support for colocalization of HRC with triadin cytoplasmic domain is provided here by experiments of mild tryptic digestion of tightly sealed TC vesicles., We demonstrate that HRC can be isolated as a complex with triadin, following equilibrium sucrose-density centrifugation in the presence of mM Ca(2+)., Here, we characterized the COOH-terminal portion of rabbit HRC, expressed and purified as a fusion protein (HRC(569-852)), with respect to Ca(2+)-binding properties, and to the interaction with triadin on blots, as a function of the concentration of Ca(2+)., Our results identify the polyglutamic stretch near the COOH terminus, as the Ca(2+)-binding site responsible, both for the acceleration in mobility of HRC on SDS-PAGE in the presence of millimolar concentrations of Ca(2+), and for the enhancement by high Ca(2+) of the interaction between HRC and triadin cytoplasmic segment., In addition to providing further evidence that HCP coenriches with RyR1, FKBP-12, triadin and calsequestrin (CS) in sucrose-density-purified TC vesicles, using specific polyclonal antibody, we show it to be expressed as a single protein species, both in fast-twitch and slow-twitch fibers, and to identically localize to the I-band., Colocalization of HCP and triadin at junctional triads is supported by the overlapping staining pattern using monoclonal antibodies to triadin. We show a specific binding interaction between digoxigenin-HCP and triadin, using ligand blot techniques., Suggesting that triadin dually interacts with HCP and with CS, at distinct sites, we have found that triadin-CS interaction in overlays does not require the presence of Ca2+., These differential effects form the basis for the hypothesis that HCP anchors to the junctional membrane domain of the SR, through binding to triadin short cytoplasmic domain at the NH2 terminus., Although the function of this interaction, as such, is not well understood, it seems of potential biological interest within the more general context of the structural-functional role of triadin at the triadic junction in skeletal muscle., BACKGROUND: Histidine-rich calcium binding protein (HRC) is located in the lumen of sarcoplasmic reticulum (SR) that binds to both triadin (TRN) and SERCA affecting Ca(2+) cycling in the SR. Chronic overexpression of HRC that may disrupt intracellular Ca(2+) homeostasis is implicated in pathogenesis of cardiac hypertrophy., Interaction of HRC (histidine-rich Ca(2+)-binding protein) and triadin in the lumen of sarcoplasmic reticulum., The histidine-rich Ca-binding protein (HRC) is an SR component that binds to triadin and may affect Ca release through the ryanodine receptor., The histidine-rich Ca-binding protein (HRC) is an SR component that binds to triadin and may affect Ca release through the ryanodine receptor, Because HRC appears to interact directly with triadin, HRC may play a role in the regulation of Ca(2+) release during excitation-contraction coupling, A direct binding of HRC (histidine-rich Ca(2+)-binding protein) to triadin, the main transmembrane protein of the junctional sarcoplasmic reticulum (SR) of skeletal muscle, seems well supported, The histidine-rich Ca-binding protein (HRC) is an SR component that binds to triadin and may affect Ca release through the ryanodine receptor[SEP]Definitions: calcium defined as following: A dietary supplement containing the mineral calcium.. RyR defined as following: A voltage-gated calcium-release channel complex of the sarcoplasmic or endoplasmic reticulum. It plays an important role in the excitation-contraction (E-C) coupling of muscle cells. RyR comprises a family of ryanodine receptors, widely expressed throughout the animal kingdom. [GOC:ame, PMID:22822064]. cytoplasmic domain defined as following: The part of a transmembrane protein which projects into the cytoplasm.. SR defined as following: Human SNCG wild-type allele is located within10q23.2-q23.3 and is approximately 13 kb in length. This allele, which encodes gamma-synuclein protein, plays a role in the modulation of axonal architecture and neurofilament integrity. This gene is highly expessed in advanced breast carcinomas, suggesting a correlation between SNCG overexpression and breast tumor development.. intracellular defined as following: The organized colloidal complex of organic and inorganic substances (as proteins and water) that constitutes the living nucleus, cytoplasm, plastids, and mitochondria of the cell. It is composed mainly of nucleic acids, proteins, lipids, carbohydrates, and inorganic salts.. FKBP-12 defined as following: A 12-KDa tacrolimus binding protein that is found associated with and may modulate the function of calcium release channels. It is a peptidyl-prolyl cis/trans isomerase which is inhibited by both tacrolimus (commonly called FK506) and SIROLIMUS.. transmembrane protein defined as following: A protein that is an integral membrane protein with a transmembrane region.. lumen defined as following: A SI derived unit of luminous flux. It is the amount of light that falls on a unit area at unit distance from a source of one candela.. sarcoplasmic reticulum defined as following: A network of tubules and sacs in the cytoplasm of SKELETAL MUSCLE FIBERS that assist with muscle contraction and relaxation by releasing and storing calcium ions.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. monoclonal antibodies defined as following: Antibodies produced by a single clone of cells.. fusion protein defined as following: Tumor suppressor candidate 2 (110 aa, ~12 kDa) is encoded by the human TUSC2 gene. This protein is involved in cell cycle regulation and tumor suppression.. muscle tissues defined as following: Contractile tissue that produces movement in animals.. sarcoplasmic reticulum Ca(2+)-ATPase defined as following: Calcium-transporting ATPases that catalyze the active transport of CALCIUM into the SARCOPLASMIC RETICULUM vesicles from the CYTOPLASM. They are primarily found in MUSCLE CELLS and play a role in the relaxation of MUSCLES.. cardiac hypertrophy defined as following: Enlargement of the HEART due to chamber HYPERTROPHY, an increase in wall thickness without an increase in the number of cells (MYOCYTES, CARDIAC). It is the result of increase in myocyte size, mitochondrial and myofibrillar mass, as well as changes in extracellular matrix.. cardiac muscles defined as following: The muscle tissue of the HEART. It is composed of striated, involuntary muscle cells (MYOCYTES, CARDIAC) connected to form the contractile pump to generate blood flow.. integral membrane protein defined as following: The component of the endoplasmic reticulum membrane consisting of the gene products and protein complexes having at least some part of their peptide sequence embedded in the hydrophobic region of the membrane. [GOC:dos, GOC:mah]. ryanodine receptor defined as following: A tetrameric calcium release channel in the SARCOPLASMIC RETICULUM membrane of SMOOTH MUSCLE CELLS, acting oppositely to SARCOPLASMIC RETICULUM CALCIUM-TRANSPORTING ATPASES. It is important in skeletal and cardiac excitation-contraction coupling and studied by using RYANODINE. Abnormalities are implicated in CARDIAC ARRHYTHMIAS and MUSCULAR DISEASES..", "label": "yes"} {"id": "converted_3900", "sentence1": "Are Toll-like receptors (TLRs) induced by microbes?", "sentence2": "The C-type lectin receptor CLEC4E and Toll-like receptor TLR4 expressed by host cells are among the first line of defense in encountering pathogens., Gram-negative bacteria and endogenous molecules coordinate to trigger inflammatory cascades via Toll-like receptor 4 to induce excessive expression of cytokines such as tumor necrosis factor-α and to activate NLRP3 inflammasome, a multiprotein complex that processes pro-interleukin-1β into its mature form. , During viral infection, viral nucleic acids are detected by virus sensor proteins including toll-like receptor 3 or retinoic acid-inducible gene I-like receptors (RLRs) in mammalian cells. , Toll-like receptor 9 (TLR9) activation is attributed to delivery of bacterial DNA, We determine that HBCs have the capacity to play a defensive role, where they are responsive to Toll-like receptor stimulation and are microbicidal.[SEP]Definitions: Toll-like receptor defined as following: Toll-like receptor 2 (784 aa, ~90 kDa) is encoded by the human TLR2 gene. This protein is involved in signal transduction that modulates innate immunity.. Toll-like receptor 9 defined as following: Toll-like receptor 9 (1032 aa, ~116 kDa) is encoded by the human TLR9 gene. This protein plays a role in the mediation of inflammatory signaling.. TLR4 defined as following: Human TLR4 wild-type allele is located within 9q32-q33 and is approximately 11 kb in length. This allele, which encodes toll-like receptor 4 protein, is involved in pathogen recognition, signal transduction and innate immunity. Mutations in the gene are associated with differences in LPS responsiveness.. molecules defined as following: An aggregate of two or more atoms in a defined arrangement held together by chemical bonds.. Toll-like receptor 4 defined as following: A pattern recognition receptor that interacts with LYMPHOCYTE ANTIGEN 96 and LIPOPOLYSACCHARIDES. It mediates cellular responses to GRAM-NEGATIVE BACTERIA.. TLR9 defined as following: This gene plays a role in innate immunity.. toll-like receptor 3 defined as following: A pattern recognition receptor that binds DOUBLE-STRANDED RNA. It mediates cellular responses to certain viral pathogens.. bacterial DNA defined as following: Deoxyribonucleic acid that makes up the genetic material of bacteria.. viral infection defined as following: A general term for diseases caused by viruses.. Toll-like receptors defined as following: A family of pattern recognition receptors characterized by an extracellular leucine-rich domain and a cytoplasmic domain that share homology with the INTERLEUKIN 1 RECEPTOR and the DROSOPHILA toll protein. Following pathogen recognition, toll-like receptors recruit and activate a variety of SIGNAL TRANSDUCING ADAPTOR PROTEINS..", "label": "yes"} {"id": "converted_1223", "sentence1": "Is there any association of the chromosomal region harboring the gene ITIH3 with schizophrenia?", "sentence2": "The most widely shared subset of genes-common to five of six disorders-included ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. , Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC., After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support., In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9))., Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. , A recent genome-wide analysis indicated that a polymorphism (rs2535629) of ITIH3 showed the strongest association signal with susceptibility to psychiatric disorders in Caucasian populations., We detected a novel association between suicide attempt and the ITIH3/4-region in a combined group of patients with BD, SCZ and related psychosis spectrum disorders. , These include variations in chromosomal structure at 16p11.2, rare de novo point mutations at the gene SCN2A, and common single nucleotide polymorphisms (SNPs) mapping near loci encoding the genes ITIH3, AS3MT, CACNA1C and CACNB2. These selected examples point to the challenges to current diagnostic approaches. , STAB1 is located in close proximity to PBMR1 and the NEK4-ITIH1-ITIH3-ITIH4 region, which are the top findings from GWAS meta-analyses of mood disorder, and a combined BD and schizophrenia data set., Our findings suggest that rs2535629 influences the susceptibility to psychiatric disorders by affecting the expression level of GLT8D1.[SEP]Definitions: chromosomal structure defined as following: Structures which are contained in or part of CHROMOSOMES.. gene SCN2A defined as following: This gene is involved in neuronal excitation.. STAB1 defined as following: Stabilin-1 (2570 aa, ~275 kDa) is encoded by the human STAB1 gene. This protein is involved in signal transduction mediated by acetylated low density lipoprotein binding.. NT5C2 defined as following: This gene plays a role in purine metabolism.. CSMD1 defined as following: CUB and sushi domain-containing protein 1 (3565 aa, ~389 kDa) is encoded by the human CSMD1 gene. This protein may play a role in the activation of complement.. mood disorder defined as following: Those disorders that have a disturbance in mood as their predominant feature.. TCF4 defined as following: Transcription factor 7-like 2 (619 aa, ~68 kDa) is encoded by the human TCF7L2 gene. This protein is involved in the positive regulation of transcription, cell cycle arrest, apoptosis regulation, cell and tissue differentiation and signal transduction.. single nucleotide polymorphisms defined as following: A single nucleotide variation in a genetic sequence that occurs at appreciable frequency in the population.. SYNE1 defined as following: This gene plays a role in subcellular spatial organization.. variants defined as following: An alteration or difference from a norm or standard.. BD defined as following: Rare chronic inflammatory disease involving the small blood vessels. It is of unknown etiology and characterized by mucocutaneous ulceration in the mouth and genital region and uveitis with hypopyon. The neuro-ocular form may cause blindness and death. SYNOVITIS; THROMBOPHLEBITIS; gastrointestinal ulcerations; RETINAL VASCULITIS; and OPTIC ATROPHY may occur as well.. polymorphism defined as following: The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level.. chromosomal region defined as following: Any subdivision of a chromosome along its length. [GOC:dos].", "label": "yes"} {"id": "converted_1450", "sentence1": "Does the 3D structure of the genome remain stable during cell differentiation?", "sentence2": "We identify large, megabase-sized local chromatin interaction domains, which we term 'topological domains', as a pervasive structural feature of the genome organization., The domains are stable across different cell types and highly conserved across species, indicating that topological domains are an inherent property of mammalian genomes, Insulators are involved in 3D genome organization at multiple spatial scales and are important for dynamic reorganization of chromatin structure during reprogramming and differentiation., The relation between alterations in chromatin structure and changes in gene expression during cell differentiation has served as a paradigm to understand the link between genome organization and function., Architectural proteins orchestrate higher-order chromatin organization through the establishment of interactions between regulatory elements across multiple spatial scales. The regulation of these proteins, their interaction with DNA, and their co-occurrence in the genome, may be responsible for the plasticity of 3D chromatin architecture that dictates cell and time-specific blueprints of gene expression., The role of 3D genome organisation in the control and execution of lineage-specific transcription programmes during the development and differentiation of multipotent stem cells into specialised cell types remains poorly understood., Chromatin structural states and their remodelling, including higher-order chromatin folding and three-dimensional (3D) genome organisation, play an important role in the control of gene expression, Here, we show that substantial remodelling of the higher-order chromatin structure of the epidermal differentiation complex (EDC), a keratinocyte lineage-specific gene locus on mouse chromosome 3, occurs during epidermal morphogenesis., Many studies have suggested a link between the spatial organization of genomes and fundamental biological processes such as genome reprogramming, gene expression, and differentiation., Moreover, we reveal that formation of such highly condensed, transcriptionally repressed heterochromatin promotes transcriptional activation of differentiation genes and loss of pluripotency., The open chromatin of embryonic stem cells (ESCs) condenses into repressive heterochromatin as cells exit the pluripotent state., we find that localized heterochromatin condensation of ribosomal RNA genes initiates establishment of highly condensed chromatin structures outside of the nucleolus, We focus on the emerging relationship between genome organization and lineage-specific transcriptional regulation, which we argue are inextricably linked., Cells face the challenge of storing two meters of DNA in the three-dimensional (3D) space of the nucleus that spans only a few microns. The nuclear organization that is required to overcome this challenge must allow for the accessibility of the gene regulatory machinery to the DNA and, in the case of embryonic stem cells (ESCs), for the transcriptional and epigenetic changes that accompany differentiation, In this review we summarize some of the recent findings illuminating the 3D structure of the eukaryotic genome, as well as the relationship between genome topology and function from the level of whole chromosomes to enhancer-promoter loops with a focus on features affecting genome organization in ESCs and changes in nuclear organization during differentiation, We observe that although self-associating chromatin domains are stable during differentiation, chromatin interactions both within and between domains change in a striking manner, altering 36% of active and inactive chromosomal compartments throughout the genome[SEP]Definitions: proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. nucleolus defined as following: Within most types of eukaryotic CELL NUCLEUS, a distinct region, not delimited by a membrane, in which some species of rRNA (RNA, RIBOSOMAL) are synthesized and assembled into ribonucleoprotein subunits of ribosomes. In the nucleolus rRNA is transcribed from a nucleolar organizer, i.e., a group of tandemly repeated chromosomal genes which encode rRNA and which are transcribed by RNA polymerase I. (Singleton & Sainsbury, Dictionary of Microbiology & Molecular Biology, 2d ed). heterochromatin defined as following: The portion of chromosome material that remains condensed and is transcriptionally inactive during INTERPHASE.. genome defined as following: Anatomical set of genes in all the chromosomes.. nucleus defined as following: Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed). multipotent stem cells defined as following: A cell that can only differentiate to a particular type of cells (e.g. hematopoietic cells or epithelial cells). --2005. embryonic stem cells defined as following: Cells derived from the BLASTOCYST INNER CELL MASS which forms before implantation in the uterine wall. They retain the ability to divide, proliferate and provide progenitor cells that can differentiate into specialized cells.. DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. EDC defined as following: A procedure that uses both a curette and hyfrecator for treatment of various skin conditions, including basal cell carcinoma, squamous cell skin carcinoma, viral warts, and pyogenic granulomas.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. chromatin defined as following: The ordered and organized complex of DNA, protein, and sometimes RNA, that forms the chromosome. [GOC:elh, PMID:20404130]. ribosomal RNA genes defined as following: Genes, found in both prokaryotes and eukaryotes, which are transcribed to produce the RNA which is incorporated into RIBOSOMES. Prokaryotic rRNA genes are usually found in OPERONS dispersed throughout the GENOME, whereas eukaryotic rRNA genes are clustered, multicistronic transcriptional units.. epidermal differentiation complex defined as following: This gene plays a role in the structure of keratinocyte cell envelopes..", "label": "no"} {"id": "converted_1766", "sentence1": "Is ocrelizumab effective for treatment of multiple sclerosis?", "sentence2": " Advances made in immunomodulation are driving the progress being made in the treatment of MS. Ocrelizumab is the first treatment with positive results in the primarily progressive forms and tocilizumab, a drug product for rheumatoid arthritis, stands out as a potential candidate for the treatment of neuromyelitis optica., Expert commentary: The recent encouraging results of the ocrelizumab trial in PP MS, the first to reach the primary disability endpoint, indicate B cells as a promising therapeutic target to prevent disease progression. , Ocrelizumab also shows efficacy in the primary progressive form of multiple sclerosis., Ocrelizumab for the treatment of relapsing-remitting multiple sclerosis., Expert commentary: The topline results of two phase-III randomized clinical trials demonstrate superiority of ocrelizumab over interferon beta in RRMS patients with regards to clinical and paraclinical outcome parameters. , The efficacy of three of them, rituximab, ocrelizumab and ofatumumab in MS has been confirmed by placebo-controlled clinical trials demonstrating a significant reduction of the annualized relapsing rate (ARR), new gadolinium-enhancing (GdE) and T2 lesions. , Ongoing PMS trials are currently being conducted with the phosphodiesterase inhibitor ibudilast, S1P modulator siponimod and anti-B-cell therapy ocrelizumab. , RECENT FINDINGS: Novel and imminently emerging DMTs for the treatment of RRMS include alemtuzumab, daclizumab, ocrelizumab, pegylated interferon-β-1a, and three times weekly glatiramer acetate. , To summarize mechanisms of action, efficacy, and safety of novel and imminently emerging disease-modifying treatments (DMTs) intended to be used in relapsing-remitting multiple sclerosis (RRMS).Novel and imminently emerging DMTs for the treatment of RRMS include alemtuzumab, daclizumab, ocrelizumab, pegylated interferon-β-1a, and three times weekly glatiramer acetate, Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial., We aimed to assess efficacy and safety of two dose regimens of the humanised anti-CD20 monoclonal antibody ocrelizumab in patients with relapsing-remitting multiple sclerosis. , In multiple sclerosis (MS), B cell-depleting therapy using monoclonal anti-CD20 Abs, including rituximab (RTX) and ocrelizumab, effectively reduces disease activity. , Ocrelizumab also shows efficacy in the primary progressive form of multiple sclerosis.Most of the presented cell-depleting and myeloablative therapies are highly effective treatment options but are also accompanied by significant risks., The armamentarium of approved disease-modifying therapies in MS and those in development include: (1) the first approved, moderately effective, injectable interferon-β and glatiramer acetate; (2) oral drugs (fingolimod, laquinimod, teriflunomide, dimethyl fumarate); (3) monoclonal antibodies (rituximab, ocrelizumab, ofatumumab, daclizumab, alemtuzumab); and (4) immunosuppressive agents (e.g. mitoxantrone)., BACKGROUND: B lymphocytes are implicated in the pathogenesis of multiple sclerosis. We aimed to assess efficacy and safety of two dose regimens of the humanised anti-CD20 monoclonal antibody ocrelizumab in patients with relapsing-remitting multiple sclerosis.METHODS: We did a multicentre, randomised, parallel, double-blind, placebo-controlled study involving 79 centres in 20 countries. Patients aged 18-55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1:1) via an interactive voice response system to receive either placebo, low-dose (600 mg) or high-dose (2000 mg) ocrelizumab in two doses on days 1 and 15, or intramuscular interferon beta-1a (30 ìg) once a week., Ocrelizumab for the treatment of relapsing-remitting multiple sclerosis., The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects., Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial., Ocrelizumab also shows efficacy in the primary progressive form of multiple sclerosis.[SEP]Definitions: ocrelizumab defined as following: A Fc-modified, humanized monoclonal antibody directed against the B-cell CD20 cell surface antigen, with immunosuppressive activity. Ocrelizumab binds to CD20 on the surfaces of B-cells, triggering complement-dependent cell lysis (CDCL) and antibody-dependent cell-mediated cytotoxicity (ADCC) of B-cells overexpressing CD20. The CD20 antigen, a non-glycosylated cell surface phosphoprotein that acts as a calcium ion channel, is found on over 90% of B-cells, B-cell lymphomas, and other lymphoid tumor cells of B-cell origin; it plays an important role in B-cell functioning.. ofatumumab defined as following: A fully human, high-affinity IgG1 monoclonal antibody directed against the B cell CD20 cell surface antigen with potential antineoplastic activity. Ofatumumab binds specifically to CD20 on the surfaces of B cells, triggering complement-dependent cell lysis (CDCL) and antibody-dependent cell-mediated cytotoxicity (ADCC) of B cells overexpressing CD20. The CD20 antigen, found on over 90% of B cells, B cell lymphomas, and other B cells of lymphoid tumors of B cell origin, is a non-glycosylated cell surface phosphoprotein that acts as a calcium ion channel; it is exclusively expressed on B cells during most stages of B cell development.. interferon beta defined as following: A recombinant protein which is chemically identical to or similar to endogenous interferon beta with antiviral and anti-tumor activities. Endogenous interferons beta are cytokines produced by nucleated cells (predominantly natural killer cells) upon exposure to live or inactivated virus, double-stranded RNA or bacterial products. These agents bind to specific cell-surface receptors, resulting in the transcription and translation of genes with an interferon-specific response element. The proteins so produced mediate many complex effects, including antiviral (the most important being inhibition of viral protein synthesis), antiproliferative and immune modulating effects. The recombinant therapeutic forms of interferon beta are interferon beta 1-a and interferon beta 1-b. (NCI05). glatiramer acetate defined as following: A random polymer of L-ALANINE, L-GLUTAMIC ACID, L-LYSINE, and L-TYROSINE that structurally resembles MYELIN BASIC PROTEIN. It is used in the treatment of RELAPSING-REMITTING MULTIPLE SCLEROSIS.. interferon beta-1a defined as following: A recombinant form of the endogenous cytokine human interferon (IFN) beta-1a, with antiproliferative, antiviral and immunomodulating activities. Upon administration, interferon beta-1a targets and binds to specific type I IFN receptors, which eventually results in the transcription and translation of genes containing an interferon-specific response element and leads to the production of various anti-viral proteins and modulates the production of various immune-modulating proteins. This reduces the production of certain pro-inflammatory cytokines while upregulating the anti-inflammatory cytokine interleukin 10 (IL-10), upregulates the expression of major histocompatibility (MHC) I proteins which allows for increased presentation of peptides derived from viral antigens, and activates CD8+ T cells as well as other immune cells. Endogenous IFN-beta-1a is produced following viral infection and it plays a key role in innate immune response against viral pathogens.. alemtuzumab defined as following: Any monoclonal antibody directed against the cell surface glycoprotein CD52, regardless of the antibody type (e.g., rat, mouse, humanized).. daclizumab defined as following: An anti-TAC (INTERLEUKIN-2 RECEPTOR ALPHA SUBUNIT) humanized monoclonal antibody (immunoglobulin G1 disulfide with human-mouse monoclonal clone 1H4 light chain, dimer) that is used in the treatment of ACUTE RELAPSING MULTIPLE SCLEROSIS.. rheumatoid arthritis defined as following: A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated.. rituximab defined as following: A murine-derived monoclonal antibody and ANTINEOPLASTIC AGENT that binds specifically to the CD20 ANTIGEN and is used in the treatment of LEUKEMIA; LYMPHOMA and RHEUMATOID ARTHRITIS.. relapsing-remitting multiple sclerosis defined as following: The most common clinical variant of MULTIPLE SCLEROSIS, characterized by recurrent acute exacerbations of neurologic dysfunction followed by partial or complete recovery. Common clinical manifestations include loss of visual (see OPTIC NEURITIS), motor, sensory, or bladder function. Acute episodes of demyelination may occur at any site in the central nervous system, and commonly involve the optic nerves, spinal cord, brain stem, and cerebellum. (Adams et al., Principles of Neurology, 6th ed, pp903-914). multiple sclerosis defined as following: An autoimmune disorder mainly affecting young adults and characterized by destruction of myelin in the central nervous system. Pathologic findings include multiple sharply demarcated areas of demyelination throughout the white matter of the central nervous system. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia, and bladder dysfunction. The usual pattern is one of recurrent attacks followed by partial recovery (see MULTIPLE SCLEROSIS, RELAPSING-REMITTING), but acute fulminating and chronic progressive forms (see MULTIPLE SCLEROSIS, CHRONIC PROGRESSIVE) also occur. (Adams et al., Principles of Neurology, 6th ed, p903). ibudilast defined as following: An orally bioavailable inhibitor of cyclic nucleotide phosphodiesterase (PDE), mainly PDE-3, -4, -10, and -11, with anti-(neuro)inflammatory, vasorelaxant, bronchodilator, analgesic, neuroprotective and potential anti-tumor activities. Ibudilast (IBD) is able to cross the blood-brain barrier (BBB). Upon administration, IBD exerts its potential anti-tumor activity against glioblastoma multiforme (GBM) cells by inhibiting PDE-4 and the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF), which results in a decrease in MIF, its receptor CD74, and AKT expression, and attenuates the immunosuppressive properties of monocytic myeloid-derived suppressor cells (MDSCs) and reduces T-regulatory cells (Tregs). This causes GBM cell apoptosis and inhibits GBM cell proliferation. In addition, IBD reduces, through its inhibitory effect on various PDEs, the production of certain pro-inflammatory cytokines, such as interleukin-6 (IL-6), IL- 1beta, leukotriene B4, and tumor necrosis factor-alpha (TNF-a). IBD also upregulates the anti-inflammatory cytokine (IL-10), and promotes the production of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-4 (NT-4). It also blocks toll-like receptor-4 (TLR-4), inhibits nitric oxide (NO) synthesis and reduces the level of reactive oxygen species (ROS). It also prevents platelet aggregation, causes cerebral vasodilation, bronchial smooth muscle relaxation, and improves cerebral blood flow. In addition, IBD attenuates the PDE-mediated activation of glial cells and abrogates PDE-mediated neuroinflammation and neurodegeneration. MIF is secreted by cancer stem cells (CSCs) and is highly expressed within GBM and plays a key role in tumor cell proliferation. Co-expression of MIF and CD74 in GBM is associated with poor patient survival.. fingolimod defined as following: An orally available derivate of myriocin and sphingosine-1-phosphate receptor 1 (S1PR1, S1P1) modulator, with potential anti-inflammatory and immunomodulating activities. Upon oral administration, fingolimod, as a structural analogue of sphingosine, selectively targets and binds to S1PR1 on lymphocytes and causes transient receptor activation followed by S1PR1 internalization and degradation. This results in the sequestration of lymphocytes in lymph nodes. By preventing egress of lymphocytes. fingolimod reduces both the amount of circulating peripheral lymphocytes and the infiltration of lymphocytes into target tissues. This prevents a lymphocyte-mediated immune response and may reduce inflammation. S1PR1, a G-protein coupled receptor, plays a key role in lymphocyte migration from lymphoid tissues. Fingolimod also shifts macrophages to an anti-inflammatory M2 phenotype, and modulates their proliferation, morphology, and cytokine release via inhibition of the transient receptor potential cation channel, subfamily M, member 7 (TRPM7).. PMS defined as following: An exceedingly rare autosomal dominant developmental anomaly reported in 1986 in nine individuals among four generations of the same family. The syndrome has clinical characteristics of four-limb postaxial polydactyly and progressive myopia. There have been no further descriptions in the literature since 1986.. low-dose defined as following: A reduced quantity of a therapeutic agent prescribed to be taken at one time or at stated intervals.. dimethyl fumarate defined as following: An orally bioavailable methyl ester of fumaric acid and activator of nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2, Nfe2l2), with potential neuroprotective, immunomodulating and radiosensitizing activities. Although the exact mechanism of action through which dimethyl fumarate exerts its neuroprotective and immunomodulatory effects have yet to be fully understood, upon oral administration, dimethyl fumarate is converted into its active metabolite monomethyl fumarate (MMF) and MMF binds to Nrf2. Subsequently, Nrf2 translocates to the nucleus and binds to the antioxidant response element (ARE). This induces the expression of a number of cytoprotective genes, including NAD(P)H quinone oxidoreductase 1 (NQO1), sulfiredoxin 1 (Srxn1), heme oxygenase-1 (HO1, HMOX1), superoxide dismutase 1 (SOD1), gamma-glutamylcysteine synthetase (gamma-GCS), thioredoxin reductase-1 (TXNRD1), glutathione S-transferase (GST), glutamate-cysteine ligase catalytic subunit (Gclc) and glutamate-cysteine ligase regulatory subunit (Gclm); this also increases the synthesis of the antioxidant glutathione (GSH). The intraneuronal synthesis of GSH may protect neuronal cells from damage due to oxidative stress. Dimethyl fumarate also appears to inhibit the nuclear factor-kappa B (NF-kB)-mediated pathway, modulates the production of certain cytokines and induces apoptosis in certain T-cell subsets. Its radiosensitizing activity is due to this agent's ability to bind to and sequester intracellular GSH, thereby depleting intracellular GSH and preventing its anti-oxidative effects. This enhances the cytotoxicity of ionizing radiation in hypoxic cancer cells. Nrf2, a leucine zipper transcription factor, plays a key role in redox homeostasis and cytoprotection against oxidative stress.. B cells defined as following: Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation.. mitoxantrone defined as following: An anthracenedione-derived antineoplastic agent.. RTX defined as following: A naturally occurring capsaicin analog found in the latex of the cactus Euphorbia resinifera with analgesic activity. Resiniferatoxin (RTX) binds to and activates the transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel in the plasma membrane of primary afferent sensory neurons. This increases the permeability to cations, and leads to an influx of calcium and sodium ions. This results in membrane depolarization, causing an irritant effect, followed by desensitization of the sensory neurons thereby inhibiting signal conduction in afferent pain pathways and causing analgesia. TRPV1, a member of the transient receptor potential channel (TRP) superfamily, is a heat- and chemo-sensitive calcium/sodium ion channel that is selectively expressed in a subpopulation of pain-sensing primary afferent neurons.. drug product defined as following: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form.. tocilizumab defined as following: A recombinant, humanized IgG1 monoclonal antibody directed against the interleukin-6 receptor (IL-6R) with immunosuppressant activity. Tocilizumab targets and binds to both the soluble form of IL-6R (sIL-6R) and the membrane-bound form (mIL-6R), thereby blocking the binding of IL-6 to its receptor. This prevents IL-6-mediated signaling. IL-6, a pro-inflammatory cytokine that plays an important role in the regulation of the immune response, is overproduced in autoimmune disorders, certain types of cancers and possibly various other inflammatory conditions..", "label": "yes"} {"id": "converted_3930", "sentence1": "Has the olive tree pollen proteome been studied?", "sentence2": "Olive pollen is a major allergenic source worldwide due to its extensive cultivation. We have combined available genomics data with a comprehensive proteomics approach to get the annotated olive tree (Olea europaea L.) pollen proteome and define its complex allergenome. [SEP]", "label": "yes"} {"id": "converted_3", "sentence1": "Are long non coding RNAs spliced?", "sentence2": "Our analyses indicate that lncRNAs are generated through pathways similar to that of protein-coding genes, with similar histone-modification profiles, splicing signals, and exon/intron lengths., For alternative exons and long noncoding RNAs, splicing tends to occur later, and the latter might remain unspliced in some cases., bosome-mapping data to identify lncRNAs of Caenorhabditis elegans. We found 170 long intervening ncRNAs (lincRNAs), which had single- or multiexonic structures that did not overlap protein-coding transcripts, and about sixty antisense lncRNAs (ancRNAs), which were complementary to protein-coding transcripts, We introduce an approach to predict spliced lncRNAs in vertebrate genomes combining comparative genomics and machine learning., Owing to similar alternative splicing pattern to mRNAs, the concept of lncRNA genes was put forward to help systematic understanding of lncRNAs. , Our synthesis of recent studies suggests that neither size, presence of a poly-A tail, splicing, direction of transcription, nor strand specificity are of importance to lncRNA function.[SEP]Definitions: strand defined as following: The orientation of a genomic element on the double stranded molecule.. lincRNAs defined as following: A molecule of RNA 200-17000 nucleotides in length that is transcribed by non-protein coding areas of DNA. These ribonucleotides may play a role in a variety of biological processes.. Caenorhabditis elegans defined as following: A species of nematode that is widely used in biological, biochemical, and genetic studies..", "label": "yes"} {"id": "converted_1615", "sentence1": "Are high-flow nasal cannulae effective for treatment of preterm infants?", "sentence2": "The use of high-flow nasal cannulae is an increasingly popular alternative to nasal continuous positive airway pressure (CPAP) for noninvasive respiratory support of very preterm infants (gestational age, <32 weeks) after extubation., The use of high-flow nasal cannulae was noninferior to the use of nasal CPAP, with treatment failure occurring in 52 of 152 infants (34.2%) in the nasal-cannulae group and in 39 of 151 infants (25.8%) in the CPAP group (risk difference, 8.4 percentage points; 95% confidence interval, -1.9 to 18.7). , Although the result for the primary outcome was close to the margin of noninferiority, the efficacy of high-flow nasal cannulae was similar to that of CPAP as respiratory support for very preterm infants after extubation. , Recently high flow nasal cannula (HFNC) is emerging as an efficient, better tolerated form of NIV, allowing better access to the baby's face, which may improve nursing, feeding and bonding., In conclusion, there is a growing evidence of the feasibility of HFNC as an alternative mode of NIV. , HHHFNC and NCPAP produced similar rates of extubation failure., The use of HFNC as a respiratory support modality is increasing in the infant, pediatric, and adult populations as an alternative to non-invasive positive pressure ventilation., Current evidence suggests that HFNC is well tolerated and may be feasible in a subset of patients who require ventilatory support with non-invasive ventilation., Heated, humidified, high-flow nasal cannula oxygen therapy (HHHFNC) has been used to improve ventilation in preterm infants. , Increasing flow rates of HHHFNC therapy are associated with linear increases in NP pressures in bronchiolitis patients. , An alternative to the use of nasal continuous positive airway pressure (NCPAP) as a non-invasive modality to support respiratory distress in premature infants has been the recent introduction of high flow nasal cannula (HFNC) devices in many neonatal units. There has been increased use of HFNC presumably because of anecdotal reports and experience that it is easy to use, and well tolerated by the infants, while experiencing decreased nasal septumerosion., High-flow nasal cannulae (HFNC) are gaining in popularity as a form of non-invasive respiratory support for preterm infants in neonatal intensive care units around the world., HFNC may be as effective as NCPAP at improving respiratory parameters such as tidal volume and work of breathing in preterm infants, but probably only at flow rates >2 litres/min. , There is growing evidence of the feasibility of HFNC as an alternative to other forms of non-invasive ventilation in preterm infants. , When used as primary respiratory support after birth, one trial found similar rates of treatment failure in infants treated with HFNC and nasal CPAP. Following extubation, one trial found that infants treated with HFNC had a significantly higher rate of reintubation than those treated with nasal CPAP. Another trial found similar rates of reintubation for humidified and non-humidified HFNC, and the fourth trial found no difference between two different models of equipment used to deliver humidified HFNC. , When used following extubation, HFNC may be associated with a higher rate of reintubation than nasal CPAP. , Early weaning from CPAP to high flow nasal cannula in preterm infants is associated with prolonged oxygen requirement: a randomized controlled trial., After randomization, the no-NC group had fewer days on oxygen [median (interquartile range): 5 (1-8) vs 14 (7.5-19.25) days, p<0.001] and shorter duration of respiratory support [10.5 (4-21) vs 18 (11.5-29) days, p=0.03]. There were no differences between groups regarding success of weaning from NCPAP. , Weaning preterm infants from NCPAP to NC is associated with increased exposure to oxygen and longer duration of respiratory support., A number of centers use high-flow nasal cannula (HFNC) in the management of AOP without measuring the positive distending pressure (PDP) generated., HFNC is as effective as NCPAP in the management of AOP.[SEP]Definitions: NIV defined as following: A type of mechanical ventilation procedure that uses a non-invasive means, such as a face mask or nasal mask, to deliver oxygenated air into the lungs.. respiratory distress defined as following: A pathological increase in the effort and frequency of breathing movements.. NC defined as following: A rare developmental skin condition consisting of abnormal pilosebaceous follicle development. It is characterized by linear or band-like distributions of groups of comedones, usually on the face, neck, upper arm, chest, and abdomen, that appear at birth or in childhood.. bronchiolitis defined as following: Inflammation of the BRONCHIOLES..", "label": "yes"} {"id": "converted_128", "sentence1": "Is MammaPrint cleared by the United States Food and Drug Administration? ", "sentence2": "Real-time RT-PCR confirmed the 5-gene prognostic signature that was distinct from an FDA-cleared 70-gene signature of MammaPrint panel and from the Oncotype DX recurrence score assay panel.[SEP]Definitions: Oncotype DX defined as following: A diagnostic assay that quantifies the likelihood of breast cancer recurrence in women with newly diagnosed, early stage breast cancer. In addition to predicting distant disease recurrence, Oncotype DX also assesses the benefit from certain types of chemotherapy. The assay, performed using formalin-fixed, paraffin-embedded tumor tissue, analyzes the expression of a panel of 21 genes and the results are provided as a Recurrence Score (0-100). The gene panel was selected and the Recurrence Score calculation was derived through extensive laboratory testing and multiple independent clinical development studies. Oncotype DX is validated for use in breast cancer patients whose disease is newly diagnosed, stage I or II, node-negative, estrogen receptor-positive and who will be treated with tamoxifen.. MammaPrint defined as following: An in vitro molecular diagnostic test that uses gene expression profiling to analyze gene activity within a breast cancer tumor sample. It looks at the activity of 70 genes and is useful in assessing the likelihood of metastasis and recurrence..", "label": "yes"} {"id": "converted_4606", "sentence1": "Is REGN5458 a single-targeted antibody?", "sentence2": "CD3-engaging bispecific antibodies (bsAbs) and chimeric antigen receptor (CAR) T cells are potent therapeutic approaches for redirecting patient T cells to recognize and kill tumors. Here we describe a fully human bsAb (REGN5458) that binds to B-cell maturation antigen (BCMA) and CD3, and compare its antitumor activities vs those of anti-BCMA CAR T cells to identify differences in efficacy and mechanism of action. [SEP]Definitions: CAR defined as following: A cytoskeletal structure composed of actin filaments and myosin that forms beneath the plasma membrane of many cells, including animal cells and yeast cells, in a plane perpendicular to the axis of the spindle, i.e. the cell division plane. In animal cells, the contractile ring is located at the cleavage furrow. In budding fungal cells, e.g. mitotic S. cerevisiae cells, the contractile ring forms at the mother-bud neck before mitosis. [GOC:expert_jrp, GOC:sgd_curators, GOC:vw, ISBN:0805319409, ISBN:0815316194, PMID:28914606]. T cells defined as following: A subset of therapeutic autologous T-lymphocytes that express a T-cell receptor (TCR) composed of one gamma chain and one delta chain, with potential immunomodulating and antineoplastic activities. Upon administration of the therapeutic gamma delta T-lymphocytes, these cells secrete interferon-gamma (IFN-g), and exert direct killing of tumor cells. In addition, these cells activate the immune system to exert a cytotoxic T-lymphocyte (CTL) response against tumor cells. Gamma delta T-lymphocytes play a key role in the activation of the immune system and do not require major histocompatibility complex (MHC)-mediated antigen presentation to exert their cytotoxic effect.. tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. chimeric antigen receptor defined as following: A cell-surface receptor that has been engineered to combine novel features and specificities from various sources in order to enhance its antigen specificity. Engineered T-cells or B-cells will produce the specialized receptor that will be capable of binding to an epitope on its target cell.. CD3 defined as following: Complex of at least five membrane-bound polypeptides in mature T-lymphocytes that are non-covalently associated with one another and with the T-cell receptor (RECEPTORS, ANTIGEN, T-CELL). The CD3 complex includes the gamma, delta, epsilon, zeta, and eta chains (subunits). When antigen binds to the T-cell receptor, the CD3 complex transduces the activating signals to the cytoplasm of the T-cell. The CD3 gamma and delta chains (subunits) are separate from and not related to the gamma/delta chains of the T-cell receptor (RECEPTORS, ANTIGEN, T-CELL, GAMMA-DELTA).. B-cell maturation antigen defined as following: A member of the tumor necrosis factor receptor superfamily found on mature B-LYMPHOCYTES. It has specificity for B CELL ACTIVATING FACTOR and TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY MEMBER 13. Signaling of the receptor occurs through its association with TNF RECEPTOR-ASSOCIATED FACTORS.. bispecific antibodies defined as following: Antibodies, often monoclonal, in which the two antigen-binding sites are specific for separate ANTIGENIC DETERMINANTS. They are artificial antibodies produced by chemical crosslinking, fusion of HYBRIDOMA cells, or by molecular genetic techniques. They function as the main mediators of targeted cellular cytotoxicity and have been shown to be efficient in the targeting of drugs, toxins, radiolabeled haptens, and effector cells to diseased tissue, primarily tumors..", "label": "no"} {"id": "converted_44", "sentence1": "Does BNP increase after intensive exercise in athletes?", "sentence2": "NT-pro-BNP was significantly elevated postexercise in both adults and adolescents and remained above baseline at 24 h in both groups., NT-pro-BNP concentrations increased significantly (28 +/- 17.1 vs 795 +/- 823 ng x L, P < 0.05), whereas postrace cTnT were elevated in just five athletes (20%)., [NT-pro-BNP] was observed immediately after the marathon (median [NT-pro-BNP] before: 39.6 pg ml(-1), after: 138.6 pg ml(-1), p=0.003) with a further increase on day one. [BNP] did not increase immediately after the marathon but increased on day one (median [BNP] before: 15 pg ml(-1), day one: 27.35 pg ml(-1), p=0.006)., Pro-BNP was significantly increased immediately post-race (27+/-21 vs 7+/-2 pmol/L pre-race, P < or = 0.007), which 12-24 h later, decreased to 19+/-14 pmol/L (P = 0.07 vs pre-race)., The relatively high NT-proBNP levels after active recovery when psychophysical stress is higher, because of cycling and cold water immersion, suggest that not only endurance exercise, but also strenuous, stressful short exercise can induce an increase in NT-proBNP concentrations., Running a marathon significantly increases NT-pro-BNP levels in healthy adults. This increase could be partially attributed to cardiac stress., Increases in NT-proBNP can be found in a major part of obviously healthy athletes after prolonged strenuous exercise. The release of BNP during and after exercise may not result from myocardial damage but may have cytoprotective and growth-regulating effects. The different nature of exercise-induced increases in BNP and cardiac troponins has to be elucidated in the future., In healthy cyclists, transient increases in NT-pro-BNP and cTnT are more likely to reflect cardiac fatigue than injury., The rise in BNP in older athletes may reflect a reversible, mainly diastolic left ventricular dysfunction. , Plasma BNP concentrations were higher in both the judo and marathon groups than in controls, and positively correlated with LV mass as well as with deceleration time., Such exercise significantly increased ANP and BNP levels in healthy men, and the increases could be partially attributed to myocardial damage during the race.[SEP]Definitions: cTnT defined as following: Troponin T, cardiac muscle (298 aa, ~36 kDa) is encoded by the human TNNT2 gene. This protein plays a role in cardiac muscle contraction.. NT-pro-BNP defined as following: N-terminal fragment brain natriuretic protein (76 aa, ~9 kDa) is encoded by the human NPPB gene. This protein is a marker for cardiac failure.. BNP defined as following: A recombinant version of the cardiac neurohormone, human B-type natriuretic peptide (hBNP) produced by the ventricular myocardium. Nesiritide binds to natriuretic peptide receptors on vascular smooth muscle and endothelial cells, through which it triggers guanylate cyclase dependent signal transduction resulting in increase of intracellular concentrations of cGMP. This leads to smooth muscle cell relaxation causing arterial and venous dilatation.. ANP defined as following: A potent natriuretic and vasodilatory peptide or mixture of different-sized low molecular weight PEPTIDES derived from a common precursor and secreted mainly by the HEART ATRIUM. All these peptides share a sequence of about 20 AMINO ACIDS..", "label": "yes"} {"id": "converted_137", "sentence1": "Is GAGA associated with nucleosome-free regions (NFR)?", "sentence2": "One of the three nuclease hypersensitive sites in the Fab-7 boundary, HS1, contains multiple consensus-binding sequences for the GAGA factor, a protein known to be involved in the formation and/or maintenance of nucleosome-free regions of chromatin., The HS3 sequence contains consensus binding sites for the GAGA factor, a protein implicated in the formation of nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group protein that is related to the mammalian transcription factor YY1., The interactions of GAGA factor and heat shock factor with their binding sites in chromatin occurred in two modes. Their interaction with binding sites in the nucleosome-free regions did not require ATP. In the presence of ATP both factors interacted also with nucleosomal binding sites, causing nucleosome rearrangements and a refinement of nucleosome positions, While chromatin remodeling upon transcription factor interaction has previously been interpreted to involve nucleosome disruption, the data suggest energy-dependent nucleosome sliding as main principle of chromatin reorganization., These (CT)n repeats are associated with a nonhistone protein(s) in vivo and are bound by a purified Drosophila protein, the GAGA factor, in vitro., This (CT)n element appears to contribute to formation of the wild-type chromatin structure of hsp26, an organized nucleosome array that leaves the HSEs in nucleosome-free, DNase I-hypersensitive (DH) site, The HS3 sequence contains consensus binding sites for the GAGA factor, a protein implicated in the formation of nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group protein that is related to the mammalian transcription factor YY1., One of the three nuclease hypersensitive sites in the Fab-7 boundary, HS1, contains multiple consensus-binding sequences for the GAGA factor, a protein known to be involved in the formation and/or maintenance of nucleosome-free regions of chromatin., The iab-7 polycomb response element maps to a nucleosome-free region of chromatin and requires both GAGA and pleiohomeotic for silencing activity., The HS3 sequence contains consensus binding sites for the GAGA factor, a protein implicated in the formation of nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group protein that is related to the mammalian transcription factor YY1. [SEP]Definitions: leaves defined as following: Expanded structures, usually green, of vascular plants, characteristically consisting of a bladelike expansion attached to a stem, and functioning as the principal organ of photosynthesis and transpiration. (American Heritage Dictionary, 2d ed). Pho defined as following: A condition chiefly characterized by thickening of the skin of the head and distal extremities, deep folds and furrows of the skin of the forehead, cheeks, and scalp, SEBORRHEA; HYPERHIDROSIS; periostosis of the long bones, digital clubbing, and spadelike enlargement of the hands and feet. It is more prevalent in the male, and is usually first evident during adolescence. Inheritance is primarily autosomal recessive, but an autosomal dominant form exists.. binding sites defined as following: The parts of a macromolecule that directly participate in its specific combination with another molecule.. transcription factor defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.. Polycomb group protein defined as following: A family of proteins that play a role in CHROMATIN REMODELING. They are best known for silencing HOX GENES and the regulation of EPIGENETIC PROCESSES.. YY1 defined as following: This gene is involved in the negative regulation of transcription.. HS1 defined as following: Human EEF1A2 wild-type allele is located in the vicinity of 20q13.3 and is approximately 11 kb in length. This allele, which encodes elongation factor 1-alpha 2 protein, is involved in the promotion of protein elongation. The gene is expressed aberrantly at elevated levels in many ovarian cancers.. nucleosome defined as following: A complex comprised of DNA wound around a multisubunit core and associated proteins, which forms the primary packing unit of DNA into higher order structures. [GOC:elh]. ATP defined as following: An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. chromatin defined as following: The ordered and organized complex of DNA, protein, and sometimes RNA, that forms the chromosome. [GOC:elh, PMID:20404130]. mammalian defined as following: Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young.. NFR defined as following: The quotient of the number of particular entities (constituents) and the number of all constituents in the system..", "label": "yes"} {"id": "converted_166", "sentence1": "Are there any statistical methods for normalizing and identifying differential regions in histone modification ChIP-seq data?", "sentence2": "ChIPnorm: a statistical method for normalizing and identifying differential regions in histone modification ChIP-seq libraries., In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. We show that the ChIPnorm method removes most of the noise and bias in the data and outperforms other normalization methods. We correlate the histone marks with gene expression data and confirm that histone modifications H3K27me3 and H3K4me3 act as respectively a repressor and an activator of genes. Compared to what was previously reported in the literature, we find that a substantially higher fraction of bivalent marks in ES cells for H3K27me3 and H3K4me3 move into a K27-only state. We find that most of the promoter regions in protein-coding genes have differential histone-modification sites., In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types., In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. , In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. We show that the ChIPnorm method removes most of the noise and bias in the data and outperforms other normalization methods. , In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types., In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. We show that the ChIPnorm method removes most of the noise and bias in the data and outperforms other normalization methods., This problem turns out to be surprisingly difficult, even in simple pairwise comparisons, because of the significant level of noise in ChIP-seq data. In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types., In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types.[SEP]Definitions: histone modifications defined as following: The covalent alteration of one or more amino acid residues within a histone protein. [GOC:krc]. H3K27me3 defined as following: A post-translationally modified form of histone H3 where the lysine residue at position 28 is trimethylated. This modification is associated with formation of heterochromatin and polycomb repressive complex 1 (PRC1).. H3K4me3 defined as following: A post-translationally modified form of histone H3 where the lysine residue at position 4 is trimethylated. This modification may be a marker for areas of active gene expression.. promoter regions defined as following: DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes.. genome defined as following: Anatomical set of genes in all the chromosomes.. repressor defined as following: Transcription Repressor/Corepressor Gene encodes Transcriptional Repressor/Corepressor, proteins that can regulate transcription by binding to the operator and causing repression. (from Glick: Glossary of Biochemistry and Molecular Biology). ChIP-seq defined as following: A molecular genetic technique that combines chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing to map the binding sites of DNA-associated proteins in a sample of cells. First, crosslinked protein-DNA complexes are isolated using ChIP. Next, the crosslinks are broken, the proteins are removed and the purified DNA is modified with adaptor oligonucleotides to facilitate massively parallel DNA sequencing. Following sequencing, the DNA sequences that are obtained can be mapped to their genomic locations.. histone modification defined as following: The covalent alteration of one or more amino acid residues within a histone protein. [GOC:krc].", "label": "yes"} {"id": "converted_1405", "sentence1": "Can tetracycline affect tooth formation?", "sentence2": "he results of that study, reported earlier (Rebich et al., 1983), indicated that over one-fifth of the American Indian children had discoloration of the dentition due to ingestion of tetracycline during the years of tooth formatio, ale Wistar rats prelabeled with tetracycline to mark surfaces of bone and tooth formation-mineralization were placed into orbit for 18.5 days aboard the Soviet COSMOS-1129 Biosatellit, It was concluded that the increased tetracycline incorporation reflected a higher rate of mineralization associated with faster tooth formation in the unimpeded toot, n this investigation an attempt has been made to determine the relationship between the staining of permanent teeth by tetracycline administered during the period of tooth formation with the dosage of the drug and the duration of therap, definite relationship between total dosage and staining and duration of administration and staining was established; the condition occurred with greater frequency (in more than one-third of the children) when the total dosage exceeded 3 g. or the duration of treatment was longer than 10 days, This case report suggests the possibility that discoloration from tetracycline may not be limited to tooth development in the child, but may also affect the adult dentition[SEP]Definitions: drug defined as following: Any natural, endogenously-derived, synthetic or semi-synthetic compound with pharmacologic activity. A pharmacologic substance has one or more specific mechanism of action(s) through which it exerts one or more effect(s) on the human or animal body. They can be used to potentially prevent, diagnose, treat or relieve symptoms of a disease. Formulation specific agents and some combination agents are also classified as pharmacologic substances.. tetracycline defined as following: Any of a group of broad spectrum naphthacene antibiotics isolated from various species of Streptomyces or produced semisynthetically. In bacteria, tetracycline antibiotics block binding of aminoacyl-tRNA to the mRNA-ribosome complex, thereby inhibiting protein synthesis. (NCI05).", "label": "yes"} {"id": "converted_285", "sentence1": "Is ospemifene effective for treatment of dyspareunia?", "sentence2": "Ospemifene, a novel selective estrogen receptor modulator, has been developed for the treatment of vulvovaginal atrophy and dyspareunia in postmenopausal women. , For the comparison of short-term ospemifene with placebo, parabasal cells (the standardized mean difference [SMD] = -37.5, 95% confidence interval [CI] = -41.83 to -33.17, P < 0.00001), superficial cells (SMD = 9.24, 95% CI = 7.70 to 10.79, P < 0.00001), vaginal PH (SMD = -0.89, 95% CI = -0.98 to -0.80, P = 0.00001), and dyspareunia (SMD = -0.37, 95% CI = -0.43 to -0.30, P = 0.00001) indicated that ospemifene was more effective than the placebo. , This meta-analysis indicates that ospemifene to be an effective and safe treatment for dyspareunia associated with postmenopausal vulvar and vaginal atrophy., Ospemifene is a selective estrogen receptor modulator (SERM), or estrogen receptor agonist/antagonist, that was recently approved by the US Food and Drug Administration for the treatment of dyspareunia associated with vulvar and vaginal atrophy, a chronic condition that affects up to 60% of postmenopausal women., In conclusion, ospemifene is a SERM with a unique estrogen agonist/antagonist tissue profile that was recently approved in the US for the treatment of dyspareunia associated with vulvar and vaginal atrophy in postmenopausal women. , To characterize the pharmacokinetics of the oral, non-estrogen agent ospemifene, an estrogen agonist/antagonist with tissue-selective effects (also called a selective estrogen receptor modulator) that was recently approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy in postmenopausal women., Here, we review the estrogen agonist/antagonist profile of ospemifene, a novel triphenylethylene derivative recently approved to treat dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause, both preclinically and clinically., Long-term studies on the endometrial safety of local estrogen and ospemifene are lacking. , Ospemifene is a tissue-selective estrogen agonist/antagonist (a selective estrogen receptor modulator) recently approved by the US Food and Drug Administration for treatment of dyspareunia, a symptom of VVA, due to menopause., SERMs with positive vaginal effects (such as improvement in the vaginal maturation index, reduced vaginal pH, and improvement in the signs and symptoms of VVA) on postmenopausal symptomatic women include lasofoxifene (clinical development on hold) and ospemifene, which was recently approved for the treatment of VVA-related dyspareunia, with a class effect warning of potential venous thrombosis risk. , Ospemifene is the first non-estrogen treatment approved for moderate to severe dyspareunia in women with menopause-related vulvar and vaginal atrophy. , This article summarizes the milestones in the development of ospemifene leading to this first approval for moderate to severe dyspareunia, a symptom of postmenopausal vulvar and vaginal atrophy., The aim of this work was to study the role of ospemifene, a novel selective estrogen receptor modulator, in the treatment of vulvar and vaginal atrophy in postmenopausal women with moderate to severe dyspareunia and physiological vaginal changes. , In this study, once-daily oral ospemifene 60 mg was effective for the treatment of vulvar and vaginal atrophy in postmenopausal women with dyspareunia., Clinical trials have confirmed that daily doses are well-tolerated and that it is effective in normalizing vaginal maturation index and pH as well as improving the symptoms associated with VVA including dyspareunia., Ospemifene was shown to be effective and well tolerated for the treatment of the symptoms of vaginal dryness and dyspareunia associated with vulvovaginal atrophy over and above the use of provided lubricants.[SEP]Definitions: vaginal atrophy defined as following: A condition characterized by the absence of squamous maturation in the vaginal epithelium. It is associated with decreased estrogen production.. SERMs defined as following: A structurally diverse group of compounds distinguished from ESTROGENS by their ability to bind and activate ESTROGEN RECEPTORS but act as either an agonist or antagonist depending on the tissue type and hormonal milieu. They are classified as either first generation because they demonstrate estrogen agonist properties in the ENDOMETRIUM or second generation based on their patterns of tissue specificity. (Horm Res 1997;48:155-63). SMD defined as following: A heterogeneous group of disorders associated with walking and growth disturbances that become evident during the second year of life. Characteristics are platyspondyly (flattened vertebrae) and marked hip and knee metaphyseal lesions. The different forms of spondylometaphyseal dysplasia are distinguished by the localization and severity of involvement of the affected metaphyses.. venous thrombosis defined as following: The formation or presence of a blood clot (THROMBUS) within a vein.. lasofoxifene defined as following: A non-steroidal, naphthalene-derived, third-generation selective estrogen receptor modulator (SERM) with potential antineoplastic and anti-osteoporotic activities. Upon oral administration, lasofoxifene selectively binds to both estrogen receptor alpha (ERalpha; ESR1) and estrogen receptor beta (ERbeta; ESR2) with high affinity and mimics the effects of endogenous estradiol with varying agonist and antagonist effects in ER-expressing tissues. Blockade of ERalpha by lasofoxifene may potentially inhibit estrogen-dependent cancer cell proliferation in ER-expressing cancers. Lasofoxifene may also bind to the certain mutant forms of ERalpha, including the Y537S ESR1 mutant, making it potentially useful in the treatment of tumors that have acquired resistance to other ER-targeting agents.. vulvar defined as following: The external genitalia of the female. It includes the CLITORIS, the labia, the vestibule, and its glands.. estrogen receptor modulator defined as following: Substances that possess antiestrogenic actions but can also produce estrogenic effects as well. They act as complete or partial agonist or as antagonist. They can be either steroidal or nonsteroidal in structure.. dyspareunia defined as following: A question about whether an individual has or had painful intercourse.. vaginal dryness defined as following: An uncomfortable feeling of itching and burning in the vaginal opening resulting from inadequate vaginal lubrication. It is commonly seen during and after menopause, childbirth, or stressful conditions. It results in painful intercourse.. vulvovaginal atrophy defined as following: A condition associated with decreased estrogen production, characterized by dryness, inflammation, and itching of the vulva and vaginal tissues. It may also be associated with dysuria and dyspareunia..", "label": "yes"} {"id": "converted_1995", "sentence1": "Are there canonical marks of active chromatin in developmentally regulated genes?", "sentence2": "Absence of canonical marks of active chromatin in developmentally regulated genes., The interplay of active and repressive histone modifications is assumed to have a key role in the regulation of gene expression. In contrast to this generally accepted view, we show that the transcription of genes temporally regulated during fly and worm development occurs in the absence of canonically active histone modifications. Conversely, strong chromatin marking is related to transcriptional and post-transcriptional stability, an association that we also observe in mammals. Our results support a model in which chromatin marking is associated with the stable production of RNA, whereas unmarked chromatin would permit rapid gene activation and deactivation during development. In the latter case, regulation by transcription factors would have a comparatively more important regulatory role than chromatin marks., Absence of canonical marks of active chromatin in developmentally regulated genes, Absence of canonical marks of active chromatin in developmentally regulated genes., In contrast to this generally accepted view, we show that the transcription of genes temporally regulated during fly and worm development occurs in the absence of canonically active histone modifications.[SEP]Definitions: chromatin defined as following: The ordered and organized complex of DNA, protein, and sometimes RNA, that forms the chromosome. [GOC:elh, PMID:20404130]. histone modifications defined as following: The covalent alteration of one or more amino acid residues within a histone protein. [GOC:krc]. transcription factors defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.. RNA defined as following: A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed). genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. mammals defined as following: Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young..", "label": "no"} {"id": "converted_443", "sentence1": "Can we detect DNA strand asymmetries using dinucleotide relative abundance \"genomic signatures\"?", "sentence2": "comparing the heterogeneities of bacterial genomes with respect to strand-independent first- and second-order features, (i) G + C content and (ii) dinucleotide relative abundance,, the concept of a genomic signature was introduced with the observation of species-type specific Dinucleotide Relative Abundance Profiles (DRAPs); dinucleotides were identified as the subsequences with the greatest bias in representation in a majority of genomes., dinucleotide relative abundance values (the genomic signature), The dinucleotide relative abundance profile can be regarded as a genomic signature because, despite diversity between species, it varies little between 50 kilobase or longer windows on a given genome., The profile is computed from the base step \"odds ratios\" that compare dinucleotide frequencies to those expected under the assumption of stochastic equilibrium (thorough shuffling). , The genome signatures (dinucleotide relative abundance values), Early biochemical experiments measuring nearest neighbor frequencies established that the set of dinucleotide relative abundance values (dinucleotide biases) is a remarkably stable property of the DNA of an organism., the set of dinucleotide biases constitutes a 'genomic signature' that can discriminate sequences from different organisms., the set of dinucleotide odds ratio (relative abundance) values constitute a signature of each DNA genome, Dinucleotide relative abundance extremes: a genomic signature., The dinucleotide relative abundance profile can be regarded as a genomic signature because, despite diversity between species, it varies little between 50 kilobase or longer windows on a given genome., Previously, the concept of a genomic signature was introduced with the observation of species-type specific Dinucleotide Relative Abundance Profiles (DRAPs); dinucleotides were identified as the subsequences with the greatest bias in representation in a majority of genomes., Comparisons within and between species sample sequences are based on the profile of dinucleotide relative abundance values (The profile is rho*XY = f*XY/f*Xf*Y for all XY, where f*X denotes the frequency of the nucleotide X and f*XY denotes the frequency of the dinucleotide XY, both computed from the sequence concatenated with its inverted complement)., Dinucleotide relative abundances (i.e., dinucleotide representations normalized by the component nucleotide frequencies) are consonant with respect to the leading and lagging strands[SEP]Definitions: Dinucleotide defined as following: A group of compounds which consist of a nucleotide molecule to which an additional nucleoside is attached through the phosphate molecule(s). The nucleotide can contain any number of phosphates.. bacterial genomes defined as following: The genetic complement of a BACTERIA as represented in its DNA.. genome defined as following: Anatomical set of genes in all the chromosomes.. DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. organisms defined as following: A living entity.. dinucleotide defined as following: A group of compounds which consist of a nucleotide molecule to which an additional nucleoside is attached through the phosphate molecule(s). The nucleotide can contain any number of phosphates..", "label": "no"} {"id": "converted_2229", "sentence1": "Does PCSK9 (Proprotein convertase subtilisin/kexin type 9) binds with HDL-receptor (HDL-R)?", "sentence2": "Recently it was revealed that the secreted Proprotein Convertase Subtilisin Kexin 9 (PCSK9) binds with LDL-receptor (LDL-R) causing its degradation in the lysosome with the result of LDL-C accumulating in the blood., The major goal of this study is to identify peptide/s from the catalytic domain of hPCSK9 that can block the binding of hPCSK9 and LDL-R and therefore can reduce LDL-R degradation leading to the clearance of LDL-C from the plasma., In vitro administration of SRT3025 to cultured AML12 hepatocytes attenuated Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake., Proprotein convertase subtilisin/kexin type 9 (PCSK9), which involves in low-density lipoprotein cholesterol (LDL-C) metabolism by interacting with the LDL receptor, is considered as a potent therapeutic target for treating hypercholesterolemia. , Taken together, these results suggested that the IgG1-PA4 can be served as a potential candidate for the treatment of hypercholesterolemia by inhibiting PCSK9-mediated degradation of cell surface LDLRs., Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein receptor, escorting it to its destruction in the lysosome and thereby preventing the recirculation of the low-density lipoprotein receptor to the hepatocyte cell surface. , However, statins have low efficiency because they also increase PCSK9 which targets LDLR for degradation., Inhibition of the enzyme PCSK9 (proprotein convertase subtilisin/kexin type 9), which is involved in depletion of the LDL-receptor, is a new pharmacologic approach. , Proprotein convertase subtilisin kexin type 9 (PCSK9) modulates LDL-c through post-translational degradation of the LDLR., Mechanistically, hepatic S1P KD was shown to decrease the liver and plasma levels of the protein proprotein convertase subtilisin/kexin type 9 (PCSK9), which degrades LDLR protein. , We report here the development of sdAbs targeting human PCSK9 (proprotein convertase subtilisin/kexin type 9) as an alternative to anti-PCSK9 mAbs., PCSK9 proprotein convertase subtilisin/kexin type (PCSK9) protein plays an important role in LDL cholesterol (LDL-C) metabolism, due to its role in the degradation of the LDL receptor., Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, leading to their degradation, Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation, Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted protein that binds to the epidermal growth factor-like-A domain of the low density lipoprotein receptor (LDLR) and mediates LDLR degradation in liver, Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds LDL receptors, targeting them for degradation, Proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds the low-density lipoprotein receptor and targets it for degradation, has emerged as an important regulator of serum cholesterol levels and cardiovascular disease risk, Secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein receptor (LDLR) at the cell surface and disrupts the normal recycling of the LDLR, Proprotein convertase, subtilisin/kexin type 9 (PCSK9), a key regulator of plasma LDL-cholesterol (LDL-c) and cardiovascular risk, is produced in liver and secreted into plasma where it binds hepatic LDL receptors (LDLR), leading to their degradation, Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the hepatic low-density lipoprotein receptor (LDL-R) and is therefore a prominent therapeutic target for reducing LDL-cholesterol, In the present study we scanned the related gene of a clinically diagnosed autosomal genetic hypercholesterolemia family for the possible mutations and established eukaryotic expression vector of mutation of proprotein convertase subtilisin/kexin type 9 (PCSK9) gene with gene recombination technique to investigate the contributions of the variation on low density lipoprotein receptor (LDL-R) metabolism and function alternation.Mutation detection was conducted for LDL-R, apolipoprotein B(100) (apoB(100)) and PCSK9 gene with nucleotide sequencing in a Chinese FH family, Proprotein convertase subtilisin-kexin type 9 (PCSK9) provides a key step in LDL metabolism by stimulating LDL receptor degradation., The proprotein convertase subtilisin-kexin type 9 (PCSK9) pathway plays a key role in lipoprotein metabolism by promoting LDL-receptor degradation., Proprotein convertase subtilisin-kexin type 9 (PCSK9) plays a key role in LDL receptor processing., Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the LDL receptor (LDLr) in hepatocytes, and its expression in mouse liver has been shown to decrease with fenofibrate treatment.We developed a sandwich ELISA using recombinant human PCSK9 protein and 2 affinity-purified polyclonal antibodies directed against human PCSK9., Proprotein convertase subtilisin kexin type 9 (PCSK9) enhances the degradation of the LDLR and modulates liver CD81 levels., Low-density lipoprotein (LDL) metabolism is governed by proprotein convertase subtilisin-kexin type 9 (PCSK9), which down-regulates LDL receptor expression, resulting in higher LDL cholesterol (LDL-C)., Proprotein convertase subtilisin kexin type 9 (PCSK9) is gaining attention as a key regulator of serum LDL-cholesterol (LDLC)., The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene regulates cholesterol homoeostasis by accelerating low-density lipoprotein receptor (LDLR) degradation resulting in the decreased catabolism of low-density lipoprotein (LDL) leading to hypercholesterolaemia., Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation., Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted protein that binds to the epidermal growth factor-like-A domain of the low density lipoprotein receptor (LDLR) and mediates LDLR degradation in liver., Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of LDL-cholesterol receptor homeostasis and emerges as a therapeutic target in the prevention of cardiovascular (CV) disease., The present study was conducted to investigate the role of plasma proprotein convertase subtilisin kexin type 9 (PCSK9) levels, a regulator of LDL-receptor expression, in the occurrence of diabetic dyslipidemia.[SEP]Definitions: PCSK9 gene defined as following: This gene is involved in both cholesterol metabolism and protein degradation.. LDL receptor defined as following: Receptors on the plasma membrane of nonhepatic cells that specifically bind LDL. The receptors are localized in specialized regions called coated pits. Hypercholesteremia is caused by an allelic genetic defect of three types: 1, receptors do not bind to LDL; 2, there is reduced binding of LDL; and 3, there is normal binding but no internalization of LDL. In consequence, entry of cholesterol esters into the cell is impaired and the intracellular feedback by cholesterol on 3-hydroxy-3-methylglutaryl CoA reductase is lacking.. low-density lipoprotein receptor defined as following: Low-density lipoprotein receptor (860 aa, ~95 kDa) is encoded by the human LDLR gene. This protein is involved in the endocytosis of cholesterol.. cell surface defined as following: The external part of the cell wall and/or plasma membrane. [GOC:jl, GOC:mtg_sensu, GOC:sm]. cholesterol defined as following: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.. lysosome defined as following: A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes MEMBRANE FUSION. (From Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed).. catalytic domain defined as following: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction.. LDL defined as following: A class of lipoproteins of small size (18-25 nm) and light (1.019-1.063 g/ml) particles with a core composed mainly of CHOLESTEROL ESTERS and smaller amounts of TRIGLYCERIDES. The surface monolayer consists mostly of PHOSPHOLIPIDS, a single copy of APOLIPOPROTEIN B-100, and free cholesterol molecules. The main LDL function is to transport cholesterol and cholesterol esters to extrahepatic tissues.. LDL cholesterol defined as following: Cholesterol which is contained in or bound to low density lipoproteins (LDL), including CHOLESTEROL ESTERS and free cholesterol.. hepatocytes defined as following: The main structural component of the LIVER. They are specialized EPITHELIAL CELLS that are organized into interconnected plates called lobules.. hypercholesterolaemia defined as following: A condition with abnormally high levels of CHOLESTEROL in the blood. It is defined as a cholesterol value exceeding the 95th percentile for the population.. PCSK9 defined as following: Proprotein convertase subtilisin/kexin type 9 (692 aa, ~74 kDa) is encoded by the human PCSK9 gene. This protein is involved in the degradation of low density lipoprotein receptor family proteins.. statins defined as following: Compounds that inhibit HYDROXYMETHYLGLUTARYL COA REDUCTASES. They have been shown to directly lower CHOLESTEROL synthesis.. Proprotein convertase subtilisin-kexin type 9 defined as following: A proprotein convertase that is essential for CHOLESTEROL homeostasis. It binds to and is required for the lysosomal degradation of the LDL RECEPTOR (LDLR); the VLDL receptor, and the APOLIPOPROTEIN E RECEPTOR. It also regulates neuronal APOPTOSIS.. CD81 defined as following: A tetraspanin protein that is involved in a variety of cellular functions including BASEMENT MEMBRANE assembly, and in the formation of a molecular complexes on the surface of LYMPHOCYTES.. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. Proprotein convertase defined as following: A serine endopeptidase that has specificity for cleavage at ARGININE. It cleaves a variety of prohormones including PRO-OPIOMELANOCORTIN, proluteinizing-hormone-releasing hormone, proenkephalins, prodynorphin, and PROINSULIN.. gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. human defined as following: Members of the species Homo sapiens.. hypercholesterolemia defined as following: A laboratory test result indicating an increased amount of cholesterol in the blood.. Proprotein convertase subtilisin/kexin type 9 defined as following: This gene is involved in both cholesterol metabolism and protein degradation..", "label": "no"} {"id": "converted_2310", "sentence1": "Is there an association between carcinoid syndrome and mitral valve disease?", "sentence2": "Other concomitant operations included mitral valve procedure (11%), aortic valve procedure (9%), patent foramen ovale or atrial septal defect closure (23%), cardiac metastasectomies or biopsy (4%), and simultaneous coronary artery bypass (11%). , High circulating serotonin (carcinoid syndrome) and serotoninergic drugs are known to cause valvulopathy that shares pathologic features with DMVD., Surgery included tricuspid valve replacement in all patients, pulmonary valve replacement in 3 and valvectomy in 7, mitral valve replacement in 6 and repair in 1, aortic valve replacement in 4 and repair in 2, CABG in 2, and patent foramen ovale closure in 5. , We report two observations of significant left heart involvement in patients with the carcinoid syndrome assessed by transthoracic and transoesophageal echocardiography. Echocardiographic lesions of this kind have only been reported twice. In the present cases, there was mitral involvement with mitral regurgitation in one case and a mitro-aortic involvement with mitral and aortic regurgitation in the other., An observation of carcinoid syndrome in a woman of 47 suffering from malignant carcinoid of the ileum with metastases into the liver and right ovary is described. The clinical picture included diarrhea, heat waves, bronchospasms, hypertension, hyperserotoninemia, affection of the mitral valve and left atrium. , A case of carcinoid syndrome, stemming from a tumor of the large intestine with hepatic metastases, is reported. Clinical features included cardiac disease with triple valvular lesion: tricuspid insufficiency with stenosis, pulmonary artery stenosis and mitral insufficiency. , High circulating serotonin (carcinoid syndrome) and serotoninergic drugs are known to cause valvulopathy that shares pathologic features with DMVD.[SEP]Definitions: mitral insufficiency defined as following: Backflow of blood from the LEFT VENTRICLE into the LEFT ATRIUM due to imperfect closure of the MITRAL VALVE. This can lead to mitral valve regurgitation.. pulmonary artery stenosis defined as following: A congenital or acquired cardiovascular abnormality characterized by the narrowing of the lumen of the main pulmonary artery or its branches. Signs and symptoms include dyspnea, tachypnea, tachycardia, fatigue, and edema.. tricuspid insufficiency defined as following: Backflow of blood from the RIGHT VENTRICLE into the RIGHT ATRIUM due to imperfect closure of the TRICUSPID VALVE.. hypertension defined as following: Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more.. bronchospasms defined as following: Spasmodic contraction of the smooth muscle of the bronchi.. mitral valve defined as following: The valve between the left atrium and left ventricle of the heart.. valvulopathy defined as following: Pathological conditions involving any of the various HEART VALVES and the associated structures (PAPILLARY MUSCLES and CHORDAE TENDINEAE).. tricuspid valve replacement defined as following: Surgery performed with the purpose of replacing a degenerated, calcified, malformed, dysfunctional, etc. tricuspid valve with bioprosthetic, homograft or autograft valve.. diarrhea defined as following: An increased liquidity or decreased consistency of FECES, such as running stool. Fecal consistency is related to the ratio of water-holding capacity of insoluble solids to total water, rather than the amount of water present. Diarrhea is not hyperdefecation or increased fecal weight.. carcinoid syndrome defined as following: A symptom complex associated with CARCINOID TUMOR and characterized by attacks of severe flushing of the skin, diarrheal watery stools, bronchoconstriction, sudden drops in blood pressure, edema, and ascites. The carcinoid tumors are usually located in the gastrointestinal tract and metastasize to the liver. Symptoms are caused by tumor secretion of serotonin, prostaglandins, and other biologically active substances. Cardiac manifestations constitute CARCINOID HEART DISEASE. (Dorland, 27th ed; Stedman, 25th ed). mitral defined as following: a valve that controls blood flow between heart chambers. intestine defined as following: The section of the alimentary canal from the STOMACH to the ANAL CANAL. It includes the LARGE INTESTINE and SMALL INTESTINE.. cardiac disease defined as following: Pathological conditions involving the HEART including its structural and functional abnormalities.. mitral valve disease defined as following: A heart disorder characterized by a defect in mitral valve structure or function..", "label": "yes"} {"id": "converted_4478", "sentence1": "Is Phospholemman a membrane protein?", "sentence2": " the transmembrane lipoprotein phospholemman (FXYD1), Phospholemman (FXYD1) is a single-transmembrane protein regulator of Na,K-ATPase, expressed strongly in heart, skeletal muscle, and brain and phosphorylated by protein kinases A and C at Ser-68 and Ser-63, respectively., We previously identified FXYD1 (encoding phospholemman; a protein containing the motif phenylalanine-X-tyrosine-aspartate), a gene encoding a transmembrane modulator of the Na, K-ATPase (NKA) enzyme,[SEP]Definitions: gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. Na defined as following: A wild-type zebrafish line, the stock of which was obtained from an area east of Calcutta in a district called Nadia.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. membrane protein defined as following: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors..", "label": "yes"} {"id": "converted_3845", "sentence1": "Do polycomb group proteins (PcG) mediate the formation of chromatin loops?", "sentence2": "A chromatin insulator driving three-dimensional Polycomb response element (PRE) contacts and Polycomb association with the chromatin fiber, the Drosophila gypsy insulator behaves as a conformational chromatin border that is able to prohibit contacts between a Polycomb response element (PRE) and a distal promoter, Polycomb action at a distance can be organized by local chromatin topology, Polycomb repressive complex 2 is recruited through the interaction of CTCF, CTCF governs gene expression by orchestrating chromatin loop structures and by serving as a DNA-binding protein scaffold to recruit and bind polycomb repressive complexes, The chromatin loops completely dissolve, accompanied by loss of PcG proteins and H3K27me3 marks, when Tera-2 cells receive differentiation signals which induce a approximately 60-fold increase in GATA-4 expression., Polycomb-mediated chromatin loops revealed by a subkilobase-resolution chromatin interaction map., es or \"anchors\" are associated with CTCF protein in mammals, loop anchors in Drosophila were found most often in association with the polycomb group (PcG) protein Polycomb (Pc), a subunit of polycomb repressive complex 1 (PRC1). Loops were frequently located within domains of PcG, We also provide novel insight that PcG-occupied and H3K27me3-enriched regions can form chromatin loops and physically interact in cis around a single gene in mammalian cells., Repressive loops within polycomb domains are formed after the midblastula transition between polycomb response elements by the action of GAGA factor and polycomb proteins., PcG proteins, DNA methylation, and gene repression by chromatin looping., Loops were frequently located within domains of PcG-repressed chromatin., iation to proliferation control. Our results revealed a chromatin looping mechanism of long-range control and argue against models involving homogeneous spreading of PcG silencers [SEP]Definitions: PRC1 defined as following: PRC1 (Polycomb repressive complex 1) contains the products of the PcG genes Polycomb, Posterior sex combs, polyhomeotic, Sex combs on midleg, and several other proteins. Preincubation of PRC1 with nucleosomal arrays blocks the ability of these arrays to be remodeled by SWI/SNF. PRC1 and SWI/SNF are likely compete with each other for the nucleosomal template.. gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. PcG defined as following: A family of proteins that play a role in CHROMATIN REMODELING. They are best known for silencing HOX GENES and the regulation of EPIGENETIC PROCESSES.. CTCF defined as following: CCN family member 2 (349 aa, ~38kDa) is encoded by the human CCN2 gene. This protein plays a role in the promotion of proliferation and differentiation of chondrocytes and also mediates heparin- and divalent cation-dependent cell adhesion in many different cell types.. H3K27me3 defined as following: A post-translationally modified form of histone H3 where the lysine residue at position 28 is trimethylated. This modification is associated with formation of heterochromatin and polycomb repressive complex 1 (PRC1).. mammals defined as following: Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young.. chromatin fiber defined as following: A level of DNA packaging in chromatin above that of the nucleosome, the fundamental subunit of chromatin structure. The chromatin fiber has a thickness of about 30 nanometers and results from the folding of a linear array of nucleosomes (thickness about 10 nm) into a more compact fiber.. DNA-binding protein defined as following: Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.. Pc defined as following: A group of inherited ectodermal dysplasias whose most prominent clinical feature is hypertrophic nail dystrophy resulting in PACHYONYCHIA. Several specific subtypes of pachyonychia congenita have been associated with mutations in genes that encode KERATINS.. CTCF protein defined as following: A repressor protein with poly(ADP)-ribose binding activity that binds CHROMATIN and DNA; its structure consisting of 11 CYS2-HIS2 ZINC FINGERS allows it to recognize many different DNA target sites. It functions as a repressor by binding to INSULATOR ELEMENTS and preventing interaction between promoters and nearby enhancers and silencers. It plays a critical role in EPIGENETIC PROCESSES, including GENOMIC IMPRINTING..", "label": "yes"} {"id": "converted_2577", "sentence1": "Is Citrobacter rodentium pathogenic?", "sentence2": "One day after colonization, mice were infected with the colonic pathogen, Citrobacter rodentium., The human pathogen enteropathogenic Escherichia coli (EPEC), as well as the mouse pathogen Citrobacter rodentium, colonize the gut mucosa via attaching and effacing lesion formation and cause diarrheal diseases., EPEC-like mouse pathogen Citrobacter rodentium, Here, we develop a model that provides that link for the investigation of Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli (EPEC). [SEP]Definitions: Escherichia coli defined as following: A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc.. Citrobacter rodentium defined as following: A species of gram-negative bacteria in the genus CITROBACTER, family ENTEROBACTERIACEAE. As an important pathogen of laboratory mice, it serves as a model for investigating epithelial hyperproliferation and tumor promotion. It was previously considered a strain of CITROBACTER FREUNDII.. EPEC defined as following: Strains of ESCHERICHIA COLI characterized by attaching-and-effacing histopathology. These strains of bacteria intimately adhere to the epithelial cell membrane and show effacement of microvilli. In developed countries they are associated with INFANTILE DIARRHEA and infantile GASTROENTERITIS and, in contrast to ETEC strains, do not produce ENDOTOXINS.. human defined as following: Members of the species Homo sapiens..", "label": "yes"} {"id": "converted_3074", "sentence1": "Has strimvelis been approved by the European Medicines Agency?", "sentence2": "Strimvelis (autologous CD34+ cells transduced to express adenosine deaminase [ADA]) is the first ex vivo stem cell gene therapy approved by the European Medicines Agency (EMA), indicated as a single treatment for patients with ADA-severe combined immunodeficiency (ADA-SCID) who lack a suitable matched related bone marrow donor. [SEP]Definitions: ADA-SCID defined as following: Severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency is a form of SCID characterized by profound lymphopenia and very low immunoglobulin levels of all isotypes resulting in severe and recurrent opportunistic infections.. adenosine deaminase defined as following: This gene is involved in nucleotide metabolism and cellular immunity.. EMA defined as following: An autosomal recessive disorder of fatty acid oxidation, and branched chain amino acids (AMINO ACIDS, BRANCHED-CHAIN); LYSINE; and CHOLINE catabolism, that is due to defects in either subunit of ELECTRON TRANSFER FLAVOPROTEIN or its dehydrogenase, electron transfer flavoprotein-ubiquinone oxidoreductase (EC 1.5.5.1).. stem cell defined as following: Relatively undifferentiated cells that retain the ability to divide and proliferate throughout postnatal life to provide progenitor cells that can differentiate into specialized cells.. ADA defined as following: Catalysis of the reaction: acetaldehyde + CoA + NAD+ = acetyl-CoA + NADH + H+. [EC:1.2.1.10].", "label": "yes"} {"id": "converted_809", "sentence1": "Are conserved noncoding elements associated with developmental genes?", "sentence2": "Some characteristics of CNEs include their high frequency in mammalian genomes, their potential regulatory role in gene expression, and their enrichment in gene deserts nearby master developmental genes, we review recent findings that disruptions of CNEs, within or at long distance from the coding sequences of key genes involved in NCC development, result in neurocristopathies via the alteration of tissue- or stage-specific long-distance regulation of gene expression, Genomic regulatory blocks are chromosomal regions spanned by long clusters of highly conserved noncoding elements devoted to long-range regulation of developmental genes, Analysis of CNEs, at least some of which are candidate regulatory elements, suggests that ancestral CNEs partitioned between gene duplicates. These results help explain the evolutionary pathways by which the developmentally important family of FgfD molecules arose and the deduced principles that guided FgfD evolution are likely applicable to the evolution of developmental regulation in many vertebrate multigene families, Pan-vertebrate developmental cis-regulatory elements are discernible as highly conserved noncoding elements (HCNEs) and are often dispersed over large areas around the pleiotropic genes whose expression they control. On the loci of two developmental transcription factor genes, SOX3 and PAX6, we demonstrate that HCNEs conserved between human and zebrafish can be systematically and reliably tested for their regulatory function in multiple stable transgenes in zebrafish, and their genomic reach estimated with confidence using synteny conservation and HCNE density along these loci. HCNEs of both human and zebrafish function as specific developmental enhancers in zebrafish, We show that human HCNEs result in expression patterns in zebrafish equivalent to those in mouse, establishing zebrafish as a suitable model for large-scale testing of human developmental enhancers, HCNEs from the same area often drive overlapping patterns, suggesting that multiple regulatory inputs are required to achieve robust and precise complex expression patterns exhibited by developmental genes, Organization of conserved elements near key developmental regulators in vertebrate genomes, Further positional analysis of these conserved noncoding elements (CNEs) in the genome demonstrates that they cluster around genes involved in developmental regulation, Ancora: a web resource for exploring highly conserved noncoding elements and their association with developmental regulatory genes, Metazoan genomes contain arrays of highly conserved noncoding elements (HCNEs) that span developmental regulatory genes and define regulatory domains, The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development, We found the largest mammal-teleost conserved chromosomal segments to be spanned by highly conserved noncoding elements (HCNEs), their developmental regulatory target genes, and phylogenetically and functionally unrelated \"bystander\" genes., Ancora: a web resource for exploring highly conserved noncoding elements and their association with developmental regulatory genes., Pan-vertebrate developmental cis-regulatory elements are discernible as highly conserved noncoding elements (HCNEs) and are often dispersed over large areas around the pleiotropic genes whose expression they control., Metazoan genomes contain arrays of highly conserved noncoding elements (HCNEs) that span developmental regulatory genes and define regulatory domains., Further positional analysis of these conserved noncoding elements (CNEs) in the genome demonstrates that they cluster around genes involved in developmental regulation., The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs)., Disruption of long-distance highly conserved noncoding elements in neurocristopathies., Fish-mammal genomic comparisons have proved powerful in identifying conserved noncoding elements likely to be cis-regulatory in nature, and the majority of those tested in vivo have been shown to act as tissue-specific enhancers associated with genes involved in transcriptional regulation of development., Despite this, attempts at unearthing genome-wide regulatory elements conserved throughout the vertebrate lineage using BLAST-like approaches have thus far detected noncoding conservation in only a few hundred genes, mostly associated with regulation of transcription and development., Further positional analysis of these conserved noncoding elements (CNEs) in the genome demonstrates that they cluster around genes involved in developmental regulation., We found the largest mammal-teleost conserved chromosomal segments to be spanned by highly conserved noncoding elements (HCNEs), their developmental regulatory target genes, and phylogenetically and functionally unrelated \"bystander\" genes., Organization of conserved elements near key developmental regulators in vertebrate genomes., Pan-vertebrate developmental cis-regulatory elements are discernible as highly conserved noncoding elements (HCNEs) and are often dispersed over large areas around the pleiotropic genes whose expression they control[SEP]Definitions: gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. PAX6 defined as following: This gene plays a role in transcriptional regulation.. genome defined as following: Anatomical set of genes in all the chromosomes.. pleiotropic genes defined as following: A single gene that influences several distinct and seemly unrelated phenotypic outcomes.. conservation defined as following: The maintenance of certain characteristics in an unchanged condition.. SOX3 defined as following: This gene is involved in neuronal differentiation.. human defined as following: Members of the species Homo sapiens.. zebrafish defined as following: An exotic species of the family CYPRINIDAE, originally from Asia, that has been introduced in North America. Zebrafish is a model organism for drug assay and cancer research.. transgenes defined as following: Genes that are introduced into an organism using GENE TRANSFER TECHNIQUES.. transcription factors defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.. developmental genes defined as following: Genes that determine the fate of a cell or CELLS in a region of the embryo during EMBRYONIC DEVELOPMENT.. vertebrate defined as following: Animals having a vertebral column, members of the phylum Chordata, subphylum Craniata comprising mammals, birds, reptiles, amphibians, and fishes..", "label": "yes"} {"id": "converted_1626", "sentence1": "Can adult humans be induced to produce fetal hemoglobin?", "sentence2": " At the time of birth, HbF accounts for approximately 70% of the total Hb. , whereas in the trace amounts of HbF that is found in the adult it reverses to 40:60 because of a gamma- to beta-globin gene switch, With the increased understanding and discovery of molecular regulators of haemoglobin switching, such as BCL11A, new avenues of research may lead ultimately to novel therapeutic, mechanism-based approaches to fetal haemoglobin reactivation in patients., The data suggest that TGF-beta reactivates gamma-globin expression, combined with a sequential stimulation and suppression of erythropoiesis. [SEP]Definitions: TGF-beta defined as following: A recombinant therapeutic agent which is chemically identical to or similar to the endogenous cytokine transforming growth factor-beta (TGF-beta) with proapoptotic and antineoplastic properties. TGF-beta may suppress tumor cell growth by decreasing the expression of cyclin D1, a cell cycle regulatory protein, and downregulating the expression of the oncogene c-myc. This agent is also involved in T cell-mediated immunosuppression by CD4+CD25+ T cells, which permits cancer cells to evade immune surveillance. (NCI04). BCL11A defined as following: B-cell lymphoma/leukemia 11A (835 aa, ~91 kDa) is encoded by the human BCL11A gene. This protein is involved in the regulation of both cell projection formation and lymphopoiesis.. gamma-globin defined as following: A type of gamma-globin encoded by the A gamma globin gene on CHROMOSOME 11.. HbF defined as following: The major component of hemoglobin in the fetus. This HEMOGLOBIN has two alpha and two gamma polypeptide subunits in comparison to normal adult hemoglobin, which has two alpha and two beta polypeptide subunits. Fetal hemoglobin concentrations can be elevated (usually above 0.5%) in children and adults affected by LEUKEMIA and several types of ANEMIA.. haemoglobin defined as following: The oxygen-carrying proteins of ERYTHROCYTES. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements.. fetal hemoglobin defined as following: The major component of hemoglobin in the fetus. This HEMOGLOBIN has two alpha and two gamma polypeptide subunits in comparison to normal adult hemoglobin, which has two alpha and two beta polypeptide subunits. Fetal hemoglobin concentrations can be elevated (usually above 0.5%) in children and adults affected by LEUKEMIA and several types of ANEMIA.. humans defined as following: Members of the species Homo sapiens..", "label": "yes"} {"id": "converted_3114", "sentence1": "Is there any association between suicide and autism in adolescents, yes or no?", "sentence2": ": In all subjects from our research on PubMed, 21.3% of subjects with autism spectrum disorder reported suicidal ideation, have attempted suicide or died by suicide (115 out of 539 subjects) and 7.7% of subjects supported for suicidal thoughts or attempted suicide exhibited an autism spectrum disorder (62 out of 806 subjects), all ages combined. , Suicide attempts are accompanied by a willingness for death and can lead to suicide. They are more common in high-functioning autism and Asperger subjects., A total sample of 10 adolescents and young adults diagnosed with AS was obtained. The high proportion of respondents with scores above the cutoff point on the overt victimization and relational victimization scales suggests that these adolescents and young adults experienced high levels of victimization. Of the sample, 20 percent met criteria for a diagnosis of Major Depressive Disorder, 30 percent met criteria for Generalized Anxiety Disorder and 50 percent had clinically significant level of suicidal ideation., Previous studies reported a high prevalence of depression among patients with autism spectrum disorder (ASD) and suggested a relationship between ASD and suicidality, Patients with ASD had an increased risk of suicide attempts compared with those without ASD., The suicidal behaviors are frequently observed in the adolescents and adults with an ASD without intellectual deficience. , Suicide is a major problem in Western society. However we have very little understanding of suicidal behaviour among individuals with autism spectrum disorders. , The available research provides little empirical evidence for the processes underlying suicidal behaviour in adolescents and young adults with autism, The present study aims to assess the rate of suicidality (suicidal ideation, behaviors and attempts) and associated risk factors for suicidality in high functioning ASD, here is a lack of clinical awareness on suicidal behaviors of children and adolescents with autism spectrum disorder (ASD), suicidality in children and adolescents with diagnosis of high functioning autism spectrum disorder , Consistent with the previous findings, rate of suicidality is higher in individuals with ASD, Detection of Suicidality in Adolescents with Autism Spectrum Disorders, Over 15% of young people with autism spectrum disorders (ASD) will contemplate or attempt suicide during adolescence. Yet,, Until recently, suicidality in autism spectrum disorder (ASD) was rarely discussed. , Suicidality in Autism Spectrum Disorder., highlighted not only that suicidal thoughts and suicide attempts can occur in adolescents and young adults with ASD, but also that suicidality is likely more common in ASD than in the general population. , The emerging studies indicate that the increased risk of self-injurious behavior in younger and less cognitively able children with ASD3,4 is matched by an increased risk of suicidality in those at a more advanced developmental level., RESULTS\nIn all subjects from our research on PubMed, 21.3% of subjects with autism spectrum disorder reported suicidal ideation, have attempted suicide or died by suicide (115 out of 539 subjects) and 7.7% of subjects supported for suicidal thoughts or attempted suicide exhibited an autism spectrum disorder (62 out of 806 subjects), all ages combined., Risk of Suicide Attempts Among Adolescents and Young Adults With Autism Spectrum Disorder: A Nationwide Longitudinal Follow-Up Study., Although the suicide risk of autism spectrum disorder (ASD) has been suggested to be higher than previously recognized, there are few case reports focusing on the process for preventing suicide reattempts.[SEP]Definitions: death defined as following: Irreversible cessation of all bodily functions, manifested by absence of spontaneous breathing and total loss of cardiovascular and cerebral functions.. autism defined as following: A disorder beginning in childhood. It is marked by the presence of markedly abnormal or impaired development in social interaction and communication and a markedly restricted repertoire of activity and interest. Manifestations of the disorder vary greatly depending on the developmental level and chronological age of the individual. (DSM-V). Autism Spectrum Disorder defined as following: A category of developmental disorders characterized by impaired communication and socialization skills. The impairments are incongruent with the individual's developmental level or mental age. These disorders can be associated with general medical or genetic conditions.. self-injurious behavior defined as following: Behavior in which persons hurt or harm themselves without the motive of suicide or of sexual deviation.. autism spectrum disorders defined as following: A spectrum of developmental disorders that includes autism, Asperger syndrome, and Rett syndrome. Signs and symptoms include poor communication skills, defective social interactions, and repetitive behaviors.. Suicidality defined as following: Thoughts of taking one's own life.. ASD defined as following: Developmental abnormalities in any portion of the ATRIAL SEPTUM resulting in abnormal communications between the two upper chambers of the heart. Classification of atrial septal defects is based on location of the communication and types of incomplete fusion of atrial septa with the ENDOCARDIAL CUSHIONS in the fetal heart. They include ostium primum, ostium secundum, sinus venosus, and coronary sinus defects..", "label": "yes"} {"id": "converted_2215", "sentence1": "Does the histone chaperone ASF1 interact with histones H1/H2?", "sentence2": "The C terminus of the histone chaperone Asf1 cross-links to histone H3 in yeast and promotes interaction with histones H3 and H4., The central histone H3/H4 chaperone Asf1 comprises a highly conserved globular core and a divergent C-terminal tail. , The histone H3-H4 chaperone Asf1 is involved in chromatin assembly (or disassembly), histone exchange, regulation of transcription, and chromatin silencing in several organisms. , An ASF1-EGFP fusion protein localizes to the nucleus. By tandem-affinity purification/mass spectrometry as well as yeast two-hybrid analysis, we identified histones H3 and H4 as ASF1 interaction partners. , This inhibition requires Asf1 binding to H3-H4 and Rtt109 KAT activity, but not tail acetylation of H3-H4 or K56 acetylation of H3. , Asf1 is a conserved histone H3/H4 chaperone that can assemble and disassemble nucleosomes and promote histone acetylation. , Here we characterize further interactions between budding yeast (Saccharomyces cerevisiae) Asf1 and Set2 using assays of intragenic transcription, H3/H4 posttranslational modification, coding region cross-linking of Asf1 and Set2, and cooccurrence of Asf1 and Set2 in protein complexes. , Consistent with this possibility, we show that Asf1 stimulates Set2 occupancy of the coding region of a highly transcribed gene by a mechanism that depends on Asf1 binding to H3/H4. , Drosophila histones H3 and H4 can also be produced as a soluble (H3H4)(2) heterotetrameric complex if they are co-expressed with the histone chaperone Asf1., Structure and function of the histone chaperone CIA/ASF1 complexed with histones H3 and H4., Newly synthesized histones H3-H4 first bind histone chaperone Asf1 and are then transferred to other chaperones for nucleosome assembly, The C terminus of the histone chaperone Asf1 cross-links to histone H3 in yeast and promotes interaction with histones H3 and H4, Histone chaperone Asf1 is required for histone H3 lysine 56 acetylation, a modification associated with S phase in mitosis and meiosis, Antisilencing function 1 (ASF1) is a major histone H3-H4 chaperone that deposits histones H3 and H4 onto DNA, Rtt109, a recently discovered histone acetyltransferase (HAT) from Saccharomyces cerevisiae, functions with the histone chaperone Asf1 to acetylate lysine K56 on histone H3 (H3K56), a modification associated with newly synthesized histones, In this issue of Cell, English et al. present the first crystal structure of a histone chaperone (Asf1) bound to histones (the H3/H4 heterodimer), By tandem-affinity purification/mass spectrometry as well as yeast two-hybrid analysis, we identified histones H3 and H4 as ASF1 interaction partners., Anti-silencing function 1 (Asf1) is a highly conserved chaperone of histones H3/H4 that assembles or disassembles chromatin during transcription, replication, and repair., Analysis of a panel of Asf1 mutations that modulate the ability of Asf1 to bind to histones H3/H4 demonstrates that the histone binding activity of Asf1 is required for the acetylation of Lys-9 and Lys-56 on newly synthesized H3., Thus Rad53 competes with histones H3-H4 and cochaperones HirA/CAF-I for binding to Asf1., Structure and function of the histone chaperone CIA/ASF1 complexed with histones H3 and H4., Currently, the best-characterized chaperone-histone interaction is that between the ubiquitous chaperone Asf1 and a dimer of H3 and H4.[SEP]Definitions: chromatin assembly defined as following: The assembly of DNA, histone proteins, other associated proteins, and sometimes RNA, into chromatin structure, beginning with the formation of the basic unit, the nucleosome, followed by organization of the nucleosomes into higher order structures, ultimately giving rise to a complex organization of specific domains within the nucleus. [PMID:20404130]. yeast defined as following: A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as \"baker's\" or \"brewer's\" yeast. The dried form is used as a dietary supplement.. DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. histones defined as following: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each.. HAT defined as following: Class of enzymes that catalyze the acetylation of specific lysine residues of histones, proteins that organize eukaryotic DNA into chromatin. Among the proteins that exhibit histone acetyltransferase activity are various transcription factor coactivators. E.C. 2.3.1.48.. H4 defined as following: This gene plays a role in mitogenesis and differentiation.. Set2 defined as following: Human SETD2 is located in the vicinity of 3p21.31 and is approximately 108 kb in length. This allele, which encodes histone-lysine N-methyltransferase SETD2 protein, may play a role in transcriptional activation and epigenetic modification of chromatin.. histone H3 defined as following: Histone H3 is a core subunit of the eukaryotic nucleosome complex. Histones are basic nuclear proteins responsible for the nucleosome structure of chromatin. Repeating nucleosome units contain two molecules each of Histones H2A, H2B, H3, and H4 that form an octamer complex around which approximately 146 base pairs of DNA is wrapped. Linker Histone H1 interacts with DNA between nucleosome units in mediating chromatin compaction into higher order structures. (NCI). chromatin defined as following: The ordered and organized complex of DNA, protein, and sometimes RNA, that forms the chromosome. [GOC:elh, PMID:20404130]. nucleosome assembly defined as following: The aggregation, arrangement and bonding together of a nucleosome, the beadlike structural units of eukaryotic chromatin composed of histones and DNA. [GOC:mah]. modification defined as following:Respond with exceptions, completions and modifications or revisions done before completion
. organisms defined as following: A living entity.. nucleus defined as following: Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed). dimer defined as following: compound formed by the union of two radicals or two molecules of a simpler compound; a polymer formed from two molecules of a monomer.. coding region defined as following: A sequence of successive nucleotide triplets that are read as CODONS specifying AMINO ACIDS and begin with an INITIATOR CODON and end with a stop codon (CODON, TERMINATOR)..", "label": "no"} {"id": "converted_1942", "sentence1": "Is pseudouridine a RNA modification?", "sentence2": "Pseudouridine (Ψ) is the most abundant of>150 nucleoside modifications in RNA. , The number and position of the pseudouridines of Haloarcula marismortui and Deinococcus radiodurans large subunit RNA have been determined by a combination of total nucleoside analysis by HPLC-mass spectrometry and pseudouridine sequencing by the reverse transcriptase method and by LC/MS/MS., Pseudouridine is the most abundant of more than 100 chemically distinct natural ribonucleotide modifications.[SEP]Definitions: position defined as following: A reference to the alignment of an object, a particular situation or view of a situation, or the location of an object.. Pseudouridine defined as following: A naturally-occurring isomer of URIDINE found in RNA, in which ribosyl is attached to a carbon instead of a nitrogen atom.. RNA defined as following: A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed). chemically defined as following: A substance with a defined atomic or molecular structure that results from, or takes part in, reactions involving changes in its structure, composition, or properties.. Haloarcula marismortui defined as following: A species of halophilic archaea distinguished by its production of acid from sugar. This species was previously called Halobacterium marismortui.. RNA modification defined as following: The covalent alteration of one or more nucleotides within an RNA molecule to produce an RNA molecule with a sequence that differs from that coded genetically. [GOC:go_curators, ISBN:1555811337].", "label": "yes"} {"id": "converted_758", "sentence1": "Is PLK2 involved in alpha-synuclein phosphorylation in the nervous system?", "sentence2": "Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system, Here we submit evidence that polo-like kinase 2 (PLK2, also known as serum-inducible kinase or SNK) is a principle contributor to alpha-synuclein phosphorylation at Ser-129 in neurons, PLK2 directly phosphorylates alpha-synuclein at Ser-129 in an in vitro biochemical assay, Inhibitors of PLK kinases inhibited alpha-synuclein phosphorylation both in primary cortical cell cultures and in mouse brain in vivo, specific knockdown of PLK2 expression by transduction with short hairpin RNA constructs or by knock-out of the plk2 gene reduced p-Ser-129 levels, These results indicate that PLK2 plays a critical role in alpha-synuclein phosphorylation in central nervous system., These results indicate that PLK2 plays a critical role in alpha-synuclein phosphorylation in central nervous system., Here we submit evidence that polo-like kinase 2 (PLK2, also known as serum-inducible kinase or SNK) is a principle contributor to alpha-synuclein phosphorylation at Ser-129 in neurons., Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system., PLK2 directly phosphorylates alpha-synuclein at Ser-129 in an in vitro biochemical assay., Two of these kinases stand out as potential drug targets for novel PD therapy, namely leucine rich repeat kinase 2 (LRRK2) and the alpha-synuclein (α-syn) phosphorylating polo-like kinase 2 (PLK2)., Also, due to the dominant mode of α-syn and LRRK2 inheritance and based on current knowledge of LRRK2 and α-syn phosphorylation by PLK2, inhibition of LRRK2 and PLK2 may constitute a potential therapy for PD., To better understand the role of PLK2 in α-synuclein phosphorylation in vivo, we further evaluated the effect of PLK2 genetic knockdown and pharmacological inhibition on Phospho-α-Syn levels in different brain regions of PLK2 knockout (KO), heterozygous (Het) and wild-type (WT) mice., This PLK2-mediated neuroprotective effect is also dependent on PLK2 activity and α-synuclein phosphorylation., PLK2-mediated degradation of α-synuclein requires both phosphorylation at S129 and PLK2/α-synuclein complex formation., Overexpression of only PLK2 increased phosphorylation of aggregated α-syn at S129, which likely is due to increased phosphorylation of soluble α-syn, which then was incorporated into aggregates., Here we submit evidence that polo-like kinase 2 (PLK2, also known as serum-inducible kinase or SNK) is a principle contributor to alpha-synuclein phosphorylation at Ser-129 in neurons., PLK2 directly phosphorylates alpha-synuclein at Ser-129 in an in vitro biochemical assay., Unlike other kinases reported to partially phosphorylate alpha-syn at Ser-129 in vitro, phosphorylation by PLK2 and PLK3 is quantitative (, Inhibitors of PLK kinases inhibited alpha-synuclein phosphorylation both in primary cortical cell cultures and in mouse brain in vivo., These results indicate that PLK2 plays a critical role in alpha-synuclein phosphorylation in central nervous system, Inhibitors of PLK kinases inhibited alpha-synuclein phosphorylation both in primary cortical cell cultures and in mouse brain in vivo, PLK2 directly phosphorylates alpha-synuclein at Ser-129 in an in vitro biochemical assay, To better understand the role of PLK2 in α-synuclein phosphorylation in vivo, we further evaluated the effect of PLK2 genetic knockdown and pharmacological inhibition on Phospho-α-Syn levels in different brain regions of PLK2 knockout (KO), heterozygous (Het) and wild-type (WT) mice, Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology[SEP]Definitions: Plk-2 defined as following: Serine/threonine-protein kinase PLK2 (685 aa, ~78 kDa) is encoded by the human PLK2 gene. This protein is involved in cell cycle progression, centriole duplication and serine/threonine phosphorylation.. serine defined as following: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from GLYCINE or THREONINE. It is involved in the biosynthesis of PURINES; PYRIMIDINES; and other amino acids.. neurons defined as following: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.. PLK3 defined as following: Serine/threonine-protein kinase PLK3 (646 aa, ~72 kDa) is encoded by the human PLK3 gene. This protein is involved in protein phosphorylation and cell cycle regulation.. alpha-synuclein defined as following: A synuclein that is a major component of LEWY BODIES and plays a role in SYNUCLEINOPATHIES, neurodegeneration and neuroprotection.. LRRK2 defined as following: Leucine-rich repeat serine/threonine-protein kinase 2 (2527 aa, ~286 kDa) is encoded by the human LRRK2 gene. This protein may play a role in protein phosphorylation.. Polo-like kinase 2 defined as following: This gene is involved in normal cell division.. leucine rich repeat kinase 2 defined as following: Leucine-rich repeat serine/threonine-protein kinase 1 (2015 aa, ~225 kDa) is encoded by the human LRRK1 gene. This protein is involved in serine/threonine phosphorylation and osteoclast resorption of bone.. Parkinson's disease defined as following: A progressive, degenerative neurologic disease characterized by a TREMOR that is maximal at rest, retropulsion (i.e. a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression. Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem. LEWY BODIES are present in the substantia nigra and locus coeruleus but may also be found in a related condition (LEWY BODY DISEASE, DIFFUSE) characterized by dementia in combination with varying degrees of parkinsonism. (Adams et al., Principles of Neurology, 6th ed, p1059, pp1067-75). polo-like kinase 2 defined as following: This gene plays a role in mitotic regulation.. PD defined as following: A score of 4 or 5 on a 5-point PET scale with an increase in intensity of uptake from baseline and/or new FDG-avid foci consistent with lymphoma at interim or end of treatment assessment.. PLK defined as following: Serine/threonine-protein kinase PLK1 (603 aa, ~68 kDa) is encoded by the human PLK1 gene. This protein is involved in protein phosphorylation and the regulation of both cell cycle progression and cytokinesis.. PLK2 defined as following: This gene is involved in normal cell division..", "label": "yes"} {"id": "converted_3402", "sentence1": "Does promoter shape vary across populations?", "sentence2": "Promoter shape varies across populations and affects promoter evolution and expression noise., Animal promoters initiate transcription either at precise positions (narrow promoters) or dispersed regions (broad promoters), a distinction referred to as promoter shape. Although highly conserved, the functional properties of promoters with different shapes and the genetic basis of their evolution remain unclear. Here we used natural genetic variation across a panel of 81 Drosophila lines to measure changes in transcriptional start site (TSS) usage, identifying thousands of genetic variants affecting transcript levels (strength) or the distribution of TSSs within a promoter (shape). Our results identify promoter shape as a molecular trait that can evolve independently of promoter strength. Broad promoters typically harbor shape-associated variants, with signatures of adaptive selection. Single-cell measurements demonstrate that variants modulating promoter shape often increase expression noise, whereas heteroallelic interactions with other promoter variants alleviate these effects. These results uncover new functional properties of natural promoters and suggest the minimization of expression noise as an important factor in promoter evolution., Promoter shape varies across populations and affects promoter evolution and expression noise[SEP]Definitions: variants defined as following: An alteration or difference from a norm or standard.. promoter defined as following: A DNA sequence at which RNA polymerase binds and initiates transcription.. TSS defined as following: A rare acute life-threatening systemic bacterial noncontagious illness caused by any of several related staphylococcal exotoxins. It is characterized by high fever, hypotension, rash, multi-organ dysfunction, and cutaneous desquamation during the early convalescent period. The toxins affect the host immune system, causing an exuberant and pathological host inflammatory response. Laboratory findings include leukocytosis, elevated prothrombin time, hypoalbuminemia, hypocalcemia, and pyuria.. transcriptional start site defined as following: The first nucleotide of a transcribed DNA sequence where RNA polymerase (DNA-DIRECTED RNA POLYMERASE) begins synthesizing the RNA transcript.. transcript defined as following: The initial RNA molecule produced by transcription..", "label": "yes"} {"id": "converted_3294", "sentence1": "Is PTEN a tumour suppressor?", "sentence2": "PTEN is a potent tumour suppressor, Genomic aberrations of the PTEN tumour suppressor gene are among the most common in prostate cancer.[SEP]Definitions: Genomic defined as following: The genetic complement of an organism, including all of its GENES, as represented in its DNA, or in some cases, its RNA.. PTEN defined as following: Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (403 aa, ~47 kDa) is encoded by the human PTEN gene. This protein plays a role in signaling and as both a dual-specificity phosphoprotein phosphatase and a lipid phosphatase.. prostate cancer defined as following: A primary or metastatic malignant tumor involving the prostate gland. The vast majority are carcinomas..", "label": "yes"} {"id": "converted_1644", "sentence1": "Is Calcium/Calmodulin dependent protein kinase II (CaMKII) involved in cardiac arrhythmias and heart failure?", "sentence2": "In human hypertrophy, both CaMKII and PKA functionally regulate RyR2 and may induce SR Ca(2+) leak. In the transition from hypertrophy to HF, the diastolic Ca(2+) leak increases and disturbed Ca(2+) cycling occurs. This is associated with an increase in CaMKII- but not PKA-dependent RyR2 phosphorylation. CaMKII inhibition may thus reflect a promising therapeutic target for the treatment of arrhythmias and contractile dysfunction., Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is an enzyme with important regulatory functions in the heart and brain, and its chronic activation can be pathological. CaMKII activation is seen in heart failure, and can directly induce pathological changes in ion channels, Ca(2+) handling and gene transcription., In the recent years, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) was suggested to be associated with cardiac hypertrophy and heart failure but also with arrhythmias both in animal models as well as in the human heart., Calcium-calmodulin-dependent protein kinase II (CaMKII) has emerged as a central mediator of cardiac stress responses which may serve several critical roles in the regulation of cardiac rhythm, cardiac contractility and growth. Sustained and excessive activation of CaMKII during cardiac disease has, however, been linked to arrhythmias, and maladaptive cardiac remodeling, eventually leading to heart failure (HF) and sudden cardiac death. , Overexpression of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in transgenic mice results in heart failure and arrhythmias., From recent studies, it appears evident that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a central role in the arrhythmogenic processes in heart failure by sensing intracellular Ca(2+) and redox stress, affecting individual ion channels and thereby leading to electrical instability in the heart. , CaMKII activation is proarrhythmic in heart failure where myocardium is stretched., The Ca-calmodulin dependent kinase II (CaMKII) seems to be involved in the development of heart failure and arrhythmias and may therefore be a promising target for the development of antiarrhythmic therapies., Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is up-regulated in heart failure and has been shown to cause I(Na) gating changes that mimic those induced by a point mutation in humans that is associated with combined long QT and Brugada syndromes., CaMKII-dependent phosphorylation of Na(V)1.5 at multiple sites (including Thr-594 and Ser-516) appears to be required to evoke loss-of-function changes in gating that could contribute to acquired Brugada syndrome-like effects in heart failure., Because CaMKII expression and activity are increased in cardiac hypertrophy, heart failure, and during arrhythmias both in animal models as well as in the human heart a clinical significance of CaMKII is implied., The multifunctional Ca(2+)- and calmodulin-dependent protein kinase II (CaMKII) is now recognized to play a central role in pathological events in the cardiovascular system. CaMKII has diverse downstream targets that promote vascular disease, heart failure, and arrhythmias, so improved understanding of CaMKII signaling has the potential to lead to new therapies for cardiovascular disease., In our opinion, the multifunctional Ca and calmodulin-dependent protein kinase II (CaMKII) has emerged as a molecule to watch, in part because a solid body of accumulated data essentially satisfy Koch's postulates, showing that the CaMKII pathway is a core mechanism for promoting myocardial hypertrophy and heart failure. Multiple groups have now confirmed the following: (1) that CaMKII activity is increased in hypertrophied and failing myocardium from animal models and patients; (2) CaMKII overexpression causes myocardial hypertrophy and HF and (3) CaMKII inhibition (by drugs, inhibitory peptides and gene deletion) improves myocardial hypertrophy and HF, In contrast, inhibiting the CaMKII pathway appears to reduce arrhythmias and improve myocardial responses to pathological stimuli. , In this review, we discuss the important role of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in the regulation of RyR2-mediated Ca(2+) release. In particular, we examine how pathological activation of CaMKII can lead to an increased risk of sudden arrhythmic death. Finally, we discuss how reduction of CaMKII-mediated RyR2 hyperactivity might reduce the risk of arrhythmias and may serve as a rationale for future pharmacotherapeutic approaches., Transgenic (TG) Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) δ(C) mice develop systolic heart failure (HF). CaMKII regulates intracellular Ca(2+) handling proteins as well as sarcolemmal Na(+) channels. We hypothesized that CaMKII also contributes to diastolic dysfunction and arrhythmias via augmentation of the late Na(+) current (late I(Na)) in early HF (8-week-old TG mice)., Thus, late I(Na) inhibition appears to be a promising option for diastolic dysfunction and arrhythmias in HF where CaMKII is found to be increased., We tested the hypothesis that increased RyR2 phosphorylation by Ca(2+)/calmodulin-dependent protein kinase II is both necessary and sufficient to promote lethal ventricular arrhythmias., CONCLUSIONS: our results suggest that Ca(2+)/calmodulin-dependent protein kinase II phosphorylation of RyR2 Ca(2+) release channels at S2814 plays an important role in arrhythmogenesis and sudden cardiac death in mice with heart failure., Excessive activation of calmodulin kinase II (CaMKII) causes arrhythmias and heart failure, but the cellular mechanisms for CaMKII-targeted proteins causing disordered cell membrane excitability and myocardial dysfunction remain uncertain., Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)delta(C) mice have heart failure and isoproterenol (ISO)-inducible arrhythmias. We hypothesized that CaMKII contributes to arrhythmias and underlying cellular events and that inhibition of CaMKII reduces cardiac arrhythmogenesis in vitro and in vivo., We conclude that CaMKII contributes to cardiac arrhythmogenesis in TG CaMKIIdelta(C) mice having heart failure and suggest the increased SR Ca leak as an important mechanism. Moreover, CaMKII inhibition reduces cardiac arrhythmias in vitro and in vivo and may therefore indicate a potential role for future antiarrhythmic therapies warranting further studies., Ca2+/calmodulin dependent protein kinase II (CaMKII) can phosphorylate RyR2 and modulate its activity. This phosphorylation positively modulates cardiac inotropic function but in extreme situations such as heart failure, elevated CaMKII activity can adversely increase Ca2+ release from the SR and lead to arrhythmogenesis. , Calcium/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase expressed abundantly in the heart. CaMKII targets numerous proteins involved in excitation-contraction coupling and excitability, and its activation may simultaneously contribute to heart failure and cardiac arrhythmias., Under stress conditions, excessive CaMKII activity promotes heart failure and arrhythmias, in part through actions at Ca(2+) homeostatic proteins., Ca-calmodulin-dependent protein kinase II (CaMKII) was recently shown to alter Na(+) channel gating and recapitulate a human Na(+) channel genetic mutation that causes an unusual combined arrhythmogenic phenotype in patients: simultaneous long QT syndrome and Brugada syndrome. CaMKII is upregulated in heart failure where arrhythmias are common, and CaMKII inhibition can reduce arrhythmias. Thus, CaMKII-dependent channel modulation may contribute to acquired arrhythmic disease. , In heart failure (HF), Ca(2+)/calmodulin kinase II (CaMKII) expression is increased. Altered Na(+) channel gating is linked to and may promote ventricular tachyarrhythmias (VTs) in HF. Calmodulin regulates Na(+) channel gating, in part perhaps via CaMKII., Thus, CaMKII-dependent regulation of Na(+) channel function may contribute to arrhythmogenesis in HF., Recent findings that CaMKII expression in the heart changes during hypertrophy, heart failure, myocardial ischemia, and infarction suggest that CaMKII may be a viable therapeutic target for patients suffering from common forms of heart disease., Overexpression of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in transgenic mice results in heart failure and arrhythmias., Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)delta(C) mice have heart failure and isoproterenol (ISO)-inducible arrhythmias., BACKGROUND: Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)delta(C) mice have heart failure and isoproterenol (ISO)-inducible arrhythmias., CaMKII targets numerous proteins involved in excitation-contraction coupling and excitability, and its activation may simultaneously contribute to heart failure and cardiac arrhythmias., Calcium/calmodulin-dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure., From recent studies, it appears evident that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a central role in the arrhythmogenic processes in heart failure by sensing intracellular Ca(2+) and redox stress, affecting individual ion channels and thereby leading to electrical instability in the heart., Ryanodine receptor phosphorylation, calcium/calmodulin-dependent protein kinase II, and life-threatening ventricular arrhythmias., CaMKII targets numerous proteins involved in excitation-contraction coupling and excitability, and its activation may simultaneously contribute to heart failure and cardiac arrhythmias, The Ca-calmodulin dependent kinase II (CaMKII) seems to be involved in the development of heart failure and arrhythmias and may therefore be a promising target for the development of antiarrhythmic therapies, Calcium-calmodulin kinase II mediates digitalis-induced arrhythmias., Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)delta(C) mice have heart failure and isoproterenol (ISO)-inducible arrhythmias[SEP]Definitions: protein kinase II defined as following: A CALMODULIN-dependent enzyme that catalyzes the phosphorylation of proteins. This enzyme is also sometimes dependent on CALCIUM. A wide range of proteins can act as acceptor, including VIMENTIN; SYNAPSINS; GLYCOGEN SYNTHASE; MYOSIN LIGHT CHAINS; and the MICROTUBULE-ASSOCIATED PROTEINS. (From Enzyme Nomenclature, 1992, p277). Calmodulin defined as following: Calmodulin (149 aa, ~17 kDa) is encoded by the human CALM1, CALM2 and CALM3 genes. This protein plays a role in the regulation of a number of enzymes, ion channels and signaling pathways.. diastolic dysfunction defined as following: Impairment in the filling of the ventricles during diastole. Causes include hypertrophic and restrictive cardiomyopathies, coronary artery disease, chronic high blood pressure, aortic stenosis, and aging.. Ryanodine receptor defined as following: A tetrameric calcium release channel in the SARCOPLASMIC RETICULUM membrane of SMOOTH MUSCLE CELLS, acting oppositely to SARCOPLASMIC RETICULUM CALCIUM-TRANSPORTING ATPASES. It is important in skeletal and cardiac excitation-contraction coupling and studied by using RYANODINE. Abnormalities are implicated in CARDIAC ARRHYTHMIAS and MUSCULAR DISEASES.. ventricular arrhythmias defined as following: A disorder characterized by an electrocardiographic finding of an atypical cardiac rhythm resulting from a pathologic process in the cardiac ventricles.. heart failure defined as following: Heart failure accompanied by EDEMA, such as swelling of the legs and ankles and congestion in the lungs.. cardiac arrhythmias defined as following: Any disturbances of the normal rhythmic beating of the heart or MYOCARDIAL CONTRACTION. Cardiac arrhythmias can be classified by the abnormalities in HEART RATE, disorders of electrical impulse generation, or impulse conduction.. intracellular defined as following: The organized colloidal complex of organic and inorganic substances (as proteins and water) that constitutes the living nucleus, cytoplasm, plastids, and mitochondria of the cell. It is composed mainly of nucleic acids, proteins, lipids, carbohydrates, and inorganic salts.. hypertrophy defined as following: General increase in bulk of a part or organ due to CELL ENLARGEMENT and accumulation of FLUIDS AND SECRETIONS, not due to tumor formation, nor to an increase in the number of cells (HYPERPLASIA).. cardiac disease defined as following: Pathological conditions involving the HEART including its structural and functional abnormalities.. VTs defined as following: The volume of air inspired or expired during each normal, quiet respiratory cycle. Common abbreviations are TV or V with subscript T.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. HF defined as following: Abnormal accumulation of serous fluid in two or more fetal compartments, such as SKIN; PLEURA; PERICARDIUM; PLACENTA; PERITONEUM; AMNIOTIC FLUID. General fetal EDEMA may be of non-immunologic origin, or of immunologic origin as in the case of ERYTHROBLASTOSIS FETALIS.. isoproterenol defined as following: Isopropyl analog of EPINEPHRINE; beta-sympathomimetic that acts on the heart, bronchi, skeletal muscle, alimentary tract, etc. It is used mainly as bronchodilator and heart stimulant.. cardiovascular disease defined as following: Pathological conditions involving the CARDIOVASCULAR SYSTEM including the HEART; the BLOOD VESSELS; or the PERICARDIUM.. hyperactivity defined as following: Increased motor activity that is not goal directed.. myocardial ischemia defined as following: Thickening and loss of elasticity of the CORONARY ARTERIES, leading to progressive arterial insufficiency (CORONARY DISEASE).. CaMKII defined as following: This gene is involved in both protein phosphorylation and signaling.. sudden cardiac death defined as following: Unexpected rapid natural death due to cardiovascular collapse within one hour of initial symptoms. It is usually caused by the worsening of existing heart diseases. The sudden onset of symptoms, such as CHEST PAIN and CARDIAC ARRHYTHMIAS, particularly VENTRICULAR TACHYCARDIA, can lead to the loss of consciousness and cardiac arrest followed by biological death. (from Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed., 2005). myocardial hypertrophy defined as following: Thickening of the myocardium often due to chronic pressure overload.. TG defined as following: Human TG wild-type allele is located in the vicinity of 8q24 and is approximately 268 kb in length. This allele, which encodes thyroglobulin protein, plays a role in the mediation of thyroid hormone production. Mutations in the gene are involved in goiter formation and genetic variants are associated with autoimmune thyroid disease type 3.. PKA defined as following: A group of enzymes that are dependent on CYCLIC AMP and catalyze the phosphorylation of SERINE or THREONINE residues on proteins. Included under this category are two cyclic-AMP-dependent protein kinase subtypes, each of which is defined by its subunit composition.. vascular disease defined as following: Pathological processes involving any of the BLOOD VESSELS in the cardiac or peripheral circulation. They include diseases of ARTERIES; VEINS; and rest of the vasculature system in the body.. point mutation defined as following: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair.. genetic mutation defined as following: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.. SR defined as following: Human SNCG wild-type allele is located within10q23.2-q23.3 and is approximately 13 kb in length. This allele, which encodes gamma-synuclein protein, plays a role in the modulation of axonal architecture and neurofilament integrity. This gene is highly expessed in advanced breast carcinomas, suggesting a correlation between SNCG overexpression and breast tumor development.. cell membrane defined as following: Any of the lipid bilayer membranes within a cell.. Brugada syndrome defined as following: An autosomal dominant defect of cardiac conduction that is characterized by an abnormal ST-segment in leads V1-V3 on the ELECTROCARDIOGRAM resembling a right BUNDLE-BRANCH BLOCK; high risk of VENTRICULAR TACHYCARDIA; or VENTRICULAR FIBRILLATION; SYNCOPAL EPISODE; and possible sudden death. This syndrome is linked to mutations of gene encoding the cardiac SODIUM CHANNEL alpha subunit.. transgenic mice defined as following: Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.. gene deletion defined as following: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus.. Transgenic defined as following: Experimental organism whose genome has been altered by the transfer of a gene or genes from another species or breed.. cardiac hypertrophy defined as following: Enlargement of the HEART due to chamber HYPERTROPHY, an increase in wall thickness without an increase in the number of cells (MYOCYTES, CARDIAC). It is the result of increase in myocyte size, mitochondrial and myofibrillar mass, as well as changes in extracellular matrix.. humans defined as following: Members of the species Homo sapiens.. infarction defined as following: Formation of an infarct, which is NECROSIS in tissue due to local ISCHEMIA resulting from obstruction of BLOOD CIRCULATION, most commonly by a THROMBUS or EMBOLUS.. myocardium defined as following: The muscle tissue of the HEART. It is composed of striated, involuntary muscle cells (MYOCYTES, CARDIAC) connected to form the contractile pump to generate blood flow.. systolic heart failure defined as following: Heart failure caused by abnormal myocardial contraction during SYSTOLE leading to defective cardiac emptying..", "label": "yes"} {"id": "converted_1010", "sentence1": "Is it possible to purify pseudopodia to be used for proteomic analysis?", "sentence2": "we developed an approach to biochemically isolate the pseudopodium from the cell body using 3.0-micrometer porous filters for large-scale quantitative proteomic and phosphoproteomic analysis., Recent work using unique subcellular fractionation methodologies combined with spatial genomic, proteomic, and phosphoproteomic profiling has provided insight into the invadopodiome and pseudopodiome signaling networks , ere, we purified the pseudopodial proteomes, tumor cells were placed on a fibronectin-coated porous membrane to form pseudopodia. According to the motile potentials of the cells, the cells formed pseudopodial microprocesses in the pores. An excimer laser, which was used for ophthalmic refractive surgeries, horizontally ablated cells at the membrane surface to remove the cell body. , we describe methods for the immunoaffinity purification of phosphotyrosine proteins (pY) from pseudopodia that have been isolated from migratory cells. These methods are compatible with current mass spectrometry-based protein identification technologies and can be utilized for the large-scale identification of the pseudopodium pY proteome in various migratory cell lines, including primary and cancer cells.[SEP]Definitions: cancer cells defined as following: Cells of, or derived from, a malignant tumor.. cell body defined as following: The portion of the cell soma (neuronal cell body) that excludes the nucleus. [GOC:jl]. cell lines defined as following: Established cell cultures that have the potential to propagate indefinitely.. tumor cells defined as following: Cells of, or derived from, a tumor.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. pseudopodium defined as following: A dynamic actin-rich extension of the surface of an animal cell used for locomotion or prehension of food..", "label": "yes"} {"id": "converted_3379", "sentence1": "Is NicVAX vaccine effective for smoking cessation?", "sentence2": "CONCLUSION: The nicotine vaccine, NicVAX, does not appear to improve the chances of stopping smoking when given in addition to varenicline and behavioural support., First efficacy results of the nicotine vaccine 3'-AmNic-rEPA (NicVAX) showed that only a subgroup of the top 30% antibody responders achieved higher abstinence rates than placebo. , FINDINGS: There was no difference in abstinence rates between NicVAX and placebo from weeks 9 to 52 [27.7 versus 30.0%, odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.62-1.29] or weeks 37 to 52 (33.8 versus 33.2%, OR = 1.03, 95% CI = 0.73-1.46). The top 30% antibody responders, compared to the placebo group, showed a non-significant tendency towards higher abstinence rates from weeks 37 to 52 (42.2 versus 33.2%, OR = 1.47, 95% CI = 0.89-2.42), Unfortunately, the only vaccine tested in two large, randomized Phase III trials, 3'-amino-methyl-nicotine r-exoprotein A conjugate vaccine (NicVAX(®), Nabi Biopharmaceuticals, MD, USA), did not demonstrate efficacy., The RR for 12 month cessation in active and placebo groups was 1.35 (95% Confidence Interval (CI) 0.82 to 2.22) in the trial of NIC002 and 1.74 (95% CI 0.73 to 4.18) in one NicVAX trial. Two Phase III NicVAX trials, for which full results were not available, reported similar quit rates of approximately 11% in both groups., AUTHORS' CONCLUSIONS: There is currently no evidence that nicotine vaccines enhance long-term smoking cessation., 3'AmNic-rEPA recipients with the highest serum antinicotine Ab response (top 30% by area under the curve (AUC)) were significantly more likely than the placebo recipients (24.6% vs. 12.0%, P = 0.024, odds ratio (OR) = 2.69, 95% confidence interval (CI), 1.14-6.37) to attain 8 weeks of continuous abstinence from weeks 19 through 26. , Recently, the most advanced candidate vaccine, NicVAX, failed to meet the primary endpoint in two large phase III studies, although the correlation of higher abstinence rates in subjects with higher immunity to nicotine was observed., CONCLUSION\n\nThe nicotine vaccine, NicVAX, does not appear to improve the chances of stopping smoking when given in addition to varenicline and behavioural support., First efficacy results of the nicotine vaccine 3'-AmNic-rEPA (NicVAX) showed that only a subgroup of the top 30% antibody responders achieved higher abstinence rates than placebo., CONCLUSION The nicotine vaccine, NicVAX, does not appear to improve the chances of stopping smoking when given in addition to varenicline and behavioural support., First efficacy results of the nicotine vaccine 3'-AmNic-rEPA ( NicVAX ) showed that only a subgroup of the top 30 % antibody responders achieved higher abstinence rates than placebo, First efficacy results of the nicotine vaccine 3'-AmNic-rEPA (NicVAX) showed that only a subgroup of the top 30% antibody responders achieved higher abstinence rates than placebo., FINDINGS\nThere was no difference in abstinence rates between NicVAX and placebo from weeks 9 to 52 [27.7 versus 30.0%, odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.62-1.29] or weeks 37 to 52 (33.8 versus 33.2%, OR = 1.03, 95% CI = 0.73-1.46)., CONCLUSION\nThe nicotine vaccine, NicVAX, does not appear to improve the chances of stopping smoking when given in addition to varenicline and behavioural support.[SEP]Definitions: varenicline defined as following: A partial agonist of the nicotinic acetylcholine receptor (nAChR) subtype alpha4beta2. Nicotine stimulation of central alpha4beta2 nAChRs located at presynaptic terminals in the nucleus accumbens causes the release of the neurotransmitter dopamine, which may be associated with the experience of pleasure; nicotine addiction constitutes a physiologic dependence related to this dopaminergic reward system. As an AChR partial agonist, varenicline attenuates the craving and withdrawal symptoms that occur with abstinence from nicotine but is not habit-forming itself.. antibody defined as following: A protein complex that in its canonical form is composed of two identical immunoglobulin heavy chains and two identical immunoglobulin light chains, held together by disulfide bonds and sometimes complexed with additional proteins. An immunoglobulin complex may be embedded in the plasma membrane or present in the extracellular space, in mucosal areas or other tissues, or circulating in the blood or lymph. [GOC:add, GOC:jl, ISBN:0781765196]. nicotine defined as following: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke..", "label": "no"} {"id": "converted_2955", "sentence1": "Are Copy Number Variants (CNVs) depleted in regions of low mappability?", "sentence2": "Human copy number variants are enriched in regions of low mappability., Applying PopSV to 640 human genomes, we find that low-mappability regions are approximately 5 times more likely to harbor germline CNVs, in stark contrast to the nearly uniform distribution observed for somatic CNVs in 95 cancer genomes. In addition to known enrichments in segmental duplication and near centromeres and telomeres, we also report that CNVs are enriched in specific types of satellite and in some of the most recent families of transposable elements. Finally, using this comprehensive approach, we identify 3455 regions with recurrent CNVs that were missing from existing catalogs. In particular, we identify 347 genes with a novel exonic CNV in low-mappability regions, including 29 genes previously associated with disease., Human copy number variants are enriched in regions of low mappability.Copy number variants (CNVs) are known to affect a large portion of the human genome and have been implicated in many diseases. [SEP]Definitions: variants defined as following: An alteration or difference from a norm or standard.. Human defined as following: Members of the species Homo sapiens.. disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. transposable elements defined as following: Discrete segments of DNA which can excise and reintegrate to another site in the genome. Most are inactive, i.e., have not been found to exist outside the integrated state. DNA transposable elements include bacterial IS (insertion sequence) elements, Tn elements, the maize controlling elements Ac and Ds, Drosophila P, gypsy, and pogo elements, the human Tigger elements and the Tc and mariner elements which are found throughout the animal kingdom.. telomeres defined as following: A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs..", "label": "no"} {"id": "converted_1430", "sentence1": "Is the UGT1A1*28 polymorphism associated with irinotecan response in Caucasians?", "sentence2": "These variants are associated with greater risk of serious toxicity., Homozygous carriers of UGT1A1*28 as well as those with additional UGT1A variants can suffer from severe irinotecan toxicity[SEP]Definitions: variants defined as following: An alteration or difference from a norm or standard.. UGT1A defined as following: Human UGT1A1 wild-type allele is located in the vicinity of 2q37 and is approximately 13 kb in length. This allele, which encodes UDP-glucuronosyltransferase 1-1 protein, plays a role in the transformation of small lipophilic molecules into water-soluble metabolites. Certain allelic variants of the UGT1A1 gene cause Crigler-Najjar syndrome type I, type II, Gilbert syndrome or transient familial neonatal hyperbilirubinemia.. irinotecan defined as following: A semisynthetic derivative of camptothecin, a cytotoxic, quinoline-based alkaloid extracted from the Asian tree Camptotheca acuminata. Irinotecan, a prodrug, is converted to a biologically active metabolite 7-ethyl-10-hydroxy-camptothecin (SN-38) by a carboxylesterase-converting enzyme. One thousand-fold more potent than its parent compound irinotecan, SN-38 inhibits topoisomerase I activity by stabilizing the cleavable complex between topoisomerase I and DNA, resulting in DNA breaks that inhibit DNA replication and trigger apoptotic cell death. Because ongoing DNA synthesis is necessary for irinotecan to exert its cytotoxic effects, it is classified as an S-phase-specific agent.. UGT1A1*28 defined as following: Human UGT1A1*28 allele is located in the vicinity of 2q37 and is approximately 13 kb in length. This allele, which encodes UDP-glucuronosyltransferase 1-1 protein, plays a role in the transformation of small lipophilic molecules into water-soluble metabolites. UGT1A1*28 allele has a polymorphism in the promoter region that is associated with decreased transferase activity and decreases in both tolerance and effectiveness of cancer therapeutics and antiviral drugs.. toxicity defined as following: The finding of bodily harm due to the poisonous effects of something.. polymorphism defined as following: The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level..", "label": "yes"} {"id": "converted_2868", "sentence1": "Is pazopanib an effective treatment of glioblastoma?", "sentence2": "RESULTS: The six-month progression-free survival (PFS) rates in phase II (n = 41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. , Single-agent pazopanib did not prolong PFS in this patient population but showed in situ biological activity as demonstrated by radiographic responses.[SEP]Definitions: glioblastoma defined as following: The most malignant astrocytic tumor (WHO grade 4). It is composed of poorly differentiated neoplastic astrocytes and is characterized by the presence of cellular polymorphism, nuclear atypia, brisk mitotic activity, vascular thrombosis, microvascular proliferation, and necrosis. It typically affects adults and is preferentially located in the cerebral hemispheres. (Adapted from WHO). pazopanib defined as following: A small molecule inhibitor of multiple protein tyrosine kinases with potential antineoplastic activity. Pazopanib selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, c-kit and platelet derived growth factor receptor (PDGF-R), which may result in inhibition of angiogenesis in tumors in which these receptors are upregulated..", "label": "no"} {"id": "converted_3803", "sentence1": "Is Tcf3 associated with the Wnt pathway?", "sentence2": "TCF3, a novel positive regulator of osteogenesis, plays a crucial role in miR-17 modulating the diverse effect of canonical Wnt signaling in different microenvironments, Furthermore, the role of miR-17 was because of its target gene TCF3 (transcription factor 3), a key transcription factor of canonical Wnt pathway., Consequently, Tcf3 knockdown in HCT-R cells restores their sensitivity to the effects of butyrate on Wnt activity and clonal cell growth. Interestingly, the effects of overexpressed Tcf3 differ between HCT-116 and HCT-R cells, In HCT-R cells, however, the overexpression of Tcf3 inhibits Wnt activity, and the cells are still able to proliferate due to the higher expression levels of cell cycle factors, particularly those driving the G(1) to S transition., TCF3 (also known as TCF7L1) is a member of the TCF/LEF transcription factor family that is central in regulating epidermal and embryonic stem cell identity., We found that in contrast to ES cells, where it represses Wnt-pathway target genes, TCF3 promotes the expression of a subset of Wnt-responsive genes in breast cancer cells while repressing another distinct target subset. In the normal mouse mammary gland, Tcf3 is highly expressed in terminal end buds, structures that lead duct development, Tcf3 is essential within the neural ectoderm to maintain anterior character and that its interaction with Hesx1 ensures the repression of Wnt targets in the developing forebrain., We report here that a terminal component of the canonical Wnt pathway in ES cells, the transcription factor T-cell factor-3 (Tcf3), co-occupies promoters throughout the genome in association with the pluripotency regulators Oct4 and Nanog. , Our results suggest that the Wnt pathway, through Tcf3, brings developmental signals directly to the core regulatory circuitry of ES cells to influence the balance between pluripotency and differentiation., The wnt pathway regulates the steady state level of beta-catenin, a transcriptional coactivator for the Tcf3/Lef1 family of DNA binding proteins., Along with evidence that a significant amount of Tcf protein is nonnuclear, these findings suggest that CK1epsilon can modulate wnt signaling in vivo by regulating both the beta-catenin-Tcf3 and the GBP-dsh interfaces., RA increases the expression of ligands and receptors of the noncanonical Wnt pathway (Wnt 5a, 7a, Fzd2 and Fzd6), downstream signaling, and Tcf3 expression., The noncanonical Wnt signaling pathway, through actions of Tcf3, can antagonize the canonical pathway., We report here that a terminal component of the canonical Wnt pathway in ES cells, the transcription factor T-cell factor-3 (Tcf3), co-occupies promoters throughout the genome in association with the pluripotency regulators Oct4 and Nanog., Both Tcf3 depletion and Wnt pathway activation cause increased expression of Oct4, Nanog, and other pluripotency factors and produce ES cells that are refractory to differentiation., Here, we show that injection of a hesx1 morpholino into a 'sensitised' zygotic headless (tcf3) mutant background leads to severe forebrain and eye defects, suggesting an interaction between Hesx1 and the Wnt pathway during zebrafish forebrain development., In addition, we reveal that Tcf3 is essential within the neural ectoderm to maintain anterior character and that its interaction with Hesx1 ensures the repression of Wnt targets in the developing forebrain., TCF3, a novel positive regulator of osteogenesis, plays a crucial role in miR-17 modulating the diverse effect of canonical Wnt signaling in different microenvironments., Our studies located the position of Wnts, downstream LEF1 and TCF3 and stem cell marker proteins, which provide new information in understanding the role of the Wnt singaling pathway in whisker follicles' growth., The transcription factor T-cell factor 3 (TCF3), one component of the Wnt pathway, is known as a cell-intrinsic inhibitor of many pluripotency genes in embryonic stem cells (ESCs) that influences the balance between pluripotency and differentiation., Overexpression of TCF3 attenuated the effect of miR-17 on modulating canonical Wnt signaling., We also find that TCF3 phosphorylation is triggered by canonical Wnt ligands, LRP6, and dominant negative mutants for Axin and GSK3, indicating that this process shares the same upstream regulators with β-catenin stabilization., Wnt pathway stimulation also triggers β-catenin association at regulatory elements with classic Lef/Tcf motifs associated with differentiation programs., We show that menin physically interacts with proteins involved in the canonical Wnt signaling pathway, including beta-catenin, TCF3 (TCFL1), and weakly with TCF4 (TCFL2)., T-cell factor 3 (Tcf3) is a component of the Wnt signaling and a dominant downstream effector in ESCs., factor 3 (Tcf3) is a component of the Wnt signaling and a dominant downstream effector in ESCs. Despit, rt here that a terminal component of the canonical Wnt pathway in ES cells, the transcription factor T-cell factor-3 (Tcf3), co-occupies promoters throughout the genome in association with the pluripotency regulators Oct4 and Nanog. Thus, Tc, Tcf3, is recruited to a palindromic motif enriched in the promoter of cell cycle repressor genes, such as p15Ink4b, p16Ink4a and p19Arf, which mediate the Wnt-dependent anti-proliferative effect in mESCs. Consistently, abl, nonical Wnt/β-catenin pathway controls mESC pluripotency via the Wnt-effector Tcf3. Howe, g increases the dissociation of Tcf1 and the association of Tcf3 at promoters of genes that regulate stemness (e.g., NR5A2, Lrh-1) or differentiation (e.g. Cyr61, Zic5). Knockdown of Tcf3 increases, pport the existence of a regulatory circuit whereby Wnt/β-catenin counteracts Tcf3 repression of Lef1, which subsequently activates target gene expression via Lef1-β-catenin complexes. We propose that the Tcf/, with a requirement for Wnt signalling repression, we highlight a synergistic gene dosage-dependent interaction between Hesx1 and Tcf3, a transcriptional repressor of Wnt target genes, to maintain anterior forebrain identity during mouse embryogenesis. In addition, expression of ligands and receptors of the noncanonical Wnt pathway (Wnt 5a, 7a, Fzd2 and Fzd6), downstream signaling, and Tcf3 expression. RA reduces the phosp, BACKGROUND AND OBJECTIVES: Transcription factor 3 (TCF3) implicates Wnt signaling pathway and regulates E-cadherin expression, which is involved i, We demonstrate that mouse Tcf3 mediates repression of both moderate and high levels of canonical Wnt signaling, by either competing with other members of the Tcf/Lef family for binding to β-catenin, or for binding to DNA., TCF3 is a transcriptional repressor that has been implicated in Wnt signaling and plays key roles in embryonic axis specification and stem cell differentiation., Our data show for the first time that Wnt signaling down-regulates Tcf3 expression, possibly at both the transcriptional and post-transcriptional levels, and thus highlight a novel mechanism through which Wnt signaling inhibits neuro-ectodermal lineage differentiation in mouse embryonic stem cells., We found Tcf3 to be a repressor of Wnt signaling in neocortical NPCs in a reporter gene assay., We found that down-regulation of Tcf3, a member of the Tcf/Lef family and a key player in the control of self-renewal and pluripotency, represents a specific and primary response to Wnt activation in ESCs., Wnt16b also activated the RhoA/Rac1 signaling cascade suggesting the activation of a non-canonical Wnt pathway in TCF3-PBX1 cells., B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with TCF3-PBX1 fusion gene expression has constitutively elevated levels of Wnt16b and ROR1 (receptor tyrosine kinase-like orphan receptor), a ligand and a receptor from the Wnt signaling pathway, respectively., We found that in contrast to ES cells, where it represses Wnt-pathway target genes, TCF3 promotes the expression of a subset of Wnt-responsive genes in breast cancer cells while repressing another distinct target subset., Together, these results suggest that Tcf3 antagonizes Wnt signaling in NPCs, thereby maintaining their undifferentiated state in the neocortex and that Wnt signaling promotes the transition from Tcf3-mediated repression to Tcf1/Lef1-mediated enhancement of Wnt signaling, constituting a positive feedback loop that facilitates neuronal differentiation., We also found that Wnt signal stimulation reduces the level of Tcf3, and increases those of Tcf1 (also known as Tcf7) and Lef1, positive mediators of Wnt signaling, in NPCs., These data suggest that in the absence of Wnt signals, Tcf3 may function in skin SCs to maintain an undifferentiated state and, through Wnt signaling, directs these cells along the hair lineage.[SEP]Definitions: neocortex defined as following: The largest portion of the CEREBRAL CORTEX in which the NEURONS are arranged in six layers in the mammalian brain: molecular, external granular, external pyramidal, internal granular, internal pyramidal and multiform layers.. ROR1 defined as following: Human RORA wild-type allele is located within 15q21-q22 and is approximately 732 kb in length. This allele, which encodes nuclear receptor ROR-alpha protein, plays a role in transcriptional activation and may play a role in organogenesis and differentiation.. genome defined as following: Anatomical set of genes in all the chromosomes.. p19Arf defined as following: Human CDKN2A wild-type allele is located in the vicinity of 9p21 and is approximately 27 kb in length. This allele, which encodes both cyclin-dependent kinase inhibitor 2A protein and and tumor suppressor ARF protein, is involved in cell cycle regulation at the G1 phase. The allele is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene.. p16Ink4a defined as following: Cyclin-dependent kinase inhibitor 2A (156 aa, ~17 kDa) is encoded by the human CDKN2A gene. This protein is involved in the inhibition of both cell proliferation and cell cycle progression.. Nanog defined as following: This gene plays a role in the underlying pluripotency of inner cell mass and embryonic stem cells.. zebrafish defined as following: An exotic species of the family CYPRINIDAE, originally from Asia, that has been introduced in North America. Zebrafish is a model organism for drug assay and cancer research.. Lef1 defined as following: This gene plays a role in both signal transduction and transcription.. RA defined as following: A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated.. p15Ink4b defined as following: Human CDKN2B wild-type allele is located within 9p21 and is approximately 27 kb in length. This allele, which encodes cyclin-dependent kinase 4 inhibitor B protein, plays roles in both the regulation of cell growth and tumor suppression.. transcription factor 3 defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.. DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. transcriptional coactivator defined as following: A transcription cofactor that activates transcription from a RNA polymerase II promoter but does not bind DNA itself.. LRP6 defined as following: Low-density lipoprotein receptor-related protein 6 (1613 aa, ~180 kDa) is encoded by the human LRP6 gene. This protein plays a role in the modulation of cell communication.. tcf3 defined as following: Human TCF7L1 wild-type allele is located in the vicinity of 2p11.2 and is approximately 177 kb in length. This allele, which encodes transcription factor 7-like 1 protein, is involved in Wnt pathway-dependent transcriptional regulation.. Fzd2 defined as following: Frizzled-2 (565 aa, ~64 kDa) is encoded by the human FZD2 gene. This protein is involved in Wnt-mediated G protein-coupled receptor signaling.. Tcf7 defined as following: Transcription factor 7 (384 aa, ~42 kDa) is encoded by the human TCF7 gene. This protein is involved in both thymocyte survival and the regulation of transcription.. TCFL2 defined as following: Human LZTR1 wild-type allele is located in the vicinity of 22q11.21 or within 22q11.1-q11.2 and is approximately 20 kb in length. This allele, which encodes leucine-zipper-like transcriptional regulator 1 protein, may play a role in transcriptional regulation or Golgi functions. Mutation of the gene is associated with Noonan syndrome 10 and increased susceptibility to schwannomatosis 2. Deletion of the gene may be associated with DiGeorge syndrome.. T-cell factor 3 defined as following: A family of DNA-binding proteins that are primarily expressed in T-LYMPHOCYTES. They interact with BETA CATENIN and serve as transcriptional activators and repressors in a variety of developmental processes.. stem cell defined as following: Relatively undifferentiated cells that retain the ability to divide and proliferate throughout postnatal life to provide progenitor cells that can differentiate into specialized cells.. abl defined as following: An autosomal recessive disorder of lipid metabolism. It is caused by mutation of the microsomal triglyceride transfer protein that catalyzes the transport of lipids (TRIGLYCERIDES; CHOLESTEROL ESTERS; PHOSPHOLIPIDS) and is required in the secretion of BETA-LIPOPROTEINS (low density lipoproteins or LDL). Features include defective intestinal lipid absorption, very low serum cholesterol level, and near absent LDL.. transcriptional repressor defined as following: Transcription Repressor/Corepressor Gene encodes Transcriptional Repressor/Corepressor, proteins that can regulate transcription by binding to the operator and causing repression. (from Glick: Glossary of Biochemistry and Molecular Biology). NR5A2 defined as following: This gene is involved in ligand-dependent transcriptional regulation.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. Axin defined as following: Human AXIN1 wild-type allele is located in the vicinity of 16p13.3 and is approximately 65 kb in length. This allele, which encodes axin-1 protein, is involved in the attenuation of the Wnt protein signaling cascade.. receptor tyrosine kinase-like orphan receptor defined as following: A family of cell surface receptors that were originally identified by their structural homology to neurotropic TYROSINE KINASES and referred to as orphan receptors because the associated ligand and signaling pathways were unknown. Evidence for the functionality of these proteins has been established by experiments showing that disruption of the orphan receptor genes results in developmental defects.. terminal defined as following: Being or situated at an end; occurring at or forming an end.. embryonic stem cells defined as following: Cells derived from the BLASTOCYST INNER CELL MASS which forms before implantation in the uterine wall. They retain the ability to divide, proliferate and provide progenitor cells that can differentiate into specialized cells.. Oct4 defined as following: This gene plays a role in early mammalian development.. mutant defined as following: An altered form of an individual, organism, population, or genetic character that differs from the corresponding wild type due to one or more alterations (mutations).. Tcf1 defined as following: Human HNF1A wild-type allele is located in the vicinity of 12q22-qter; 12q24.2 and is approximately 25 kb in length. This allele, which encodes hepatocyte nuclear factor 1-alpha protein, is involved in both transcriptional regulation and DNA binding. Mutation of the gene is associated with familial hepatic adenoma, maturity-onset diabetes of the young type 3 and diabetes mellitus insulin-dependent type 20.. promoter defined as following: A DNA sequence at which RNA polymerase binds and initiates transcription.. GSK3 defined as following: A family of serine/threonine protein kinases that is involved in intracellular signaling, cellular proliferation, cell migration, inflammation and immune responses, glucose regulation, and apoptosis.. miR-17 defined as following: The human MIR17 wild-type allele is located in the vicinity of 13q31.3 and is 83 bases in length. This allele, which encodes MIR17 pre-miRNA, plays a role in many cancers, including lung, liver, colorectal, thyroid, breast, neuroblastoma, leukemia and lymphoma.. TCF4 defined as following: Transcription factor 7-like 2 (619 aa, ~68 kDa) is encoded by the human TCF7L2 gene. This protein is involved in the positive regulation of transcription, cell cycle arrest, apoptosis regulation, cell and tissue differentiation and signal transduction.. TCF7L1 defined as following: Transcription factor 7-like 1 (588 aa, ~63 kDa) is encoded by the human TCF7L1 gene. This protein plays a role in transcriptional regulation that is modulated by the Wnt signaling pathway.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. HCT-116 defined as following: A carcinoma cell line established from an adult male patient with colon carcinoma. HCT-116 cells have a mutation in codon 13 of the ras proto-oncogene.. position defined as following: A reference to the alignment of an object, a particular situation or view of a situation, or the location of an object.. B-cell precursor acute lymphoblastic leukemia defined as following: A type of ALL characterized by elevated levels of B-cell lymphoblasts in the bone marrow and the blood. [NCIT:C8644]. Fzd6 defined as following: Frizzled-6 (706 aa, ~79 kDa) is encoded by the human FZD6 gene. This protein plays a role in G protein-coupled receptor signaling and Wnt binding.. forebrain defined as following: The anterior of the three primitive cerebral vesicles of the embryonic brain arising from the NEURAL TUBE. It subdivides to form DIENCEPHALON and TELENCEPHALON. (Stedmans Medical Dictionary, 27th ed). Tc defined as following: Human CD55 wild-type allele is located in the vicinity of 1q32 and is approximately 40 kb in length. This allele, which encodes complement decay-accelerating factor protein, is involved in the modulation of complement activity.. beta-catenin defined as following: This gene is involved in signal transduction and regulation of transcription.. Cyr61 defined as following: Human CCN1 wild-type allele is located in the vicinity of 1p22.3 and is approximately 3 kb in length. This allele, which encodes CCN family member 1 protein, is involved in heart morphogenesis, angiogenesis, cell proliferation, cell adhesion and the positive regulation of apoptosis.. mouse embryonic stem cells defined as following: PLURIPOTENT STEM CELLS derived from the BLASTOCYST INNER CELL MASS of day 3.5 mouse embryos.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. Tcf3 defined as following: This gene plays a role in catenin beta-1-dependent transcriptional regulation..", "label": "yes"} {"id": "converted_2783", "sentence1": "Can pets affect infant microbiomed?", "sentence2": "Since there is some evidence that pets also alter the gut microbial composition of infants, changes to the gut microbiome are putative pathways by which pet exposure can reduce these risks to health., The impact of pet ownership varies under different birth scenarios; however, in common, exposure to pets increased the abundance of two bacteria, Ruminococcus and Oscillospira, which have been negatively associated with childhood atopy and obesity., As a common effect in all birth scenarios, pre- and postnatal pet exposure enriched the abundance of Oscillospira and/or Ruminococcus (P < 0.05) with more than a twofold greater likelihood of high abundance. Among vaginally born infants with maternal intrapartum antibiotic prophylaxis exposure, Streptococcaceae were substantially and significantly reduced by pet exposure (P < 0.001, FDRp = 0.03), reflecting an 80% decreased likelihood of high abundance (OR 0.20, 95%CI, 0.06-0.70) for pet exposure during pregnancy alone and a 69% reduced likelihood (OR 0.31, 95%CI, 0.16-0.58) for exposure in the pre- and postnatal time periods., Exposure to household furry pets influences the gut microbiota of infant at 3-4 months following various birth scenarios.[SEP]Definitions: atopy defined as following: Human MS4A2 wild-type allele is located within 11q12-q13 and is approximately 10 kb in length. This allele, which encodes high affinity immunoglobulin epsilon receptor subunit beta protein, plays a role in both immunoglobulin binding and mast cell responses.. pet defined as following: An imaging technique using compounds labelled with short-lived positron-emitting radionuclides (such as carbon-11, nitrogen-13, oxygen-15 and fluorine-18) to measure cell metabolism. It has been useful in study of soft tissues such as CANCER; CARDIOVASCULAR SYSTEM; and brain. SINGLE-PHOTON EMISSION-COMPUTED TOMOGRAPHY is closely related to positron emission tomography, but uses isotopes with longer half-lives and resolution is lower.. bacteria defined as following: One of the three domains of life (the others being Eukarya and ARCHAEA), also called Eubacteria. They are unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. Bacteria can be classified by their response to OXYGEN: aerobic, anaerobic, or facultatively anaerobic; by the mode by which they obtain their energy: chemotrophy (via chemical reaction) or PHOTOTROPHY (via light reaction); for chemotrophs by their source of chemical energy: CHEMOLITHOTROPHY (from inorganic compounds) or chemoorganotrophy (from organic compounds); and by their source for CARBON; NITROGEN; etc.; HETEROTROPHY (from organic sources) or AUTOTROPHY (from CARBON DIOXIDE). They can also be classified by whether or not they stain (based on the structure of their CELL WALLS) with CRYSTAL VIOLET dye: gram-negative or gram-positive..", "label": "yes"} {"id": "converted_4701", "sentence1": "Is ASF1 phopshorylated by the Tousled-like kinases?", "sentence2": "Asf1, a key histone H3-H4 chaperone required for this process, is phosphorylated by Tousled-like kinases (TLKs). , The Tousled-like kinases 1 and 2 (TLK1/2) control histone deposition through the ASF1 histone chaperone, The Tousled-like kinases (TLKs) are involved in chromatin assembly, DNA repair, and transcription. Two TLK genes exist in humans, and their expression is often dysregulated in cancer. TLKs phosphorylate Asf1 , TLKs interact specifically (and phosphorylate) with the chromatin assembly factor Asf1, a histone H3-H4 chaperone, TLK1 substrates were identified as the histone H3 and Asf1 (a histone H3/H4 chaperone)[SEP]Definitions: cancer defined as following: A malignant tumor at the original site of growth.. chromatin assembly defined as following: The assembly of DNA, histone proteins, other associated proteins, and sometimes RNA, into chromatin structure, beginning with the formation of the basic unit, the nucleosome, followed by organization of the nucleosomes into higher order structures, ultimately giving rise to a complex organization of specific domains within the nucleus. [PMID:20404130]. humans defined as following: Members of the species Homo sapiens.. histone H3 defined as following: Histone H3 is a core subunit of the eukaryotic nucleosome complex. Histones are basic nuclear proteins responsible for the nucleosome structure of chromatin. Repeating nucleosome units contain two molecules each of Histones H2A, H2B, H3, and H4 that form an octamer complex around which approximately 146 base pairs of DNA is wrapped. Linker Histone H1 interacts with DNA between nucleosome units in mediating chromatin compaction into higher order structures. (NCI). chromatin assembly factor defined as following: A histone chaperone protein that plays a role in the deposition of NUCLEOSOMES on newly synthesized DNA. It is comprised of three different subunits of 48, 60, and 150 kDa molecular size. The 48 kDa subunit, RETINOBLASTOMA-BINDING PROTEIN 4, is also a component of several other protein complexes involved in chromatin remodeling.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "yes"} {"id": "converted_2267", "sentence1": "Is there any role of 5hmC in T-cell development and differentiation?", "sentence2": "We have mapped 5-hydroxymethylcytosine (5hmC) at different stages of T-cell development in the thymus and T-cell differentiation in the periphery. We show that 5hmC is enriched in the gene body of highly expressed genes at all developmental stages and that its presence correlates positively with gene expression. Further emphasizing the connection with gene expression, we find that 5hmC is enriched in active thymus-specific enhancers and that genes encoding key transcriptional regulators display high intragenic 5hmC levels in precursor cells at those developmental stages where they exert a positive effect. Our data constitute a valuable resource that will facilitate detailed analysis of the role of 5hmC in T-cell development and differentiation., We show that 5hmC is enriched in the gene body of highly expressed genes at all developmental stages and that its presence correlates positively with gene expression., Further emphasizing the connection with gene expression, we find that 5hmC is enriched in active thymus-specific enhancers and that genes encoding key transcriptional regulators display high intragenic 5hmC levels in precursor cells at those developmental stages where they exert a positive effect., We show that 5hmC is enriched in the gene body of highly expressed genes at all developmental stages and that its presence correlates positively with gene expression., Here, we report early and widespread 5mC/5hmC remodeling during human CD4(+) T cell differentiation ex vivo at genes and cell-specific enhancers with known T cell function., Our results support 5hmC-mediated DNA de-methylation as a key component of CD4(+) T cell biology in humans, with important implications for gene regulation and lineage commitment., 5hmC plays important roles in regulation of gene expression and differentiation and has been implicated in T cell malignancies and autoimmunity.[SEP]Definitions: T-cell defined as following: Lymphocytes responsible for cell-mediated immunity. Two types have been identified - cytotoxic (T-LYMPHOCYTES, CYTOTOXIC) and helper T-lymphocytes (T-LYMPHOCYTES, HELPER-INDUCER). They are formed when lymphocytes circulate through the THYMUS GLAND and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen.. humans defined as following: Members of the species Homo sapiens.. autoimmunity defined as following: Disorders that are characterized by the production of antibodies that react with host tissues or immune effector cells that are autoreactive to endogenous peptides.. thymus defined as following: A plant genus of the family LAMIACEAE best known for the thyme spice added to foods.. precursor cells defined as following: Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "yes"} {"id": "converted_2421", "sentence1": "Is patisiran currently (November 2017) in clinical phase II trials?", "sentence2": "This review addresses nine small-interfering RNAs (siRNAs) and one unique microRNA (miRNA) inhibitor, which entered the phase 2-3 clinical trials. The siRNAs in focus are PF-04523655, TKM-080301, Atu027, SYL040012, SYL1001, siG12D-LODER (phase 2), QPI-1002, QPI-1007, and patisiran (phase 3). , patisiran (phase 3), Phase 3 APOLLO study, a randomized, double-blind, placebo-controlled, global study to evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy, Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study.[SEP]Definitions: microRNA defined as following: Small double-stranded, non-protein coding RNAs, 21-25 nucleotides in length generated from single-stranded microRNA gene transcripts by the same RIBONUCLEASE III, Dicer, that produces small interfering RNAs (RNA, SMALL INTERFERING). They become part of the RNA-INDUCED SILENCING COMPLEX and repress the translation (TRANSLATION, GENETIC) of target RNA by binding to homologous 3'UTR region as an imperfect match. The small temporal RNAs (stRNAs), let-7 and lin-4, from C. elegans, are the first 2 miRNAs discovered, and are from a class of miRNAs involved in developmental timing.. polyneuropathy defined as following: Diseases of multiple peripheral nerves simultaneously. Polyneuropathies usually are characterized by symmetrical, bilateral distal motor and sensory impairment with a graded increase in severity distally. The pathological processes affecting peripheral nerves include degeneration of the axon, myelin or both. The various forms of polyneuropathy are categorized by the type of nerve affected (e.g., sensory, motor, or autonomic), by the distribution of nerve injury (e.g., distal vs. proximal), by nerve component primarily affected (e.g., demyelinating vs. axonal), by etiology, or by pattern of inheritance..", "label": "no"} {"id": "converted_3570", "sentence1": "Is palbociclib effective for glioblastoma?", "sentence2": "Although further research is needed, cyclin-dependent kinase 4/6 inhibitors represent intriguing developments in the treatment of various malignancies, including those with such poor prognoses as glioblastoma multiforme, mantle cell lymphoma, and metastatic melanoma., CONCLUSION: In this trial, despite adequate tissue PK, palbociclib monotherapy was not an effective treatment for recurrent glioblastoma., CONCLUSION\n\nIn this trial, despite adequate tissue PK, palbociclib monotherapy was not an effective treatment for recurrent glioblastoma., CONCLUSION In this trial, despite adequate tissue PK, palbociclib monotherapy was not an effective treatment for recurrent glioblastoma., CONCLUSION\nIn this trial, despite adequate tissue PK, palbociclib monotherapy was not an effective treatment for recurrent glioblastoma.[SEP]Definitions: mantle cell lymphoma defined as following: A form of non-Hodgkin lymphoma having a usually diffuse pattern with both small and medium lymphocytes and small cleaved cells. It accounts for about 5% of adult non-Hodgkin lymphomas in the United States and Europe. The majority of mantle-cell lymphomas are associated with a t(11;14) translocation resulting in overexpression of the CYCLIN D1 gene (GENES, BCL-1).. malignancies defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. PK defined as following: ATP:pyruvate 2-O-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (L, R, M1, and M2). Deficiency of the enzyme results in hemolytic anemia. EC 2.7.1.40.. glioblastoma defined as following: The most malignant astrocytic tumor (WHO grade 4). It is composed of poorly differentiated neoplastic astrocytes and is characterized by the presence of cellular polymorphism, nuclear atypia, brisk mitotic activity, vascular thrombosis, microvascular proliferation, and necrosis. It typically affects adults and is preferentially located in the cerebral hemispheres. (Adapted from WHO). cyclin-dependent kinase defined as following: This gene is involved in the cellular transition from the G1/S phase and from the G2/M phase of the cell cycle..", "label": "no"} {"id": "converted_3707", "sentence1": "Has MLE4901 been tested in phase III clinical trials?", "sentence2": "METHODS\n\nThis phase 2, randomised, double-blind, placebo-controlled, single-centre, crossover trial assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901) on menopausal hot flushes., Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial.[SEP]Definitions: Neurokinin 3 receptor defined as following: A class of cell surface receptors for tachykinins that prefers neurokinin B (neurokinin beta, neuromedin K) over other tachykinins. Neurokinin-3 (NK-3) receptors have been cloned and are members of the G-protein coupled receptor superfamily. They have been found in the central nervous system and in peripheral tissues..", "label": "no"} {"id": "converted_1302", "sentence1": "Does thyroid hormone signaling affect microRNAs expression in the heart?", "sentence2": "e show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a., On the other hand, T₃ treatment increased miR-350 expression., Through a bioinformatics screening using TargetScan, we identified thyroid hormone receptor β1 (TRβ1), which negatively regulates β-MHC transcription, as a target of miR-27a, hese findings suggested that miR-27a regulates β-MHC gene expression by targeting TRβ1 in cardiomyocytes., We found that a cardiac-specific microRNA (miR-208) encoded by an intron of the alphaMHC gene is required for cardiomyocyte hypertrophy, fibrosis, and expression of betaMHC in response to stress and hypothyroidism., Moreover, miR-27a was demonstrated to modulate β-MHC gene regulation via thyroid hormone signaling and to be upregulated during the differentiation of mouse embryonic stem (ES) cells or in hypertrophic hearts in association with β-MHC gene upregulation.[SEP]Definitions: fibrosis defined as following: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury.. thyroid hormone defined as following: Natural hormones secreted by the THYROID GLAND, such as THYROXINE, and their synthetic analogs.. MED13 defined as following: This gene is involved in mediator complex-dependent transcriptional regulation.. intron defined as following: Sequences of DNA in the genes that are located between the EXONS. They are transcribed along with the exons but are removed from the primary gene transcript by RNA SPLICING to leave mature RNA. Some introns code for separate genes.. nuclear hormone receptors defined as following: Nuclear hormone receptors constitute a superfamily of structurally related ligand binding transcription factors that includes the steroid receptors, thyroid hormone receptors, vitamin D and retinoid receptors, and orphan receptors for which ligands have not yet been found.. Mediator complex defined as following: A protein complex that is involved in the initiation of transcription. This complex is composed of over 30 protein subunits, which binds to the RNA polymerase II holoenzyme complex and facilitates the interaction of transcription factors with the polymerase.. thyroid hormone receptor β1 defined as following: Specific high affinity binding proteins for THYROID HORMONES in target cells. They are usually found in the nucleus and regulate DNA transcription. These receptors are activated by hormones that leads to transcription, cell differentiation, and growth suppression. Thyroid hormone receptors are encoded by two genes (GENES, ERBA): erbA-alpha and erbA-beta for alpha and beta thyroid hormone receptors, respectively.. hypothyroidism defined as following: A syndrome that results from abnormally low secretion of THYROID HORMONES from the THYROID GLAND, leading to a decrease in BASAL METABOLIC RATE. In its most severe form, there is accumulation of MUCOPOLYSACCHARIDES in the SKIN and EDEMA, known as MYXEDEMA. It may be primary or secondary due to other pituitary disease, or hypothalamic dysfunction.. cardiomyocytes defined as following: Striated muscle cells found in the heart. They are derived from cardiac myoblasts (MYOBLASTS, CARDIAC).. microRNAs defined as following: Small double-stranded, non-protein coding RNAs, 21-25 nucleotides in length generated from single-stranded microRNA gene transcripts by the same RIBONUCLEASE III, Dicer, that produces small interfering RNAs (RNA, SMALL INTERFERING). They become part of the RNA-INDUCED SILENCING COMPLEX and repress the translation (TRANSLATION, GENETIC) of target RNA by binding to homologous 3'UTR region as an imperfect match. The small temporal RNAs (stRNAs), let-7 and lin-4, from C. elegans, are the first 2 miRNAs discovered, and are from a class of miRNAs involved in developmental timing..", "label": "yes"} {"id": "converted_835", "sentence1": "Is metabolic syndrome related with cardiovascular disease?", "sentence2": "The metabolic syndrome (MetS) is characterized by a cluster of risk factors including central obesity, hypertension, dyslipidemia and insulin resistance, The MetS is associated with an increased risk for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). , As a molecular link between metabolic signals, inflammation, and vascular dysfunction, resistin can be proposed as playing a significant role in the heightened inflammatory state induced by metabolic stress linked to excessive caloric intake, thus contributing to the risk for metabolic syndrome (MetS), type 2 diabetes (T2DM), and cardiovascular disease (CVD). , The metabolic syndrome (MetS) is associated with a higher risk for both, type 2 diabetes mellitus and cardiovascular disease. , arotid intima-media thickness (CIMT) has been widely used as a surrogate marker of atherosclerosis and cardiovascular disease (CVD)[SEP]Definitions: resistin defined as following: Resistin (108 aa, ~11 kDa) is encoded by the human RETN gene. This protein plays a role in the regulation of insulin-mediated glucose metabolism.. MetS defined as following: Human ETV3 wild-type allele is located within 1q21-q23 and is approximately 17 kb in length. This allele, which encodes ETS translocation variant 3 protein, is involved in the repression of transcription by RNA polymerase II.. hypertension defined as following: Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more.. atherosclerosis defined as following: Thickening and loss of elasticity of the walls of ARTERIES of all sizes. There are many forms classified by the types of lesions and arteries involved, such as ATHEROSCLEROSIS with fatty lesions in the ARTERIAL INTIMA of medium and large muscular arteries.. inflammation defined as following: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.. cardiovascular disease defined as following: Pathological conditions involving the CARDIOVASCULAR SYSTEM including the HEART; the BLOOD VESSELS; or the PERICARDIUM.. CVD defined as following: A spectrum of pathological conditions of impaired blood flow in the brain. They can involve vessels (ARTERIES or VEINS) in the CEREBRUM, the CEREBELLUM, and the BRAIN STEM. Major categories include INTRACRANIAL ARTERIOVENOUS MALFORMATIONS; BRAIN ISCHEMIA; CEREBRAL HEMORRHAGE; and others.. metabolic syndrome defined as following: A combination of medical conditions that when present, increase the risk of heart attack, stroke, and diabetes mellitus. It includes the following medical conditions: increased blood pressure, central obesity, dyslipidemia, impaired glucose tolerance, and insulin resistance.. dyslipidemia defined as following: A lipoprotein metabolism disorder characterized by decreased levels of high-density lipoproteins, or elevated levels of plasma cholesterol, low-density lipoproteins and/or triglycerides..", "label": "yes"} {"id": "converted_1487", "sentence1": "Does Serca2a bind PLN in the heart?", "sentence2": "The human phospholamban Arg14-deletion mutant localizes to plasma membrane and interacts with the Na/K-ATPase., Moreover, PLN-R14Del did not co-immunoprecipitate with SERCA2a (as did WT-PLN),, n this review, we attempted to highlight the functional significance of PLN in vertebrate cardiac physiology. We will refer to the huge literature on mammals in order to describe the molecular characteristics of this protein, its interaction with SERCA2a, There is clear evidence for direct regulatory protein-protein interactions between phospholamban (PLN) and the Ca2+-ATPase of cardiac sarcoplasmic reticulum (SERCA2a) in cytoplasmic domains, These results suggest that PLN modulates the apparent Ca2+ affinity of SERCA2a through intramembrane interactions, which are disrupted at long range and in concert with disruption of the well characterized cytoplasmic interactions., Phospholamban (PLN), a homopentameric, integral membrane protein, reversibly inhibits cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity through intramembrane interactions., The concentration of this inhibited complex is determined by the dissociation constant for the PLN pentamer (which is mutation-sensitive) and by the dissociation constant for the PLN/SERCA2a heterodimer (which is likely to be mutation-sensitive)., These results support the proposal that PLN inhibition of SERCA2a involves, first, depolymerization of PLN and, second, the formation of inhibitory interactions between monomeric PLN and SERCA2a., SLN and PLN appear to bind to the same regulatory site in SERCA. However, in a ternary complex, PLN occupies the regulatory site and SLN binds to the exposed side of PLN and to SERCA., Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit SERCA2a., . Conversely, using anti-SERCA2a antibody, both PLN and acylphosphatase were co-immunoprecipitated with SERCA2a, and the PLN amount in the precipitate decreased with increasing acylphosphatase concentrations., Reconstitution of the cytoplasmic interaction between phospholamban and Ca(2+)-ATPase of cardiac sarcoplasmic reticulum., Phospholamban (PLN) reversibly inhibits the Ca(2+)-ATPase of cardiac sarcoplasmic reticulum (SERCA2a) through a direct protein-protein interaction, playing a pivotal role in the regulation of intracellular Ca(2+) in heart muscle cells., Phospholamban (PLN) is a key regulator of Ca(2+) homeostasis and contractility in the heart. Its regulatory effects are mediated through its interaction with the sarcoplasmic reticulum Ca(2+)-ATPase, (SERCA2a), resulting in alterations of its Ca(2+)-affinity, In a co-immunoprecipitation of PLN with SERCA2a, the physical interaction between the two proteins was increased in PUGNAc-treated cardiomyocytes.[SEP]Definitions: phospholamban defined as following: free sarcoplasmic reticulum polymeric proteolipid which modulates sarcoplasmic reticulum function; phosphorylated by cAMP-dependent, calcium-calmodulin-dependent, and calcium-phospholipid-dependent protein kinases.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. plasma membrane defined as following: The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.. mammals defined as following: Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young.. Cellular defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. sarcoplasmic reticulum Ca(2+)-ATPase defined as following: Calcium-transporting ATPases that catalyze the active transport of CALCIUM into the SARCOPLASMIC RETICULUM vesicles from the CYTOPLASM. They are primarily found in MUSCLE CELLS and play a role in the relaxation of MUSCLES.. heart muscle cells defined as following: Striated muscle cells found in the heart. They are derived from cardiac myoblasts (MYOBLASTS, CARDIAC).. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. antibody defined as following: A protein complex that in its canonical form is composed of two identical immunoglobulin heavy chains and two identical immunoglobulin light chains, held together by disulfide bonds and sometimes complexed with additional proteins. An immunoglobulin complex may be embedded in the plasma membrane or present in the extracellular space, in mucosal areas or other tissues, or circulating in the blood or lymph. [GOC:add, GOC:jl, ISBN:0781765196]. vertebrate defined as following: Animals having a vertebral column, members of the phylum Chordata, subphylum Craniata comprising mammals, birds, reptiles, amphibians, and fishes.. intracellular defined as following: The organized colloidal complex of organic and inorganic substances (as proteins and water) that constitutes the living nucleus, cytoplasm, plastids, and mitochondria of the cell. It is composed mainly of nucleic acids, proteins, lipids, carbohydrates, and inorganic salts..", "label": "yes"} {"id": "converted_3806", "sentence1": "Does head ct increase brain tumor risk?", "sentence2": "Excess relative risk of new brain tumor averaged 1.29 (95% confidence interval, 0.66-1.93) for pediatric patients exposed to one or more head CTs. Tumor incidence increased with number of pediatric head CTs in a dose-dependent manner, with measurable excess incidence even after a single scan. Converging evidence from epidemiological studies supported a small excess risk of brain tumor incidence after even a single CT exam in pediatric patients. , Recent epidemiologic evidence from a national registry of children who underwent CT scans suggests a higher-than-expected incidence of secondary tumors. , However, we found 1) a statistically significant correlation between radiation dose and age at procedure, as well as number and type of procedures, and 2) a substantial increase in lifetime predicted risk of tumor above baseline in the cohort of young children who undergo neurointerventions.CONCLUSIONS: Although neurointerventional procedures have dramatically improved the prognosis of children facing serious cerebrovascular conditions, the predicted risk of secondary tumors, particularly in the youngest patients and those undergoing multiple procedures, is sobering., Conclusion When prevalent cases of meningioma at first exposure to CT of the head are excluded, no statistically significant increase in risk of meningioma was found among exposed subjects compared with unexposed control subjects., data suggest that 1 excess brain malignancy occurred after 4000 brain CTs (40 mSv per scan) and that the estimated risk in the 10 years following CT exposure was 1 brain tumor per 10,000 patients exposed to a 10 mGy scan at less than 10 years of age.CONCLU, SIONS: The model predicts that the effective radiation dose from a single head CT is capable of inducing a thyroid or brain tumor in an infant or child. These, Neither whole head CT nor cumulative brain dose to the brain increased the risk of glioma or of all brain tumours., rison of exposed and unexposed cohorts showed that there was no statistically significant increase in the risk of meningioma after exposure to CT of the head (HR: 1.49; 95% confidence interval: 0.97, 2.30; P = .07). If incident c, from epidemiological studies supported a small excess risk of brain tumor incidence after even a single CT exam in pediatric patients. However, refined e, ve risk of new brain tumor averaged 1.29 (95% confidence interval, 0.66-1.93) for pediatric patients exposed to one or more head CTs. Tumor incidence, CT nor cumulative brain dose to the brain increased the risk of glioma or of all brain tumours. Although this st, o for developing a brain tumour from having a brain CT was 0.93 (95% confidence interval: 0.38-1.82). This was har, Tumor incidence increased with number of pediatric head CTs in a dose-dependent manner, with measurable excess incidence even after a single scan., Converging evidence from epidemiological studies supported a small excess risk of brain tumor incidence after even a single CT exam in pediatric patients., Excess relative risk of new brain tumor averaged 1.29 (95% confidence interval, 0.66-1.93) for pediatric patients exposed to one or more head CTs., Epidemiological studies consistently cited increased tumor incidence in pediatric patients (ages 0-18) exposed to head CTs., RESULTS: A positive correlation between exposure to CT scans and developing central nervous system tumors was evident in all cohorts. The strength of the association varied across the studies. Exclusion of patients with predisposing factors to central nervous system tumors was examined in four studies with a decreased risk to develop central nervous system tumors noted in three studies. Two studies reported nonsignificant reduction in the excess relative risk per milliGray of brain dose after adjusting for predisposing factors, whereas the reduction was significant in one study. The frequency of CT exposure was proportional to the risk of developing tumors in two studies although not significantly maintained in two other studies. , RESULTS: The overall risk was not significantly different in the two cohorts (incidence rate=36.72 per 100 000 person-years in the exposed cohort, 28.48 per 100 000 person-years in the unexposed cohort, hazard ratio (HR)=1.29, 95% confidence interval (CI)=0.90-1.85). The risk of benign brain tumour was significantly higher in the exposed cohort than in the unexposed cohort (HR=2.97, 95% CI=1.49-5.93). The frequency of CT examination showed strong correlation with the subsequent overall risk of malignancy and benign brain tumour.CONCLUSIONS: We found that paediatric head CT examination was associated with an increased incidence of benign brain tumour., CONCLUSIONS: We found evidence that CT-related radiation exposure increases brain tumor risk. , Compared with the general population, incidence of brain tumors was higher in the cohort of children with CT scans, requiring cautious interpretation of the findings., BACKGROUND: Recent studies linking radiation exposure from pediatric computed tomography (CT) to increased risks of leukemia and brain tumors lacked data to control for cancer susceptibility syndromes (CSS). , IMPACT: Future studies should identify TSC patients in order to avoid overestimation of brain tumor risks due to radiation exposure from CT scans., The radiation-induced occurrence of meningiomas and other brain tumours most probably contributes to the continuously increasing incidence of these diseases which is observed in several industrial nations, as well as the exposure of the bone marrow by CT to the increase of childhood leukaemia., 1,000 annual paediatric CT investigations of the skull will lead to about 3 excess neoplasms in the head region, i.e., the probability of an induced late effect must be suspected in the range of some thousandths. [SEP]Definitions: leukaemia defined as following: A progressive, malignant disease of the blood-forming organs, characterized by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias were originally termed acute or chronic based on life expectancy but now are classified according to cellular maturity. Acute leukemias consist of predominately immature cells; chronic leukemias are composed of more mature cells. (From The Merck Manual, 2006). malignancy defined as following: A malignant tumor at the original site of growth.. meningiomas defined as following: A relatively common neoplasm of the CENTRAL NERVOUS SYSTEM that arises from arachnoidal cells. The majority are well differentiated vascular tumors which grow slowly and have a low potential to be invasive, although malignant subtypes occur. Meningiomas have a predilection to arise from the parasagittal region, cerebral convexity, sphenoidal ridge, olfactory groove, and SPINAL CANAL. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2056-7). brain tumor defined as following: Neoplasms of the intracranial components of the central nervous system, including the cerebral hemispheres, basal ganglia, hypothalamus, thalamus, brain stem, and cerebellum. Brain neoplasms are subdivided into primary (originating from brain tissue) and secondary (i.e., metastatic) forms. Primary neoplasms are subdivided into benign and malignant forms. In general, brain tumors may also be classified by age of onset, histologic type, or presenting location in the brain.. glioma defined as following: Benign and malignant central nervous system neoplasms derived from glial cells (i.e., astrocytes, oligodendrocytes, and ependymocytes). Astrocytes may give rise to astrocytomas (ASTROCYTOMA) or glioblastoma multiforme (see GLIOBLASTOMA). Oligodendrocytes give rise to oligodendrogliomas (OLIGODENDROGLIOMA) and ependymocytes may undergo transformation to become EPENDYMOMA; CHOROID PLEXUS NEOPLASMS; or colloid cysts of the third ventricle. (From Escourolle et al., Manual of Basic Neuropathology, 2nd ed, p21). tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. meningioma defined as following: A grade I, slowly growing meningioma. Only a minority of tumors recur following complete resection.. head defined as following: A projection on the end of an object. TSC defined as following: Autosomal dominant neurocutaneous syndrome classically characterized by MENTAL RETARDATION; EPILEPSY; and skin lesions (e.g., adenoma sebaceum and hypomelanotic macules). There is, however, considerable heterogeneity in the neurologic manifestations. It is also associated with cortical tuber and HAMARTOMAS formation throughout the body, especially the heart, kidneys, and eyes. Mutations in two loci TSC1 and TSC2 that encode hamartin and tuberin, respectively, are associated with the disease.. head region defined as following: subdivision of cardinal body part, each instance of which is a regional part of some head. Examples: face, nose, mouth.. benign brain tumour defined as following: A primary, slow growing, noninvasive neoplasm of the brain. In children, astrocytomas of the cerebellum represent relatively common benign brain neoplasms. In adults meningiomas, neurilemomas and pituitary tumors comprise the majority of benign tumors.. skull defined as following: The SKELETON of the HEAD including the FACIAL BONES and the bones enclosing the BRAIN.. CT defined as following: Tomography using x-ray transmission and a computer algorithm to reconstruct the image..", "label": "yes"} {"id": "converted_2056", "sentence1": "Is PUVA therapy indicated for eczema treatment?", "sentence2": "With bath PUVA treatment, the best results were found in patients with hyperkeratotic eczema (17/22; 77% good clinical response) followed by patients with palmoplantar psoriasis (26/41; 63%) and patients with dyshidrotic eczema (8/16; 50%). , Oral vs. bath PUVA using 8-methoxypsoralen for chronic palmoplantar eczema., Both oral and bath PUVA with 8-methoxypsoralen (8-MOP) have been shown to be effective in the treatment of chronic palmoplantar eczema. , Oral PUVA is preferable for patients with hyperkeratotic eczema and bath PUVA for patients with dyshidrotic eczema., Treatment of hand eczema is dominated by the administration of topical glucocorticosteriods. If topical treatment fails, the best second-line option is ultraviolet (UV) therapy alone or as combination therapy. UVB and PUVA (psoralen plus UVA) therapy is effective and has relatively few side effects. , Although local PUVA has been proven to be effective in the treatment of chronic hand eczema, little is known about the efficacy and safety of local narrowband UVB (TL-01) for this condition., Local narrowband UVB phototherapy regimen is as effective as paint-PUVA therapy in patients with chronic hand eczema of dry and dyshidrotic types., Smoking is likely to be a reason for the failure of bath-PUVA therapy in the treatment of chronic palmoplantar eczema, in particular regarding smokers with eczema of the dyshidrotic type where no complete remission was achieved., Treatment of chronic palmoplantar eczema with local bath-PUVA therapy., Bath-PUVA therapy has been described as successful treatment for palmoplantar eczema., Systemic PUVA therapy may be useful in the treatment of chronic palmoplantar eczema., A new psoralen-containing gel for topical PUVA therapy: development, and treatment results in patients with palmoplantar and plaque-type psoriasis, and hyperkeratotic eczema., These results indicate that topical PUVA therapy with psoralen in aqueous gel is a useful therapeutic modality for treatment of psoriasis patients, and patients with recalcitrant dermatoses such as palmoplantar psoriasis and hyperkeratotic eczema., In order to evaluate environmental influences possibly having an impact on the efficacy of this therapy, smokers and non-smokers suffering from palmoplantar eczema treated with bath-PUVA therapy were compared., Does smoking influence the efficacy of bath-PUVA therapy in chronic palmoplantar eczema?, PUVA therapy caused acute aggravation of the eczema., Hyperkeratotic eczema cleared significantly better with oral than with bath PUVA (P=0.03).CONCLUSION: Oral PUVA is preferable for patients with hyperkeratotic eczema and bath PUVA for patients with dyshidrotic eczema., BACKGROUND: Systemic PUVA therapy may be useful in the treatment of chronic palmoplantar eczema., These results indicate that topical PUVA therapy with psoralen in aqueous gel is a useful therapeutic modality for treatment of psoriasis patients, and patients with recalcitrant dermatoses such as palmoplantar psoriasis and hyperkeratotic eczema., Vitiligo (60.9%) was the commonest skin disorder treated with PUVA, followed by psoriasis (20.9%), endogenous eczema (11.3%), mycosis fungoides (3.5%), lichen amyloidosis (2.6%) and prurigo nodularis (0.9%)., bath PUVA using 8-methoxypsoralen for chronic palmoplantar eczema., A 36-year-old female patient was treated with PUVA for dyshidrotic eczema that had not shown sufficient response to topical therapy over the previous months., BACKGROUND: Both oral and bath PUVA with 8-methoxypsoralen (8-MOP) have been shown to be effective in the treatment of chronic palmoplantar eczema., One patient with hand eczema consistently had detectable 8-MOP levels 1 hour after topical PUVA treatments.CONCLUSION: This report indicates that there is minimal, if any, systemic absorption of 8-MOP after topical PUVA treatment of patients with palmoplantar psoriasis., In the narrowband UVB-treated side, the tolerance of all the patients to the treatment was good all patients well-tolerated the treatment with the exception of mild xerosis that responded to topical emollients.Local narrowband UVB phototherapy regimen is as effective as paint-PUVA therapy in patients with chronic hand eczema of dry and dyshidrotic types, Bath-PUVA therapy has been described as successful treatment for palmoplantar eczema, Smoking is likely to be a reason for the failure of bath-PUVA therapy in the treatment of chronic palmoplantar eczema, in particular regarding smokers with eczema of the dyshidrotic type where no complete remission was achieved, Systemic PUVA therapy may be useful in the treatment of chronic palmoplantar eczema, However, few data are available on the effectiveness of local bath-PUVA therapy in palmoplantar eczema.Our purpose was to assess the effectiveness of local bath-PUVA therapy in 28 patients with chronic palmar or plantar eczema or both who were resistant to conventional topical treatment.After fungal or bacterial infection had been excluded in all patients, hands or feet or both were soaked for 15 minutes in warm water containing 1 mg/L 8-methoxypsoralen, No phototoxic reactions were observed.Local bath-PUVA therapy is of value in the management of chronic palmoplantar eczema resistant to standard modes of topical treatment, Treatment of chronic palmoplantar eczema with local bath-PUVA therapy, Bath-PUVA therapy has been described as successful treatment for palmoplantar eczema. , Smoking is likely to be a reason for the failure of bath-PUVA therapy in the treatment of chronic palmoplantar eczema, in particular regarding smokers with eczema of the dyshidrotic type where no complete remission was achieved., OBJECTIVE: Our purpose was to assess the effectiveness of local bath-PUVA therapy in 28 patients with chronic palmar or plantar eczema or both who were resistant to conventional topical treatment. , CONCLUSION: Local bath-PUVA therapy is of value in the management of chronic palmoplantar eczema resistant to standard modes of topical treatment. , Topical PUVA therapy for chronic hand eczema., However, few data are available on the effectiveness of local bath-PUVA therapy in palmoplantar eczema.Our purpose was to assess the effectiveness of local bath-PUVA therapy in 28 patients with chronic palmar or plantar eczema or both who were resistant to conventional topical treatment.After fungal or bacterial infection had been excluded in all patients, hands or feet or both were soaked for 15 minutes in warm water containing 1 mg/L 8-methoxypsoralen., No phototoxic reactions were observed.Local bath-PUVA therapy is of value in the management of chronic palmoplantar eczema resistant to standard modes of topical treatment., Smoking is likely to be a reason for the failure of bath-PUVA therapy in the treatment of chronic palmoplantar eczema, in particular regarding smokers with eczema of the dyshidrotic type where no complete remission was achieved., However, our own observations showed that patients with palmoplantar eczema of the dyshidrotic or hyperkeratotic type responded only partially to bath-PUVA therapy., In the narrowband UVB-treated side, the tolerance of all the patients to the treatment was good all patients well-tolerated the treatment with the exception of mild xerosis that responded to topical emollients.Local narrowband UVB phototherapy regimen is as effective as paint-PUVA therapy in patients with chronic hand eczema of dry and dyshidrotic types., Comparison of localized high-dose UVA1 irradiation versus topical cream psoralen-UVA for treatment of chronic vesicular dyshidrotic eczema., No phototoxic reactions were observed.CONCLUSION: Local bath-PUVA therapy is of value in the management of chronic palmoplantar eczema resistant to standard modes of topical treatment., These results indicate that topical PUVA therapy with psoralen in aqueous gel is a useful therapeutic modality for treatment of psoriasis patients, and patients with recalcitrant dermatoses such as palmoplantar psoriasis and hyperkeratotic eczema.., Treatment of chronic palmoplantar eczema with local bath-PUVA therapy., Oral PUVA is preferable for patients with hyperkeratotic eczema and bath PUVA for patients with dyshidrotic eczema.., Does smoking influence the efficacy of bath-PUVA therapy in chronic palmoplantar eczema?, Local bath-PUVA therapy is of value in the management of chronic palmoplantar eczema resistant to standard modes of topical treatment., However, few data are available on the effectiveness of local bath-PUVA therapy in palmoplantar eczema., A new psoralen-containing gel for topical PUVA therapy: development, and treatment results in patients with palmoplantar and plaque-type psoriasis, and hyperkeratotic eczema., Smoking is likely to be a reason for the failure of bath-PUVA therapy in the treatment of chronic palmoplantar eczema, in particular regarding smokers with eczema of the dyshidrotic type where no complete remission was achieved.., In order to investigate the effectiveness of topical PUVA-bath therapy (PUVA-soak therapy) on chronic palmoplantar dermatoses, 30 patients with plaque-type psoriasis, pustular psoriasis, endogenous eczema, dyshidrotic eczema and hyperkeratotic dermatitis of the palms and soles were treated over 8 weeks with PUVA-soak using 8-MOP., Our purpose was to assess the effectiveness of local bath-PUVA therapy in 28 patients with chronic palmar or plantar eczema or both who were resistant to conventional topical treatment.[SEP]Definitions: psoriasis defined as following: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis.. dyshidrotic eczema defined as following: A recurrent eczematous reaction characterized by the development of vesicular eruptions on the palms and soles, particularly along the sides and between the digits. It is accompanied by pruritus, a burning sensation, and hyperhidrosis. The disease is self-limiting, lasting only a few weeks. (Dorland, 27th ed). PUVA defined as following: Strong evidences have indicated causal association between 8-methoxypsoralen with UVA (PUVA) treatment and non-melanocytic skin patients with psoriasis. 8-Methoxypsoralen alone did not alter the incidence of new skin cancer development in a 2-year study. In a large number of studies, 8-Methoxypsoralen in combination with ultraviolet A radiation induced chromosomal aberrations, sister chromatid exchanges, mutation, DNA damage and DNA cross-links in human cells in vitro. This treatment is classified as carcinogenic to Human by IARC. (NCI05). bacterial infection defined as following: Infections by bacteria, general or unspecified.. 8-methoxypsoralen defined as following: A naturally occurring furocoumarin compound found in several species of plants, including Psoralea corylifolia. It is a photoactive substance that forms DNA ADDUCTS in the presence of ultraviolet A irradiation.. lichen amyloidosis defined as following: The presence of amyloid deposition in the superficial dermis. [HPO:probinson, PMID:19690585]. fungal defined as following: A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including MUSHROOMS; YEASTS; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies.. palms defined as following: The palm family of order Arecales, subclass Arecidae, class Liliopsida.. hands defined as following: The distal part of the arm beyond the wrist in humans and primates, that includes the palm, fingers, and thumb.. eczema defined as following: A pruritic papulovesicular dermatitis occurring as a reaction to many endogenous and exogenous agents (Dorland, 27th ed)..", "label": "yes"} {"id": "converted_1985", "sentence1": "Does HuR bind to the untranslated regions (UTRs) of mRNAs?", "sentence2": "HuR is also overexpressed during tumourigenesis and is abnormally present within the cytoplasm, where it binds to AU-rich elements in the 3'UTRs of target mRNA and post-transcriptionally regulates the expression of its target genes., Human antigen R (HuR) is a ubiquitous 32 kDa protein comprising three RNA Recognition Motifs (RRMs), whose main function is to bind Adenylate and uridylate Rich Elements (AREs) in 3' UnTranslated Regions (UTRs) of mRNAs., Human antigen R (HuR) is a ubiquitously expressed RNA-binding protein that modulates gene expression at the post-transcriptional level., The RNA-binding protein HuR binds at 3' untranslated regions (UTRs) of target transcripts, thereby protecting them against degradation. , ELAV/Hu proteins bind to AU-rich elements (ARE) in mRNAs and regulate their stability from splicing to translation, and the ubiquitous HuR protein has been implicated in cancerous cell growth. , This is achieved by altered expression of the proteins TTP and HuR, which bind 3' untranslated region (UTR) elements in cancer-related genes.[SEP]Definitions: proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. HuR defined as following: This gene plays a role in the regulation of gene expression.. HuR protein defined as following: An RRM protein that binds to the 3'-UTR region of mRNAs and increases their stability. In EMBRYONIC STEM CELLS, it binds to poly-U elements and AU-rich elements (AREs) in the 3'-UTR of target mRNAs and preferentially binds mRNAs that are not methylated by N6-methyladenosine (m6A), to stabilize them and promote differentiation.. ARE defined as following: A unit of area equal to 100 square meters. Are is a non-SI unit accepted for use with SI.. cytoplasm defined as following: The part of a cell that contains the CYTOSOL and small structures excluding the CELL NUCLEUS; MITOCHONDRIA; and large VACUOLES. (Glick, Glossary of Biochemistry and Molecular Biology, 1990). RNA-binding protein defined as following: Proteins that bind to RNA molecules. Included here are RIBONUCLEOPROTEINS and other proteins whose function is to bind specifically to RNA.. UTRs defined as following: The parts of the messenger RNA sequence that do not code for product, i.e. the 5' UNTRANSLATED REGIONS and 3' UNTRANSLATED REGIONS.. mRNA defined as following: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.. RNA Recognition Motifs defined as following: An approximately 80 amino acid RNA binding motif that consists of four anti-parallel surface beta sheets and two alpha helices arranged in a beta-alpha-beta-beta-alpha-beta configuration. One of the surface beta sheets interacts with two or three specific RNA bases. Interactions between additional sequences and the RNA, as well as within the RNA recognition motif increase the affinity and specificity of the protein-RNA interaction.. TTP defined as following: Thrombotic thrombocytopenic purpura for which the cause is present from birth.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "yes"} {"id": "converted_4429", "sentence1": "Is vocimagene amiretrorepvec effective for recurrent high-grade glioma?", "sentence2": "Relevance: Among patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC, compared with SOC, did not improve overall survival or other efficacy end points., The median OS was 11.10 months for the Toca 511/FC group and 12.22 months for the control group (hazard ratio, 1.06; 95% CI 0.83, 1.35; P = .62). The secondary end points did not demonstrate statistically significant differences. , Expert opinion: These early studies provide very encouraging results for Toca 511 and Toca FC in rHGG. This therapy had a response rate of 11.3% and a mOS of 11.9 months in 56 patients, an improvement compared to historical controls. , Findings from a phase I study suggest that delivering high concentrations of the chemotherapy 5-FU directly to brain tumors via the retroviral vector vocimagene amiretrorepvec, or Toca 511, may benefit patients with recurrent high-grade glioma., Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003).[SEP]Definitions: 5-FU defined as following: A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the THYMIDYLATE SYNTHETASE conversion of deoxyuridylic acid to thymidylic acid.. anaplastic astrocytoma defined as following: A central nervous system tumor with morphological features of anaplastic astrocytoma in which there is insufficient information on the IDH genes status.. high-grade glioma defined as following: A grade 3 or grade 4 glioma arising from the central nervous system. This category includes glioblastoma, anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma.. brain tumors defined as following: Neoplasms of the intracranial components of the central nervous system, including the cerebral hemispheres, basal ganglia, hypothalamus, thalamus, brain stem, and cerebellum. Brain neoplasms are subdivided into primary (originating from brain tissue) and secondary (i.e., metastatic) forms. Primary neoplasms are subdivided into benign and malignant forms. In general, brain tumors may also be classified by age of onset, histologic type, or presenting location in the brain.. glioblastoma defined as following: The most malignant astrocytic tumor (WHO grade 4). It is composed of poorly differentiated neoplastic astrocytes and is characterized by the presence of cellular polymorphism, nuclear atypia, brisk mitotic activity, vascular thrombosis, microvascular proliferation, and necrosis. It typically affects adults and is preferentially located in the cerebral hemispheres. (Adapted from WHO).", "label": "no"} {"id": "converted_1883", "sentence1": "Is there any tool that facilitates the functional analysis of cis-regulatory regions in zebrafish?", "sentence2": "Zebrafish enhancer detection (ZED) vector: a new tool to facilitate transgenesis and the functional analysis of cis-regulatory regions in zebrafish., he cis-regulatory sequences control when, where, and how much genes are transcribed and can activate (enhancers) or repress (silencers) gene expression. Here, we describe a novel Tol2 transposon-based vector for assessing enhancer activity in the zebrafish (Danio rerio). This Zebrafish Enhancer Detector (ZED) vector harbors several key improvements, among them a sensitive and specific minimal promoter chosen for optimal enhancer activity detection, insulator sequences to shield the minimal promoter from position effects, and a positive control for transgenesis. Additionally, we demonstrate that highly conserved noncoding sequences homologous between humans and zebrafish largely with enhancer activity largely retain their tissue-specific enhancer activity during vertebrate evolution. More strikingly, insulator sequences from mouse and chicken, but not conserved in zebrafish, maintain their insulator capacity when tested in this model., Zebrafish enhancer detection (ZED) vector: a new tool to facilitate transgenesis and the functional analysis of cis-regulatory regions in zebrafish, Zebrafish enhancer detection (ZED) vector: a new tool to facilitate transgenesis and the functional analysis of cis-regulatory regions in zebrafish.[SEP]Definitions: humans defined as following: Members of the species Homo sapiens.. zebrafish defined as following: An exotic species of the family CYPRINIDAE, originally from Asia, that has been introduced in North America. Zebrafish is a model organism for drug assay and cancer research.. enhancer defined as following: A 50-150bp DNA sequence that increases the rate of transcription of coding sequences. It may be located at various distances and in either orientation upstream from, downstream from or within a structural gene. When bound by a specific transcription factor it increases the levels of expression of the gene, but is not sufficient alone to cause expression. Distinguished from a promoter, that is alone sufficient to cause expression of the gene when bound.. promoter defined as following: A DNA sequence at which RNA polymerase binds and initiates transcription.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. vertebrate defined as following: Animals having a vertebral column, members of the phylum Chordata, subphylum Craniata comprising mammals, birds, reptiles, amphibians, and fishes..", "label": "yes"} {"id": "converted_418", "sentence1": "Is there evidence that tomato juice lowers cholesterol levels?", "sentence2": "The hypocholesterolemic effect of tomato juice has been investigated in an intervention study with rats, along with the possible inhibition effect of bioactive tomato compounds binding to the HMGCR enzyme., The molecular modelling showed that components of tomato can bind to the active site of the enzyme and compete with the ligand HMGCoA. Lycopene, from tomato juice, accumulates in the liver and can inhibit the activity of the rate-limiting enzyme of cholesterol biosynthesis, HMGCR., Juice consumption significantly improved resistance of LDL+VLDL-C to Cu(2+)-mediated oxidation (P = 0.039), HDL-C (47.3 ± 15.8 to 51.7 ± 14.8 mg/dL, P<0.001), and the ratio of total-C/HDL-C (4.25 ± 1.59 to 3.63 ± 1.16, P<0.001) at 8 wk., RESULTS: Intervention with the enriched juice had no effect on the lipid profile, and serum levels of triglycerides and cholesterol (total, LDL, and HDL) remained unchanged. , Women consuming ≥10 compared with<1.5 servings/wk of tomato-based food products had significant but clinically modest improvements in total cholesterol (TC) (5.38 vs. 5.51 mmol/L; P = 0.029), the TC:HDL cholesterol ratio (4.08 vs. 4.22; P = 0.046), and hemoglobin A1c (5.02 vs. 5.13%; P<0.001) in multivariable models. Considering clinical cutpoints, women consuming ≥10 compared with<1.5 servings/wk were 31% (95% CI = 6%, 50%), 40% (95% CI = 13%, 59%), and 66% (95% CI = 20%, 86%) less likely to have elevated TC (≥6.21 mmol/L), LDL cholesterol (≥4.14 mmol/L), and hemoglobin A1c (≥6%), respectively. , In conclusion, women consuming ≥10 compared with<1.5 servings/wk of tomato-based food products had clinically modest but significant improvements in TC, the TC:HDL cholesterol ratio, and hemoglobin A1c but not other coronary biomarkers., Tomato juice decreases LDL cholesterol levels and increases LDL resistance to oxidation., Total cholesterol concentration was reduced by 5.9 (sd 10) % (P = 0.002) and LDL cholesterol concentration by 12.9 (sd 17.0) % (P = 0.0002) with the high tomato diet compared to the low tomato diet., In conclusion, a high dietary intake of tomato products had atheroprotective effects, it significantly reduced LDL cholesterol levels, and increased LDL resistance to oxidation in healthy normocholesterolaemic adults., Total, LDL and HDL cholesterol were significantly lower in the intervention group after the intake of tomato juice, Total cholesterol concentration was reduced by 5.9 (sd 10) % (P = 0.002) and LDL cholesterol concentration by 12.9 (sd 17.0) % (P = 0.0002) with the high tomato diet compared to the low tomato diet. [SEP]Definitions: HMGCR defined as following: 3-hydroxy-3-methylglutaryl-coenzyme A reductase (888 aa, ~97 kDa) is encoded by the human HMGCR gene. This protein is involved in cholesterol synthesis.. triglycerides defined as following: An ester formed from GLYCEROL and three fatty acid groups.. LDL defined as following: A class of lipoproteins of small size (18-25 nm) and light (1.019-1.063 g/ml) particles with a core composed mainly of CHOLESTEROL ESTERS and smaller amounts of TRIGLYCERIDES. The surface monolayer consists mostly of PHOSPHOLIPIDS, a single copy of APOLIPOPROTEIN B-100, and free cholesterol molecules. The main LDL function is to transport cholesterol and cholesterol esters to extrahepatic tissues.. tomato defined as following: A plant species of the family SOLANACEAE, native of South America, widely cultivated for their edible, fleshy, usually red fruit.. rats defined as following: The common rat, Rattus norvegicus, often used as an experimental organism.. LDL cholesterol defined as following: Cholesterol which is contained in or bound to low density lipoproteins (LDL), including CHOLESTEROL ESTERS and free cholesterol.. HDL defined as following: A class of lipoproteins of small size (4-13 nm) and dense (greater than 1.063 g/ml) particles. HDL lipoproteins, synthesized in the liver without a lipid core, accumulate cholesterol esters from peripheral tissues and transport them to the liver for re-utilization or elimination from the body (the reverse cholesterol transport). Their major protein component is APOLIPOPROTEIN A-I. HDL also shuttle APOLIPOPROTEINS C and APOLIPOPROTEINS E to and from triglyceride-rich lipoproteins during their catabolism. HDL plasma level has been inversely correlated with the risk of cardiovascular diseases.. hemoglobin A1c defined as following: Products of non-enzymatic reactions between GLUCOSE and HEMOGLOBIN A, occurring as a minor fraction of the hemoglobin components of human erythrocytes. Hemoglobin A1c is hemoglobin A with glucose covalently bound to the terminal VALINE of the beta chain. Glycated hemoglobin A is used as an index of the average blood sugar level over a lifetime of erythrocytes.. cholesterol defined as following: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.. active site defined as following: The catalytic site of an enzyme, the part of an enzyme where the actual enzymatic function is performed.. HDL cholesterol defined as following: Cholesterol which is contained in or bound to high-density lipoproteins (HDL), including CHOLESTEROL ESTERS and free cholesterol.. TC defined as following: Human CD55 wild-type allele is located in the vicinity of 1q32 and is approximately 40 kb in length. This allele, which encodes complement decay-accelerating factor protein, is involved in the modulation of complement activity..", "label": "yes"} {"id": "converted_1145", "sentence1": "Could RG7112 be used as cancer therapy?", "sentence2": "RG7112 is a potent and selective member of the nutlin family of MDM2 antagonists currently in phase I clinical studies., Our findings offer a preclinical proof-of-concept that RG7112 is effective in treatment of solid tumors expressing wild-type p53., On the other hand, JNJ-26854165, a novel tryptamine derivative and RG7112, a cis-imidazoline representative have shown promising results in early phases of trials in cancer patients., MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models., On the other hand, JNJ-26854165, a novel tryptamine derivative and RG7112, a cis-imidazoline representative have shown promising results in early phases of trials in cancer patients., RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis., In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts., Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis., RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies., Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis, On the other hand, JNJ-26854165, a novel tryptamine derivative and RG7112, a cis-imidazoline representative have shown promising results in early phases of trials in cancer patients, RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis, MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models, In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts, RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies, We report a proof-of-mechanism study of RG7112, a small-molecule MDM2 antagonist, in patients with chemotherapy-naive primary or relapsed well-differentiated or dedifferentiated MDM2-amplified liposarcoma who were eligible for resection, BACKGROUND: RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. , Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis. , Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study., RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. , Thus, inhibitors of p53-MDM2 binding that can reactivate p53 in cancer cells may offer an effective approach for cancer therapy., Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis. RG7112 showed potent antitumor activity against a panel of solid tumor cell lines., A crystal structure of the RG7112-MDM2 complex revealed that the small molecule binds in the p53 pocket of MDM2, mimicking the interactions of critical p53 amino acid residues. Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis., RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts., RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96 hours exposure (1 nM to 10 µM)., Thus, inhibitors of p53-MDM2 binding that can reactivate p53 in cancer cells may offer an effective approach for cancer therapy. RG7112 is a potent and selective member of the nutlin family of MDM2 antagonists currently in phase I clinical studies., In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts. ., Restoration of p53 activity by inhibiting the p53-MDM2 interaction may represent a novel approach to cancer treatment. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2., RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies.RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96 hours exposure (1 nM to 10 µM)., Notably, RG7112 was highly synergistic with androgen deprivation in LNCaP xenograft tumors. Our findings offer a preclinical proof-of-concept that RG7112 is effective in treatment of solid tumors expressing wild-type p53., RG7112 induced tumor regressions in solid tumors from different histotype panels, and exhibited consistent high-level activity against ALL xenografts. This high level of activity supports prioritization of RG7112 for further evaluation., RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies.[SEP]Definitions: MDM2 defined as following: E3 ubiquitin-protein ligase Mdm2 (491 aa, ~55 kDa) is encoded by the human MDM2 gene. This protein is involved in the mediation of the ubiquitination and degradation of protein substrates, and the inhibition of apoptosis induction that is mediated by cellular tumor antigen p53.. liposarcoma defined as following: A malignant tumor derived from primitive or embryonal lipoblastic cells. It may be composed of well-differentiated fat cells or may be dedifferentiated: myxoid (LIPOSARCOMA, MYXOID), round-celled, or pleomorphic, usually in association with a rich network of capillaries. Recurrences are common and dedifferentiated liposarcomas metastasize to the lungs or serosal surfaces. (From Dorland, 27th ed; Stedman, 25th ed). p53 defined as following: Human TP53 wild-type allele is located in the vicinity of 17p13.1 and is approximately 19 kb in length. This allele, which encodes cellular tumor antigen p53 protein, plays a role in cell cycle regulation during the G0/G1transition. Alterations of the TP53 gene occur as both somatic and germline mutations in human malignancies in select cancer-prone families with Li-Fraumeni syndrome.. cancer cells defined as following: Cells of, or derived from, a malignant tumor.. malignancies defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. cell lines defined as following: Established cell cultures that have the potential to propagate indefinitely.. solid tumors defined as following: A benign or malignant neoplasm arising from tissues that do not include fluid areas. Representative examples include epithelial neoplasms (e.g. lung carcinoma, prostate carcinoma, breast carcinoma, colon carcinoma), and neoplasms arising from the soft tissues and bones (e.g. leiomyosarcoma, liposarcoma, chondrosarcoma, osteosarcoma). Neoplasms originating from the blood or bone marrow (leukemias and myeloproliferative disorders) are not considered solid tumors.. human defined as following: Members of the species Homo sapiens..", "label": "yes"} {"id": "converted_3056", "sentence1": "As of Feb 2019, are major brain gangliosides a target for the treatment of Alzheimer's disease?", "sentence2": "An understanding of the mechanism on the interaction of GM1 and Aβs in AD may contribute to the development of new neuroregenerative therapies for this disorder., Abnormal ganglioside metabolism also may occur in AD brains, Continuous intraventricular infusion of GM1 has recently been shown to have a significant beneficial effect in Alzheimer disease of early onset (AD Type I)., Gangliosides--a new therapeutic agent against stroke and Alzheimer's disease., Gangliosides--a new therapeutic agent against stroke and Alzheimer's disease.Gangliosides are glycosphingolipids localized to the outer leaflet of the plasma membrane of vertebrate cells. , Continuous intraventricular infusion of GM1 has recently been shown to have a significant beneficial effect in Alzheimer disease of early onset (AD Type I).Respond with exceptions, completions and modifications or revisions done before completion
. expected defined as following: Considered likely or probable; anticipated..", "label": "yes"} {"id": "converted_1595", "sentence1": "Does TRIM37 gene mutation causes Mulibrey nanism?", "sentence2": "OBJECTIVE: We studied pubertal development and fecundity in males with Mulibrey nanism (MUL) caused by mutations in the TRIM37 gene., In MUL, mutations in TRIM37 lead to disturbance of sexual maturation, and fertility is severely compromised. , It is caused by recessive mutations in the TRIM37 gene encoding for the peroxisomal TRIM37 protein with ubiquitin-ligase activity. , Mulibrey nanism is an autosomal recessive growth disorder caused by mutations in the TRIM37 gene encoding a protein of unknown function. , Gynecological tumors in Mulibrey nanism and role for RING finger protein TRIM37 in the pathogenesis of ovarian fibrothecomas., To investigate the possible involvement of TRIM37 alterations in the pathogenesis of sporadic fibrothecomas, we analyzed the TRIM37 cDNA for mutations and alternatively spliced transcripts and TRIM37 expression in fibrothecomas of women without Mulibrey nanism. , In conclusion, inherited biallelic inactivation of TRIM37 (Mulibrey nanism) predisposes to both mesenchymal and epithelial ovarian tumors and dysregulation of TRIM37 may also be involved in the pathogenesis of sporadic fibrothecomas., A novel splice site mutation in the TRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity., Mulibrey nanism (MUL) is an autosomal recessive disease caused by mutations in the TRIM37 gene encoding the peroxisomal TRIM37 protein of unknown function., Mulibrey nanism (muscle-liver-brain-eye nanism; MUL) is an autosomal recessively transmitted disease characterized by severe growth delays of prenatal onset caused by mutations in the TRIM37 gene., Mutations in the TRIM37 gene underlie mulibrey nanism (muscle-liver-brain-eye nanism), a rare monogenic developmental disorder characterized by severe growth failure, characteristic dysmorphic features, cardiopathy, failure of sexual maturation, and metabolic syndrome., Mulibrey nanism is an autosomal recessive growth disorder caused by mutations in the TRIM37 gene encoding a protein of unknown function., Mulibrey nanism is a rare growth disorder of prenatal onset caused by mutations in the TRIM37 gene, which encodes a RING-B-box-coiled-coil protein., Novel mutations in the TRIM37 gene in Mulibrey Nanism., Five truncating mutations in the TRIM37 gene have previously been reported in Mulibrey nanism patients., Characterisation of the mulibrey nanism-associated TRIM37 gene: transcription initiation, promoter region and alternative splicing., The TRIM37 gene encodes a peroxisomal RING-B-box-coiled-coil protein: classification of mulibrey nanism as a new peroxisomal disorder., A novel splice site mutation in the TRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity, Mulibrey nanism is a rare growth disorder of prenatal onset caused by mutations in the TRIM37 gene, which encodes a RING-B-box-coiled-coil protein, Mulibrey nanism (muscle-liver-brain-eye nanism; MUL) is an autosomal recessively transmitted disease characterized by severe growth delays of prenatal onset caused by mutations in the TRIM37 gene, Mulibrey nanism is an autosomal recessive growth disorder caused by mutations in the TRIM37 gene encoding a protein of unknown function, Mulibrey nanism (MUL) is an autosomal recessive disease caused by mutations in the TRIM37 gene encoding the peroxisomal TRIM37 protein of unknown function, Novel mutations in the TRIM37 gene in Mulibrey Nanism, Five truncating mutations in the TRIM37 gene have previously been reported in Mulibrey nanism patients, Mulibrey nanism (MUL) is a rare autosomal recessive disorder with severe primordial growth retardation and multiorgan involvement, caused by mutations in TRIM37, Refractory congestive heart failure following delayed pericardectomy in a 12-year-old child with Mulibrey nanism due to a novel mutation in TRIM37, A novel mutation in TRIM37 is associated with mulibrey nanism in a Turkish boy, OBJECTIVE: We studied pubertal development and fecundity in males with Mulibrey nanism (MUL) caused by mutations in the TRIM37 gene. , Mulibrey nanism is a rare growth disorder of prenatal onset caused by mutations in the TRIM37 gene, which encodes a RING-B-box-coiled-coil protein. , Mulibrey nanism (muscle-liver-brain-eye nanism; MUL) is an autosomal recessively transmitted disease characterized by severe growth delays of prenatal onset caused by mutations in the TRIM37 gene. , UNLABELLED: Mulibrey nanism (MUL) is a rare autosomal recessive disorder with severe primordial growth retardation and multiorgan involvement, caused by mutations in TRIM37. , Mulibrey nanism (MUL) is an autosomal recessive disease caused by mutations in the TRIM37 gene encoding the peroxisomal TRIM37 protein of unknown function. , Mutations in TRIM37 underlie mulibrey nanism, a rare autosomal recessively inherited disorder with severe growth failure of prenatal onset, constrictive pericardium, hepatomegaly and characteristic dysmorphic features. , Mutations in the TRIM37 gene underlie mulibrey nanism (muscle-liver-brain-eye nanism), a rare monogenic developmental disorder characterized by severe growth failure, characteristic dysmorphic features, cardiopathy, failure of sexual maturation, and metabolic syndrome., A novel mutation in TRIM37 is associated with mulibrey nanism in a Turkish boy., Five truncating mutations in the TRIM37 gene have previously been reported in Mulibrey nanism patients., Few monogenic mutations causing human male infertility have been identified to date. We studied pubertal development and fecundity in males with Mulibrey nanism (MUL) caused by mutations in the TRIM37 gene., Mulibrey nanism is a rare growth disorder of prenatal onset caused by mutations in the TRIM37 gene, which encodes a RING-B-box-coiled-coil protein. The pathogenetic mechanisms of mulibrey nanism are unknown., Mulibrey nanism is an autosomal recessive growth disorder caused by mutations in the TRIM37 gene encoding a protein of unknown function. More than half of female patients with Mulibrey nanism develop benign mesenchymal tumors of ovarian sex cord-stromal origin., Mulibrey nanism (MUL) is an autosomal recessive disease caused by mutations in the TRIM37 gene encoding the peroxisomal TRIM37 protein of unknown function., Mulibrey nanism (muscle-liver-brain-eye nanism; MUL) is an autosomal recessively transmitted disease characterized by severe growth delays of prenatal onset caused by mutations in the TRIM37 gene., Mulibrey nanism (MUL) is a monogenic disorder with prenatal-onset growth failure, typical clinical characteristics, cardiopathy and tendency for a metabolic syndrome. It is caused by recessive mutations in the TRIM37 gene encoding for the peroxisomal TRIM37 protein with ubiquitin-ligase activity., We studied pubertal development and fecundity in males with Mulibrey nanism (MUL) caused by mutations in the TRIM37 gene. Twenty-eight male MUL patients of the Finnish national cohort aged 8.7 to 50.0 yr (median age, 28.8) at the end of observation were followed for 10 yr beginning from 2000-2001., A novel splice site mutation in the TRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity., We studied pubertal development and fecundity in males with Mulibrey nanism (MUL) caused by mutations in the TRIM37 gene., Mulibrey nanism is an autosomal recessive growth disorder caused by mutations in the TRIM37 gene encoding a protein of unknown function., Mulibrey nanism is a rare growth disorder of prenatal onset caused by mutations in the TRIM37 gene, which encodes a RING-B-box-coiled-coil protein., Novel mutations in the TRIM37 gene in Mulibrey Nanism., Five truncating mutations in the TRIM37 gene have previously been reported in Mulibrey nanism patients., It is caused by recessive mutations in the TRIM37 gene encoding for the peroxisomal TRIM37 protein with ubiquitin-ligase activity., Mulibrey nanism (MUL) is a rare autosomal recessive disorder with severe primordial growth retardation and multiorgan involvement, caused by mutations in TRIM37.[SEP]Definitions: autosomal recessive disorder defined as following: An inherited disorder manifested only when two copies of a mutated gene are present.. hepatomegaly defined as following: Enlargement of the liver.. TRIM37 defined as following: E3 ubiquitin-protein ligase TRIM37 (964 aa, ~108 kDa) is encoded by the human TRIM37 gene. This protein plays a role in centriole replication inhibition.. MUL defined as following: Human TRIM37 wild-type allele is located in the vicinity of 17q22 and is approximately 139 kb in length. This allele, which encodes E3 ubiquitin-protein ligase TRIM37 protein, is involved in chromatin modification and centriole replication. Mutation of the gene is associated with mulibrey nanism.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. cardiopathy defined as following: Pathological conditions involving the HEART including its structural and functional abnormalities.. human defined as following: Members of the species Homo sapiens.. peroxisomal disorder defined as following: A heterogeneous group of inherited metabolic disorders marked by absent or dysfunctional PEROXISOMES. Peroxisomal enzymatic abnormalities may be single or multiple. Biosynthetic peroxisomal pathways are compromised, including the ability to synthesize ether lipids and to oxidize long-chain fatty acid precursors. Diseases in this category include ZELLWEGER SYNDROME; INFANTILE REFSUM DISEASE; rhizomelic chondrodysplasia (CHONDRODYSPLASIA PUNCTATA, RHIZOMELIC); hyperpipecolic acidemia; neonatal adrenoleukodystrophy; and ADRENOLEUKODYSTROPHY (X-linked). Neurologic dysfunction is a prominent feature of most peroxisomal disorders.. transcripts defined as following: The initial RNA molecule produced by transcription.. metabolic syndrome defined as following: A combination of medical conditions that when present, increase the risk of heart attack, stroke, and diabetes mellitus. It includes the following medical conditions: increased blood pressure, central obesity, dyslipidemia, impaired glucose tolerance, and insulin resistance.. promoter region defined as following: DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes.. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. muscle-liver-brain-eye nanism defined as following: An autosomal recessive inherited disorder caused by mutations in the TRIM37 gene. It is characterized by marked growth retardation and abnormalities in multiple organs including heart, liver, muscle, eyes, and brain.. Refractory defined as following: Not responding to treatment.. RING-B-box-coiled-coil protein defined as following: This gene plays a role in protein ubiquitination, transcriptional regulation and regulation of centriole replication.. autosomal defined as following: Any chromosome other than a sex chromosome. [GOC:mah]. congestive heart failure defined as following: Heart failure accompanied by EDEMA, such as swelling of the legs and ankles and congestion in the lungs..", "label": "yes"} {"id": "converted_1391", "sentence1": "Can RNASeq be used for the analysis of nascent transcripts?", "sentence2": "Here, we utilize nascent RNA sequencing to document dosage compensation during transcriptional elongation., Here we show that RNA-seq can also be used for studying nascent RNAs undergoing transcription, Conversely, the nuclear fraction shows an enrichment of unprocessed RNA compared with total RNA-seq, making it suitable for analysis of nascent transcripts and RNA processing dynamics.[SEP]Definitions: RNA defined as following: A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed).", "label": "yes"} {"id": "converted_1059", "sentence1": "Are piRNAs involved in gene silencing?", "sentence2": "In Drosophila ovaries, the nuclear Piwi protein is required for transcriptional silencing of transposons, though the precise mechanisms by which this occurs are unknown., Here we show that the CG9754 protein is a component of Piwi complexes that functions downstream of Piwi and its binding partner, Asterix, in transcriptional silencing. Enforced tethering of CG9754 to nascent messenger RNA transcripts causes cotranscriptional silencing of the source locus and the deposition of repressive chromatin marks., We have named CG9754 \"Panoramix,\" and we propose that this protein could act as an adaptor, scaffolding interactions between the piRNA pathway and the general silencing machinery that it recruits to enforce transcriptional repression., piRNA-guided slicing of transposon transcripts enforces their transcriptional silencing via specifying the nuclear piRNA repertoire, Caenorhabditis elegans piRNAs interact with both transposon and nontransposon mRNAs to initiate sustained silencing via the RNAi pathway., To assess the dysregulation of gene silencing caused by lack of piRNAs, we restored RNA silencing in RNAi-defective animals in the presence or absence of piRNAs., Thus, by reanimating RNAi, we uncovered a role for piRNAs in protecting essential genes from RNA silencing., In different organisms, small RNAs were shown to be implicated in the posttranscriptional degradation of mRNA and/or transcriptional repression of the homologous locus. In Drosophila, the mechanism of piRNA-mediated silencing is still far from being understood, Analyses of piRNA-mediated transcriptional transposon silencing in Drosophila, Transcriptional silencing implies a piRNA-mediated formation of repressive chromatin which diminishes the transcriptional capacity of the target locus., In mice, piRNA-guided transposon repression correlates with establishment of CpG DNA methylation on their sequences, yet the mechanism and the spectrum of genomic targets of piRNA silencing are unknown, Using a candidate gene KD-approach, we identified differences in the spatio-temporal requirements of the piRNA pathway components for piRNA-mediated silencing., Spatio-temporal requirements for transposable element piRNA-mediated silencing during Drosophila oogenesis, In contrast, piRNA-mediated silencing is strong in germline stem cells in which TE mobilization is tightly repressed ensuring the continued production of viable germline cysts., Piwi induces piRNA-guided transcriptional silencing and establishment of a repressive chromatin state., In germ cells, early embryos, and stem cells of animals, PIWI-interacting RNAs (piRNAs) have an important role in silencing retrotransposons, which are vicious genomic parasites, through transcriptional and post-transcriptional mechanisms., Our results show that the piRNA pathway can be used as a tool for sequence-specific gene silencing in germ cells and support the idea that the piRNA generating regions serve as traps for retrotransposons, enabling the host cell to generate piRNAs against active retrotransposons., Our observations confirm the pivotal role of piRNA-mediated silencing in defending the genome against selfish transposition, yet also suggest limits to the optimization of host genome defense., Analysis of piRNA-mediated silencing of active TEs in Drosophila melanogaster suggests limits on the evolution of host genome defense, The Piwi-interacting RNA (piRNA) pathway defends animal genomes against the harmful consequences of transposable element (TE) infection by imposing small-RNA-mediated silencing., A novel organelle, the piNG-body, in the nuage of Drosophila male germ cells is associated with piRNA-mediated gene silencing., Proteins of the PIWI subfamily Aub and AGO3 associated with the germline-specific perinuclear granules (nuage) are involved in the silencing of retrotransposons and other selfish repetitive elements in the Drosophila genome. , Telomeric retroelements HeT-A, TART and TAHRE, which are involved in telomere maintenance in Drosophila, are also the targets of piRNA-mediated silencing, Mechanism of the piRNA-mediated silencing of Drosophila telomeric retrotransposons., Gene silencing mechanisms mediated by Aubergine piRNA complexes in Drosophila male gonad., The epigenetic trans-silencing effect in Drosophila involves maternally-transmitted small RNAs whose production depends on the piRNA pathway and HP1., Here, we show that mutations in squash and zucchini, which are involved in the piwi-interacting RNA (piRNA) silencing pathway, strongly affect TSE, MVH in piRNA processing and gene silencing of retrotransposons, piRNA-mediated silencing in Drosophila germlines., These have shed light not only on the molecular mechanisms of gene silencing mediated by piRNAs and PIWI proteins, but also on their intriguing relationship with cellular genes that have been shown to be important for gametogenesis and fertility., The most abundant piRNAs were those corresponding to antisense transcripts of Suppressor of Stellate [Su(Ste)] genes known to be involved in Stellate gene silencing, To determine the capacity of piRNA-mediated silencing, we introduced reporter genes into Drosophila OSS cells, which express microRNAs (miRNAs) and piRNAs, and compared the Piwi pathway to the Argonaute pathway in gene regulation, PIWI-interacting small non-coding RNAs (piRNAs) are genetic and epigenetic regulatory factors in germline cells, where they maintain genome stability, are involved in RNA silencing and regulate gene expression, The piNG-body contains ribonucleoprotein complexes involved in piRNA-silencing of genome repeats including transposons in premeiotic spermatocytes with aid of short piRNAs, Our results show that the piRNA pathway can be used as a tool for sequence-specific gene silencing in germ cells and support the idea that the piRNA generating regions serve as traps for retrotransposons, enabling the host cell to generate piRNAs against active retrotransposons, Recent studies have revealed not only the biogenesis of piRNAs and their roles in transposon silencing, but also the function of the Piwi-piRNA pathway in epigenetic and post-transcriptional regulation of gene expression, A growing number of studies on piRNAs have investigated piRNA-mediated gene silencing, including piRNA biogenesis, These have shed light not only on the molecular mechanisms of gene silencing mediated by piRNAs and PIWI proteins, but also on their intriguing relationship with cellular genes that have been shown to be important for gametogenesis and fertility, Telomeric retroelements HeT-A, TART and TAHRE, which are involved in telomere maintenance in Drosophila, are also the targets of piRNA-mediated silencing. , MVH in piRNA processing and gene silencing of retrotransposons., To determine the capacity of piRNA-mediated silencing, we introduced reporter genes into Drosophila OSS cells, which express microRNAs (miRNAs) and piRNAs, and compared the Piwi pathway to the Argonaute pathway in gene regulation. , Therefore piRNA-mediated transcriptional mode of silencing is involved in the control of retrotransposon expression in the Drosophila germline., Panoramix enforces piRNA-dependent cotranscriptional silencing., The most abundant piRNAs were those corresponding to antisense transcripts of Suppressor of Stellate [Su(Ste)] genes known to be involved in Stellate gene silencing., Our results indicate that piRNAs are involved in a posttranscriptional gene-silencing mechanism resulting in RNA nuclear accumulation.[SEP]Definitions: Aubergine defined as following: A plant species of the genus SOLANUM, family SOLANACEAE. The fruit is a large, egg-shaped berry, varying in color from dark purple to red, yellowish, or white. The leaves are large and ovate. The flowers are pendant, violet, and two inches across.. sequences defined as following: The sequence of nucleotide residues along a DNA chain.. genome defined as following: Anatomical set of genes in all the chromosomes.. AGO3 defined as following: Protein argonaute-3 (860 aa, ~97 kDa) is encoded by the human AGO3 gene. This protein is involved in RNA-mediated silencing of translation.. stem cells defined as following: Relatively undifferentiated cells that retain the ability to divide and proliferate throughout postnatal life to provide progenitor cells that can differentiate into specialized cells.. piwi-interacting RNA defined as following: Single-stranded RNA molecules that are expressed in animal cells and form complexes with Piwi proteins. They are involved in transcriptional gene silencing.. genetic defined as following: Having to do with information that is passed from parents to offspring through genes in sperm and egg cells.. mRNA defined as following: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.. complexes defined as following: A molecular entity formed by loose association involving two or more component molecular entities. The bonding between the components is normally weaker than in a covalent bond.. Proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. nuage defined as following: A small cytoplasmic, non-membranous RNA/protein complex aggregate in the primordial germ cells of many higher eukaryotes. [GOC:dph, GOC:kmv, PMID:11262230]. HP1 defined as following: A protein family comprised of chromo and chromo shadow domain-containing, methyl-lysine binding proteins that are localized to heterochromatin. These proteins are involved in gene silencing, transcriptional activation, and the formation and stabilization of heterochromatin.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. chromatin defined as following: The ordered and organized complex of DNA, protein, and sometimes RNA, that forms the chromosome. [GOC:elh, PMID:20404130]. microRNAs defined as following: Small double-stranded, non-protein coding RNAs, 21-25 nucleotides in length generated from single-stranded microRNA gene transcripts by the same RIBONUCLEASE III, Dicer, that produces small interfering RNAs (RNA, SMALL INTERFERING). They become part of the RNA-INDUCED SILENCING COMPLEX and repress the translation (TRANSLATION, GENETIC) of target RNA by binding to homologous 3'UTR region as an imperfect match. The small temporal RNAs (stRNAs), let-7 and lin-4, from C. elegans, are the first 2 miRNAs discovered, and are from a class of miRNAs involved in developmental timing.. spermatocytes defined as following: Male germ cells derived from SPERMATOGONIA. The euploid primary spermatocytes undergo MEIOSIS and give rise to the haploid secondary spermatocytes which in turn give rise to SPERMATIDS.. essential genes defined as following: Those genes found in an organism which are necessary for its viability and normal function.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. germ cells defined as following: The reproductive cells in multicellular organisms at various stages during GAMETOGENESIS.. transposable element defined as following: Discrete segments of DNA which can excise and reintegrate to another site in the genome. Most are inactive, i.e., have not been found to exist outside the integrated state. DNA transposable elements include bacterial IS (insertion sequence) elements, Tn elements, the maize controlling elements Ac and Ds, Drosophila P, gypsy, and pogo elements, the human Tigger elements and the Tc and mariner elements which are found throughout the animal kingdom.. Stellate defined as following: A term that refers to lesions or cells that are shaped like stars.. organisms defined as following: A living entity.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. locus defined as following: The position of a gene or a chromosomal marker on a chromosome; also, a stretch of DNA at a particular place on a particular chromosome. The use of locus is sometimes restricted to mean regions of DNA that are expressed.. RNA defined as following: A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed). infection defined as following: An illness caused by an infectious agent or its toxins that occurs through the direct or indirect transmission of the infectious agent or its products from an infected individual or via an animal, vector or the inanimate environment to a susceptible animal or human host.. telomere defined as following: A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs.. TE defined as following: A noninvasive test that is used to stage fibrosis in the liver. A 50-MHz wave is passed into the liver from a small transducer on the end of an ultrasound probe which measures the velocity of the shear wave (in meters per second) as this wave passes through the liver. The shear wave velocity can then be converted into liver stiffness. This technique is an alternative to liver biopsy.. piRNAs defined as following: Single-stranded RNA molecules that are expressed in animal cells and form complexes with Piwi proteins. They are involved in transcriptional gene silencing..", "label": "yes"} {"id": "converted_3635", "sentence1": "Can LB-100 downregulate miR-33?", "sentence2": "PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation., LB100 profoundly upregulates miR-181b-1, which we show directly binds to the 3' untranslated region of Bcl-2 mRNA leading to its translational inhibition. MiR-181b-1 ectopic overexpression further diminishes Bcl-2 expression leading to suppression of sAML cell growth, and enhancement of DNR cytotoxicity. [SEP]Definitions: Bcl-2 defined as following: The B-cell leukemia/lymphoma-2 genes, responsible for blocking apoptosis in normal cells, and associated with follicular lymphoma when overexpressed. Overexpression results from the t(14;18) translocation. The human c-bcl-2 gene is located at 18q24 on the long arm of chromosome 18.. PP2A defined as following: PP2A core enzyme consists of a 36-kDa catalytic C subunit and a constant 65-kDa regulatory/structural A subunit that interact with either a B regulatory subunit or with cell signaling molecules, that likely modulate substrate selectivity, catalytic activity, and subcellular localization, yielding the trimeric holoenzyme. Combinations of different subunit isoforms can generate many forms of PP2A, which may differ in substrate specificity, subcellular localization, or tissue specific expression.. daunorubicin defined as following: A very toxic anthracycline aminoglycoside antineoplastic isolated from Streptomyces peucetius and others, used in treatment of LEUKEMIA and other NEOPLASMS..", "label": "no"} {"id": "converted_2347", "sentence1": "Do bacteria from the genus Morexella cause respiratory infections?", "sentence2": "gainst pathogens associated with respiratory tract ailments [Staphylococcus aureus (ATCC 25923), Klebsiella pneumoniae (ATCC 13883) and Morexella cattarhalis (ATCC 14468)] , The efficacy and safety of oral ofloxacin, 400 mg once daily, for the treatment of patients with lower respiratory tract infections were studied. The most common species recovered from the sputum specimens of these patients were Haemophilus influenzae, followed by Streptococcus pneumoniae (S. pneumoniae), Staphylococcus aureus (S. aureus), Gram positive cocci unidentified, Pseudomonas aeruginosa (P. aeruginosa), Morexella catarrhalis,, the efficacy and safety of oral ofloxacin 400 mg once daily for the treatment of patients with lower respiratory tract infections were studied the most common species recovered from the sputum specimens of these patients were haemophilus influenzae followed by streptococcus pneumoniae s pneumoniae staphylococcus aureus s aureus gram positive cocci unidentified pseudomonas aeruginosa p aeruginosa morexella catarrhalis streptococcus epidermidis and another haemophilus species in this order all these bacteria were susceptible to ofloxacin except for one strain of methicillin resistant s aureus a satisfactory clinical outcome was achieved in 34 of 40 patients 85 it is concluded that ofloxacin 400 mg once daily is useful for patients with respiratory tract infections.[SEP]Definitions: ofloxacin defined as following: A synthetic fluoroquinolone antibacterial agent that inhibits the supercoiling activity of bacterial DNA GYRASE, halting DNA REPLICATION.. methicillin defined as following: One of the PENICILLINS which is resistant to PENICILLINASE but susceptible to a penicillin-binding protein. It is inactivated by gastric acid so administered by injection.. respiratory tract infections defined as following: Invasion of the host RESPIRATORY SYSTEM by microorganisms, usually leading to pathological processes or diseases.. Streptococcus pneumoniae defined as following: A gram-positive organism found in the upper respiratory tract, inflammatory exudates, and various body fluids of normal and/or diseased humans and, rarely, domestic animals.. S. aureus defined as following: Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications.. bacteria defined as following: One of the three domains of life (the others being Eukarya and ARCHAEA), also called Eubacteria. They are unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. Bacteria can be classified by their response to OXYGEN: aerobic, anaerobic, or facultatively anaerobic; by the mode by which they obtain their energy: chemotrophy (via chemical reaction) or PHOTOTROPHY (via light reaction); for chemotrophs by their source of chemical energy: CHEMOLITHOTROPHY (from inorganic compounds) or chemoorganotrophy (from organic compounds); and by their source for CARBON; NITROGEN; etc.; HETEROTROPHY (from organic sources) or AUTOTROPHY (from CARBON DIOXIDE). They can also be classified by whether or not they stain (based on the structure of their CELL WALLS) with CRYSTAL VIOLET dye: gram-negative or gram-positive.. respiratory infections defined as following: Invasion of the host RESPIRATORY SYSTEM by microorganisms, usually leading to pathological processes or diseases..", "label": "yes"} {"id": "converted_3697", "sentence1": "Is SATB1 necessary for T-cell maturation?", "sentence2": "Special AT-rich binding protein 1 (SATB1) nuclear protein, expressed predominantly in T cells, regulates genes through targeting chromatin remodeling during T-cell maturation., the transcription factor SATB1 that regulates the T-cell maturation, SATB1 is a transcriptional regulator controlling the gene expression that is essential in the maturation of the immune T-cell. , Special AT-rich sequence binding protein 1 (SATB1) regulates gene expression essential in immune T-cell maturation and switching of fetal globin species, by binding to matrix attachment regions (MARs) of DNA and inducing a local chromatin remodeling. [SEP]Definitions: T cells defined as following: Lymphocytes responsible for cell-mediated immunity. Two types have been identified - cytotoxic (T-LYMPHOCYTES, CYTOTOXIC) and helper T-lymphocytes (T-LYMPHOCYTES, HELPER-INDUCER). They are formed when lymphocytes circulate through the THYMUS GLAND and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen.. SATB1 defined as following: DNA-Binding Protein SATB1 (763 aa, ~86 kDa) is encoded by the human SATB1 gene. This protein binds DNA and may be involved in the regulation of transcription.. nuclear protein defined as following: Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.. DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. matrix attachment regions defined as following: Regions of the CHROMATIN or DNA that bind to the NUCLEAR MATRIX. They are found in INTERGENIC DNA, especially flanking the 5' ends of genes or clusters of genes. Many of the regions that have been isolated contain a bipartite sequence motif called the MAR/SAR recognition signature sequence that binds to MATRIX ATTACHMENT REGION BINDING PROTEINS.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "yes"} {"id": "converted_2247", "sentence1": "Does TFIIS affect nucleosome positioning?", "sentence2": "Transcript cleavage factor TFIIS reactivates the backtracked complexes and promotes pol II transcription through the nucleosome. , The same nucleosomes transcribed in the opposite orientation form a weaker, more diffuse barrier that is largely relieved by higher salt, TFIIS, or FACT, The system contains natural or recombinant histones, chromatin assembly factors, the histone-acetyltransferase p300, all components of the general transcription machinery, general coactivators and the elongation factor SII (TFIIS)., Efficient and rapid nucleosome traversal by RNA polymerase II depends on a combination of transcript elongation factors., We now show that although TFIIF or TFIIS alone is modestly stimulatory for nucleosome traversal, both factors together increase transcription through nucleosomes in a synergistic manner., Significantly, we found that nucleosomes with a Sin mutant histone are traversed to the same extent and at nearly the same rate as equivalent pure DNA templates if both TFIIS and TFIIF are present., After partial uncoiling of nucleosomal DNA from histone octamer by Pol II and backtracking of the enzyme, nucleosomal DNA recoils on the octamer, locking Pol II in the arrested state. Histone chaperones and transcription factors TFIIS, TFIIF and FACT facilitate transcription through chromatin using different molecular mechanisms., Transcript cleavage factor TFIIS reactivates the backtracked complexes and promotes pol II transcription through the nucleosome., The highly conserved eukaryotic transcriptional elongation factor TFIIS enables RNA polymerase II (RNAPII) to read though pause or termination sites, nucleosomes and sequence-specific DNA-binding proteins., We also studied the effect of TFIIF and TFIIS on transcription of nucleosomes containing a Sin mutant histone., The same nucleosomes transcribed in the opposite orientation form a weaker, more diffuse barrier that is largely relieved by higher salt, TFIIS, or FACT.[SEP]Definitions: nucleosomes defined as following: The repeating structural units of chromatin, each consisting of approximately 200 base pairs of DNA wound around a protein core. This core is composed of the histones H2A, H2B, H3, and H4.. RNA polymerase II defined as following: A DNA-dependent RNA polymerase present in bacterial, plant, and animal cells. It functions in the nucleoplasmic structure and transcribes DNA into RNA. It has different requirements for cations and salt than RNA polymerase I and is strongly inhibited by alpha-amanitin. EC 2.7.7.6.. FACT defined as following: A non-profit corporation co-founded by the International Society for Cellular Therapy and the American Society of Blood and Marrow Transplantation for the purposes of voluntary inspection and accreditation in the field of cellular therapy. Founded in 1996, FACT establishes standards for high quality medical and laboratory practice in cellular therapies. FACT Standards are evidence-based requirements set by world-renowned experts vested in the improvement and progress of cellular therapy.. salt defined as following: Sodium chloride used in foods.. TFIIS defined as following: Human TCEA1 wild-type allele is located in the vicinity of 8q11.2 and is approximately 56 kb in length. This allele, which encodes transcription elongation factor A protein 1, plays a role in transcriptional elongation. A chromosomal insertion ins(8)(q12;q11q11) of this gene and the PLAG1 gene may be associated with salivary gland pleomorphic adenoma.. nucleosome defined as following: The repeating structural units of chromatin, each consisting of approximately 200 base pairs of DNA wound around a protein core. This core is composed of the histones H2A, H2B, H3, and H4.. chromatin defined as following: The ordered and organized complex of DNA, protein, and sometimes RNA, that forms the chromosome. [GOC:elh, PMID:20404130]. transcript defined as following: The initial RNA molecule produced by transcription.. Histone chaperones defined as following: Proteins involved in the assembly and disassembly of HISTONES into NUCLEOSOMES.. complexes defined as following: A molecular entity formed by loose association involving two or more component molecular entities. The bonding between the components is normally weaker than in a covalent bond..", "label": "yes"} {"id": "converted_4152", "sentence1": "Are there sex differences in oncogenic mutational processes?", "sentence2": "Sex differences in oncogenic mutational processes.[SEP]", "label": "yes"} {"id": "converted_1651", "sentence1": "Does SCRIB deregulation promote cancer?", "sentence2": "human homologs of Drosophila dlg, scrib, and lgl are cancer-associated genes., Aberrant overexpression of the cell polarity module scribble in human cancer., we show that Scrib is nearly universally overexpressed in cultured tumor cell lines and genetically disparate cancer patient series compared with matched normal tissues in vivo. , These data uncover a previously unrecognized exploitation of Scrib for aberrant tumor cell motility and invasion, thus potentially contributing to disease progression in humans., oss of miR-296 causes aberrantly increased and mislocalized Scrib in human tumors, resulting in exaggerated random cell migration and tumor cell invasiveness. , Scrib levels predict tumor relapse in hepatocellular carcinoma patients., Scrib heterozygosity predisposes to lung cancer, loss of Scrib and activated oncogenic KRas cooperate in vivo, resulting in more aggressive lung tumors, l, Scribble, a product of a well-known tumor suppressor gene, CD74-dependent deregulation of the tumor suppressor scribble in human epithelial and breast cancer cells., scribble (SCRIB) complexes) is intricately related to advanced stages of tumour progression and invasiveness. , SCRIB expression is deregulated in human prostate cancer,, Scrib heterozygosity initiated prostate hyperplasia, The clinical significance of the work in mice was highlighted by our observation that SCRIB deregulation strongly correlated with poor survival in human prostate cancer., we demonstrate that scribble inhibits breast cancer formation and that deregulation of polarity pathways promotes dysplastic and neoplastic growth in mammals by disrupting morphogenesis and inhibiting cell death., Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma., loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system., Scribble expression is decreased in many invasive human cancers., Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling.[SEP]Definitions: Scribble defined as following: Protein scribble homolog (1630 aa, ~175 kDa) is encoded by the human SCRIB gene. This protein is involved in cell polarization.. cancer defined as following: A malignant tumor at the original site of growth.. prostate cancer defined as following: A primary or metastatic malignant tumor involving the prostate gland. The vast majority are carcinomas.. tumor suppressor gene defined as following: Genes that inhibit expression of the tumorigenic phenotype. They are normally involved in holding cellular growth in check. When tumor suppressor genes are inactivated or lost, a barrier to normal proliferation is removed and unregulated growth is possible.. mammals defined as following: Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young.. humans defined as following: Members of the species Homo sapiens.. tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. H-Ras defined as following: Human HRAS wild-type allele is located in the vicinity of 11p15.5 and is approximately 3 kb in length. This allele, which encodes GTPase HRas protein, is involved in cellular mitogenesis. Mutations of HRAS are implicated in Costello syndrome, bladder cancer and oral squamous cell carcinoma.. prostate hyperplasia defined as following: A disease caused by hyperplastic process of non-transformed prostatic cells.. MAPK defined as following: A superfamily of PROTEIN SERINE-THREONINE KINASES that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by MITOGEN-ACTIVATED PROTEIN KINASE KINASES, which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP KINASE KINASE KINASES).. Scrib defined as following: This gene is involved in the establishment of cell polarity.. carcinoma defined as following: A malignant neoplasm made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. It is a histological type of neoplasm and not a synonym for \"cancer.\". breast cancer defined as following: A primary or metastatic malignant neoplasm involving the breast. The vast majority of cases are carcinomas arising from the breast parenchyma or the nipple. Malignant breast neoplasms occur more frequently in females than in males.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. product defined as following:Participant material that is brought forth (produced) in the act (e.g., specimen in a specimen collection, access or drainage in a placement service, medication package in a dispense service). It does not matter whether the material produced had existence prior to the service, or whether it is created in the service (e.g., in supply services the product is taken from a stock).
. tumor cell defined as following: Cells of, or derived from, a tumor.. extracellular matrix defined as following: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere.. mammary defined as following: Glandular tissue in the BREAST of human that is under the influence of hormones such as ESTROGENS; PROGESTINS; and PROLACTIN. In WOMEN, after PARTURITION, the mammary glands secrete milk (MILK, HUMAN) for the nourishment of the young.. lgl defined as following: A form of ventricular pre-excitation characterized by a short PR interval and a normal QRS complex. In this syndrome, the atrial impulse conducts via the JAMES FIBERS which connect the atrium to BUNDLE OF HIS bypassing the upper ATRIOVENTRICULAR NODE. HEART VENTRICLES are depolarized normally through the His-Purkinje system.. hepatocellular carcinoma defined as following: A primary malignant neoplasm of epithelial liver cells. It ranges from a well-differentiated tumor with EPITHELIAL CELLS indistinguishable from normal HEPATOCYTES to a poorly differentiated neoplasm. The cells may be uniform or markedly pleomorphic, or form GIANT CELLS. Several classification schemes have been suggested.. SCRIB defined as following: This gene is involved in the establishment of cell polarity..", "label": "yes"} {"id": "converted_375", "sentence1": "Is lambrolizumab effective for treatment of patients with melanoma ?", "sentence2": "However, through parallel efforts that have showcased the efficacy of small-molecule BRAF and MAP-ERK kinase (MEK) inhibitors, as well as the immune checkpoint inhibitors, namely ipilimumab and the anti-PD1/PDL1 antibodies (lambrolizumab, nivolumab, MPDL3280), an opportunity exists to transform the treatment of melanoma specifically and cancer generally by exploring rational combinations of molecularly targeted therapies, immunotherapies, and molecular targeted therapies with immunotherapies. , Programmed death-1 receptor (PD-1)/its ligand (PD-L1) antibodies have changed the landscape in oncology in 2013. The most mature results have been obtained in advanced melanoma patients. , Merck's lambrolizumab (MK-3475) monoclonal antibody received \"Breakthrough Therapy\" designation from the U.S. Food and Drug Administration in April for treating patients with advanced melanoma., The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. We tested the anti-PD-1 antibody lambrolizumab (previously known as MK-3475) in patients with advanced melanoma. , In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. , Because of all these reasons PD-1/PD-L1 antibodies are considered 'drug of the year'.[SEP]Definitions: MEK defined as following: A dual-specific protein kinase family whose members are components in protein kinase cascades activated by diverse stimuli. These MAPK kinases phosphorylate MITOGEN-ACTIVATED PROTEIN KINASES and are themselves phosphorylated by MAP KINASE KINASE KINASES. JNK kinases (also known as SAPK kinases) are a subfamily.. drug defined as following: Any natural, endogenously-derived, synthetic or semi-synthetic compound with pharmacologic activity. A pharmacologic substance has one or more specific mechanism of action(s) through which it exerts one or more effect(s) on the human or animal body. They can be used to potentially prevent, diagnose, treat or relieve symptoms of a disease. Formulation specific agents and some combination agents are also classified as pharmacologic substances.. melanoma defined as following: A benign or malignant, primary or metastatic neoplasm affecting the melanocytes.. cancer defined as following: A malignant tumor at the original site of growth.. lambrolizumab defined as following: A humanized monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1) with potential immune checkpoint inhibitory and antineoplastic activities. Upon administration, pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells. The ligands for PD-1 include programmed cell death ligand 1 (PD-L1), overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on APCs. Activated PD-1 negatively regulates T-cell activation and plays a key role in in tumor evasion from host immunity.. PD-L1 defined as following: Human CD274 wild-type allele is located in the vicinity of 9p24 and is approximately 20 kb in length. This allele, which encodes programmed cell death 1 ligand 1 protein, plays a role in the regulation of T cell stimulation and proliferation.. T-cell effector defined as following: A mature T-lymphocyte that has differentiated into a form that can mount an antigen-specific immune response.. ipilimumab defined as following: A recombinant human immunoglobulin (Ig) G1 monoclonal antibody directed against the human T-cell receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), with immune checkpoint inhibitory and antineoplastic activities. Ipilimumab binds to CTLA4 expressed on T-cells and inhibits the CTLA4-mediated downregulation of T-cell activation. This leads to a cytotoxic T-lymphocyte (CTL)-mediated immune response against cancer cells. CTLA4, an inhibitory receptor and member of the immunoglobulin superfamily, plays a key role in the downregulation of the immune system.. immune checkpoint inhibitors defined as following: An agent that inhibits any of the immune checkpoint inhibitory proteins.. PD-1 defined as following: Human PDCD1 wild-type allele is located in the vicinity of 2q37.3 and is approximately 9 kb in length. This allele, which encodes programmed cell death protein 1, plays a role in the modulation of both apoptosis and cellular immunity. Mutation of the gene is associated with systemic lupus erythematosus type 2.. toxic defined as following: The finding of bodily harm due to the poisonous effects of something.. nivolumab defined as following: A fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1, PCD-1) with immune checkpoint inhibitory and antineoplastic activities. Upon administration, nivolumab binds to and blocks the activation of PD-1, an immunoglobulin superfamily (IgSF) transmembrane protein, by its ligands programmed cell death ligand 1 (PD-L1), which is overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on antigen-presenting cells (APCs). This results in the activation of T-cells and cell-mediated immune responses against tumor cells. Activated PD-1 negatively regulates T-cell activation and plays a key role in tumor evasion from host immunity.. BRAF defined as following: Serine/threonine-protein kinase B-raf (766 aa, ~84 kDa) is encoded by the human BRAF gene. This protein plays a role in protein phosphorylation, mitogenesis and neuronal signal transduction..", "label": "yes"} {"id": "converted_3375", "sentence1": "Are breaks in double stranded DNA associated with ionizing radiation?", "sentence2": "DNA double-strand breaks (DSBs) are major DNA lesions that are constantly formed during physiological processes such as DNA replication, transcription, and recombination, or as a result of exogenous agents such as ionizing radiation, radiomimetic drugs, and genome editing nucleases, Whereas most endogenous and exogenous DNA damaging agents typically generate lesions that are relatively isolated and can be repaired easily, ionizing radiation (IR) also induces clustered lesions causing DNA double strand breaks (DSBs), The induction of DNA interstrand cross-links by ionizing radiation has been largely ignored in favour of studies on double-strand break formation and repair., While much is known about radiation-induced DNA double-strand breaks (DSBs) and their repair, , Exposure of cells to ionizing radiation induces DNA double-strand breaks., DNA double-strand breaks are considered to be the most deleterious lesion induced by ionizing radiation., Influence of chromatin structure on the induction of DNA double strand breaks by ionizing radiation., Ionizing radiation and radiomimetic drugs such as bleomycin, calichieamycin, neocarzinostatin chromophore, and other synthetic agents can produce both single and double strand breaks in DNA., RESULTS BRCA2-defective cells were unable to repair the double-strand DNA breaks induced by ionizing radiation., BACKGROUND Induction of DNA double strand breaks and alterations in the repair of these breaks is implicated in breast carcinogenesis., Double-stranded breaks ( DSBs ) are the most injurious type of DNA damage , being induced by ionizing radiation ( IR ) and cytotoxic agents used in cancer treatment, Double-stranded breaks ( DSBs ) are cytotoxic DNA lesions caused by oxygen radicals , ionizing radiation , and radiomimetic chemicals, Gamma-ray irradiation introduces single and/or double strand breaks into the DNA molecule of the cells.[SEP]Definitions: DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. lesions defined as following: A localized pathological or traumatic structural change, damage, deformity, or discontinuity of tissue, organ, or body part.. oxygen radicals defined as following: Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include SINGLET OXYGEN; SUPEROXIDES; PEROXIDES; HYDROXYL RADICAL; and HYPOCHLOROUS ACID. They contribute to the microbicidal activity of PHAGOCYTES, regulation of SIGNAL TRANSDUCTION and GENE EXPRESSION, and the oxidative damage to NUCLEIC ACIDS; PROTEINS; and LIPIDS.. chemicals defined as following: A substance with a defined atomic or molecular structure that results from, or takes part in, reactions involving changes in its structure, composition, or properties.. bleomycin defined as following: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors..", "label": "yes"} {"id": "converted_72", "sentence1": "Are transcribed ultraconserved regions involved in cancer?", "sentence2": "Although most cancer research has focused in mRNA, non-coding RNAs are also an essential player in tumorigenesis. In addition to the well-recognized microRNAs, recent studies have also shown that epigenetic silencing by CpG island hypermethylation of other classes of non-coding RNAs, such as transcribed ultraconserved regions (T-UCRs) or small nucleolar RNAs (snoRNAs), also occur in human neoplasia, Starting from a genome-wide expression profiling, we demonstrate for the first time a functional link between oxygen deprivation and the modulation of long noncoding transcripts from ultraconserved regions, termed transcribed-ultraconserved regions (T-UCRs). Interestingly, several hypoxia-upregulated T-UCRs, henceforth named 'hypoxia-induced noncoding ultraconserved transcripts' (HINCUTs), are also overexpressed in clinical samples from colon cancer patients, Consistent with the hypothesis that T-UCRs have important function in tumor formation, The importance of other classes of non-coding RNAs, such as long intergenic ncRNAs (lincRNAs) and transcribed ultraconserved regions (T-UCRs) as altered elements in neoplasia, is also gaining recognition, Expression levels of transcribed ultraconserved regions uc.73 and uc.388 are altered in colorectal cancer, Transcribed ultraconserved regions (T-UCRs) are a subset of 481 sequences longer than 200 bp, which are absolutely conserved between orthologous regions of human, rat and mouse genomes, and are actively transcribed. It has recently been proven in cancer systems that differentially expressed T-UCRs could alter the functional characteristics of malignant cells. Genome-wide profiling revealed that T-UCRs have distinct signatures in human leukemia and carcinoma, Our preliminary results suggest that uc.73 and uc.388 could be potential diagnostic and prognostic biomarkers in CRC patients, The transcribed-ultraconserved regions: a novel class of long noncoding RNAs involved in cancer susceptibility, This review gives a picture of the state of the art of a novel class of long ncRNA known as transcribed-ultraconserved regions (T-UCRs). Most recent studies show that they are significantly altered in adult chronic lymphocytic leukemias, carcinomas, and pediatric neuroblastomas, leading to the hypothesis that UCRs may play a role in tumorigenesis and promising innovative future T-UCR-based therapeutic approaches, CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer, We focused on the transcribed-ultraconserved regions (T-UCRs), a subset of DNA sequences that are absolutely conserved between orthologous regions of the human, rat and mouse genomes and that are located in both intra- and intergenic regions. We used a pharmacological and genomic approach to reveal the possible existence of an aberrant epigenetic silencing pattern of T-UCRs by treating cancer cells with a DNA-demethylating agent followed by hybridization to an expression microarray containing these sequences. We observed that DNA hypomethylation induces release of T-UCR silencing in cancer cells. Among the T-UCRs that were reactivated upon drug treatment, Uc.160+, Uc283+A and Uc.346+ were found to undergo specific CpG island hypermethylation-associated silencing in cancer cells compared with normal tissues. The analysis of a large set of primary human tumors (n=283) demonstrated that hypermethylation of the described T-UCR CpG islands was a common event among the various tumor types. Our finding that, in addition to microRNAs, another class of ncRNAs (T-UCRs) undergoes DNA methylation-associated inactivation in transformed cells supports a model in which epigenetic and genetic alterations in coding and non-coding sequences cooperate in human tumorigenesis, An integrative genomics screen uncovers ncRNA T-UCR functions in neuroblastoma tumours, Different classes of non-coding RNAs, including microRNAs, have recently been implicated in the process of tumourigenesis. In this study, we examined the expression and putative functions of a novel class of non-coding RNAs known as transcribed ultraconserved regions (T-UCRs) in neuroblastoma, our results define a T-UCR expression landscape in neuroblastoma and suggest widespread T-UCR involvement in diverse cellular processes that are deregulated in the process of tumourigenesis, Moreover, the recent demonstration that other ncRNAs, the ultraconserved genes (UCGs) or transcribed ultraconserved regions (T-UCRs), are involved in human cancerogenesis, suggests that the wider family of ncRNAs (including both miRNAs and UCGs) could contribute to the development of the malignant phenotype. Here we review the main studies investigating the role of miRNAs and UCRs in both normal hemopoiesis and hematological malignancies, and identify the molecular, clinical and therapeutic implications of these recent findings, The transcribed-ultraconserved regions: a novel class of long noncoding RNAs involved in cancer susceptibility., Expression levels of transcribed ultraconserved regions uc.73 and uc.388 are altered in colorectal cancer., CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer., Starting from a genome-wide expression profiling, we demonstrate for the first time a functional link between oxygen deprivation and the modulation of long noncoding transcripts from ultraconserved regions, termed transcribed-ultraconserved regions (T-UCRs)., The importance of other classes of non-coding RNAs, such as long intergenic ncRNAs (lincRNAs) and transcribed ultraconserved regions (T-UCRs) as altered elements in neoplasia, is also gaining recognition., Moreover, the recent demonstration that other ncRNAs, the ultraconserved genes (UCGs) or transcribed ultraconserved regions (T-UCRs), are involved in human cancerogenesis, suggests that the wider family of ncRNAs (including both miRNAs and UCGs) could contribute to the development of the malignant phenotype., Moreover, the recent demonstration that other ncRNAs, the ultraconserved genes (UCGs) or transcribed ultraconserved regions (T-UCRs), are involved in human cancerogenesis, suggests that the wider family of ncRNAs (including both miRNAs and UCGs) could contribute to the development of the malignant phenotype, Starting from a genome-wide expression profiling, we demonstrate for the first time a functional link between oxygen deprivation and the modulation of long noncoding transcripts from ultraconserved regions, termed transcribed-ultraconserved regions (T-UCRs)[SEP]Definitions: sequences defined as following: The sequence of nucleotide residues along a DNA chain.. neuroblastomas defined as following: A common neoplasm of early childhood arising from neural crest cells in the sympathetic nervous system, and characterized by diverse clinical behavior, ranging from spontaneous remission to rapid metastatic progression and death. This tumor is the most common intraabdominal malignancy of childhood, but it may also arise from thorax, neck, or rarely occur in the central nervous system. Histologic features include uniform round cells with hyperchromatic nuclei arranged in nests and separated by fibrovascular septa. Neuroblastomas may be associated with the opsoclonus-myoclonus syndrome. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2099-2101; Curr Opin Oncol 1998 Jan;10(1):43-51). colon cancer defined as following: A primary or metastatic malignant neoplasm that affects the colon. Representative examples include carcinoma, lymphoma, and sarcoma.. mRNA defined as following: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.. chronic lymphocytic leukemias defined as following: A chronic leukemia characterized by abnormal B-lymphocytes and often generalized lymphadenopathy. In patients presenting predominately with blood and bone marrow involvement it is called chronic lymphocytic leukemia (CLL); in those predominately with enlarged lymph nodes it is called small lymphocytic lymphoma. These terms represent spectrums of the same disease.. cancer cells defined as following: Cells of, or derived from, a malignant tumor.. rat defined as following: The common rat, Rattus norvegicus, often used as an experimental organism.. carcinomas defined as following: A malignant neoplasm made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. It is a histological type of neoplasm and not a synonym for \"cancer.\". miRNAs defined as following: Small double-stranded, non-protein coding RNAs, 21-25 nucleotides in length generated from single-stranded microRNA gene transcripts by the same RIBONUCLEASE III, Dicer, that produces small interfering RNAs (RNA, SMALL INTERFERING). They become part of the RNA-INDUCED SILENCING COMPLEX and repress the translation (TRANSLATION, GENETIC) of target RNA by binding to homologous 3'UTR region as an imperfect match. The small temporal RNAs (stRNAs), let-7 and lin-4, from C. elegans, are the first 2 miRNAs discovered, and are from a class of miRNAs involved in developmental timing.. lincRNAs defined as following: A molecule of RNA 200-17000 nucleotides in length that is transcribed by non-protein coding areas of DNA. These ribonucleotides may play a role in a variety of biological processes.. CRC defined as following: The disappearance of all signs of cancer, including the absence of a detectable disease-related genetic abnormality, as determined by techniques such as karyotyping or FISH, in response to treatment.. genetic alterations defined as following: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.. molecular defined as following: Relating to or produced by or consisting of molecules.. human defined as following: Members of the species Homo sapiens.. tissues defined as following: Collections of differentiated CELLS, such as EPITHELIUM; CONNECTIVE TISSUE; MUSCLES; and NERVE TISSUE. Tissues are cooperatively arranged to form organs with specialized functions such as RESPIRATION; DIGESTION; REPRODUCTION; MOVEMENT; and others.. neoplasia defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. hematological malignancies defined as following: Neoplasms located in the blood and blood-forming tissue (the bone marrow and lymphatic tissue). The commonest forms are the various types of LEUKEMIA, of LYMPHOMA, and of the progressive, life-threatening forms of the MYELODYSPLASTIC SYNDROMES.. CpG island defined as following: Areas of increased density of the dinucleotide sequence cytosine--phosphate diester--guanine. They form stretches of DNA several hundred to several thousand base pairs long. In humans there are about 45,000 CpG islands, mostly found at the 5' ends of genes. They are unmethylated except for those on the inactive X chromosome and some associated with imprinted genes.. cancer defined as following: A malignant tumor at the original site of growth..", "label": "yes"} {"id": "converted_2463", "sentence1": "Can Logic Alignment Free (LAF) be used for bacterial genomes classification?", "sentence2": "LAF: Logic Alignment Free and its application to bacterial genomes classification., In this paper, we present Logic Alignment Free (LAF), a method that combines alignment-free techniques and rule-based classification algorithms in order to assign biological samples to their taxa. This method searches for a minimal subset of k-mers whose relative frequencies are used to build classification models as disjunctive-normal-form logic formulas (if-then rules). We apply LAF successfully to the classification of bacterial genomes to their corresponding taxonomy. In particular, we succeed in obtaining reliable classification at different taxonomic levels by extracting a handful of rules, each one based on the frequency of just few k-mers. State of the art methods to adjust the frequency of k-mers to the character distribution of the underlying genomes have negligible impact on classification performance, suggesting that the signal of each class is strong and that LAF is effective in identifying it., In this paper, we present Logic Alignment Free (LAF), a method that combines alignment-free techniques and rule-based classification algorithms in order to assign biological samples to their taxa., LAF: Logic Alignment Free and its application to bacterial genomes classification.[SEP]Definitions: LAF defined as following: A soluble factor produced by MONOCYTES; MACROPHAGES, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. Interleukin-1 is a general term refers to either of the two distinct proteins, INTERLEUKIN-1ALPHA and INTERLEUKIN-1BETA. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation.. bacterial genomes defined as following: The genetic complement of a BACTERIA as represented in its DNA..", "label": "yes"} {"id": "converted_68", "sentence1": "Is there any algorithm for enhancer identification from chromatin state?", "sentence2": "RFECS: a random-forest based algorithm for enhancer identification from chromatin state., However, only a limited number of cell types or chromatin marks have previously been investigated for this purpose, leaving the question unanswered whether there exists an optimal set of histone modifications for enhancer prediction in different cell types. Here, we address this issue by exploring genome-wide profiles of 24 histone modifications in two distinct human cell types, embryonic stem cells and lung fibroblasts. We developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer identification from Chromatin States) to integrate histone modification profiles for identification of enhancers, and used it to identify enhancers in a number of cell-types. We show that RFECS not only leads to more accurate and precise prediction of enhancers than previous methods, but also helps identify the most informative and robust set of three chromatin marks for enhancer prediction., We developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer identification from Chromatin States) to integrate histone modification profiles for identification of enhancers, and used it to identify enhancers in a number of cell-types., Here, we address this issue by exploring genome-wide profiles of 24 histone modifications in two distinct human cell types, embryonic stem cells and lung fibroblasts. We developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer identification from Chromatin States) to integrate histone modification profiles for identification of enhancers, and used it to identify enhancers in a number of cell-types. , ChromaGenSVM selects optimum combinations of specific histone epigenetic marks to predict enhancers. , We developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer identification from Chromatin States) to integrate histone modification profiles for identification of enhancers, and used it to identify enhancers in a number of cell-types.[SEP]Definitions: histone modifications defined as following: The covalent alteration of one or more amino acid residues within a histone protein. [GOC:krc]. embryonic stem cells defined as following: Cells derived from the BLASTOCYST INNER CELL MASS which forms before implantation in the uterine wall. They retain the ability to divide, proliferate and provide progenitor cells that can differentiate into specialized cells.. enhancer defined as following: A 50-150bp DNA sequence that increases the rate of transcription of coding sequences. It may be located at various distances and in either orientation upstream from, downstream from or within a structural gene. When bound by a specific transcription factor it increases the levels of expression of the gene, but is not sufficient alone to cause expression. Distinguished from a promoter, that is alone sufficient to cause expression of the gene when bound..", "label": "yes"} {"id": "converted_1402", "sentence1": "Are there Conserved Noncoding Elements (CNEs) in plant genomes?", "sentence2": "Conservation and functional element discovery in 20 angiosperm plant genomes, The detailed view of conservation across angiosperms revealed not only high coding-sequence conservation but also a large set of previously uncharacterized intergenic conservation, Conserved noncoding sequences highlight shared components of regulatory networks in dicotyledonous plants, Using a comparative genomics approach with four dicotyledonous plant species (Arabidopsis thaliana, papaya [Carica papaya], poplar [Populus trichocarpa], and grape [Vitis vinifera]), we detected hundreds of CNSs upstream of Arabidopsis genes, Long identical multispecies elements in plant and animal genomes., Using an alignment-free information-retrieval approach, we have comprehensively identified all long identical multispecies elements (LIMEs), which include both syntenic and nonsyntenic regions, of at least 100 identical base pairs shared by at least two genomes, In contrast, among six plant genomes, we only found nonsyntenic LIMEs, Although complex LIMEs were found in both animal and plant genomes, they differed significantly in their composition and copy number, Ultraconserved elements between the genomes of the plants Arabidopsis thaliana and rice, We consequently compared the genomes of Arabidopsis thaliana and rice, which diverged about 200 million years ago, and identified 25 ultraconserved elements that are longer than 100 bp, ultraconserved elements in plants tend to occur in clusters and locate at noncoding regions, the functions of these plant ultraconserved elements and the reasons why they are practically frozen during the evolution of millions of years remain a mystery, Conserved noncoding sequences in the grasses, Using a local sequence alignment set to deliver only significant alignments, we found one or more CNSs in the noncoding regions of the majority of genes studied. Grass genes have dramatically fewer and much smaller CNSs than mammalian genes, Conserved noncoding sequences among cultivated cereal genomes identify candidate regulatory sequence elements and patterns of promoter evolution, Surveys for conserved noncoding sequences (CNS) among genes from monocot cereal species were conducted to assess the general properties of CNS in grass genomes and their correlation with known promoter regulatory elements, Comparisons of orthologous maize-rice and maize-sorghum gene pairs identified 20 bp as a minimal length criterion for a significant CNS among grass genes, with few such CNS found to be conserved across rice, maize, sorghum, and barley[SEP]Definitions: cereal defined as following: Seeds from grasses (POACEAE) which are important in the diet.. conservation defined as following: The maintenance of certain characteristics in an unchanged condition.. genomes defined as following: The genetic complement of an organism, including all of its GENES, as represented in its DNA, or in some cases, its RNA.. promoter defined as following: A DNA sequence at which RNA polymerase binds and initiates transcription.. CNS defined as following: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges.. plants defined as following: Multicellular, eukaryotic life forms of kingdom Plantae. Plants acquired chloroplasts by direct endosymbiosis of CYANOBACTERIA. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (MERISTEMS); cellulose within cells providing rigidity; the absence of organs of locomotion; absence of nervous and sensory systems; and an alternation of haploid and diploid generations. It is a non-taxonomical term most often referring to LAND PLANTS. In broad sense it includes RHODOPHYTA and GLAUCOPHYTA along with VIRIDIPLANTAE.. plant genomes defined as following: The genetic complement of a plant (PLANTS) as represented in its DNA.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "yes"} {"id": "converted_1952", "sentence1": "Can telomere length shortening be reversed by telomerase?", "sentence2": "Telomere length is regulated around an equilibrium set point. Telomeres shorten during replication and are lengthened by telomerase. Disruption of the length equilibrium leads to disease; thus, it is important to understand the mechanisms that regulate length at the molecular level. , High telomerase activity is detected in nearly all human cancers but most human cells are devoid of telomerase activity. There is well-documented evidence that reactivation of telomerase occurs during cellular transformation. In humans, tumors can rely in reactivation of telomerase or originate in a telomerase positive stem/progenitor cell, or rely in alternative lengthening of telomeres, a telomerase-independent telomere-length maintenance mechanism., Together, these observations may provoke a re-evaluation of telomere and telomerase based therapies, both in telomerase inhibition for cancer therapy and telomerase activation for tissue regeneration and anti-ageing strategies., Telomeres progressively shorten throughout life. A hallmark of advanced malignancies is the ability for continuous cell divisions that almost universally correlates with the stabilization of telomere length by the reactivation of telomerase., Telomerase-mediated telomere elongation provides cell populations with the ability to proliferate indefinitely. Telomerase is capable of recognizing and extending the shortest telomeres in cells;, Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia.[SEP]Definitions: Telomeres defined as following: A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs.. molecular defined as following: Relating to or produced by or consisting of molecules.. telomerase defined as following: An essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic CHROMOSOMES.. humans defined as following: Members of the species Homo sapiens.. tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. cancers defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. aplastic anemia defined as following: A form of anemia in which the bone marrow fails to produce adequate numbers of peripheral blood elements.. disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. bone marrow aplasia defined as following: Depletion of stem cells in the bone marrow that results in the lack of production of hematopoietic cells.. telomere defined as following: A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs..", "label": "yes"} {"id": "converted_3984", "sentence1": "Should minocycline be used for mild Alzheimer disease?", "sentence2": "Conclusions and Relevance: Minocycline did not delay the progress of cognitive or functional impairment in people with mild AD during a 2-year period. [SEP]Definitions: Minocycline defined as following: A TETRACYCLINE analog, having a 7-dimethylamino and lacking the 5 methyl and hydroxyl groups, which is effective against tetracycline-resistant STAPHYLOCOCCUS infections.. minocycline defined as following: A TETRACYCLINE analog, having a 7-dimethylamino and lacking the 5 methyl and hydroxyl groups, which is effective against tetracycline-resistant STAPHYLOCOCCUS infections..", "label": "no"} {"id": "converted_2106", "sentence1": "Does GATA-1 regulate ribosomal protein genes?", "sentence2": "Mutations in exon 2 interfere with the synthesis of the full-length isoform of GATA-1 and lead to the production of a shortened isoform, GATA-1s. These mutations have been found in patients with Diamond-Blackfan anemia (DBA), a congenital erythroid aplasia typically caused by mutations in genes encoding ribosomal proteins., Sixteen of the corresponding transcription factors are of particular interest, as they are housekeeping genes or show a direct link to hematopoiesis, tumorigenesis or leukemia (e.g. GATA-1/2, PU.1, MZF-1)., Deletion of PKC1 relieves the repression of both ribosomal protein and rRNA genes that occurs in response to a defect in the secretory pathway., This stress is monitored by Pkc1p, which initiates a signal transduction pathway that leads to repression of transcription of the rRNA and ribosomal protein genes., The importance of the transcription of the 137 ribosomal protein genes to the economy of the cell is apparent from the existence of at least three distinct pathways that can effect the repression of this set of genes.[SEP]Definitions: PU.1 defined as following: The human SPI1 wild-type allele is located in the vicinity of 11p11.2 and is approximately 24 kb in length. This allele, which encodes transcription factor PU.1 protein, is involved in the activation of transcription by RNA polymerase II.. Pkc1p defined as following: Catalysis of the reaction: ATP + a protein = ADP + a phosphoprotein. This reaction requires diacylglycerol. [EC:2.7.11.13]. rRNA genes defined as following: Genes, found in both prokaryotes and eukaryotes, which are transcribed to produce the RNA which is incorporated into RIBOSOMES. Prokaryotic rRNA genes are usually found in OPERONS dispersed throughout the GENOME, whereas eukaryotic rRNA genes are clustered, multicistronic transcriptional units.. leukemia defined as following: A progressive, malignant disease of the blood-forming organs, characterized by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias were originally termed acute or chronic based on life expectancy but now are classified according to cellular maturity. Acute leukemias consist of predominately immature cells; chronic leukemias are composed of more mature cells. (From The Merck Manual, 2006). GATA-1 defined as following: Human GATA1 wild-type allele is located in the vicinity of Xp11.23 and is approximately 8 kb in length. This allele, which encodes erythroid transcription factor protein, is involved in the regulation of both transcription by RNA polymerase II and erythroid development.. ribosomal proteins defined as following: Proteins found in ribosomes. They are believed to have a catalytic function in reconstituting biologically active ribosomal subunits.. DBA defined as following: Congenital pure red cell aplasia caused by autosomal dominant mutation(s) in the RPS19 gene, encoding 40S ribosomal protein S19.. housekeeping genes defined as following: Constitutively and evenly expressed genes involved in routine cellular metabolisms.. isoform defined as following: Refers to variants of the same protein which can be separated on special conducting media using electrophoresis. The differences may arise from genetically determined differences in primary structure or by modification of the same primary sequence.. transcription factors defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.. Mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "yes"} {"id": "converted_2658", "sentence1": "Does International Citicoline Trial on acUte Stroke trial supports efficacy of citicoline for stroke treatment?", "sentence2": "The meta-analysis showed that no significant differences were found in the long-term mortality (OR=0.91, 95% CI 0.07 to 1.09, P=0.30), the rate of dependency (OR=1.02, 95% CI 0.87 to 1.24, P=0.85), and the effective rate (OR=0.98, 95% CI 0.84 to 1.14, P=0.82) between citicoline group and control group. , In conclusion, citicolne cannot reduce long-term mortality and dependence rate in the treatment of acute stroke, and the effective rate of citivoline may be not better than that of controls but with reliable safety., In humans, although a recent trial International Citicoline Trial on Acute Stroke (ICTUS) has shown that global recovery is similar in CDP-choline and placebo groups, CDP-choline was shown to be more beneficial in some patients, such as those with moderate stroke severity and not treated with t-PA. , INTERPRETATION: Under the circumstances of the ICTUS trial, citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke., The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients., Global recovery was similar in both groups (odds ratio 1·03, 95% CI 0·86-1·25; p=0·364)., INTERPRETATION Under the circumstances of the ICTUS trial, citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke., In humans, although a recent trial International Citicoline Trial on Acute Stroke (ICTUS) has shown that global recovery is similar in CDP-choline and placebo groups, CDP-choline was shown to be more beneficial in some patients, such as those with moderate stroke severity and not treated with t-PA. Several mechanisms have been proposed to explain the beneficial actions of CDP-choline., In humans, although a recent trial International Citicoline Trial on Acute Stroke (ICTUS) has shown that global recovery is similar in CDP-choline and placebo groups, CDP-choline was shown to be more beneficial in some patients, such as those with moderate stroke severity and not treated with t-PA.[SEP]Definitions: CDP-choline defined as following: Donor of choline in biosynthesis of choline-containing phosphoglycerides.. t-PA defined as following: Tissue-type plasminogen activator (562 aa, ~63 kDa) is encoded by the human PLAT gene. This protein plays a role in the cleavage of plasminogen between Arg-580 and Val-581 to form the fibrinolytic enzyme plasmin.. stroke defined as following: A group of pathological conditions characterized by sudden, non-convulsive loss of neurological function due to BRAIN ISCHEMIA or INTRACRANIAL HEMORRHAGES. Stroke is classified by the type of tissue NECROSIS, such as the anatomic location, vasculature involved, etiology, age of the affected individual, and hemorrhagic vs. non-hemorrhagic nature. (From Adams et al., Principles of Neurology, 6th ed, pp777-810). humans defined as following: Members of the species Homo sapiens.. citicoline defined as following: Donor of choline in biosynthesis of choline-containing phosphoglycerides..", "label": "no"}