{"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.", "label": "yes"}
{"id": "converted_22", "sentence1": "Are transcription and splicing connected?", "sentence2": ", as splicing is often cotranscriptional, a complex picture emerges in which splicing regulation not only depends on the balance of splicing factor binding to their pre-mRNA target sites but also on transcription-associated features such as protein recruitment to the transcribing machinery and elongation kinetics., recent evidence shows that chromatin structure is another layer of regulation that may act through various mechanisms, hese span from regulation of RNA polymerase II elongation, which ultimately determines splicing decisions, to splicing factor recruitment by specific histone marks., Chromatin may not only be involved in alternative splicing regulation but in constitutive exon recognition as well, Moreover, splicing was found to be necessary for the proper 'writing' of particular chromatin signatures, giving further mechanistic support to functional interconnections between splicing, transcription and chromatin structure., These links between chromatin configuration and splicing raise the intriguing possibility of the existence of a memory for splicing patterns to be inherited through epigenetic modifications., Spliceosome assembly occurs co-transcriptionally, raising the possibility that DNA structure may directly influence alternative splicing., upporting such an association, recent reports have identified distinct histone methylation patterns, elevated nucleosome occupancy and enriched DNA methylation at exons relative to introns, Moreover, the rate of transcription elongation has been linked to alternative splicing., ere we provide the first evidence that a DNA-binding protein, CCCTC-binding factor (CTCF), can promote inclusion of weak upstream exons by mediating local RNA polymerase II pausing both in a mammalian model system for alternative splicing, CD45, and genome-wide, We recently showed that cotranscriptional splicing occurs efficiently in Drosophila,, In recent years it became apparent that splicing is predominantly cotranscriptional, To determine the prevalence of cotranscriptional splicing in Drosophila, we sequenced nascent RNA transcripts from Drosophila S2 cells as well as from Drosophila heads. Eighty-seven percent of the introns assayed manifest >50% cotranscriptional splicing. The remaining 13% are cotranscriptionally spliced poorly or slowly, with ∼3% being almost completely retained in nascent pre-mRNA., We estimate that > or =90% of endogenous yeast splicing is posttranscriptional, consistent with an analysis of posttranscriptional snRNP-associated pre-mRNA., Notably, the topoisomerase I inhibitor camptothecin, which stalls elongating Pol II, increased cotranscriptional splicing factor accumulation and splicing in parallel. This provides direct evidence for a kinetic link between transcription, splicing factor recruitment and splicing catalysis., Recent evidence indicates that transcriptional elongation and splicing can be influenced reciprocally: Elongation rates control alternative splicing and splicing factors can, in turn, modulate pol II elongation., The presence of transcription factors in the spliceosome and the existence of proteins, such as the coactivator PGC-1, with dual activities in splicing and transcription can explain the links between both processes and add a new level of complexity to the regulation of gene expression in eukaryotes.", "label": "yes"}
{"id": "converted_2090", "sentence1": "Can methylenetetrahydrofolate reductase (MTHFR) gene mutations cause homocystinuria?", "sentence2": "Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. , Several mutations seen in methylenetetrahydrofolate reductase (MTHFR) give rise to the formation of hyperhomocysteinemia and homocystinuria, a considerable risk factor for cardiovascular and cerebrovascular disorders, by leading to enzymatic inactivation., At admission, he had significantly elevated plasma and urine levels of total homocysteine, significantly decreased levels of folate in serum and cerebrospinal fluid, and a normal blood concentration of methionine., Response to treatment demonstrated B(6)-non-responsive homocystinuria. Molecular study showed compound heterozygous T353 N and D444 N mutations of the cystathionine beta-synthase (CBS) gene, and also a C667T homozygous mutation of the methylenetetrahydrofolate-reductase (MTHFR) gene. , Our case is atypical because of the absence of thromboembolism and the mild phenotype, in spite of being B(6)-non-responsive, and the association of a rare compound heterozygous mutation of the CBS gene and also an homozygous mutation of the MTHFR gene., Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency., Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate and homocysteine metabolism. Research performed during the past decade has clarified our understanding of MTHFR deficiencies that cause homocystinuria or mild hyperhomocysteinemia. Our cloning of the MTHFR coding sequence was initially followed by the identification of the first deleterious mutations in MTHFR, in patients with homocystinuria and marked hyperhomocysteinemia., Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the regulation of plasma homocysteine levels. MTHFR deficiency, an autosomal recessive disorder, results in homocystinuria and hypomethioninaemia and presents with highly variable symptoms affecting many organs but predominantly the central nervous system. , Some methylenetetrahydrofolate reductase (MTHFR) gene mutations cause hyperhomocysteinemia and homocystinuria., Rare mutations in the MTHFR gene have been associated with autosomal recessive MTHFR deficiency leading to homocystinuria., Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria., Five patients suspected of having non-classical homocystinuria due to MTHFR deficiency were examined with respect to their symptoms, MTHFR enzyme activity and genotypes of the MTHFR gene., The results of our study render the full-length characterisation of affected alleles in severe homocystinuria and moderate hyperhomocysteinaemia due to MTHFR deficiency and provide a basis for investigating the regulation of the human MTHFR gene., Our cloning of the MTHFR coding sequence was initially followed by the identification of the first deleterious mutations in MTHFR, in patients with homocystinuria and marked hyperhomocysteinemia., Different MTHFR mutations lead either to severe homocystinuria as a multisystem disorder or to moderate hyperhomocysteinaemia, which is a common risk factor for disorders ranging from cardiovasculopathy to spina bifida., We studied 24 patients with homocystinuria caused by homozygous CBS deficiency from 18 unrelated kindreds for FVL and for the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and investigated their possible interaction in the risk of venous thrombosis., On the contrary, thermolabile MTHFR caused by the 677C-->T mutation, was frequently observed among homocystinuria patients, especially among those with thromboembolic complications: three of six homocystinuria patients who had suffered from a thromboembolic event had thermolabile MTHFR., We studied 24 patients with homocystinuria caused by homozygous CBS deficiency from 18 unrelated kindreds for FVL and for the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and investigated their possible interaction in the risk of venous thrombosis., Some methylenetetrahydrofolate reductase (MTHFR) gene mutations cause hyperhomocysteinemia and homocystinuria, We studied 24 patients with homocystinuria caused by homozygous CBS deficiency from 18 unrelated kindreds for FVL and for the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and investigated their possible interaction in the risk of venous thrombosis, Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria, The most common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, The 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is an important cause of mild hyperhomocysteinemia, but this polymorphism does not seem to be a risk factor for venous thrombosis, Hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) gene mutation have been postulated as a possible cause of recurrent miscarriage (RM), The 677C>T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is an important cause of mild hyperhomocysteinaemia, We studied 24 patients with homocystinuria caused by homozygous CBS deficiency from 18 unrelated kindreds for FVL and for the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and investigated their possible interaction in the risk of venous thrombosis. , AIM: Some methylenetetrahydrofolate reductase (MTHFR) gene mutations cause hyperhomocysteinemia and homocystinuria. , Betaine for treatment of homocystinuria caused by methylenetetrahydrofolate reductase deficiency., Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) with homocystinuria can result in early demise or later-onset neurological impairment, including developmental delay, motor dysfunction, and seizures. , Deficiency of 5,10-methylenetetrahydrofolate reductase (MTHFR) leads to deficient remethylation of homocysteine and is one of the causes of homocystinuria. , Neurological disturbances have been described in homocystinuria caused by severe MTHFR deficiency. , The 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is an important cause of mild hyperhomocysteinemia, but this polymorphism does not seem to be a risk factor for venous thrombosis., Research performed during the past decade has clarified our understanding of MTHFR deficiencies that cause homocystinuria or mild hyperhomocysteinemia., The 677C>T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is an important cause of mild hyperhomocysteinaemia., The most common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene., Our cloning of the MTHFR coding sequence was initially followed by the identification of the first deleterious mutations in MTHFR, in patients with homocystinuria and marked hyperhomocysteinemia., Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria., Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency., On the contrary, thermolabile MTHFR caused by the 677C-->T mutation, was frequently observed among homocystinuria patients, especially among those with thromboembolic complications: three of six homocystinuria patients who had suffered from a thromboembolic event had thermolabile MTHFR.", "label": "yes"}
{"id": "converted_370", "sentence1": "Is intense physical activity associated with longevity?", "sentence2": "Our major finding is that repeated very intense exercise prolongs life span in well trained practitioners., Death rates declined with increased levels of total activity (estimated in kilocalories), and declined also with increased intensity of effort measured as from none, to light, to moderately vigorous or vigorous sports play. Death rates at any given quantity of physical exercise were lower for men playing moderately intense sports than for less vigorous men., he purpose of this study was to investigate if jogging, which can be very vigorous, is associated with increased all-cause mortality in men and women., This long-term study of joggers showed that jogging was associated with significantly lower all-cause mortality and a substantial increase in survival for both men and women., Light activities (<4 multiples of resting metabolic rate (METs)) were not associated with reduced mortality rates, moderate activities (4-<6 METs) appeared somewhat beneficial, and vigorous activities (> or =6 METs) clearly predicted lower mortality rates (p, trend = 0.72, 0.07, and <0.001, respectively)., These data demonstrate a graded inverse relationship between total physical activity and mortality. Furthermore, vigorous activities but not nonvigorous activities were associated with longevity., The capacity for prolonged and vigorous physical exercise, particularly if the exercise is recreational, is a strong indicator of longevity.", "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.", "label": "yes"}
{"id": "converted_520", "sentence1": "Does ziconotide bind to N-type calcium channels?", "sentence2": "Since this region partially overlaps with residues previously implicated in block of the channel by omega-conotoxin GVIA, we assessed the effects of mutations in the putative EF hand domain on channel block by omega-conotoxin GVIA and the structurally related omega-conotoxin MVIIA. Both of the toxins irreversibly block the activity of wild type alpha(1B) N-type channels. , Despite their high sequence homology, the peptide neurotoxins omega-conotoxin MVIIA and MVIIC selectively block N- and P/Q-type calcium channels, respectively. ,  Binding assay for both N- and P/Q-type calcium channels showed that amino acid residues restricted to the N-terminal half are important for the recognition of N-type channels, whereas essential residues for P/Q-type channel recognition are widely spread over the whole omega-conotoxin molecule., Ziconotide is a novel peptide that blocks the entry of calcium into neuronal N-type voltage-sensitive calcium channels, preventing the conduction of nerve signals., Ziconotide is a selective, potent and reversible blocker of neuronal N-type voltage-sensitive calcium channels (VSCCs)., The therapeutic benefit of ziconotide derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels., Interactions of intrathecally administered ziconotide, a selective blocker of neuronal N-type voltage-sensitive calcium channels, with morphine on nociception in rats., Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain., Ziconotide, an intrathecally administered N-type calcium channel antagonist for the treatment of chronic pain., Thus, ziconotide is the first of a new class of agents--N-type calcium channel blockers, or NCCBs., Ziconotide, formerly known also as SNX- 111, represents a new class of agents, the N-type calcium channel blockers., The selective N-type calcium channel blocker ziconotide ameliorates severe chronic pain but has a narrow therapeutic window and requires intrathecal administration., A selective N-type calcium channel inhibitor, ziconotide (Prialt), is a neuroactive peptide recently marketed as a novel nonopioid treatment for severe chronic pain., As the clinically available analgesics, pregabalin (alpha2delta-subunit calcium channel ligand), ziconotide (N-type calcium channel blocker), mexiletine (sodium channel blocker), and duloxetine (serotonin and norepinephrine reuptake inhibitors) were evaluated in these neurochemically-induced allodynia models., The present investigation was designed to assess the safety and analgesic efficacy of ziconotide, a new N-type calcium channel blocker, when administered intrathecally to patients with acute postoperative pain., Inhibition of the N-type calcium channel by intrathecal administration of the channel-specific blocker omega-conotoxin MVIIA (ziconotide) is efficacious in the treatment of severe chronic pain., Ziconotide is a powerful analgesic drug that has a unique mechanism of action involving potent and selective block of N-type calcium channels, which control neurotransmission at many synapses., In conclusion, present findings provide implication that the spinal anti-nociceptive mechanistic site of pregabalin is different from that of ziconotide, mexiletine, and duloxetine, and pregabalin could have a broader anti-nociceptive mechanism other than N-type calcium channel blockade., Ziconotide (SNX-111), a selective blocker of neuronal N-type voltage-sensitive calcium channels, is antinociceptive when it is administered intrathecally., Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain., A state-dependent Ca(V)2.2 inhibitor may provide an improved therapeutic window over ziconotide, the peptidyl Ca(V)2.2 inhibitor used clinically. , There is also human validation data from ziconotide, the CaV2.2-selective peptidyl inhibitor used clinically to treat refractory pain. , A selective N-type calcium channel inhibitor, ziconotide (Prialt), is a neuroactive peptide recently marketed as a novel nonopioid treatment for severe chronic pain. , The neuroprotective effects of intrathecal administration of the selective N-type calcium channel blocker ziconotide in a rat model of spinal ischemia.", "label": "yes"}
{"id": "converted_822", "sentence1": "Could transcription factors act as cell-cell signalling molecules?", "sentence2": "Pax6 is a transcription factor essential for the development of tissues including the eyes, central nervous system and endocrine glands of vertebrates and invertebrates. It regulates the expression of a broad range of molecules, including transcription factors, cell adhesion and short-range cell-cell signalling molecules, hormones and structural proteins, Recent data support the view that transcription factors - in particular, homeoproteins - can be transferred from cell to cell and have direct non-cell-autonomous (and therefore paracrine) activities", "label": "yes"}
{"id": "converted_1950", "sentence1": "Do T-Cells regulate neuropathic pain?", "sentence2": "here is evidence for a considerable impact of the immune system also in neuropathic pain. However, the role of the adaptive immune system is still unclear.,  Our investigation revealed a clear shift of T-cell subsets towards anti-inflammation in patients with neuropathic pain. ,  GITRL expressed on macrophages drives cytokine release and T cell activation, resulting in neuropathic pain via GITR-dependent actions. , Thus, this T-cell subset may be specifically targeted to alleviate chronic neuropathic pain.<CopyrightInformation>Copyright © 2012 International Association for the Study of Pain, Recent studies show that T cells play an important role in neuropathic pain following nerve injury in rats, These results show a peripheral pivotal role of CatS in the development of neuropathic pain through the antigen-specific activation of CD4(+) T-cells, Chemokine (C-C motif) ligand 1 (CCL-1), a well-characterized chemokine secreted by activated T cells, has been shown to play an important role in neuropathic pain induced by nerve injury and is also produced in various cell types in the CNS, especially in dorsal root ganglia (DRG), In the present study, we investigated systemic T-cell subset responses and T-cell related cytokine profiles in patients with chronic neuropathic pain., Anti-inflammatory T-cell shift in neuropathic pain., Thus, this T-cell subset may be specifically targeted to alleviate chronic neuropathic pain.., Regulatory T cells attenuate neuropathic pain following peripheral nerve injury and experimental autoimmune neuritis., Macrophage-T cell interactions mediate neuropathic pain through the glucocorticoid-induced tumor necrosis factor ligand system.", "label": "yes"}
{"id": "converted_1152", "sentence1": "Does thyroid hormone affect cardiac remodeling ?", "sentence2": "Thyroid hormones exert important effects on heart remodeling through mir-208., RV and RA function and mechanics are significantly affected by SHT. l-T4 therapy and 1-year maintenance of euthyroid status improved but did not completely recover RV and RA function and deformation in the SHT patients, which implies that right heart remodeling caused by SHT is not reversible in a 1-year period., These results suggest that long-term T4 treatment after MI has beneficial effects on myocyte, arteriolar, and collagen matrix remodeling in the non-infarcted area. Most importantly, results suggest improved survival of myocytes in the peri-infarct area.", "label": "yes"}
{"id": "converted_4352", "sentence1": "Does atemoya juice inhibit tye CYP3A4 enzyme?", "sentence2": "Atemoya juice significantly inhibited CYP1A2 activity in human liver microsomes, but not the activities of CYP2C9 and CYP3A.", "label": "no"}
{"id": "converted_207", "sentence1": "Does administration of triiodothyronine improve outcome following coronary artery bypass grafting?", "sentence2": "Serum T3 concentrations were significantly higher with fewer patients having T3 concentrations below the normal range in the T3 group than the placebo group throughout the postoperative period. Hemodynamic variables, postoperative inotrope requirement, and outcome variables showed no differences between the groups, We conclude that although widespread interest has been shown on the use of thyroid hormones in the perioperative period, and the effect of cardiopulmonary bypass on thyroid hormone metabolism widely studied, there is no substantial evidence to justify routine use of thyroid hormones in patients undergoing coronary artery bypass grafting., Treatment with GIK, T3, and GIK/T3 improves hemodynamic performance and results in reduced cTnI release in patients undergoing on-pump CABG surgery., Perioperative administration of triiodothyronine increased cardiac output slightly and decreased systemic vascular resistance, but it had no effect on operative outcome., Parenteral triiodothyronine given after crossclamp removal during elective coronary artery bypass grafting significantly improved postoperative ventricular function, reduced the need for treatment with inotropic agents and mechanical devices, and decreased the incidence of myocardial ischemia. The incidence of atrial fibrillation was slightly decreased, and the need for postoperative pacemaker support was reduced., Perioperative T3 administration decreased the incidence and need for treatment of postoperative atrial fibrillation.,  Intravenous T(3) does not have dramatic effects on hemodynamic variables in this setting as has been previously suggested. , Raising serum triiodothyronine concentrations in patients undergoing coronary-artery bypass surgery increases cardiac output and lowers systemic vascular resistance, but does not change outcome or alter the need for standard postoperative therapy., No significant differences were noted in the pre and post CPB hemodynamics between the two groups for the most part of the study except that heart rate was increased in T3 group., The haemodynamic parameters were no different between the two groups at any postoperative time point. Likewise, density and affinity of lymphocyte beta-adrenoceptors were not significantly different from pre-operative values in either group.", "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", "label": "no"}
{"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.", "label": "yes"}
{"id": "converted_3580", "sentence1": "Can discharge destinations be accurately predicted using the Risk Assessment and Prediction Tool (RAPT)?", "sentence2": "CONCLUSION: Our analysis identified age, lower lumbar/lumbosacral surgery, and RAPT walk score as independent predictors of discharge to SNF, and demonstrated superior predictive power compared with the total RAPT Score when combined in a novel grading scale. , PURPOSE: The aim of this study was to evaluate the value of conventional factors, the Risk Assessment and Predictor Tool (RAPT) and performance-based functional tests as predictors of delayed recovery after total hip arthroplasty (THA)., CONCLUSIONS: The RAPT accurately predicted discharge disposition for high- and low-risk patients in our cohort. , The RAPT allows for identification of patients who are likely to be discharged home or to rehabilitation, which may facilitate preoperative planning of postoperative care. Additionally, it identifies intermediate-risk patients and could be used to implement targeted interventions to facilitate discharge home in this group of patients., RESULTS: Overall predictive accuracy was 78%. , OBJECTIVE: To assess the relevance of the RAPT (Risk Assessment and Prediction Tool), among a cohort of patients undergoing total hip arthroplasty (THA)., CONCLUSION: This study confirmed the usefulness of the RAPT to help in patient orientation decision after total hip arthroplasty. , CONCLUSIONS\n\nThe RAPT accurately predicted discharge disposition for high- and low-risk patients in our cohort., RAPT scores<6 and >10 (of 12) predicted with >90% accuracy discharge to inpatient rehabilitation and home, respectively., The RAPT allows for identification of patients who are likely to be discharged home or to rehabilitation, which may facilitate preoperative planning of postoperative care., The Risk Assessment and Prediction Tool (RAPT) is a preoperative survey constructed to predict discharge disposition after total joint arthroplasty (TJA)., CONCLUSIONS The RAPT accurately predicted discharge disposition for high- and low-risk patients in our cohort., The Risk Assessment and Prediction Tool (RAPT) is a preoperative survey constructed to predict discharge disposition after total joint arthroplasty (TJA)., A low RAPT score is reported to indicate a high risk of needing any form of inpatient rehabilitation after TJA, including short-term nursing facilities., CONCLUSIONS\nThe RAPT accurately predicted discharge disposition for high- and low-risk patients in our cohort., CONCLUSIONS: The RAPT accurately predicted discharge disposition for high- and low-risk patients in our cohort., BACKGROUND: The Risk Assessment and Prediction Tool (RAPT) is used to predict patient discharge disposition after total joint arthroplasty., CONCLUSIONS: The RAPT accurately predicted discharge disposition for high- and low-risk patients in our cohort.", "label": "yes"}
{"id": "converted_475", "sentence1": "Can venlafaxine block NET and SERT?", "sentence2": "Treatment for 14 days with 70 mg/kg per day venlafaxine, which inhibits both the NET and SERT, or 10 mg/kg per day phenelzine, a monoamine oxidase inhibitor, produced antidepressant-like effects on behavior without altering NET or SERT expression., Venlafaxine blocks both serotonin and norepinephrine transporters (SERT and NET), with higher affinity for SERT., Chronic venlafaxine treatment affected SERT and NET binding differently from paroxetine or desipramine., Venlafaxine blocks both serotonin and norepinephrine transporters (SERT and NET), with higher affinity for SERT, Paroxetine and venlafaxine are potent serotonin transporter (SERT) antagonists and weaker norepinephrine transporter (NET) antagonists, Using a novel blood assay that estimates CNS transporter occupancy we estimated the relative SERT and NET occupancy of paroxetine and venlafaxine in human subjects to assess the relative magnitude of SERT and NET inhibition, Treatment for 14 days with 70 mg/kg per day venlafaxine, which inhibits both the NET and SERT, or 10 mg/kg per day phenelzine, a monoamine oxidase inhibitor, produced antidepressant-like effects on behavior without altering NET or SERT expression, We then performed the first reported investigation of epistasis between the SERT gene and norepinephrine transporter gene (SLC6A2, alias NET) in AN, as an earlier study suggested that atypical AN responds to the dual serotonin-norepinephrine reuptake inhibitor venlafaxine, Of particular interest were the findings that paroxetine, generally thought of as a selective SERT antagonist, possesses moderately high affinity for the NET and that venlafaxine, which has been described as a &quot;dual uptake inhibitor&quot;, possesses weak affinity for the NET, The ratios of measured occupancy ED(50) values (doses at which 50% occupancy occurs) among SERT, NET and DAT sites for duloxetine, venlafaxine, nomifensine, indatraline, DOV 21,947 and DOV 216,303 were consistent with the ratios of the in vitro affinities between these target binding sites, SERT and NET occupancy by venlafaxine and milnacipran in nonhuman primates: a PET study, In this study in nonhuman primates, we aimed to investigate the relationship between SERT and NET affinity by measuring the in vivo occupancy at both transporters of venlafaxine and milnacipran, We hypothesized that venlafaxine would affect monoamine transporters dose-dependently, with low doses causing selective reduction of SERT binding sites and higher doses reducing both SERT and NET binding sites, Comparative studies with clinically used antidepressants showed that venlafaxine possessed a profile similar to S33005 but was less potent. Clomipramine likewise interacted with SERTs and NETs but also with several other receptors types, while citalopram and reboxetine were preferential ligands of SERTs and NETs, respectively. In conclusion, S33005 interacts potently with SERTs and, less markedly, with NETs. , Venlafaxine blocks both serotonin and norepinephrine transporters (SERT and NET), with higher affinity for SERT. Serotonergic effects occur with lower doses, whereas both serotonergic and noradrenergic effects occur with higher doses of venlafaxine., Taken together, the results from this study indicate that the low dose of venlafaxine blocked selectively the reuptake of 5-HT, whereas the high dose blocked the reuptake of both 5-HT and NE. Moreover, an enhancement of serotonergic neurotransmission by venlafaxine was only achieved under conditions whereby the desensitization of the terminal 5-HT(1B) autoreceptor is appended to that of the somatodendritic 5-HT(1A) receptor.", "label": "yes"}
{"id": "converted_2357", "sentence1": "Is Kummell’s disease an avascular necrosis of the vertebral body?", "sentence2": " Kummell's disease is an avascular necrosis of the vertebral body, secondary to a vertebral compression fracture. This entity is characterised by the gradual development in time of a vertebral body collapse following a trivial spinal trauma, involving a worsening back pain associated with a progressive kyphosis., Kummell's disease is a rare spinal disorder characterized as avascular necrosis of a vertebral body occurring in a delayed fashion after minor trauma., Kummell's disease is a spinal disorder characterized by delayed post-traumatic collapse of a vertebral body with avascular necrosis., Kummell disease, or avascular necrosis of a vertebral body, presents as vertebral osteonecrosis typically affecting a thoracic vertebra with compression deformity, intravertebral vacuum cleft, and exaggerated kyphosis weeks to months after a minor traumatic injury., INTRODUCTION Kummell's disease is an avascular necrosis of the vertebral body, secondary to a vertebral compression fracture., Kummel disease is the eponym for avascular necrosis of the vertebral body after a vertebral compression fracture., kummell s disease delayed post traumatic osteonecrosis of the vertebral body, Kummell's disease, caused by osteonecrosis of the vertebral body, is a cause of vertebral collapse., Kummell's disease is a post-traumatic vertebral body collapse, Kummell's disease is a rare, delayed posttraumatic collapse of a vertebral body that can occur several months or even years after an osteoporotic compression fracture. , Avascular necrosis of a vertebral body, a relatively uncommon entity, is caused by malignancy, infection, radiation, systemic steroid treatment, trauma, and the like.1 Vertebral osteonecrosis induced by trauma is called Kvmell's disease", "label": "yes"}
{"id": "converted_3255", "sentence1": "Can Daptacel be used instead of IPOL?", "sentence2": "Our goal was to compare the safety and immunogenicity of a combination vaccine (DTaP(5)-IPV-Hib; Pentacel) with that of its separately administered, US-licensed equivalent vaccines (diphtheria, tetanus, 5-component acellular pertussis vaccine [DTaP(5); Daptacel], inactivated poliovirus vaccine [IPV; IPOL], and Haemophilus influenzae type b [Hib] vaccine [ActHIB]), when administered to infants and toddlers concomitantly with other routinely recommended vaccines and to assess antibody persistence from the fourth dose in toddlers to the fifth (preschool) DTaP(5) dose., DTaP(5)-IPV-Hib is a suitable replacement for separately administered DTaP, IPV, and Hib vaccines.,  In this randomized, multicenter study, 1939 healthy infants were immunized at 2, 4, and 6 months of age with 1 of 3 lots of DTaP(5) coadministered with IPV and Hib vaccines or 1 lot of DTaP(5)-IPV-Hib combination vaccine., DTaP(5)-IPV-Hib elicited similar or fewer solicited injection-site and systemic reactions as compared with the separate administration of US-licensed DTaP(5), IPV, and Hib vaccines. ", "label": "no"}
{"id": "converted_4390", "sentence1": "Can IFNg induce the expression of IDO?", "sentence2": "IFNG inducible IDO/GTPCH inflammation cascade, IFNG-induced up-regulation of indoleamine 2,3-dioxygenase (IDO), IFN-γ-induced indoleamine-2,3-dioxgenase (IDO) , strong and positive correlation between IDO1 and IFNG mRNA expression levels ,  The tryptophan-degrading activity of IDO1 was not induced significantly by Chlamydia infection alone, but the addition of IFNG greatly increased its activity. ", "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.<br>, There has been an increasing trend of subacute sclerosing panencephalitis in southern China after the measles outbreak in 1988., The prevalence rate of subacute sclerosing panencephalitis in Hong Kong and Macau in 2002 was 1 per million total population or 5.5 per million children., Because a positive correlation was found between the prevalence of measles and the onset of subacute sclerosing panencephalitis, particularly among children infected at an early age, it is vital to eradicate measles infection by vaccination.<br>, Incidence of subacute sclerosing panencephalitis following measles and measles vaccination in Japan., UNLABELLED Subacute sclerosing panencephalitis (SSPE), in the majority of cases, is caused by the wild measles virus, although there are some reports relating SSPE to vaccination., Subacute sclerosing panencephalitis (SSPE) is a progressive neurodegenerative disease caused by the measles (rubeola) virus and is most often seen in children., There was no indication that measles vaccine can induce SSPE., Subacute Sclerosing Panencephalitis (SSPE), a rare lethal disease of children and young adults due to persistence of measles virus (MeV) in the brain, is caused by wild type (wt) MeV., Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder of childhood and early adolescence caused by persistent defective measles virus., Subacute sclerosing panencephalitis (SSPE) is a devastating disease of the central nervous system (CNS) caused by persistent mutant measles virus infection., Subacute sclerosing panencephalitis (SSPE) caused by persistent defective measles virus strains, is a progressive neurological disorder of children and adolescents., Subacute sclerosing panencephalitis (SSPE), in the majority of cases, is caused by the wild measles virus, although there are some reports relating SSPE to vaccination., Measles can persist in the central nervous system and cause subacute sclerosing panencephalitis (SSPE), a progressive disease that is almost always fatal., However, because of the median 8-year interval between measles and onset of SSPE,, The prevention of endemic circulation of measles virus in England and Wales through the high coverage achieved with MMR vaccine, together with the measles/rubella vaccination campaign of 1994, has resulted in the near elimination of SSPE., We applied the polymerase chain reaction (PCR) to detect the measles virus genome in specimens from a 12-year-old boy with SSPE who had received measles vaccine 10 years before and had no history of apparent natural measles. The oligonucleotide primers for PCR were prepared based on the nucleotide sequence of the F and NP genes of the measles virus Edmonston strain.RESULTS: F and NP genes were detected in both the cerebrospinal fluid and peripheral blood lymphocytes. Nucleotide and deduced amino acid sequence analysis of the F gene showed that the patient's virus was different from that of the vaccine strain. Judging from these results, it was likely that the SSPE-associated strain in this case was derived from the wild-type rather than the vaccine strain, subacute sclerosing panencephalitis (SSPE) is a late, rare and usually fatal complication of measles infection., Subacute sclerosing panencephalitis (SSPE) is a chronic central nervous (CNS) system infection caused by measles virus,  Epidemiological and virological data suggest that measles vaccine does not cause SSPE., Subacute sclerosing panencephalitis, a rare, progressive, fatal central nervous system disease of children, is caused by measles virus., Subacute sclerosing panencephalitis is a form of chronic persistent measles encephalitis in childhood which rarely manifests after wild virus infection., Subacute sclerosing panencephalitis is a fatal infectious disease of childhood caused by persistence of the measles virus in the brain. , Subacute sclerosing panencephalitis (SSPE) is a fatal encephalitis manifesting a number of years after a primary measles infection. , Subacute sclerosing panencephalitis (SSPE) is a fatal complication of measles infection., In 2015, the Oregon Health Authority was notified of the death of a boy with subacute sclerosing panencephalitis (SSPE), a rare and fatal complication of measles., Subacute sclerosing panencephalitis (SSPE) is a rare progressive neurological disorder of early adolescence caused by persistent infection of the measles virus, which remains prevalent worldwide despite an effective vaccine. , Subacute Sclerosing Panencephalitis (SSPE) is a debilitating disorder associated with the measles infection in childhood.", "label": "no"}
{"id": "converted_2316", "sentence1": "Can the CEP290 gene mutations be targeted by AAV-mediated gene therapy?", "sentence2": "The large size of the CEP290 gene prevents its use in adeno-associated virus (AAV)-mediated gene augmentation therapy.", "label": "no"}
{"id": "converted_3210", "sentence1": "Are cardenolides inhibitors of Na+/K+ ATPase?", "sentence2": ". Previously, we reported that a variety of cardenolides impart anti-transmissible gastroenteritis coronavirus (TGEV) activity in swine testicular (ST) cells, through targeting of the cell membrane sodium/potassium pump, Na+/K+-ATPase. , : We found evidence for low cardenolides by HPLC, but substantial toxicity when extracts were assayed on Na+ /K+ -ATPases., Cardenolides have shown significant antitumor activity due to their ability to inhibit the Na+K+ATPase enzyme, and the expression of this enzyme is increased in tumor cells. ", "label": "yes"}
{"id": "converted_2605", "sentence1": "Does verubecestat activate BACE?", "sentence2": "Verubecestat is a potent BACE1 enzyme inhibitor currently being investigated in Phase III trials for the treatment of mild-to-moderate and prodromal Alzheimer's disease. ", "label": "no"}
{"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).<br>", "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", "label": "yes"}
{"id": "converted_3169", "sentence1": "Is it possible to analyze exosomes with FACS?", "sentence2": "whose presence was validated by a bead-exosome FACS assay., We analyzed exosomes from mouse (C57Bl/6) and breast, lung, and ovarian cancer patient samples and cultured cancer cells with different approaches, including nanoparticle tracking analysis, biolayer interferometry, FACS, and electron microscopy., we applied a technique to generate native fluorescent exosomes characterized by vesicles integrity, size, density, markers expression, and quantifiable by direct FACS analysis, we used a novel strategy for generating metabolically-labeled fluorescent exosomes that can be counted by flow cytometry assay (FACS) and characterized.", "label": "yes"}
{"id": "converted_1270", "sentence1": "Can administration of the thyrotropin releasing hormone reduce fatigue in cancer patients?", "sentence2": "TRH administration was associated with significant improvement (p < 0.05) in fatigue levels as measured by the Visual Analog Scale-Energy (VAS-E), was associated with significant (p < 0.05) improvement in sleep disturbances and improved quality of life. , This decrease in CRP level with TRH administration was associated with improvement in energy levels as measured by the VAS-E. , In the present pilot, randomized, placebo-controlled, crossover study, we investigated the efficacy and safety of TRH as a treatment for CF., TRH administration was associated with significant improvement in fatigue level as measured by the VAS-E, the fatigue and vigor subscales of the POMS, and the fatigue subscale of FACIT-F (p < 0.05). , TRH administration was efficacious, safe, and tolerable in the treatment of CF with a positive impact on quality of life. These results provide a crucial impetus for pursuing TRH therapeutics to treat CF., Thyrotropin-releasing hormone can relieve cancer-related fatigue: hypothesis and preliminary observations., Global assessment using both subjective and objective parameters showed that TRH exerted clear anti-fatigue effects in four of the six TRH treatments. , These initial findings support the proposal that TRH can ameliorate cancer-related fatigue.", "label": "yes"}
{"id": "converted_867", "sentence1": "Are psammoma bodies characteristic to meningiomas?", "sentence2": "Psammoma bodies (PBs) are concentric lamellated calcified structures, observed most commonly in papillary thyroid carcinoma (PTC), meningioma, and papillary serous cystadenocarcinoma of ovary but have rarely been reported in other neoplasms and nonneoplastic lesions., Studies on serous cystadenocarcinoma of ovary and meningioma, however, revealed that collagen production by neoplastic cells and subsequent calcification was responsible for the formation of PBs., The existence of some precursor forms of PBs was reported in meningiomas and more recently in PTC, which were mostly in the form of extracellular hyaline globules surrounded by well-preserved neoplastic cells or in a smaller number of cases intracytoplasmic bodies liberated from intact tumor cells., Light microscopy revealed abundant microcysts of varied size throughout the tumor tissue with the presence of whorl formation and psammoma body, but no malignancy was indicated. Electron microscopy further demonstrated interdigitation of the neighboring cell membranes, desmosomes, and intracytoplasmic filaments, which are pathognomonic findings of meningiomas., Unlike SFT, FMs were glycogen-containing and variously exhibited a storiform pattern (13 of 20), psammoma body formation (9 of 20), and calcification of collagen (4 of 20). Immunoreactivities included vimentin (100%), focal to patchy EMA (80%), S-100 protein (80%), collagen IV (25%), and patchy, mild-to-moderate CD34 staining (60%)., In contrast to the inner structure, three-dimensional structure of psammona bodies in meningiomas is not well defined., This study examined three cultured meningiomas, in which surface observation of psammoma bodies might be easier than in the tumor tissues since influence of interposing connective tissue is minimized in tissue culture., The results suggest that psammoma bodies in meningiomas arise in part from meningothelial whorls due to collagen production by tumor cells followed by obliteration and disappearance of tumor cell processes, although some of the alternative pathways for psammoma body formation proposed by other investigators cannot be ruled out by this study., To demonstrate that psammoma bodies in human meningiomas contain type VI collagen and laminin., This is the first report to describe the involvement of type VI collagen in psammoma bodies and whorl formations in meningiomas., Calcification such as psammoma body is sometimes found especially in spinal cord meningioma but ossification of the meningeal tumor was rarely observed., Histological diagnosis was transitional meningioma with psammoma body., In this study we analyzed the morphologic and ultrastructural characteristics of the psammoma bodies in ten meningiomas of different histologic subtypes, characterizing the components of the psammoma body and the elements of the tumor, such as the capillaries and degenerative cells that have been classically considered as initiators of the formation of these calcareous is structures., It is concluded that the mineralization of the psammoma bodies is induced principally by the collagen fibers synthesized by the meningocytes and that the form of mineralization is spherical and growth is radial, controlled by the tumoral cells., CSF cytology revealed benign fibroblastic or meningotheliomatous meningioma with whorl formation and psammoma body., Electron microscopic examination of the calculi showed membrane-bound vesicles and radially precipitated crystals that simulated hydroxyapatite of psammoma body in meningioma., Psammoma bodies in meningiomas resembled those in the choroid plexus stroma., The results of this study suggest that psammoma bodies in the choroid plexus, as in meningiomas, form by a process of dystrophic calcification associated with arachnoid cells and collagen fibres., An early stage of psammoma body formation was seen more frequently in these villous microcores than in the meningocytic whorls., Psammoma bodies in meningocytic whorls were investigated by electron microscopy., Psammoma body formation in the meningocytic whorls may represent degeneration in some whorls of the central cells which contain connective tissue fibers, producing cell debris such as membrane invested vesicles., Twenty human meningiomas were examined for IgG and IgM by the direct immunofluorescence of immunoperoxidase methods, or both. IgG was conspicuously found in and around the blood vessels, whorls, and psammoma bodies. It was also clearly present on the cytoplasmic membranes of the tumour cells., Significance of these findings is briefly discussed including possible humoral immune reactions in regard to whorl and psammoma body formation in meningioma., The fine structure of psammoma bodies was examined in four cases of fibroblastic meningioma., In general, large numbers of various-sized calcified bodies (psammoma bodies) were scattered among the interstitial fibers., These findings suggest that both matrix giant bodies and matrix vesicles may serve as initial nidus of calcification of psammoma bodies in fibroblastic meningioma., Psammoma body formation or dystrophic mineralization and gliosis of the intervening parenchyma was observed in all three cases.", "label": "yes"}
{"id": "converted_4315", "sentence1": "Is Keutel syndrome a common genetic disorder?", "sentence2": "Keutel syndrome (OMIM 245150) is a very rare syndrome , Keutel syndrome is a rare autosomal-recessive condition characterized by abnormal cartilage calcification., MGP-deficiency in humans leads to Keutel syndrome, a rare genetic disease hallmarked by abnormal soft tissue calcification. ", "label": "no"}
{"id": "converted_2785", "sentence1": "Are whole-genome duplications more divergent than small-scale duplications in yeast?", "sentence2": " Also, we observe that transporter and glycolytic genes have a higher probability to be retained in duplicate after WGD and subsequent gene loss, both in the model as in S. cerevisiae, which leads to an increase in glycolytic flux after WGD, We show that the retention of genes in duplicate in the model, corresponds nicely with those retained in duplicate after the ancestral WGD in S. cerevisiae, Thus, our model confirms the hypothesis that WGD has been important in the adaptation of yeast to the new, glucose-rich environment that arose after the appearance of angiosperms., Whole-genome duplicates tend to exhibit less profound phenotypic effects when deleted, are functionally less divergent, and are associated with a different set of functions than their small-scale duplicate counterparts., The results uncover the WGD as a major source for the evolution of a complex interconnected block of transcriptional pathways., These selected pairs, both WGD and SSD, tend to have decelerated functional evolution, have higher propensities of co-clustering into the same protein complexes, and share common interacting partners., Moreover, we find additional transcriptional profiles that are suggestive of neo- and subfunctionalization of duplicate gene copies. These patterns are strongly correlated with the functional dependencies and sequence divergence profiles of gene copies., Functional and transcriptional divergence between the copies after gene duplication has been considered the main driver of innovations ., Whole-genome duplicates tend to exhibit less profound phenotypic effects when deleted, are functionally less divergent, and are associated with a different set of functions than their small-scale duplicate counterparts., Empirical data shows that whole-genome duplications (WGDs) are more likely to be retained than small-scale duplications (SSDs), though their relative contribution to the functional fate of duplicates remains unexplored.", "label": "yes"}
{"id": "converted_1876", "sentence1": "Has small pox been eradicated from the world?", "sentence2": "small pox has been eradicated., smallpox is now eradicated, In May 1980 the World Health Assembly in Geneva announced in solemn form the world-wide eradication of the small-pox and gave recommendations to the member countries for concluding measures concerning the small-pox vaccination, the foundation of vaccine reserves and the control of the epidemiological situation in the world., As a result of vaccination, diseases such as polio and measles have been controlled and small pox has been eradicated, Small pox eradication from the world is the perfect example of the role of mass vaccination of the entire community of the universe. , The French owe a lot to this Central Committee of Vaccine, which greatly contributed to fighting small pox and eradicating the disease finally., Small pox eradication from the world is the perfect example of the role of mass vaccination of the entire community of the universe., Also, the vaccine that Jenner used, which decreased the prevalence of Small Pox worldwide in his own time, and later was used to eradicate Small Pox altogether, is discussed in light of recent data.., the only known cases of smallpox happened from an outbreak in Birmingham, England caused by a laboratory accident in the year of 1979. On May the 8 th 1980 the disease was declared as eliminated from the world by the WHO (WHO-Resolution 33.33).", "label": "yes"}
{"id": "converted_419", "sentence1": "Are there transposon-free regions in mammalian genomes?", "sentence2": "Transposon-free regions in mammalian genomes., Despite the presence of over 3 million transposons separated on average by approximately 500 bp, the human and mouse genomes each contain almost 1000 transposon-free regions (TFRs) over 10 kb in length. The majority of human TFRs correlate with orthologous TFRs in the mouse, despite the fact that most transposons are lineage specific. Many human TFRs also overlap with orthologous TFRs in the marsupial opossum, indicating that these regions have remained refractory to transposon insertion for long evolutionary periods. Over 90% of the bases covered by TFRs are noncoding, much of which is not highly conserved. Most TFRs are not associated with unusual nucleotide composition, but are significantly associated with genes encoding developmental regulators, suggesting that they represent extended regions of regulatory information that are largely unable to tolerate insertions, a conclusion difficult to reconcile with current conceptions of gene regulation., All three elements insert only rarely within many Polycomb-regulated regions, a property that may contribute to the origin of \"transposon-free regions\" (TFRs) in metazoan genomes., Despite the presence of over 3 million transposons separated on average by approximately 500 bp, the human and mouse genomes each contain almost 1000 transposon-free regions (TFRs) over 10 kb in length., RESULTS: Here we report that transposon-free regions (TFRs) are prominent genomic features of amphibian and fish lineages, and that many have been maintained throughout vertebrate evolution, although most transposon-derived sequences have entered these lineages after their divergence. , Despite the presence of over 3 million transposons separated on average by approximately 500 bp, the human and mouse genomes each contain almost 1000 transposon-free regions (TFRs) over 10 kb in length. , All three elements insert only rarely within many Polycomb-regulated regions, a property that may contribute to the origin of \"transposon-free regions\" (TFRs) in metazoan genomes. , Despite the presence of over 3 million transposons separated on average by approximately 500 bp, the human and mouse genomes each contain almost 1000 transposon-free regions (TFRs) over 10 kb in length., Here we report that transposon-free regions (TFRs) are prominent genomic features of amphibian and fish lineages, and that many have been maintained throughout vertebrate evolution, although most transposon-derived sequences have entered these lineages after their divergence.", "label": "yes"}
{"id": "converted_3595", "sentence1": "Can LB-100 sensitize ovarian carcinoma to cisplatin?", "sentence2": "The protein phosphatase 2A inhibitor LB100 sensitizes ovarian carcinoma cells to cisplatin-mediated cytotoxicity., LB100 sensitized ovarian carcinoma lines to cisplatin-mediated cell death. , Our results suggest that LB100 sensitizes ovarian cancer cells to cisplatin in vitro and in vivo by modulation of the DDR pathway and cell-cycle checkpoint abrogation.", "label": "yes"}
{"id": "converted_2780", "sentence1": "Is cariprazine effective for treatment of bipolar disorder?", "sentence2": "BACKGROUND: We evaluated the safety/tolerability of longer-term open-label treatment with cariprazine in patients who had responded to cariprazine for acute bipolar mania., Clinically relevant response and remission outcomes in cariprazine-treated patients with bipolar I disorder., Cariprazine is FDA approved for the acute treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults., DISCUSSION: Cariprazine-treated patients with bipolar I disorder attained clinically significant improvement in manic symptoms as shown by significantly greater rates of response and remission versus placebo; improvement in manic symptoms did not induce depressive symptoms., OBJECTIVE: Cariprazine, a dopamine D3/D2 partial agonist atypical antipsychotic with preferential binding to D3 receptors, is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder., <b>BACKGROUND</b>: Cariprazine was approved for treating schizophrenia and bipolar disorder, and currently is being evaluated for treating depression in clinical trials in the United States.", "label": "yes"}
{"id": "converted_999", "sentence1": "Has single guide RNA been used on human cells?", "sentence2": "We used a library containing 73,000 sgRNAs to generate knockout collections and performed screens in two human cell lines., Here we engineer this system to enable RNA-guided genome regulation in human cells by tethering transcriptional activation domains either directly to a nuclease-null Cas9 protein or to an aptamer-modified single guide RNA (sgRNA)., The type II CRISPR/Cas system from Streptococcus pyogenes and its simplified derivative, the Cas9/single guide RNA (sgRNA) system, have emerged as potent new tools for targeted gene knockout in bacteria, yeast, fruit fly, zebrafish and human cells., Here we engineer this system to enable RNA-guided genome regulation in human cells by tethering transcriptional activation domains either directly to a nuclease-null Cas9 protein or to an aptamer-modified single guide RNA (sgRNA). , Using synthetic single RNA guides, Cas9 can be reprogrammed to create specific double-stranded DNA breaks in the genomes of a variety of organisms, ranging from human cells to bacteria, and thus constitutes a powerful tool for genetic engineering. , Here we engineer this system to enable RNA-guided genome regulation in human cells by tethering transcriptional activation domains either directly to a nuclease-null Cas9 protein or to an aptamer-modified single guide RNA (sgRNA).", "label": "yes"}
{"id": "converted_4240", "sentence1": "Is Cabotegravir effective for HIV prevention?", "sentence2": "A new paradigm for antiretroviral delivery: long-acting cabotegravir and rilpivirine for the treatment and prevention of HIV., PURPOSE OF REVIEW: Cabotegravir (CAB) and rilpivirine (RPV) is the first long-acting injectable antiretroviral therapy (ART) option approved for virologically suppressed adults with HIV-1. In addition, long-acting CAB is a promising agent for HIV preexposure prophylaxis (PrEP). , SUMMARY: Clinical trial results support the use of long-acting CAB for HIV PrEP and long-acting CAB and RPV as a switch strategy for adults with HIV-1 who are first virologically suppressed with oral ART. , OBJECTIVE: We had previously shown that long-acting cabotegravir (CAB-LA) injections fully protected macaques from vaginal simian HIV (SHIV) infection., The Potential Impact of Long-Acting Cabotegravir for HIV Prevention in South Africa: A Mathematical Modeling Study.,  Long-acting cabotegravir (CAB LA) is a potential new injectable formulation for human immunodeficiency virus (HIV) PrEP being tested in phase III trials., Design and Testing of a Cabotegravir Implant for HIV Prevention., Cabotegravir and rilpivirine long-acting injectable antiretroviral therapy for the treatment of HIV-1 infection brings promise of a new mode of delivery and potential solutions to some problems of oral therapy, but also new challenges and unanswered questions., Cabotegravir is an investigational integrase inhibitor in development for the treatment and pre-exposure prophylaxis of HIV-1 infection., Bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir are members of the latest class of antiretrovirals available to treat human immunodeficiency virus (HIV) infection, the integrase strand transfer inhibitors., PURPOSE OF REVIEW: Long-acting cabotegravir may provide a novel therapeutic option for both the treatment and prevention of HIV-1 infection that does not necessitate adherence, Long-acting injectable cabotegravir for the prevention of HIV infection, BACKGROUND: The HIV Prevention Trials Network (HPTN) 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was more effective than tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) in preventing human immunodeficiency virus (HIV) in cisgender men and transgender women who have sex with, Areas covered: Here, we review trials of cabotegravir (CAB) as treatment of HIV-1 infection and its potential use as pre-exposure prophylaxis (PrEP) in high risk individuals, including issues around oral lead in and potential resistance emergence. Exper, frequent dosing. This review focuses on the potential benefits and considerations for the study and use of 2 long-acting injectable agents, cabotegravir (GSK1265744LA, CAB LA) and rilpivirine (TMC278LA, RPV LA), for use as chemoprophylaxis for HIV , An evaluation of cabotegravir for HIV treatment and prevention., Cabotegravir long-acting for HIV-1 prevention., Our findings suggest that cabotegravir should be evaluated in clinical trials as a potential option for antiretroviral therapy and preexposure prophylaxis in HIV-2-prevalent settings., Profile of cabotegravir and its potential in the treatment and prevention of HIV-1 infection: evidence to date., Long-Acting Cabotegravir for HIV/AIDS Prophylaxis., Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women., Cabotegravir is a novel human immunodeficiency virus integrase enzyme inhibitor used for prevention and treatment of HIV infection., PURPOSE OF REVIEW: Long-acting cabotegravir may provide a novel therapeutic option for both the treatment and prevention of HIV-1 infection that does not necessitate adherence , Cabotegravir in the treatment and prevention of Human Immunodeficiency Virus-1., Cabotegravir: its potential for antiretroviral therapy and preexposure prophylaxis., Satisfaction and acceptability of cabotegravir long-acting injectable suspension for prevention of HIV: Patient perspectives from the ECLAIR trial.", "label": "yes"}
{"id": "converted_3380", "sentence1": "Does natalizumab improve disease course of secondary progressive multiple sclerosis?", "sentence2": "INTERPRETATION: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component., In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. , INTERPRETATION\n\nNatalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component., Natalizumab did not achieve a statistically significant primary composite disability outcome in a trial of 887 patients with secondary progressive MS , but it did demonstrate a benefit on a prespecified component of the 9-Hole Peg Test . , INTERPRETATION\nNatalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component., In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS., Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component.", "label": "no"}
{"id": "converted_3543", "sentence1": "Does an interferon (IFN) signature exist for SLE patients?", "sentence2": "Interferon regulatory factor 7 activation correlates with the IFN signature and recurrent disease., In SLE post-transplant, recurrent disease activity and induction of IRF7 protein expression correlated with activation of the IFN signature., JAK inhibitor has the amelioration effect in lupus-prone mice: the involvement of IFN signature gene downregulation., We also detected decreased expression of several IFN-signature genes Ifit3 and Isg15 in CD4+ from SLE-prone mice following TOFA and DEXA treatment, and IFIT3 in CD3+ T cells from human patients following immunosuppressant therapy including steroid, respectively, We found that cDCs from prediseased TCSle male mice express the IFN signature as female TCSle cDCs do. Estrogens are necessary but not sufficient to express this IFN signature, but high doses of E2 can compensate for other steroidal components., Conventional DCs from Male and Female Lupus-Prone B6.NZM Sle1/Sle2/Sle3 Mice Express an IFN Signature and Have a Higher Immunometabolism That Are Enhanced by Estrogen., Type I IFN signature in childhood-onset systemic lupus erythematosus,  Interferon type I (IFN-I) plays a pivotal role in the pathogenesis of SLE. , The IFN-I score (positive or negative), as a measure of IFN-I activation, was assessed using real-time quantitative PCR (RT-PCR) expression values of IFN-I signature genes (IFI44, IFI44L, IFIT1, Ly6e, MxA, IFITM1) in CD14+ monocytes of cSLE patients and healthy controls (HCs)", "label": "yes"}
{"id": "converted_384", "sentence1": "Is nintedanib effective for Idiopathic Pulmonary Fibrosis?", "sentence2": "In this review, we present the positive results of recently published clinical trials regarding therapy for IPF, with emphasis on pirfenidone and nintedanib., Nintedanib: evidence for its therapeutic potential in idiopathic pulmonary fibrosis,  In the Phase II TOMORROW trial, treatment with 150 mg of nintedanib twice daily showed a trend to slow the decline in lung function and significantly decrease acute exacerbations in patients with IPF, while showing an acceptable safety profile. The Phase III INPULSIS trials demonstrated a significant decrease in the annual rate of decline in forced vital capacity in IPF patients treated with 150 mg nintedanib twice daily. In the INPULSIS-2 trial, the time to the first acute exacerbation significantly increased in IPF patients who were treated with 150 mg of nintedanib twice daily.,  Effects on collagen secretion were compared with those of the drugs nintedanib and pirfenidone, recently approved for IPF., Nintedanib, an orally available, small-molecule tyrosine kinase inhibitor with selectivity for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptors has recently been shown, in two pivotal phase III studies, to effectively slow IPF disease progression. Consequently, nintedanib was given accelerated approval by the FDA in October 2014 for the treatment of IPF. , Most recently, pirfenidone and nintedanib, two compounds with pleiotropic anti-fibrotic properties, have been proven effective in reducing functional decline and disease progression in IPF. , Meningococcal group B vaccine (Trumenba) to prevent more types of invasive meningococcal disease; antihemophilic factor (recombinant), porcine sequence (Obizur) to treat bleeding from acquired hemophilia A; and pirfenidone (Esbriet) and nintedanib (Ofev) for idiopathic pulmonary fibrosis.,  More importantly, the period ends with the publication of two groundbreaking studies that confirmed that two drugs, pirfenidone and nintedanib, slowed disease progression, leading to a historic approval by the FDA. , Nintedanib (Ofev(®)) is an orally available, small, multiple receptor tyrosine kinase inhibitor developed by Boehringer Ingelheim for the treatment of idiopathic pulmonary fibrosis (IPF) and cancer. Nintedanib received its first global approval in the US in October 2014 for the treatment of IPF. Nintedanib has received a positive opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use for the treatment of IPF, and for the second-line treatment in combination with docetaxel of locally advanced, metastatic or locally recurrent non-small cell lung cancer of adenocarcinoma tumour histology. , This article summarizes the milestones in the development of nintedanib leading to this first approval for IPF., Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis., Nintedanib: a novel therapeutic approach for idiopathic pulmonary fibrosis., Nintedanib is in clinical development as a treatment for idiopathic pulmonary fibrosis (IPF)., Reducing lung function decline in patients with idiopathic pulmonary fibrosis: potential of nintedanib., These results suggest that nintedanib may impact the progressive course of fibrotic lung diseases such as idiopathic pulmonary fibrosis., Findings from recently published placebo-controlled trials in idiopathic pulmonary fibrosis have established that pirfenidone and nintedanib prevent about 50% of the decline in forced vital capacity typically seen in this disease; future trials are therefore unlikely to use placebo as a control group for ethical reasons., The tyrosine kinase inhibitor nintedanib (BIBF 1120) is in clinical development for the treatment of idiopathic pulmonary fibrosis., A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis., A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. , Data from the Phase II TOMORROW study suggested that nintedanib 150�mg twice daily had clinical benefits with an acceptable safety profile.METHODS: The INPULSIS� trials are replicate Phase III, randomized, double-blind, studies comparing the efficacy and safety of nintedanib 150�mg twice daily with placebo in patients with IPF. , Nintedanib received its first global approval in the US in October 2014 for the treatment of IPF. , The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. , A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. , Nintedanib (Ofev(�)) is an orally available, small, multiple receptor tyrosine kinase inhibitor developed by Boehringer Ingelheim for the treatment of idiopathic pulmonary fibrosis (IPF) and cancer. Nintedanib received its first global approval in the US in October 2014 for the treatment of IPF. , Nintedanib: evidence for its therapeutic potential in idiopathic pulmonary fibrosis., A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis.", "label": "yes"}
{"id": "converted_3353", "sentence1": "Is there a vaccine for peanut allergy?", "sentence2": "Currently, two forms of peanut immunotherapy, oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT), are in Phase III clinical trials and have shown promise to induce desensitization in many subjects, This article presents an overview of potential treatments of food allergy, with an emphasis on various forms of immunotherapy (including oral immunotherapy, sublingual immunotherapy, epicutaneous immunotherapy, immunotherapy with modified food antigens, and immunotherapy with a recombinant peanut vaccine)., Recent advances in immunotherapy and vaccine development for peanut allergy., Efforts have been made to develop a vaccine for peanut allergy., So far, results, especially from oral immunotherapy studies, have shown good efficacy in achieving desensitization to peanut with a good safety profile.", "label": "yes"}
{"id": "converted_3431", "sentence1": "Is ozanezumab effective for amyotrophic lateral sclerosis?", "sentence2": "The adjusted mean of the joint-rank score was -14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of -30·0 (95% CI -67·9 to 7·9; p=0·12). , INTERPRETATION: Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS., INTERPRETATION\n\nOzanezumab did not show efficacy compared with placebo in patients with ALS., The adjusted mean of the joint-rank score was -14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of -30·0 (95% CI -67·9 to 7·9; p=0·12)., INTERPRETATION Ozanezumab did not show efficacy compared with placebo in patients with ALS., The adjusted mean of the joint-rank score was -14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of -30·0 (95% CI -67·9 to 7·9; p=0·12).", "label": "no"}
{"id": "converted_2409", "sentence1": "Are mouse chromosomes acrocentric?", "sentence2": " Based on combined fluorescence in situ hybridization and linkage mapping, the gene order on CFA9 is similar to that of the homologous genes on HSA17q and mouse chromosome 11 (MMU11), but in the dog the gene order is inverted with respect to the centromere. , In murine models of human carcinogenesis, however, karyotype analysis is technically demanding because mouse chromosomes are acrocentric and of similar size., The minor satellite is closer to the short arms of the acrocentric chromosomes than the major satellite,  These cells contain Robertsonian translocated chromosomes 1 and 7 as the only submetacentric chromosome in an otherwise acrocentric genome.,  The resulting metacentric chromosomes are very different in size and in morphology from normal mouse acrocentric chromosomes.,  Because of 35 independent primary hybrids used in this study were derived from two types of feral mice, each with a different combination of Robertsonian translocation chromosomes, as well as from mice with a normal complement of acrocentric chromosomes, analysis of 16 selected mouse enzyme markers provided data on the segregation of all 20 mouse chromosomes in these hybrids, The two mouse stocks exhibit karyotypes consisting of nine pairs of metacentric chromosomes as a result of centric fusions of acrocentric chromosomes in different combinations., Physical gene mapping by in situ hybridization is a difficult task in an all-acrocentric mouse karyotype, because all of the chromosomes are morphologically very similar., The resulting metacentric chromosomes are very different in size and in morphology from normal mouse acrocentric chromosomes., murine models of human carcinogenesis are exceedingly valuable tools to understand genetic mechanisms of neoplastic growth the identification of recurrent chromosomal rearrangements by cytogenetic techniques serves as an initial screening test for tumour specific aberrations in murine models of human carcinogenesis however karyotype analysis is technically demanding because mouse chromosomes are acrocentric and of similar size fluorescence in situ hybridization fish with mouse chromosome specific painting probes can complement conventional banding analysis although sensitive and specific fish analyses are restricted to the visualization of only a few mouse chromosomes at a time here we apply a novel imaging technique that we developed recently for the visualization of human chromosomes to the simultaneous discernment of all mouse chromosomes the approach is based on spectral imaging to measure chromosome specific spectra after fish with differentially labelled mouse chromosome painting probes utilizing a combination of fourier spectroscopy ccd imaging and conventional optical microscopy spectral imaging allows simultaneous measurement of the fluorescence emission spectrum at all sample points a spectrum based classification algorithm has been adapted to karyotype mouse chromosomes we have applied spectral karyotyping sky to chemically induced plasmocytomas mammary gland tumours from transgenic mice overexpressing the c myc oncogene and thymomas from mice deficient for the ataxia telangiectasia atm gene results from these analyses demonstrate the potential of sky to identify complex chromosomal aberrations in mouse models of human carcinogenesis.", "label": "yes"}
{"id": "converted_1447", "sentence1": "Has silicon been used in treatment of  incontinence ?", "sentence2": "an artificial anal sphincter. Worldwide, there are two established devices on the market: the artificial bowel sphincter® (ABS) from A. M. S. (Minnetonka, MN, USA) and the soft anal band® from A. M. I. (Feldkirch, Austria). How to implant the artificial anal sphincter? Both devices consist of a silicon cuff which can be filled with fluid., The InVance™ system uses a silicon-coated polyester sling positioned under the bulbar urethra via a perineal incision., Through a perineal incision three titanium screws with a polipropylene suture were inserted in each ischiopubic rami, and a silicon/polipropylene mesh (Invance) is affixed to them, compressing the bulbar urethra, surgical treatment of female stress urinary incontinence with a trans-obturator sub-urethral tape of Uratape (Porgés). METHODS: Treatment and follow up of their complication were performed at the CHRU of Lille. RESULTS: In both cases, this complication is related to prolonged vaginal exposition of the tape. Vaginal erosion always occurs next to the silicon coated section of the tape, A non-elastic, polypropylene tape (UraTape, Mentor-Porgès) with a silicon coated central part was placed under the mid-urethra.,  Stress incontinence is a rare complication in men, usually following prostatic surgery. It can be treated conservatively with pelvic floor training and alpha-adrenergic receptor agonists and if necessary surgically with submucosal collagen or silicon injections in the sphincter area or implantation of a sphincter prosthesis, The Femassist is a medical-grade silicon dome-shaped device, worn over the urethra and held securely via suction and a commercially available adhesive lotion., To examine the performance of a silicon urinary control device for nonsurgical management of women with genuine stress incontinence, The \"FemAssist\" is a dome-shaped medical grade silicon device intended to be worn over the external urethral meatus and held in place by suction and an adhesive gel. Thirty eight women with varying degrees of genuine stress urinary incontinence (GSUI) or mixed incontinence on multichannel urodynamic testing were fitted with one of two sizes of \"FemAssist", "label": "yes"}
{"id": "converted_807", "sentence1": "Is transcapillary  albumin escape altered in diabetic patients?", "sentence2": "On the contrary, altered TERalb and increased carotid artery intimal thickness are shown by all hypertensive type 2 diabetic patients, both with normal and altered patterns of AER., Altered systemic capillary permeability characterizes insulin-resistant hypertensive patients with Metabolic Syndrome., TERalb is increased in normo-albuminuric type 1 diabetic patients. ", "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.", "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.", "label": "yes"}
{"id": "converted_3703", "sentence1": "Does radiotherapy for Hodgkin disease increases risk for lung cancer?", "sentence2": "Risks of lung, breast, and gastrointestinal (GI) cancers increase with higher radiation dose. , CONCLUSIONS: RT treatment, especially with doses higher than 42 Gy, and smoking increase the risk of SN after HL. In this series, LC patients with early stages had a shorter elapsed time from HL diagnosis and longer OS, therefore the role of LC screening in HL survivors should be prospectively evaluated and smoking cessation counseling ought to be a key aspect during follow-up., BACKGROUND: Long-term Hodgkin lymphoma (HL) survivors have an increased risk of late cardiac morbidity and secondary lung cancer after chemotherapy and mediastinal radiotherapy. , PURPOSE: Hodgkin lymphoma (HL) survivors have an increased risk of cardiovascular disease (CD), lung cancer, and breast cancer., Lung cancer (LC) represents the most common solid tumor in survivors of Hodgkin's disease (HD), and the assessment of the mutational status of oncogenic driver mutations in LC is now standard. , PURPOSE: Hodgkin lymphoma (HL) survivors face an increased risk of treatment-related lung cancer. , Increased risk of second lung cancer in Hodgkin's lymphoma survivors: a meta-analysis., BACKGROUND: Patients treated for Hodgkin's lymphoma (HL) have a higher risk of developing second lung cancer (SLC) compared with the general population. , The pooled relative risk (RR) of SLC was 4.62 (95 % confidence interval [CI], 3.18-6.70], I (2) = 98 %), with a median absolute excess rate of 10.4 per 10,000 person-years. , CONCLUSIONS: The current meta-analysis provided a detailed estimate of the risk of SLC among HL survivors. , CONCLUSIONS\n\nThe excess risk of lung cancer in Hodgkin's disease patients treated with radiotherapy is related to the radiation dose received by the affected area of the lung., BACKGROUND\n\nLung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described., CONCLUSIONS\n\nPast treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion., BACKGROUND\n\nSeveral studies have shown that survivors of Hodgkin's disease have increased risk of lung cancer, but the factors responsible for this excess risk are not well known., PURPOSE\n\nThis study was undertaken to investigate the effects of radiation dose, chemotherapy, and smoking on the risk of lung cancer following treatment of Hodgkin's disease., Increased risk of lung cancer, non-Hodgkin's lymphoma, and leukemia following Hodgkin's disease., It is recognized that survivors of Hodgkin's disease are at a substantially increased risk of lung cancer., The risk of lung and breast cancer is significantly increased after therapy for Hodgkin 's disease ( HD) , but there are few data that describe the molecular profiles of these tumors . , Hodgkin lymphoma ( HL ) survivors have an increased risk of cardiovascular disease ( CD) , lung cancer , and breast cancer . , BACKGROUND\nLung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described., CONCLUSIONS\nPast treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion., Lung cancer in Hodgkin's disease: association with previous radiotherapy., Twenty-eight (94%) of 30 patients developing metachronous lung cancer received supradiaphragmatic irradiation as primary therapy for HD., The risk ratio for the development of lung cancer among HD patients was 5.6 times that expected in the general population., Seven cases of lung cancer were observed in patients with Hodgkin's disease (HD) since 1970., BACKGROUND\nSeveral studies have shown that survivors of Hodgkin's disease have increased risk of lung cancer, but the factors responsible for this excess risk are not well known., The excess risk of lung cancer in Hodgkin's disease patients treated with radiotherapy is related to the radiation dose received by the affected area of the lung., Lung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described., Past treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion., Several studies have shown that survivors of Hodgkin's disease have increased risk of lung cancer, but the factors responsible for this excess risk are not well known.", "label": "yes"}
{"id": "converted_992", "sentence1": "Are the Fanconi anemia genes a part of the same signalling pathway?", "sentence2": "Mutations in at least 14 different genes have been shown to cause FA, The FA genes code for proteins that act in complexes to coordinate the repair of damaged DNA,  The current review describes the structure and function of the Fanconi anemia genes and describes the role of the encoded Fanconi anemia proteins in a cellular pathway controlling chromosome stability., Fanconi anemia (FA) is a rare human genetic disease caused by mutations in any one of 13 known genes that encode proteins functioning in one common signaling pathway, the FA pathway, or in unknown genes., Fanconi anemia (FA) is a rare inherited recessive disease caused by mutations in one of fifteen genes known to encode FA pathway components., Fanconi anemia (FA) proteins function in a DNA damage response pathway that appears to be part of the network including breast cancer susceptibility gene products, BRCA1 and BRCA2., Fanconi anemia (FA) proteins function in a DNA damage response pathway that appears to be part of the network including breast cancer susceptibility gene products, BRCA1 and BRCA2, Fanconi anemia (FA) is a rare human genetic disease caused by mutations in any one of 13 known genes that encode proteins functioning in one common signaling pathway, the FA pathway, or in unknown genes, The Fanconi anemia (FA) gene family comprises at least 12 genes interacting in a common pathway involved in DNA repair, These findings show that the newly identified FANCE protein is an integral part of the FA pathway, and support the concept of a functional link between all known proteins encoded by the genes that are mutated in this disorder", "label": "yes"}
{"id": "converted_3832", "sentence1": "Is the Paramyxovirus geneome segmented, negative-sense RNA?", "sentence2": "The paramyxovirus family has a genome consisting of a single strand of negative sense RNA, The avian paramyxovirus type 1 (APMV-1), or Newcastle disease virus (NDV), comprise a diverse group of viruses with a single-stranded, negative-sense RNA genome., Members of the Paramyxoviridae such as measles, mumps, and parainfluenza viruses have pleomorphic, enveloped virions that contain negative-sense unsegmented RNA genomes., UNLABELLED: Mumps virus (MuV), a paramyxovirus containing a negative-sense nonsegmented RNA genome, is a human pathogen that causes an acute infection with symptoms ranging from parotitis to mild meningitis and severe encephalitis., UNLABELLED: Mumps virus (MuV) is a paramyxovirus with a negative-sense nonsegmented RNA genome., Paramyxoviridae, a large family of enveloped viruses harboring a nonsegmented negative-sense RNA genome, include important human pathogens as measles, mumps, respiratory syncytial virus (RSV), parainfluenza viruses, and henipaviruses, which cause some of the deadliest emerging zoonoses. There , Parainfluenza virus 5 (PIV5) is a member of the Paramyxoviridae family of membrane-enveloped viruses with a negative-sense RNA genome that is packaged and protected by long filamentous nucleocapsid-helix structures (RNPs). , The paramyxovirus genome, a nonsegmented, negative-polarity, single-stranded RNA of approximately 15 kb, contains six transcription units flanked at the 3' and 5' ends by a short (approximately 50- to 60-nucleotide) extracistronic sequence, dubbed the positive and negative leader regions. These, The replication of nonsegmented minus-strand RNA genomes, like that of Sendai paramyxovirus (SeV), are controlled by the short leader regions present at each end of the linear genomes and antigenomes; the left and right promoters (PL and PR), respectively. Wil, UNLABELLED: Mumps virus (MuV), a paramyxovirus containing a negative-sense nonsegmented RNA genome, is a human pathogen that causes an acute infection with symptoms ranging from parotitis to mild meningitis and severe enc, s viral glycoprotein cytoplasmic domains may play a role in this coordination, we have investigated the importance of the hemagglutinin-neuraminidase (HN) protein cytoplasmic domain in the assembly of the nonsegmented negative-strand RNA paramyxovirus simian virus 5 (SV5). By, Beilong virus, a novel paramyxovirus with the largest genome of non-segmented negative-stranded RNA viruses., The paramyxovirus genome, a nonsegmented, negative-polarity, single-stranded RNA of approximately 15 kb, contains six transcription units flanked at the 3' and 5' ends by a short (approximately 50- to 60-nucleotide) extracistronic sequence, dubbed the positive and negative leader regions., Paramyxovirus particles are pleomorphic, with a lipid envelope, nonsegmented RNA genomes of negative polarity, and densely packed glycoproteins on the virion surface., An alternative method to determine the 5' extremities of non-segmented, negative sense RNA viral genomes using positive replication intermediate 3' tailing: application to two members of the Paramyxoviridae family., Simian parainfluenza virus 5 (SV5) is a prototype of the Paramyxoviridae family of nonsegmented negative-sense RNA viruses., Human metapneumovirus (HMPV), a single-stranded negative-sense RNA virus belonging to the family Paramyxoviridae, is associated with respiratory tract illness, primarily in young children and persons with underlying disease.", "label": "no"}
{"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", "label": "yes"}
{"id": "converted_3829", "sentence1": "Is there any role of genotoxic pks + E. coli in cancer?", "sentence2": "Mutational signature in colorectal cancer caused by genotoxic pks+, Various species of the intestinal microbiota have been associated with the development of colorectal cancer1,2, but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin3. This compound is believed to alkylate DNA on adenine residues4,5 and induces double-strand breaks in cultured cells3. Here we expose human intestinal organoids to genotoxic pks+ E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.", "label": "yes"}
{"id": "converted_15", "sentence1": "Is the monoclonal antibody Trastuzumab (Herceptin) of potential use in the treatment of prostate cancer?", "sentence2": "Herceptin is widely used in treating Her2-overexpressing breast cancer. However, the application of Herceptin in prostate cancer is still controversial., Our data demonstrate that Re-188-labeled Herceptin effectively inhibited the growth of DU145 cells compared to the Herceptin- and Re-188-treated cohorts. This implies that targeting Her2 by both radio- and immuno- therapy might be a potential strategy for treating patients with androgen-independent prostate cancer., epidermal growth factor receptor (EGFR) family members are potential targets for therapy using extra-cellular domain receptor binding agents, such as the antibodies trastuzumab and cetuximab,  there were tendencies for upregulation of HER2, increased co-expression of EGFR and HER2 and downregulation of HER3 in the prostate cancer lymph node metastases in comparison to the primary tumors. , We performed a comparative analysis in vitro and in vivo of the antitumor effects of three different antibodies targeting different epitopes of ErbB2: Herceptin (trastuzumab), 2C4 (pertuzumab) and Erb-hcAb (human anti-ErbB2-compact antibody), a novel fully human compact antibody produced in our laboratory. Herein, we demonstrate that the growth of both androgen-dependent and independent prostate cancer cells was efficiently inhibited by Erb-hcAb. The antitumor effects induced by Erb-hcAb on some cell lines were more potent than those observed for either Herceptin or 2C4., These findings suggest that a systemic delivery of 212Pb-trastuzumab could             be an effective modality for management of advanced human prostate cancer., Human epidermal growth factor receptor type 2 (HER2) overexpression supports proliferation of androgen-independent prostate cancer (PC), Radiolabeled ABY-025 Affibody molecule provides higher contrast in imaging of HER2-expressing PC xenografts than radiolabeled trastuzumab. , These studies indicate that dual EGFR/HER2 inhibition, administered together with AWT, sensitize prostate cancer cells to apoptosis during AWT, The overall goal of these studies is to determine whether dual inhibition of the receptor tyrosine kinases epidermal growth factor receptor (EGFR) and HER2 would prolong the effectiveness of this treatment in prostate cancer. , The expression of HER2 was demonstrated and quantified in all three tested prostate cancer cell-lines., Such features would definitely favor the use of radiometal labels for trastuzumab and, most likely, for affibody molecules, our data demonstrate that Her2 plays an important role in the support of AR protein stability in the transition of androgen requirement in prostate cancer cells. We hope these findings will provide novel insight into the treatment of hormone-refractory prostate cancer., These two cell lines exhibited distinct responses to Her2 activation (by heregulin treatment) on Her2 phosphorylation and Her2 inhibition (by AG825 or Herceptin treatments) on proliferation,  While prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by lentiviruses with envelope proteins engineered to bind to this therapeutic antibody, Overexpression of ErbB-2 and EGFR has been associated with aggressive disease and poor patient prognosis in a range of human tumour types (e.g. breast, lung, ovarian, prostate, Various approaches have been developed to target the ErbB signalling pathways including monoclonal antibodies (trastuzumab/Herceptin, The data from these in vitro and in vivo studies supported advancement of radiolabeled trastuzumab into two clinical studies, Tumor targeting was evaluated in mice bearing subcutaneous (s.c.) xenografts of colorectal, pancreatic, ovarian, and prostate carcinomas., we found that although prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by viruses with envelope proteins engineered to bind this antibody, detection of prostate cancer (PCa) and advances in hormonal and chemotherapy treatments have provided great clinical benefits to patients with early stages of the disease., MAbs directed to established targets include those approved for other solid tumors, including anti-human epidermal growth factor receptor-2 (HER2) MAb trastuzumab, We conclude that Her2/neu expression in the peripheral blood mononuclear cell fraction of prostate cancer patients is frequent and therefore this assay may potentially be useful to detect the presence of micrometastatic disease in men with prostate cancer and for monitoring patients enrolled in trastuzumab-based therapeutic protocols., This study suggests that the docetaxel/trastuzumab combination may prove an effective therapeutic approach for HER2-expressing hormone-refractory prostate cancer., there was no significant difference in antimetastatic activity between the emulsion and the immunoemulsion despite the affinity of the immunoemulsion towards the HER2 receptor. , a targeted drug delivery system based on cationic emulsion covalently linked to anti-HER2 monoclonal antibody (Herceptin), in a well-established in vivo pharmacologic model of metastatic prostate cancer that overexpresses the HER2 receptor, The finding of strong, consistent HER-2/neu expression in ACBCC suggests that treatment with Herceptin (trastuzumab) may be effective in patients with this rare tumour., Although HER2 can be over-expressed in prostate cancer, there is no clinical data to support the use of trastuzumab for prostate cancer patients., whereas the effect of the trastuzumab-RT combination was inferior to that predicted by the individual effects., HER 1-2 targeting of hormone-refractory prostate cancer by ZD1839 and trastuzumab, Trastuzumab (Herceptin) as a single agent demonstrated poor efficacy in treating HRPC., To investigate the efficacy and toxicity of the antibody to the HER-2/neu receptor (trastuzumab, Herceptin) in the treatment of advanced hormone-refractory prostate cancer (HRPC), Conclusions regarding the predictive value of HER-2 status on outcome after trastuzumab-based therapy were not reached and were only drawn after larger-scale screening efforts. , rastuzumab plus docetaxel in HER-2/neu-positive prostate carcinoma, clinical trials are currently in progress in patients with prostate cancer testing novel agents that selectively interfere with these receptors, such as trastuzumab,, ytotoxicity of human prostate cancer cell lines in vitro and induction of apoptosis using 213Bi-Herceptin alpha-conjugate, The clinical interpretation of c-erbB-2 abnormalities should reflect the complexity of c-erbB-2 mediated regulatory pathway and explain why tumours with overexpression/amplification of c-erbB-2 very often do not respond to therapy using Herceptin, HER-2 overexpression also has been reported in up to 60% of patients with hormone-refractory prostate carcinoma (HRPC) and was correlated with shortened survival, Unlike breast carcinoma and contrary to prior reports, HER-2 overexpression by IHC in archival prostate tissue from patients who eventually developed hormone-refractory disease was infrequent. There did not appear to be any correlation between HER-2 overexpression by IHC and shed HER-2 antigen levels in serum by ELISA in this tumor type., Further development of trastuzumab for the treatment of patients with metastatic prostate carcinoma is not feasible until more reliable and practical methods of sampling metastatic disease are developed to identify patients with HER-2 positive tumors., the expression of ERBB2 in prostate cancer is relatively low, and is not altered during disease progression. Thus, it is unlikely that treatment modalities relying on the overexpression of ERBB2 gene will be useful in treating prostate cancer., A phase I study was designed to evaluate docetaxel/estramustine plus trastuzumab, a humanized monoclonal antibody that binds to the HER2 receptor, in patients with metastatic androgen-independent prostate cancer (AIPC), Laboratory evidence also supports the clinical evaluation of docetaxel-based combinations that include agents such as trastuzumab and/or estramustine, trastuzumab, a monoclonal antibody binding to the HER2 receptor; immunotoxin conjugates use an antibody directed against EGFR joined to a cell toxin. All are in clinical trials for a number of cancers, including prostate cancer, we investigated the antitumor efficacy of Herceptin, a new recombinant humanized anti-HER2/neu antibody, which exhibits cytostatic activity on breast and prostate cancer cells that overexpress the HER2 oncogene., trastuzumab was found to have additive and synergistic effects with some chemotherapeutic agents, ER-2/neu as a therapeutic target in non-small cell lung cancer, prostate cancer, in these prostate cancer model systems, Herceptin alone has clinical activity only in the androgen-dependent tumor and has at least an additive effect on growth,, anti-HER2 receptor monoclonal antibody Herceptin significantly enhanced growth inhibition of the MDA PCa 2a cells.", "label": "yes"}
{"id": "converted_2931", "sentence1": "Are Mesenchymal stem cells (MSC) multipotent cells?", "sentence2": "multipotent mesenchymal bone marrow-derived stem cells, multipotent hESC-derived mesenchymal cells (MCs)", "label": "yes"}
{"id": "converted_2934", "sentence1": "Have machine learning methods been used to predict the severity of major depressive disorder(MDD)?", "sentence2": "Here, we conduct a meta-review to identify predictors of response to antidepressant therapy in order to select robust input features for machine learning models of treatment response. , machine learning framework involving EEG-based functional connectivity to diagnose major depressive disorder (MDD)., Identification of risk factors of treatment resistance may be useful to guide treatment selection, avoid inefficient trial-and-error, and improve major depressive disorder (MDD) care. We extended the work in predictive modeling of treatment resistant depression (TRD) via partition of the data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) cohort into a training and a testing dataset., persistence and severity of major depressive disorder from baseline self-reports,  These results confirm that clinically useful MDD risk-stratification models can be generated from baseline patient self-reports and that ML methods improve on conventional methods in developing such models, Furthermore, machine learning weighting factors may reflect an objective biomarker of major depressive disorder illness severity, based on abnormalities of brain structure., Notably, while the only information provided for training the classifiers was T(1)-weighted scans plus a categorical label (major depressive disorder versus controls), both relevance vector machine and support vector machine 'weighting factors' (used for making predictions) correlated strongly with subjective ratings of illness severity., BACKGROUND\nAlthough variation in the long-term course of major depressive disorder (MDD) is not strongly predicted by existing symptom subtype distinctions, recent research suggests that prediction can be improved by using machine learning methods., BACKGROUND Although variation in the long-term course of major depressive disorder (MDD) is not strongly predicted by existing symptom subtype distinctions, recent research suggests that prediction can be improved by using machine learning methods., BACKGROUND Growing evidence documents the potential of machine learning for developing brain based diagnostic methods for major depressive disorder (MDD)., OBJECTIVE We aimed to integrate neural data and an advanced machine learning technique to predict individual major depressive disorder (MDD) patient severity., Furthermore, machine learning weighting factors may reflect an objective biomarker of major depressive disorder illness severity, based on abnormalities of brain structure., <b>BACKGROUND</b>: Although variation in the long-term course of major depressive disorder (MDD) is not strongly predicted by existing symptom subtype distinctions, recent research suggests that prediction can be improved by using machine learning methods.", "label": "yes"}
{"id": "converted_1032", "sentence1": "Is there association of matrix metalloproteinases with behaviour of pituitary adenomas?", "sentence2": "While detailed histological subtyping remains the best independent predictor of aggressive behavior in the majority of cases, evidence suggests that the additional analyses of FGFR4, MMP, PTTG, Ki-67, p53, and deletions in chromosome 11 may contribute to decisions concerning management of aggressive pituitary adenomas., We observed elevation of MMP-2 and -9 expression and consequent 3-D cell invasion in cells under-expressing RECK. ,  Based on the significance of matrix metalloproteinases (MMPs) for tumor growth and angiogenesis, we have studied the effect of batimastat (BB-94), a synthetic MMPs inhibitor (MMPI) on the progression of prolactin-secreting pituitary adenoma in rats. , Inhibition of estrogen-induced pituitary tumor growth and angiogenesis in Fischer 344 rats by the matrix metalloproteinase inhibitor batimastat., The results of our study provide evidence for an inhibitory effect of batimastat, a synthetic MMPI, on the growth and angiogenesis in an experimental model of human prolactinoma., In summary, the differential expression of extracellular matrix components, integrins and matrix metalloproteinase contributes to the control of pituitary hormone production and cell proliferation during tumorigenesis., Data on the dural invasiveness of pituitary adenomas have been correlated to the expression of matrix metalloproteinases (e.g. MMP-9). , We found no correlation of MMP-9 expression and tumour invasion., The matrix metalloproteinases (MMPs) and their nature inhibitors-the tissue inhibitors of metalloproteinases (TIMPs) may play a central role in these processes., CONCLUSIONS: TIMP-1 and TIMP-2 may play a key role in invasive pituitary adenomas to biological behavior., The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that are able to degrade the extracellular matrix and allow angiogenesis and tumor invasion. , MMP-9 expression did not differ between noninvasive tumors and normal pituitary gland, or between different sized prolactinomas. MMP-9 expression was related to aggressive tumor behavior. It was higher in invasive macroprolactinomas (P = 0.003) when compared with noninvasive macroprolactinomas or the normal anterior pituitary gland. In addition, although there was no difference in whether MMP-9 was present or not when nonfunctioning adenomas that recurred were compared with those that did not, samples of recurrent tumor at the second presentation were more likely to express MMP-9 (P = 0.01). Pituitary carcinomas were significantly more likely to be MMP-9 positive compared with normal anterior pituitary gland (P = 0.05), but there was no difference from invasive adenomas. Angiogenesis assessed by vascular density was related to MMP-9 expression (P<0.05). In summary, we have shown the presence of MMP-9 expression in some invasive and recurrent pituitary adenomas, and in the majority of pituitary carcinoma. The mechanisms whereby MMP-9 expression influences tumor recurrence and invasiveness, and its association with angiogenesis, remains to be elucidated. , Beside the digestion of the extracellular matrix during tumor invasion and metastasis, more recently, new functions for matrix metalloproteinases (MMPs) have been proposed. , CONCLUSION: No correlation could be established between the invasive potential of tumors and MMP-1, -2, and -3 expression levels. , Matrix metalloproteinase 2 and 9 expression correlated with cavernous sinus invasion of pituitary adenomas., Data on the dural invasiveness of pituitary adenomas have been correlated to the expression of matrix metalloproteinases (e.g., We found surprisingly high levels of MMP activity and low levels of tissue inhibitor of metalloproteinases, indicating a high level of extracellular matrix-degrading activity in pituitary adenomas., The matrix metalloproteinases (MMPs) and their nature inhibitors-the tissue inhibitors of metalloproteinases (TIMPs) may play a central role in these processes. , We found surprisingly high levels of MMP activity and low levels of tissue inhibitor of metalloproteinases, indicating a high level of extracellular matrix-degrading activity in pituitary adenomas., There was an association between the invasion of pituitary adenomas and Ki-67 LI (P = 0.039) or the expression of VEGF (P &lt; 0.001) and MMP-9 (P &lt; 0.001). But c-myc LI and bcl-2 expression have no association with invasiveness of pituitary adenomas (P = 0.061 vs., nm23 and MMP-9 have associations with invasiveness of pituitary adenomas,, Matrix metalloproteinase secreted by pituitary cells can release growth factors from the extracellular matrix that, in turn, control pituitary cell proliferation and hormone secretion. In summary, the differential expression of extracellular matrix components, integrins and matrix metalloproteinase contributes to the control of pituitary hormone production and cell proliferation during tumorigenesis., There was an association between the invasion of pituitary adenomas and Ki-67 LI (P = 0.039) or the expression of VEGF (P &lt; 0.001) and MMP-9 (P &lt; 0.001)., Although our study has shown that MVD and the expression of VEGF, Ki-67, nm23 and MMP-9 have associations with invasiveness of pituitary adenomas, they are lack of specificity.", "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.", "label": "yes"}
{"id": "converted_2887", "sentence1": "Is the enzyme ERAP2 associated with the disease birdshot chorioretinopathy?", "sentence2": "Allele-specific Alterations in the Peptidome Underlie the Joint Association of HLA-A*29:02 and Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) with Birdshot Chorioretinopathy., BSCR is also associated with endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme involved in processing HLA class I ligands, thus implicating the A*29:02 peptidome in this disease. , A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy.", "label": "yes"}
{"id": "converted_87", "sentence1": "Can Levoxyl (levothyroxine sodium) cause insomnia?", "sentence2": "METHODS: Seventy-one patients diagnosed with primary hypothyroidism were randomly allocated into two study groups: the first group received usual dose of levothyroxine and the second group received combination of levothyroxine and liothyronine for at least 4 months. The main outcomes were psychosocial problems (Goldberg's General Health Questionnaire, GHQ-28), bodyweight, heart rate, blood pressure, and serum lipid levels. RESULTS: In both groups serum thyroid-stimulating hormone levels remained unchanged compared with baseline. Psychosocial scores, body weight, heart rate, blood pressure, and lipid profile in the two groups remained constant. The only exception was a small but significant reduction in anxiety/insomnia in combined treatment group as compared with monotherapy. ", "label": "yes"}
{"id": "converted_3856", "sentence1": "Does an antiphlogistic promotes inflammation?", "sentence2": "The therapeutic effect of olipiphate was demonstrated for chronic inflammation of advanced arthritis and concanavalin A-related acute edema. The best systemic effect was obtained with 50 mg/kg, symptomatic--100 mg/kg. Skin wounds treated with 5% olipiphate (26 + 2) healed faster than those treated with 2% solcoseryl (30 + 0.8) or in control (33 + 0.6). It was shown histologically that the proliferative and antiphlogistic effect of olipiphate involved no scars., Moreover, we observed an in vitro-inhibition of human neutrophil elastase, a protease involved in the inflammatory process, by extracts and fractions from yarrow, which suggests additional mechanisms of antiphlogistic action., Blood 5-HT in adrenalectomized rats with inflammationadrenalectomized rats 42 days and 3 months old with inflammation after injection of phenylbutazone an increase of 5-HT was observed, but in 18-month-old animals in which antiphlogistic action is highest a decrease of 5-HT was observed., These results indicate that methotrexate is a nonsteroidal antiinflammatory agent, the antiphlogistic action of which is due to increased adenosine release at inflamed sites., The antiphlogistic Ibuprofen incorporated in liposomes caused a decrease of the inflammatory edema induced by Carrageenan in the distal part of the rat's hind leg after both the intramuscular and percutaneous administration., Enhancement of the immunoreactivity inhibition caused by the drugs was not proportional to the increase in their antiphlogistic effects determined by the Selye model of inflammation., Antiinflammatory agents: new series of N-substituted amino acids with complex pyrimidine structures endowed with antiphlogistic activity.,  investigate whether the antiphlogistic ingredient may suppress the inflammatory response to ultraviolet (UV) irradiation, the SPF was determined in vivo. F, Antiphlogistics were found to enhance the membrane viscosity both in control and under inflammation., e in vivo determination of the SPF. Evidence of anti-inflammatory activity of the sunscreen antiphlogistics bisabolol and panthenol was also not apparent in the UV model over a time course of 48 h. Conlusion: The antiphlogistic ingredients panthenol and bisabolol incorporated in the tested sunscreen formula do not interfere with erythema reddening and thus , nts was analyzed in vitro. To investigate whether the antiphlogistic ingredient may suppress the inflammatory response to ultraviolet (UV) irradiation, the , The aim of this study was to analyze the formation of the most relevant inflammation mediators including proteins and lipids in human fibroblasts upon inflammatory stimulation and subsequent treatment with dexamethasone, a powerful antiphlogistic drug.", "label": "no"}
{"id": "converted_1105", "sentence1": "Are thyroid hormone receptor alpha1 mutations  implicated in thyroid hormone resistance syndrome?", "sentence2": "Mutations in human TRα1 mediate RTH with features of hypothyroidism in particular tissues (e.g. skeleton, gastrointestinal tract), but are not associated with a markedly dysregulated pituitary-thyroid axis., Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRα1 receptor", "label": "yes"}
{"id": "converted_2428", "sentence1": "Is autosomal dominant inheritanced form of Osteogenesis imperfecta caused by mutations in the genes associated with collagen production?", "sentence2": "steogenesis imperfecta (OI) is a heterogeneous bone disorder characterized by recurrent fractures. Although most cases of OI have heterozygous mutations inCOL1A1orCOL1A2and show autosomal dominant inheritance,, Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by decreased bone mass and increased fracture risk. The majority of OI cases have an autosomal dominant pattern of inheritance and are usually caused by mutations in genes encoding type I collagen,  Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by low bone mass and recurrent fractures. Most OI cases follow an autosomal dominant pattern of inheritance and are attributed to mutations in genes encoding type I collagen (COL1A1/COL1A2). , Osteogenesis imperfecta (OI) is a genetic disorder characterised by low bone mineral density resulting in fractures. 85-90% of patients with OI carry a variant in the type 1 collagen genes, COL1A1 and COL1A2, which follows an autosomal dominant pattern of inheritance., Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal-dominant inheritance, but many autosomal-recessive genes have been reported., To investigate mutation of COL1A1 gene and analyze the relationship between genotype and clinical phenotype in a family with osteogenesis imperfecta, Dominant inheritance of osteogenesis imperfecta (OI) is caused by mutations in COL1A1 or COL1A2, the genes that encode type I collagen,, Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. It exhibits a broad spectrum of clinical severity, ranging from multiple fractures in utero and perinatal death, to normal adult stature and low fracture incidence. Extra-skeletal features of OI include blue sclera, hearing loss, skin hyperlaxity, joint hyperextensibility, and dentinogenesis imperfecta. The proα1(I) and proα2(I) chains of collagen 1 are encoded by the COL1A1 and COL1A2 genes, respectively; quantitative or qualitative defects in type I collagen synthesis usually manifest as types of OI or some sub-types of EDS. The majority of patients (about 90%) with a clinical diagnosis of OI have a mutation in the COL1A1 or COL1A2, Osteogenesis imperfecta (OI) type I is characterized by bone fragility without significant deformity, osteopenia, normal stature, blue sclerae, and autosomal dominant inheritance. Dermal fibroblasts from most affected individuals produce about half the expected amount of type I collagen, suggesting that the OI type I phenotype results from a variety of mutations which alter the apparent expression of either COL1A1 or COL1A2, the genes encoding the chains of type I collagen., Autosomal dominant osteogenesis imperfecta is caused by mutations in the COL1A2 and COL1A1 genes of type I collagen. , Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure., Osteogenesis imperfecta (OI) is a heterogeneous group of disorders of connective tissue, mainly caused by mutations in the collagen type I genes (COL1A1 and COL1A2)., Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen., In approximately 90% of individuals with osteogenesis imperfecta, mutations in either of the genes encoding the pro-alpha1 or pro-alpha2 chains of type I collagen (COL1A1 or COL1A2) can be identified., Autosomal dominant OI is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen., ext-generation sequencing technology was used to screen a panel of known OI genes.RESULTS: In 41 probands, we identified 28 different disease-causing variants of 9 different known OI genes. Eleven of the variants are novel. Ten of the 28 variants are located in COL1A1, five in COL1A2, three in BMP1, three in FKBP10, two in TMEM38B, two in P3H1, and one each in CRTAP, SERPINF1, and SERPINH1. , Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disorder associated with bone fragility and susceptibility to fractures after minimal trauma. OI type V has an autosomal-dominant pattern of inheritance and is not caused by mutations in the type I collagen genes COL1A1 and COL1A2. , Detection of a high frequency RsaI polymorphism in the human pro alpha 2(I) collagen gene which is linked to an autosomal dominant form of osteogenesis imperfecta., Osteogenesis imperfecta due to recurrent point mutations at CpG dinucleotides in the COL1A1 gene of type I collagen., Osteogenesis imperfecta (OI), commonly known as \"brittle bone disease\", is a dominant autosomal disorder characterized by bone fragility and abnormalities of connective tissue. Biochemical and molecular genetic studies have shown that the vast majority of affected individuals have mutations in either the COL1A1 or COL1A2 genes that encode the chains of type I procollagen. , Osteogenesis imperfecta is normally caused by an autosomal dominant mutation in the type I collagen genes COL1A1 and COL1A2.", "label": "yes"}
{"id": "converted_28", "sentence1": "Proteomic analyses need prior knowledge of the organism complete genome. Is the complete genome of the bacteria of the genus Arthrobacter available?", "sentence2": "Complete genome sequence of Arthrobacter phenanthrenivorans type strain (Sphe3)., Complete genome sequence and metabolic potential of the quinaldine-degrading bacterium Arthrobacter sp. Rue61a., Here, we described the high quality draft genome sequence, annotations and the features ofArthrobactersp. B6., Complete genome sequence of Arthrobacter sp. ZXY-2 associated with effective atrazine degradation and salt adaptation., We announce here the draft genome sequence ofArthrobactersp. strain EpSL27, isolated from the stem and leaves of the medicinal plantEchinacea purpureaand able to inhibit human-pathogenic bacterial strains. , We report here the 4.6-Mb genome sequence of a nylon oligomer-degrading bacterium,Arthrobactersp. strain KI72., Arthrobacter alpinusR3.8 is a psychrotolerant bacterial strain isolated from a soil sample obtained at Rothera Point, Adelaide Island, close to the Antarctic Peninsula. Strain R3.8 was sequenced in order to help discover potential cold active enzymes with biotechnological applications. ", "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.", "label": "yes"}
{"id": "converted_3336", "sentence1": "Are genomic regulatory blocks (GRBs) any different than TADs?", "sentence2": "Topologically associating domains are ancient features that coincide with Metazoan clusters of extreme noncoding conservation., Clusters of CNEs define the span of regulatory inputs for many important developmental regulators and have been described previously as genomic regulatory blocks (GRBs). Their function and distribution around important regulatory genes raises the question of how they relate to 3D conformation of these loci. Here, we show that clusters of CNEs strongly coincide with topological organisation, predicting the boundaries of hundreds of topologically associating domains (TADs) in human and Drosophila. The set of TADs that are associated with high levels of noncoding conservation exhibit distinct properties compared to TADs devoid of extreme noncoding conservation. The close correspondence between extreme noncoding conservation and TADs suggests that these TADs are ancient, revealing a regulatory architecture conserved over hundreds of millions of years.Metazoan genomes contain many clusters of conserved noncoding elements. Here, the authors provide evidence that these clusters coincide with distinct topologically associating domains in humans and Drosophila, revealing a conserved regulatory genomic architecture.", "label": "no"}
{"id": "converted_1913", "sentence1": "Is avanafil indicated for treatment of erectile dysfunction?", "sentence2": "CONTEXT: Avanafil (AVA) is used in the treatment of erectile dysfunction, but is reported for its poor aqueous solubility. , BACKGROUND: Phosphodiesterase 5 inhibitors (PDE5-Is) sildenafil, vardenafil, tadalafil and the recently approved avanafil represent the first-line choice for both on-demand and chronic treatment of erectile dysfunction (ED). , A survey on the experience of 136 Italian urologists in the treatment of erectile dysfunction with PDE5 inhibitors and recommendations for the use of Avanafil in the clinical practice., Efficacy of Avanafil 15 Minutes after Dosing in Men with Erectile Dysfunction: A Randomized, Double-Blind, Placebo Controlled Study., PURPOSE: We examined the therapeutic effects of avanafil 15 minutes after dosing in men with mild to severe erectile dysfunction., Sildenafil, vardenafil, tadalafil and avanafil are FDA approved drugs in market as PDE5 inhibitors for treating erectile dysfunction., CONCLUSION: Avanafil along with the other PDE5Is has shown to be a safe and effective oral treatment for ED, with avanafil's possible place in therapy for patients who want an on-demand option or as an alternative in patients who experience visual disturbances with the other agents., Avanafil (STENDRA™, SPEDRA™, Zepeeed™) is an oral phosphodiesterase type 5 inhibitor indicated for the treatment of erectile dysfunction., In a 12-week, randomized, double-blind, placebo-controlled, multicentre trial in patients with erectile dysfunction, avanafil 50, 100 and 200 mg recipients had significantly greater improvements from baseline than placebo recipients in mean international index of erectile dysfunction-erectile function domain scores and in successful vaginal penetration and sexual intercourse attempts (coprimary endpoints)., Avanafil for the treatment of erectile dysfunction. An updated review., Selectivity of avanafil, a PDE5 inhibitor for the treatment of erectile dysfunction: implications for clinical safety and improved tolerability., A randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of avanafil in subjects with erectile dysfunction., Avanafil, a potent and highly selective phosphodiesterase-5 inhibitor for erectile dysfunction., Avanafil, a highly selective phosphodiesterase type 5 inhibitor for erectile dysfunction, shows good safety profiles for retinal function and hemodynamics in anesthetized dogs., Cumulative data suggest that avanafil has a promising pharmacological profile for erectile dysfunction., These findings suggest that intracavernosal administration of avanafil might be beneficial for the treatment of erectile dysfunction in patients with T2DM., An open-label, long-term evaluation of the safety, efficacy and tolerability of avanafil in male patients with mild to severe erectile dysfunction., The effect of intracavernosal avanafil, a newer phosphodiesterase-5 inhibitor, on neonatal type 2 diabetic rats with erectile dysfunction., A phase 3, placebo controlled study of the safety and efficacy of avanafil for the treatment of erectile dysfunction after nerve sparing radical prostatectomy., Avanafil is a potent selective phosphodiesterase type 5 (PDE5) inhibitor newly developed for treating erectile dysfunction (ED)., Adverse events most commonly reported with avanafil treatment were headache, nasopharyngitis, flushing, and sinus congestion.Avanafil was safe and effective for treating erectile dysfunction in men with diabetes and was effective as early as 15 minutes and more than 6 hours after dosing, Avanafil (STENDRA™, SPEDRA™, Zepeeed™) is an oral phosphodiesterase type 5 inhibitor indicated for the treatment of erectile dysfunction, Avanafil is rapidly absorbed after oral administration, with a median time to maximum plasma concentration of 30 to 45 min. In a 12-week, randomized, double-blind, placebo-controlled, multicentre trial in patients with erectile dysfunction, avanafil 50, 100 and 200 mg recipients had significantly greater improvements from baseline than placebo recipients in mean international index of erectile dysfunction-erectile function domain scores and in successful vaginal penetration and sexual intercourse attempts (coprimary endpoints), A phase II, single-blind, randomized, crossover evaluation of the safety and efficacy of avanafil using visual sexual stimulation in patients with mild to moderate erectile dysfunction, To evaluate the safety, efficacy and time course of three doses of avanafil (50 mg, 100 mg and 200 mg) compared with sildenafil 50 mg or placebo, given in conjunction with visual sexual stimulation (VSS) videos in men with mild to moderate erectile dysfunction (ED).Male patients, 35-70 years of age, with mild to moderate ED of ≥6 months duration, were included in the study, Avanafil for erectile dysfunction, To review the pharmacology, pharmacokinetics, safety, and efficacy of avanafil and evaluate relevant clinical trial data.A MEDLINE, International Pharmaceutical Abstracts, ClinicalTrials.gov, and Google Scholar searches (1966 to July 2013) were conducted using the key words: avanafil, erectile dysfunction, and phosphodiesterase type 5 (PDE5) inhibitor.Articles evaluating avanafil for erectile dysfunction (ED) published in English and using human subjects were selected, In trials in patients with erectile dysfunction in association with diabetes mellitus, and after nerve-sparing radical prostatectomy, avanafil 100 or 200 mg was significantly more efficacious than placebo for primary and most secondary endpoints, However, the potentiating effect of avanafil at 1 mg/kg was significantly weaker than that of sildenafil (p &lt;0.05).Data suggest that avanafil has a favorable safety profile for erectile dysfunction, which is attributable to its high inhibitory selectivity for phosphodiesterase type 5 against type 6 (retina) and 1 (vessels, etc), respectively, and its short acting pharmacodynamic property.<CopyrightInformation>Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.</, Avanafil for the treatment of erectile dysfunction: a multicenter, randomized, double-blind study in men with diabetes mellitus., The discovery of avanafil for the treatment of erectile dysfunction: a novel pyrimidine-5-carboxamide derivative as a potent and highly selective phosphodiesterase 5 inhibitor., Efficacy and safety of avanafil for treating erectile dysfunction: results of a multicentre, randomized, double-blind, placebo-controlled trial., Phosphodiesterase 5 inhibitors (PDE5-Is) sildenafil, vardenafil, tadalafil and the recently approved avanafil represent the first-line choice for both on-demand and chronic treatment of erectile dysfunction (ED)., The phosphodiesterese-5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), tadalafil (Cialis™) and avanafil (Stendra™) have been developed for the treatment of erectile dysfunction., To compare the efficacy and safety between different dosages of avanafil for the treatment of erectile dysfunction (ED).PubMed, Cochrane Library, and Embase were searched to identify randomized controlled trials which compared avanafil with placebo, or compared different dosages of avanafil for ED., We evaluated the safety and efficacy of 100 and 200 mg avanafil for the treatment of adult males with erectile dysfunction after bilateral nerve sparing radical prostatectomy.This was a double-blind, placebo controlled, parallel group, phase 3 study in males age 18 to 70 years with a history of erectile dysfunction of 6 months or more after bilateral nerve sparing radical prostatectomy., To determine the effect of avanafil, a novel phosphodiesterase-5 inhibitor, on the treatment of erectile dysfunction associated with type 2 diabetes mellitus (T2DM).In 2-day-old rats, T2DM was induced by single intraperitoneal injection of 90 mg/kg of streptozotocin (STZ; i.p.)., These findings suggest that intracavernosal administration of avanafil might be beneficial for the treatment of erectile dysfunction in patients with T2DM.<CopyrightInformation>Copyright © 2014 Elsevier Inc. All rights reserved.</C, Avanafil, a potent new selective phosphodiesterase type 5 (PDE5) inhibitor, has been developed for the treatment of erectile dysfunction (ED)., Adverse events most commonly reported with avanafil treatment were headache, nasopharyngitis, flushing, and sinus congestion.Avanafil was safe and effective for treating erectile dysfunction in men with diabetes and was effective as early as 15 minutes and more than 6 hours after dosing., Coprimary end points assessed changes in the percentage of sexual attempts in which men were able to maintain an erection of sufficient duration to have successful intercourse (Sexual Encounter Profile [SEP] 3), percentage of sexual attempts in which men were able to insert the penis into the partner's vagina (SEP 2), and International Index of Erectile Function erectile function domain score.RESULTS: Compared with placebo, least-squares mean change from baseline to study end in SEP 3, SEP 2, and International Index of Erectile Function erectile function domain score were significantly improved with both avanafil, 100 mg (P?.002), and avanafil, 200 mg (P<.001)., Adverse events most commonly reported with avanafil treatment were headache, nasopharyngitis, flushing, and sinus congestion.CONCLUSION: Avanafil was safe and effective for treating erectile dysfunction in men with diabetes and was effective as early as 15 minutes and more than 6 hours after dosing., Avanafil for the treatment of erectile dysfunction. An updated review., Avanafil for erectile dysfunction., Avanafil for the treatment of erectile dysfunction: a multicenter, randomized, double-blind study in men with diabetes mellitus., To compare the efficacy and safety between different dosages of avanafil for the treatment of erectile dysfunction (ED)., Selectivity of avanafil, a PDE5 inhibitor for the treatment of erectile dysfunction: implications for clinical safety and improved tolerability., A phase 3, placebo controlled study of the safety and efficacy of avanafil for the treatment of erectile dysfunction after nerve sparing radical prostatectomy., We evaluated the safety and efficacy of 100 and 200 mg avanafil for the treatment of adult males with erectile dysfunction after bilateral nerve sparing radical prostatectomy.", "label": "yes"}
{"id": "converted_8", "sentence1": "Has Denosumab (Prolia) been approved by FDA?", "sentence2": "Denosumab is a RANK-ligand antibody that was approved by the FDA in 2010 for the prevention of skeletal fractures in patients with bone metastases from solid tumors.,  The authors present the imaging findings and technical report of an attempted percutaneous vertebroplasty in the only patient found to be actively under treatment with denosumab after a retrospective review of the databank of patients with pathological fractures referred to the Department Radiology of the Ohio State University for percutaneous vertebroplasty (a total sample of 20 patients) since the FDA approval of denosumab (November 2010) until June of 2013 (a 30-month period)., On the basis of this data, the FDA approved denosumab for the treatment of patients whose GCTB is unresectable, or when surgery is likely to result in severe morbidity., Denosumab (Prolia®) is a fully human monoclonal antibody for RANKL, which selectively inhibits osteoclastogenesis, being recently approved for the treatment of postmenopausal osteoporosis in women at a high or increased risk of fracture by the FDA in the United Sates and by the European Medicines Agency in Europe since June 2010., Recent phase II clinical trials with denosumab in skeletally mature adolescents over age 12 years and adults with GCTB, have shown both safety and efficacy, leading to its accelerated US FDA approval on 13 June 2013. , Zoledronic acid (ZA), an intravenously administered bisphosphonate, and Denosumab, a subcutaneously administered inhibitor of nuclear factor B ligand (RANKL), have already been approved by Food and Drug Administration (FDA) for their use in treatment of bone metastases., These results led to the approval of denosumab by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), for the prevention of SREs in adults with bone metastases from solid tumors, including breast cancer., Alendronate, risedronate, zoledronic acid, denosumab, and teriparatide are Food and Drug Administration (FDA)-approved therapeutic options. , Several of these therapies have recently been approved by the FDA to treat bone cancer pain (bisphosphonates, denosumab) and others are currently being evaluated in human clinical trials (tanezumab)., A fourth agent, denosumab (bone targeted therapy) was also recently approved by the FDA for patients with bone metastasis after showing a reduction in the occurrence of skeletal-related events. , AHRQ published an updated review in March 2012 that summarized the benefits and risks of osteoporosis medications in treatment and prevention of osteoporosis, including bisphosphonates (aledronate, risedronate, ibandronate, zoledronic acid), parathyroid hormone, teriparatide, calcitonin, estrogens (for prevention in postmenopausal women), selective estrogen receptor modulators (raloxifene), and denosumab(approved by the FDA in 2010). , Four new drugs have received U.S. Food and Drug Administration (FDA)-approval in 2010 and 2011: sipuleucel-T, an immunotherapeutic agent; cabazitaxel, a novel microtubule inhibitor; abiraterone acetate, a new androgen biosynthesis inhibitor; and denosumab, a bone-targeting agent. , Recently, the US FDA and the EMA approved denosumab (a fully human monoclonal antibody) to treat skeletal-related events in bone-metastatic prostate cancer., In addition to these new and emerging therapeutic agents, denosumab was approved for the prevention of skeletal complications in patients with bone metastases due to solid tumor malignancies, providing an alternative to zoledronic acid. , Recently, denosumab was FDA-approved for prevention of SREs in patients with bone metastases from solid tumors. , In the 2010s to date, an additional 3 antibodies (denosumab, belimumab, ipilimumab) have been approved and one antibody-drug conjugate (brentuximab vedotin) is undergoing regulatory review and may be approved in the US by August 30, 2011., We also review the evidence supporting the FDA's approval of denosumab (bone-targeted therapy) as a treatment option for men with CRPC and bony metastases. ,  It has been approved for clinical use by the FDA in the US and by the European Medicines Agency in Europe since June 2010 (trade name Prolia(™), Amgen, Thousand Oaks, CA, USA). , The fully human monoclonal antibody denosumab (Prolia(®)) has been recently approved by the European Medical Agency (EMEA) and the Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis. , Raloxifene and denosumab are only FDA approved for postmenopausal osteoporosis., The new antiresorptive drug, denosumab, although FDA-approved only for postmenopausal women, has been shown in a study of men on ADT to increase bone density in spine, hip, and forearm and decrease vertebral fractures on x-ray. ,  Since then, an additional six human mAbs have received FDA approval: panitumumab, golimumab, canakinumab, ustekinumab, ofatumumab and denosumab. ", "label": "yes"}
{"id": "converted_2130", "sentence1": "Have studies shown that there is no link between DNA methylation patterns and Post Traumatic Stress Disorder?", "sentence2": "Using pre-deployment SKA2 methylation levels and childhood trauma exposure, we found that the previously published suicide prediction rule significantly predicted post-deployment PTSD symptoms (AUC=0.66, 95% CI: 0.53-0.79) with an optimal sensitivity of 0.81 and specificity of 0.91. Permutation analysis using random methylation loci supported these findings. Together, these data establish the importance of SKA2 for cortisol stress responsivity and the development of PTSD and provide further evidence that SKA2 is a promising biomarker for stress-related disorders including PTSD.,  Results provide novel support for PTSD-related accelerated aging in DNAm and extend the evidence base of known DNAm age correlates to the domains of neural integrity and cognition., We investigated serum DNA methylation patterns in genomic repetitive elements, LINE-1 and Alu, for post-traumatic stress disorder (PTSD) cases and controls who were US military service members recently deployed to Afghanistan or Iraq., In light of its role in glucocorticoid receptor transactivation, we investigated whether SKA2 DNA methylation influences cortisol stress reactivity and is involved in the development of post-traumatic stress disorder (PTSD)., These results suggest that alterations in global methylation pattern are involved in behavioural adaptation to environmental stress and pinpoint Dlgap2 as a possible target in PTSD., Here we examined whether there was a link between an established rat model of post-traumatic stress disorder (PTSD) and Bdnf DNA methylation, We investigated serum DNA methylation patterns in genomic repetitive elements, LINE-1 and Alu, for post-traumatic stress disorder (PTSD) cases and controls who were US military service members recently deployed to Afghanistan or Iraq.Cases (n = 75) had a postdeployment diagnosis of PTSD, DNA methylation in repetitive elements and post-traumatic stress disorder: a case-control study of US military service members, Here we examined whether there was a link between an established rat model of post-traumatic stress disorder (PTSD) and Bdnf DNA methylation. , DNA methylation in repetitive elements and post-traumatic stress disorder: a case-control study of US military service members., AIM: We investigated serum DNA methylation patterns in genomic repetitive elements, LINE-1 and Alu, for post-traumatic stress disorder (PTSD) cases and controls who were US military service members recently deployed to Afghanistan or Iraq. , Together, these results suggest that psychosocial stress may alter global and gene-specific DNA methylation patterns potentially associated with peripheral immune dysregulation., DNA methylation in vulnerability to post-traumatic stress in rats: evidence for the role of the post-synaptic density protein Dlgap2., Subjects with PTSD showed a higher DNA methylation of four CpG sites at the BDNF promoter compared with those without PTSD, Cumulatively, the data suggest that epigenetic variation at SKA2 mediates vulnerability to suicidal behaviors and PTSD through dysregulation of the HPA axis in response to stress.", "label": "no"}
{"id": "converted_4400", "sentence1": "Does the royal jelly contain proteins?", "sentence2": " We observed differences in the metabolome, proteome, and phytosterol compositions of royal jelly synthesized by nurse bees from multi-pesticide exposed colonies, including significant reductions of key nutrients such as 24-methylenecholesterol, major royal jelly proteins, and 10-hydroxy-2-decenoic acid. ,  Two-dimensional electrophoresis was used for the fractionation of royal jelly proteins, the main bioactive compounds of RJ, such as proteins, peptides, fatty acids, and phenolic,  the expression of four of the major royal jelly proteins (MRJP1, MRJP2, MRJP4, and MRJP5) and also several proteins associated with carbohydrate metabolism and energy synthesis, the antioxidant system, detoxification, biosynthesis, amino acid metabolism, transcription and translation, protein folding and binding, olfaction, and learning and memory.", "label": "yes"}
{"id": "converted_1559", "sentence1": "Are the proteins Erbin (LAP2) and Merlin cooperating?", "sentence2": "Erbin and the NF2 tumor suppressor Merlin cooperatively regulate cell-type-specific activation of PAK2 by TGF-beta., The results show that the epithelial-enriched protein Erbin controls the function of the NF2 tumor suppressor Merlin by determining the output of Merlin's physical interactions with active PAK2. , Erbin controls Merlin tumor suppressor function by switching the functional valence of PAK2 binding", "label": "yes"}
{"id": "converted_4434", "sentence1": "Is Satb1 a transcription factor?", "sentence2": "Special AT-rich sequence binding protein-1 (SATB1) is localized to the nucleus and remodels chromatin structure in T cells, chromatin organizers SATB2 and SATB1 , transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2, and SATB1. , Staining for the transcription factors Foxp2, Satb1 and Satb2 labeled most ganglion cells in the avian ganglion cell layer.", "label": "yes"}
{"id": "converted_690", "sentence1": "Are retroviruses used for gene therapy?", "sentence2": "Several immunodeficiencies have been treated successfully by stem cell-targeted, retroviral-mediated gene transfer with reconstitution of the immune system following infusion of the transduced cells., In this work we have developed and tested a self-inactivating (SIN) gammaretroviral vector (SINfes.gp91s) containing a codon-optimized transgene (gp91(phox)) under the transcriptional control of a myeloid promoter for the gene therapy of the X-linked form of CGD (X-CGD).,  We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen, We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. , We assessed lentiviral vectors (LVs) targeted to the EC surface marker CD105 for in vivo gene delivery., gef and apoptin genes were cloned into a doxycycline-regulated retrovirus-mediated gene expression system.", "label": "yes"}
{"id": "converted_1134", "sentence1": "Are Drosophila ultraconserved elements candidate ncRNAs?", "sentence2": "Highly constrained intergenic Drosophila ultraconserved elements are candidate ncRNAs., Here, we report the discovery and characterization of UCEs from 12 sequenced Drosophila species. We identified 98 elements ≥80 bp long with very high conservation across the Drosophila phylogeny. Population genetic analyses reveal that these UCEs are not present in mutational cold spots. Instead we infer that they experience a level of selective constraint almost 10-fold higher compared with missense mutations in protein-coding sequences, which is substantially higher than that observed previously for human UCEs. About one-half of these Drosophila UCEs overlap the transcribed portion of genes, with many of those that are within coding sequences likely to correspond to sites of ADAR-dependent RNA editing. For the remaining UCEs that are in nongenic regions, we find that many are potentially capable of forming RNA secondary structures. Among ten chosen for further analysis, we discovered that the majority are transcribed in multiple tissues of Drosophila melanogaster. We conclude that Drosophila species are rich with UCEs and that many of them may correspond to novel noncoding RNAs., Highly Constrained Intergenic Drosophila Ultraconserved Elements Are Candidate ncRNAs", "label": "yes"}
{"id": "converted_393", "sentence1": "Is there an association between bruxism and reflux?", "sentence2": "Sleep bruxism is prevalent in GERD patients, and GERD is highly associated with SB., There was a statistical trend towards tooth wear progression being associated with gastric risk factors (p < 0.05). , This article presents a case report of a 27-year-old male smoker with tooth wear and dentin sensitivity caused by GERD associated with bruxism. , The aim of this cross-over, randomized, single-blinded trial was to examine whether intra-esophageal acidification induces sleep bruxism (SB). , RMMA episodes including SB were induced by esophageal acidification. , Chronic regurgitation of gastric acids in patients with gastroesophageal reflux disease may cause dental erosion, which can lead in combination with attrition or bruxism to extensive loss of coronal tooth tissue., This clinical report describes treatment of severe tooth wear of a gastroesophageal reflux disease patient who is 54-year-old Turkish male patient. After his medical treatment, severe tooth wear, bruxism and decreased vertical dimensions were determined. , Gastroesophageal reflux disease by itself or in combination with attrition, abrasion or bruxism may be responsible for the loss., The association between bruxism, feeding and smoking habits and digestive disorders may lead to serious consequences to dental and related structures, involving dental alterations (wear, fractures and cracks), periodontal signs (gingival recession and tooth mobility) and muscle-joint sensitivity, demanding a multidisciplinary treatment plan. This paper presents a case report in which bruxism associated with acid feeding, smoking habit and episodes of gastric reflow caused severe tooth wear and great muscular discomfort with daily headache episodes. , The frequencies of RMMA, single short-burst, and clenching episodes were significantly higher during decreased esophageal pH episodes than those during other times. , These results suggest that most jaw muscle activities, ie, RMMA, single short-burst, and clenching episodes, occur in relation to gastroesophageal reflux mainly in the supine position., Nocturnal bruxism may be secondary to nocturnal gastroesophageal reflux, occurring via sleep arousal and often together with swallowing.", "label": "yes"}
{"id": "converted_908", "sentence1": "Is miR-126 involved in heart failure?", "sentence2": "he miRNAs miR-126 and miR-508-5p are associated with the outcome of ICM and NICM patients with CHF. These two miRNAs could be useful in the diagnosis of CHF patients, and might provide novel targets for prevention and treatment of CHF., The plasma concentration of miR-126 was negatively correlated with age and NYHA class, and could be a useful biomarker for heart failure., In 10 patients with heart failure, plasma concentrations of miR-126 were up-regulated with improvement of the NYHA class from IV to III.", "label": "yes"}
{"id": "converted_1129", "sentence1": "Is Wnt16b secreted in response to chemotherapy?", "sentence2": " In this study, we found WNT16B could be expressed and secreted into the microenvironment by human ovarian fibroblasts after DNA damage-associated treatment, including chemotherapy drugs and radiation., In a recent article in Nature Medicine, Sun et al. show that increased expression of Wnt family member wingless-type MMTV integration site family member 16B (WNT16B) by the tumor microenvironment in response to cytotoxic damage and signals through the canonical Wnt pathway to promote tumor growth and chemotherapy resistance. , Using a genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics, we identified a spectrum of secreted proteins derived from the tumor microenvironment that includes the Wnt family member wingless-type MMTV integration site family member 16B (WNT16B).", "label": "yes"}
{"id": "converted_2854", "sentence1": "Is pacritinib effective for treatment of myelofibrosis?", "sentence2": "Pacritinib and its use in the treatment of patients with myelofibrosis who have thrombocytopenia., Pacritinib, a dual JAK2 and FLT3 inhibitor which also inhibits IRAK1, has demonstrated the ability to favorably impact MF-associated splenomegaly and symptom burden, while having limited myelosuppression with manageable gastrointestinal toxicity., Other JAKis, such as fedratinib and pacritinib, proved to be useful in MF. , Conclusions and Relevance: In patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib twice daily was more effective than BAT, including ruxolitinib, for reducing splenomegaly and symptoms., Developments of JAK inhibitors, such as ruxolitinib, pacritinib, momelotinib, and febratinib enabled the effective management in MF patients. ,  Pacritinib (PAC), a multi-kinase inhibitor with specificity for JAK2, FLT3, and IRAK1 but sparing JAK1, has demonstrated clinical activity in MF with minimal myelosuppression. , Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited., Conclusions and Relevance\nIn patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib twice daily was more effective than BAT, including ruxolitinib, for reducing splenomegaly and symptoms., Expert commentary: Pacritinib has demonstrated promising results in patients with myelofibrosis and thrombocytopenia., Pacritinib, a dual JAK2 and FLT3 inhibitor, improves disease-related symptoms and signs with manageable gastrointestinal toxicity in patients with myelofibrosis with splenomegaly and high-risk features, without causing overt myelosuppression, and therefore may provide an important treatment option for a range of patients with myelofibrosis., Pacritinib is an active agent in patients with MF, offering a potential treatment option for patients with preexisting anemia and thrombocytopenia., Pacritinib (PAC), a multi-kinase inhibitor with specificity for JAK2, FLT3, and IRAK1 but sparing JAK1, has demonstrated clinical activity in MF with minimal myelosuppression., This article examines the role of JAK2 and FLT3 signaling in myelofibrosis and provides an overview of the clinical development of pacritinib as a new therapy for myelofibrosis., Pacritinib appears to be an effective agent for the control of MF-related symptoms and splenomegaly with potentially fewer haematological side-effects when compared with ruxolitinib and seems a particularly promising agent for anaemic and thrombocytopenic patients. , Expert commentary: Pacritinib has demonstrated promising results in patients with myelofibrosis and thrombocytopenia.", "label": "yes"}
{"id": "converted_687", "sentence1": "Is the Miller-Fisher syndrome considered to be a variant of Guillain-Barré?", "sentence2": "Miller Fisher syndrome is a variant of Guillain-Barre syndrome characterized by the classic triad of ophthalmoplegia, ataxia, and areflexia, We are reporting a rare case of Miller-Fisher (MFS) variant of Guillain-Barré syndrome (GBS) as the first manifestation of SLE in a 41-year-old female, Miller-Fisher syndrome is defined as ophthalmoplegia, ataxia and areflexia. Considered as a variant of Guillain-Barré syndrome, it differs in its clinical presentation and by anti-GQ1b antibody positivity, Guillain-Barré syndrome (GBS) and its variant, Miller Fisher syndrome (MFS), exist as several clinical subtypes with different neurological features and presentations, Using in vitro and in vivo models of the Guillain-Barré syndrome variant, Miller Fisher syndrome, we have shown previously that anti-GQ1b ganglioside antibodies target the presynaptic motor nerve terminal axon and surrounding perisynaptic Schwann cells, thereby mediating destructive injury through deposition of membrane attack complex., Miller Fisher syndrome is a variant of Guillain-Barré syndrome, characterized by ophthalmoplegia, ataxia and areflexia., Miller Fisher syndrome is a localized variant of Guillain-Barré syndrome, characterized by ophthalmoplegia, areflexia and ataxia., Miller Fisher syndrome, a variant of Guillain-Barré syndrome, is associated with IgG antibody to GQ1b ganglioside., Miller Fisher syndrome (MFS), a variant of Guillain-Barré syndrome, is a rare disorder typically characterized by a triad of ataxia, areflexia, and ophthalmoplegia, which may have a highly variable clinical presentation., Miller Fisher syndrome is an acute inflammatory polyradiculoneuropathy that is generally considered a variant of Guillain-Barré syndrome and is characterized by the clinical triad of ataxia, areflexia, and ophthalmoplegia., The objective of this study was to review the occurrence and clinical features of Guillain-Barré syndrome and its variant, the Miller Fisher syndrome, during TNFalpha antagonist therapy., Miller Fisher variant of Guillain-Barré syndrome masquerading as acute sphenoid sinusitis with orbital apex syndrome., Controversy exists concerning whether Miller Fisher syndrome (MFS) is the result of a predominantly axonal or demyelinating polyneuropathy and whether the Guillain-Barré syndrome variant of acute ataxia and areflexia without ophthalmoplegia, ataxic Guillain-Barré syndrome (atxGBS), has a distinct pathophysiology., Miller Fisher syndrome is characterised by the triad ophthalmoparesis, ataxia and areflexia and is considered to be a variant of Guillain-Barré syndrome; its differential diagnosis includes Wernicke&apos;s encephalopathy, Miller Fisher syndrome is an acute inflammatory polyradiculoneuropathy that is generally considered a variant of Guillain-Barré syndrome and is characterized by the clinical triad of ataxia, areflexia, and ophthalmoplegia, Miller-Fisher syndrome is characterised by the clinical triad of ophthalmoplegia, ataxia and areflexia and is considered a variant form of Guillain-Barré syndrome, The syndrome of ataxia, areflexia and ophthalmoplegia, or Miller-Fisher syndrome, has been considered to be a variant of Guillain-Barré syndrome with pathology restricted to the peripheral nervous system, Miller-Fisher syndrome (MFS) is considered the most common variant of Guillain-Barré syndrome (GBS) and is characterized by the clinical triad of ophthalmoplegia, ataxia and areflexia, Miller Fisher syndrome (MFS), characterized as ataxia, areflexia and ophthalmoplegia, is generally considered as a variant of Guillain-Barré syndrome (GBS), Miller Fisher Syndrome (MFS), which is characterized by ophthalmoplegia, ataxia and tendon areflexia, is generally considered as a clinical variant of Guillain-Barré Syndrome, Miller-Fisher syndrome (MFS), a variant of Guillain-Barré syndrome (GBS) is a self-limiting demyelinating disease of the peripheral nervous system, BACKGROUND: Miller-Fisher syndrome is characterised by the clinical triad of ophthalmoplegia, ataxia and areflexia and is considered a variant form of Guillain-Barré syndrome. , BACKGROUND AND OBJECTIVE: Miller-Fisher syndrome (MFS) is considered the most common variant of Guillain-Barré syndrome (GBS) and is characterized by the clinical triad of ophthalmoplegia, ataxia and areflexia. , Miller Fisher syndrome is characterised by the triad ophthalmoparesis, ataxia and areflexia and is considered to be a variant of Guillain-Barré syndrome; its differential diagnosis includes Wernicke's encephalopathy. , A recent report described serum anti-GQ1b ganglioside antibodies in Miller Fisher syndrome (MFS), a clinical variant of Guillain-Barré syndrome (GBS)., The syndrome of ataxia, areflexia and ophthalmoplegia, or Miller-Fisher syndrome, has been considered to be a variant of Guillain-Barré syndrome with pathology restricted to the peripheral nervous system., Guillain-Barré syndrome (GBS), an acute inflammatory polyneuropathy, is preceded in most cases by an infectious illness, and Campylobacter jejuni, a leading cause of acute gastroenteritis, is the most common antecedent to GBS and its ocular variant, Miller Fisher syndrome (MFS)., Miller-Fisher syndrome is characterised by the clinical triad of ophthalmoplegia, ataxia and areflexia and is considered a variant form of Guillain-Barré syndrome., Miller-Fisher syndrome is characterised by the clinical triad of ophthalmoplegia, ataxia and areflexia and is considered a variant form of Guillain-Barré syndrome.,  The syndrome of ataxia, areflexia and ophthalmoplegia, or Miller-Fisher syndrome, has been considered to be a variant of Guillain-Barré syndrome with pathology restricted to the peripheral nervous system. A patient with Miller-Fisher syndrome and bilateral demyelinating optic neuropathy suggesting associated central nervous system pathology is presented., Miller Fisher syndrome is an acute inflammatory polyradiculoneuropathy that is generally considered a variant of Guillain-Barré syndrome and is characterized by the clinical triad of ataxia,,  Miller Fisher syndrome is an uncommon disease and it is a variant of Guillain-Barre syndrome. Miller Fisher syndrome also has rarer variants., Miller Fisher syndrome is characterised by the triad ophthalmoparesis, ataxia and areflexia and is considered to be a variant of Guillain-Barré syndrome; its differential diagnosis includes Wernicke's encephalopathy., Miller Fisher syndrome is an acute inflammatory polyradiculoneuropathy that is generally considered a variant of Guillain-Barré syndrome and is characterized by the clinical triad of ataxia, areflexia, and ophthalmoplegia., Data were separately analysed for Miller Fisher syndrome and other Guillain-Barré syndrome variants., Guillain-Barré syndrome variants alone (excluding Miller Fisher syndrome) accounted for 10.5% of total cases., The syndrome of ataxia, areflexia and ophthalmoplegia, or Miller-Fisher syndrome, has been considered to be a variant of Guillain-Barré syndrome with pathology restricted to the peripheral nervous system.", "label": "yes"}
{"id": "converted_2486", "sentence1": "Is vorinostat effective for glioblastoma?", "sentence2": "Conclusions: Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials., LESSONS LEARNED: Combination regimen with bevacizumab (BEV) and vorinostat is well tolerated in patients with recurrent glioblastoma., CONCLUSION: Combination treatment of BEV and VOR was well tolerated. This combination therapy for this study population did not improve PFS6 or median OS when compared with BEV monotherapy., We present two patients with glioblastoma multiforme who developed severe hemolytic anemia shortly after initiating therapy with vorinostat, a pan-active histone deacetylase inhibitor, while on prophylactic dapsone., Vorinostat is the most advanced HDAC inhibitor that entered clinical trials in glioblastoma, showing activity in recurrent disease. Multiple phase II trials with vorinostat in combination with targeted agents, temozolomide and radiotherapy are currently recruiting. , . On the basis of the results of this phase II study, further evaluation of the vorinostat-bortezomib combination in GBM patients in this dose and schedule is not recommended., ith the increased toxicities associated with CPT-11 coupled with its unclear clinical significance, investigating the efficacy of vorinostat combined with bevacizumab alone may represent a more promising strategy to evaluate in the context of a phase II clinical trial., CONCLUSION: Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway.", "label": "no"}
{"id": "converted_2959", "sentence1": "Is Adar3 involved in learning and memory?", "sentence2": "Adar3 Is Involved in Learning and Memory in Mice.,  The newest member of the A-I editing family of ADAR proteins, the vertebrate-specific ADAR3, is highly expressed in the brain, but its functional significance is unknown. In vitro studies have suggested that ADAR3 acts as a negative regulator of A-I RNA editing but the scope and underlying mechanisms are also unknown. Meta-analysis of published data indicates that mouse Adar3 expression is highest in the hippocampus, thalamus, amygdala, and olfactory region. Consistent with this, we show that mice lacking exon 3 of Adar3 (which encodes two double stranded RNA binding domains) have increased levels of anxiety and deficits in hippocampus-dependent short- and long-term memory formation. RNA sequencing revealed a dysregulation of genes involved in synaptic function in the hippocampi of Adar3-deficient mice. We also show that ADAR3 transiently translocates from the cytoplasm to the nucleus upon KCl-mediated activation in SH-SY5Y cells. These results indicate that ADAR3 contributes to cognitive processes in mammals., Adar3 Is Involved in Learning and Memory in Mice.-deficient mice. ", "label": "yes"}
{"id": "converted_406", "sentence1": "Can botulism poisoning of a pregnant woman harm her fetus?", "sentence2": "Two botulism outbreaks were attributed to commercial ready-to-eat meat products and 3 to foods served in restaurants; several cases were attributed to non-Native home-prepared foods. Three affected pregnant women delivered healthy infants., Botulinum toxin is not expected to be present in systemic circulation following proper intramuscular or intradermal injection. Moreover, BTX-A, which has a high molecular weight, does not appear to cross the placenta. From the 38 pregnancies reported in the literature, including women who had botulism poisoning during pregnancy, exposure to BTX-A does not appear to increase the risk of adverse outcome in the fetus., From the 38 pregnancies reported in the literature, including women who had botulism poisoning during pregnancy, exposure to BTX-A does not appear to increase the risk of adverse outcome in the fetus.", "label": "no"}
{"id": "converted_4311", "sentence1": "Does bleomycin cause lung toxicity?", "sentence2": "bleomycin-induced pulmonary fibrosis, bleomycin (BLM)-induced pulmonary , Pulmonary toxicity is a devastating complication of bleomycin chemotherapy. , Bleomycin containing regimen is routinely employed in the treatment of HL. Pulmonary toxicity due to this drug is the most feared side effect in these regimens where the mortality rate is approximately 2%-3%. , Bleomycin might cause pulmonary fibrosis at higher cumulative doses as toxic effect directly to the lungs or most likely in addition by the formation of vascular microthrombi., The comparative pulmonary toxicity induced by bleomycin and talisomycin (former trivial name: tallysomycin A) was evaluated by measuring lung hydroxyproline content., Clinicians should always remember that bleomycin toxicity may lead to fatal complications in patients with comorbid conditions., CONTEXT: The application of bleomycin is limited due to its side effects including lung toxicity., Bleomycin is an antineoplastic agent that causes a dose-related lung fibrosis that limits its therapeutic effectiveness., Acute Lung Toxicity After Intralesional Bleomycin Sclerotherapy., We report a case of a severe acute lung toxicity after a low dose of a second bleomycin intralesional injection in a 5-year-old girl., Renal damage, following cisplatin administration, with subsequent accumulation of bleomycin was the likely cause of the high lung toxicity., Whenever possible, bleomycin should precede cisplatin infusion to minimize the risk of lung toxicity., The most severe form of BLM-induced pulmonary toxicity is lung fibrosis., Results from this study suggest that an excess production of superoxide anions by alveolar macrophages may be the underlying cause of bleomycin pulmonary toxicity., Bleomycin lung toxicity is well established and can manifest as bleomycin-induced pneumonitis, but pneumomediastinum and pneumothorax are very rare complications., High doses of bleomycin administered to patients with lymphomas and other tumors lead to significant lung toxicity in general, and to apoptosis of epithelial cells, in particular. , sis of bleomycin-induced lung toxicity is based on the combination of clinical and radiological features, and requires to rule out differential diagnoses including pneumocystis. \"Bleo, Doxorubicin, bleomycin, vinblastine sulfate, and dacarbazine (ABVD) is associated with severe toxicity in older patients, particularly from bleomycin-induced lung toxicity (BLT). Ther, s studies have proposed that the lung toxicity caused by bleomycin is related to the C-terminal regions of these drugs, which have been shown to closely interact with DNA in metal-bleomycin-DNA complexes. Some o, OBJECTIVES: Bleomycin, etoposide, and cisplatin (BEP) is the most common and successful chemotherapy regimen for germ-cell tumor (GCT) patients, accompanied by a bleomycin-induced dose-dependent lung toxicity in certain pat, e been no respiratory problems attributable to bleomycin lung toxicity in this study compared with four (3 associated with patient deaths) seen in 91 previously treated patients. The relat, Mechanisms of bleomycin-induced lung damage., Previous studies have proposed that the lung toxicity caused by bleomycin is related to the C-terminal regions of these drugs, which have been shown to closely interact with DNA in metal-bleomycin-DNA complexes., g V30 cutoff value of 32% was estimated.CONCLUSION: Bleomycin and RT may cause lung injury , Postmortem lung studies were performed in all six patients and revealed findings compatible with bleomycin-induced lung toxicity., However, the cytotoxic effects of bleomycin cause a number of adverse responses, in particular in the lung and the skin., Bleomycin, a widely used anti-cancer drug, may give rise to pulmonary fibrosis, a serious side effect which is associated with significant morbidity and mortality., Bleomycin is a cancer therapeutic known to cause lung injury which progresses to fibrosis., and repair. Bleomycin pulmonary toxicity is mediated, at least in part, by the generation of active oxy, This report suggests that bleomycin lung toxicity may be reversible if treated aggressively., Although all bleomycin-treated animals had some evidence of lung toxicity, histologic examination of the lungs revealed markedly reduced bleomycin toxicity in the rats exposed to hypoxia., Low temperature inhibits bleomycin lung toxicity in the rat., Results at day 22, 3 wk after bleomycin treatment, showed that airway delivery of liposomes before and after intratracheal administration of bleomycin significantly reduced bleomycin-induced lung toxicity as evidenced by less body weight loss, chronic lung inflammation, and fibrosis as well as improved lung compliance compared with controls., Protective effect of hypoxia on bleomycin lung toxicity in the rat., N-acetyl cysteine (NAC) has recently been shown to have antioxidant properties, and since bleomycin produces pulmonary damage via free oxygen radical toxicity, the possible protective effect of NAC on bleomycin lung toxicity was investigated., All rats treated with bleomycin only had typical changes of bleomycin lung toxicity whereas the animals treated with bleomycin and NAC had minimal pathology., atic compliance on day 15 was severely decreased with bleomycin alone and showed a further significant decrease when granulocyte colony-stimulating factor was added (controls, 3.85 +/- 0.14 mL/kPa; bleomycin, 1.44 +/- 0.06 mL/kPa; and bleomycin + granulocyte colony-stimulating factor, 0.65 +/- 0.09 mL/kPa; control vs. bleomycin, p <.0001; and bleomycin vs. bleomycin + granulocyte colony-stimulating factor, p =.0003). Lung m, Bleomycin sometimes causes fatal pulmonary toxicity, including bleomycin-induced pneumonitis., Bleomycin is an antineoplastic agent causing fatal pulmonary toxicity., Pulmonary toxicity is an important adverse effect of bleomycin treatment., Pulmonary toxicity is the most significant complication of bleomycin administration., It is possible, however, that the low incidence of clinically significant and fatal pulmonary toxicity, as experienced in this group of patients, may be related to the infusion of bleomycin., Bleomycin-mediated pulmonary toxicity: evidence for a p53-mediated response., Occurrence of bleomycin lung toxicity requires an immediate and often permanent discontinuation., All three developed bleomycin induced pulmonary toxicity in the form of pulmonary fibrosis during treatment of the disease., One of the fatal side effect of bleomycin is pulmonary toxicity., Pulmonary Toxicity of Bleomycin - A Case Series from a Tertiary Care Center in Southern India., Bleomycin is potentially capable of inducing a diffuse interstitial fibrosis of the lung, the pathogenesis of which has not yet been elucidated., Intratracheal instillation of bleomycin 1.5 mg resulted in a severe pneumonitis with influx of inflammatory cells into the alveoli as assessed by alveolar lavage, oedema of the alveolar walls, and up to an eight fold increase in the total pulmonary extravascular albumin space, maximal at 72 hours., Development of acute lung injury after the combination of intravenous bleomycin and exposure to hyperoxia in rats., Bleomycin is a highly effective antitumor agent, but pulmonary toxicity, characterized by an acute inflammatory reaction and associated pulmonary edema, limits clinical use of the drug., In this study we investigated bleomycin-induced pulmonary toxicity in patients with germ-cell tumour by means of technetium-99m diethylene triamine penta-acetic acid aerosol scintigraphy.", "label": "yes"}
{"id": "converted_4647", "sentence1": "Is telomestatin, a novel statin drug used to treat high cholesterol?", "sentence2": "Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor., Telomestatin, a potent telomerase inhibitor that interacts quite specifically with the human telomeric intramolecular g-quadruplex., Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), ,  G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095),,  We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines, A novel telomerase inhibitor, telomestatin, isolated from Streptomyces anulatus is the most potent telomerase inhibitor so far., Telomerase inhibitor, telomestatin, a specific mechanism to interact with telomere structure, Telomestatin specifically inhibited telomerase without affecting reverse transcriptases and polymerases., In addition, telomestatin induced telomere shortening, but its ratio was extremely faster than that observed in physiological telomere shortening., A novel telomerase inhibitor, telomestatin, isolated from Streptomyces anulatus is the most potent telomerase inhibitor so far. , ructure has been yet resolved for the complex with telomestatin, one of the most promising G-quadruplex-targeting anticancer drug candidates. Here, Telomestatin, a strong telomerase inhibitor with G-quadruplex stabilizing activity, is a potential therapeutic agent for treating cancers., Thus, telomestatin provide the novel therapeutic molecular target for cancer chemotherapy., Telomerase inhibition with a novel G-quadruplex-interactive agent, telomestatin: in vitro and in vivo studies in acute leukemia., Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways.", "label": "no"}
{"id": "converted_1745", "sentence1": "Are microtubules marked by glutamylation?", "sentence2": "Together with detyrosination, glutamylation and other modifications, tubulin acetylation may form a unique 'language' to regulate microtubule structure and function., Glutamylation, the most prevalent tubulin posttranslational modification, marks stable microtubules and regulates recruitment and activity of microtubule- interacting proteins., Enzymes of the tubulin tyrosine ligase-like (TTLL) family posttranslationally modify and thereby mark microtubules by glutamylation, generating specific recognition sites for microtubule-interacting proteins.,  PTMs of the cytoskeleton, including phosphorylation, glycosylation, ubiquitination, detyrosination/tyrosination, (poly)glutamylation and (poly)glycylation, acetylation, sumoylation, and palmitoylation, will be addressed in this chapter., The tubulin posttranslational modifications: acetylation, detyrosination, polyglutamylation, and polyglycylation play important roles in microtubule functions, In most eukaryotic cells, tubulin is subjected to posttranslational glutamylation, a conserved modification of unclear function.", "label": "yes"}
{"id": "converted_3445", "sentence1": "Does radiation for tinea capitis increases brain tumor risk?", "sentence2": "Emphasis is placed on meningiomas resulting from childhood treatment for primary brain tumor or tinea capitis, exposure to dental x-rays, and exposure to atomic explosions in Hiroshima and Nagasaki. , It is well known that radiation can induce meningiomas. These tumors usually arise in patients with a history of low-dose radiation to the scalp for treatment of tinea capitis or high-dose radiation for a previous brain tumor. , This paper describes six cases of radiation-associated intracranial meningiomas in patients previously treated with low-dose radiation to the scalp for tinea capitis., After a median follow-up of 40 years, an ERR/Gy of 4.63 and 1.98 (95% CI = 2.43-9.12 and 0.73-4.69) and an EAR/Gy per 10(4) PY of 0.48 and 0.31 (95% CI = 0.28-0.73 and 0.12-0.53) were observed for benign meningiomas and malignant brain tumors, respectively. , The estimated ERR/Gy for malignant brain tumors decreased with increasing age at irradiation from 3.56 to 0.47 (P = 0.037), while no trend with age was seen for benign meningiomas. The ERR for both types of tumor remains elevated at 30-plus years after exposure., Although meningiomas are known to be induced by low doses of cranial irradiation, such as those given to treat tinea capitis, little experience has been reported on the induction of meningiomas by high-dose cranial irradiation. , The exposed rats had a greater incidence of pituitary chromophobe adenomas, epithelial and mesothelial cell tumors than the unexposed controls but the excessive occurrence of malignant gliomas that was observed in the monkeys was absent in the rats.  , We have analyzed 60 cases of intra-axial brain tumors associated with antecedent radiation therapy. These include four new cases. The patients had originally received radiation therapy for three reasons: (a) cranial irradiation for acute lymphoblastic leukemia (ALL), (b) definitive treatment of CNS neoplasia, and (c) treatment of benign disease (mostly cutaneous infections). , Long-term follow-up for brain tumor development after childhood exposure to ionizing radiation for tinea capitis., Benign and malignant thyroid neoplasms after childhood irradiation for tinea capitis., There is evidence to show that moderate doses of ionising radiations given in childhood for tinea capitis are associated with a late risk of developing a meningioma, This paper describes six cases of radiation-associated intracranial meningiomas in patients previously treated with low-dose radiation to the scalp for tinea capitis., These tumors usually arise in patients with a history of low-dose radiation to the scalp for treatment of tinea capitis or high-dose radiation for a previous brain tumor., There is evidence to show that moderate doses of ionising radiations given in childhood for tinea capitis are associated with a late risk of developing a meningioma., In addition to high dose radiation-induced meningiomas, intracranial meningiomas were observed in patients who underwent low-dose radiation for tinea capitis in childhood, applied en mass to immigrants coming to Israel from the North Africa and the Middle East during the 1950., A 39-year-old male developed primary brain lymphoma 33 years after receiving scalp irradiation for tinea capitis., Secondary glioblastoma multiforme (sGBM) can occur after a long latency period following radiation treatment of various diseases including brain tumors, leukemia, and more benign disorders like tinea capitis., The main data come from series of patients who underwent radiotherapy during childhood: a high incidence of tumors of the nervous system is found after irradiation of one to a few grays as treatment of a benign disease (especially tinea capitis), as well as after irradiation at higher doses of a few tens of grays for the treatment of cancer (in particular cerebral irradiation in acute lymphoblastic leukaemia).", "label": "yes"}
{"id": "converted_3655", "sentence1": "Does gavestinel improve outcomes of stroke patients?", "sentence2": "CONCLUSION: Consistent with the clinical outcomes in the GAIN trials, no effects of gavestinel on ischemic infarction was observed., No effects of gavestinel on infarct volume were observed in the primary or other analyses. , Gavestinel does not improve outcome after acute intracerebral hemorrhage: an analysis from the GAIN International and GAIN Americas studies., Both trials reported that gavestinel was ineffective in ischemic stroke. , CONCLUSIONS: These observations from the combined GAIN International and GAIN Americas trials suggest that gavestinel is not of substantial benefit or harm to patients with primary intracerebral hemorrhage. , Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists such as Selfotel, Aptiganel, Gavestinel and others failed to show neuroprotective efficacy in human clinical trials or produced intolerable central nervous system adverse effects., METHODS: We studied all patients of the Glycine Antagonist (gavestinel) In Neuroprotection (GAIN) International Trial with ischemic stroke alive at day 7, excluding patients with hemorrhagic events and deaths from nonstroke-related causes. The GAIN International Trial was a randomized, double-blind, placebo-controlled, and parallel-group trial; because the study drug had no effect on stroke outcome, treatment groups were combined for this analysis. , Gavestinel produces no benefit for stroke patients, study finds., The wonder drug, gavestinel, failed to produce any significant treatment benefits for patients treated within six hours after experiencing an acute ischemic stroke, according to the recent results of a major clinical trial of the neuroprotectant. , INTERPRETATION: Treatment with gavestinel within 6 h of acute ischaemic stroke did not improve outcome., INTERPRETATION\n\nTreatment with gavestinel within 6 h of acute ischaemic stroke did not improve outcome., CONCLUSION\n\nIn this study, gavestinel administered up to 6 hours after an acute ischemic stroke did not improve functional outcome at 3 months., Both trials reported that gavestinel was ineffective in ischemic stroke., INTERPRETATION Treatment with gavestinel within 6 h of acute ischaemic stroke did not improve outcome., Both trials reported that gavestinel was ineffective in ischemic stroke., Gavestinel produces no benefit for stroke patients , study finds ., The wonder drug, gavestinel, failed to produce any significant treatment benefits for patients treated within six hours after experiencing an acute ischemic stroke, according to the recent results of a major clinical trial of the neuroprotectant., The wonder drug, gavestinel, failed to produce any significant treatment benefits for patients treated within six hours after experiencing an acute ischemic stroke, according to the recent results of a major clinical trial of the neuroprotectant., Treatment with gavestinel within 6 h of acute ischaemic stroke did not improve outcome., In this study, gavestinel administered up to 6 hours after an acute ischemic stroke did not improve functional outcome at 3 months.", "label": "no"}
{"id": "converted_4695", "sentence1": "Was ALVAC-HIV effective for HIV prevention in the HVTN 702 trial?", "sentence2": "During the 24-month follow-up, HIV-1 infection was diagnosed in 138 participants in the vaccine group and in 133 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.81 to 1.30; P = 0.84).CONCLUSIONS: The ALVAC-gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity. (HVTN 702 ClinicalTrials.gov number, NCT02968849.)., The advanced-phase HIV prevention vaccine trials done in South Africa (HVTN 702) and in Thailand (RV144), which both investigated canarypox vectors and adjuvanted gp120 proteins, gave rise to different results. The South African trial did not find vaccine efficacy, whereas the Thai trial had modest, but statistically significant, success with the modified intention-to-treat analysis prespecified in the protocols of both studies. , However, with the recent failure of the HVTN 702 clinical trial, comprehensive profiling of humoral immune responses may provide insight for these disappointing results. , A canarypox-protein HIV vaccine regimen (ALVAC-HIV plus AIDSVAX B/E) showed modest efficacy in reducing infection in Thailand., e vaccine and placebo groups. During the 24-month follow-up, HIV-1 infection was diagnosed in 138 participants in the vaccine group and in 133 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.81 to 1.30; P = 0.84).CONCLUSIONS: The ALVAC-gp120 regimen did not prevent HIV-1 infection among participants in South Africa d", "label": "no"}
{"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 ", "label": "yes"}
{"id": "converted_4699", "sentence1": "Are there roles for cohesin mutations in AML?", "sentence2": "Several landmark studies have shown that cohesin mutations perturb the balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPC). Emerging data now begin to uncover the molecular mechanisms that underpin this phenotype. Among these mechanisms is a role for cohesin in the control of inflammatory responses in HSPCs and myeloid cells. Inflammatory signals limit HSPC self-renewal and drive HSPC differentiation. Consistent with this, cohesin mutations promote resistance to inflammatory signals, and may provide a selective advantage for AML progression. ", "label": "yes"}
{"id": "converted_281", "sentence1": "Are reduced-nicotine cigarettes effective for smoking cessation?", "sentence2": "CONCLUSIONS: In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. , RESULTS: Significant reductions in nicotine intake were observed between usual brand smoking (∼1.2 mg nicotine) and the 0.3 and 0.05 mg nicotine emission cigarettes, but not the 0.6 mg cigarette., CONCLUSIONS: The study adds to the evidence that cigarettes with markedly reduced nicotine content are not associated with increased smoking intensity or exposure to smoke toxicants., BACKGROUND: When switching from usual brand cigarettes, very low nicotine content (VLNC) cigarettes lead to a reduction in the number of cigarettes smoked, toxicant exposure, withdrawal symptoms and dependence. , Moreover, while nicotine patches were well tolerated when subjects smoked nicotine-containing cigarettes, the use of nicotine skin patches with reduced-nicotine cigarettes potentially offers the advantage of increased efficacy without introducing concern about toxic effects of excessive nicotine intake., Results showed that Quest plus NRT was more effective than active control plus NRT in achieving 4 weeks of continuous abstinence (32.8% vs. 21.9%)., Quest plus NRT offers promise as a new smoking cessation treatment., We identified three clinical trials (total n = 489) that suggest that smokers can dissociate nicotine delivery from the act of smoking if they use reduced-nicotine content cigarettes in combination with nicotine replacement therapy., CONCLUSION: The 0.05 mg nicotine yield cigarettes may be a tobacco product that can facilitate cessation; however, future research is clearly needed to support these preliminary findings., Preliminary studies suggest an extinction-based smoking cessation treatment using reduced nicotine content (RNC) cigarettes decreases self-report craving for cigarettes prior to quitting and may be an effective smoking cessation treatment., Reduced nicotine content (RNC) cigarettes have led to smoking fewer cigarettes, withdrawal relief, and facilitation of cessation., Evidence from a number of small smoking cessation studies suggests that the use of cigarettes with reduced nicotine content, in combination with nicotine replacement therapy (NRT), may help reduce withdrawal symptoms and increase quit rates., The concept for a reduced-nicotine cigarette designed to progressively wean smokers from the smoking habit is based on research demonstrating that successful smoking cessation is not only dependent on withdrawal of nicotine, but also on weaning from the habitual sensory and behavioral reinforcement of smoking., Preliminary studies suggest an extinction-based smoking cessation treatment using reduced nicotine content (RNC) cigarettes decreases self-report craving for cigarettes prior to quitting and may be an effective smoking cessation treatment, Specifically, standards that required substantially reduced nicotine content in cigarettes could enable cessation in smokers and prevent future smoking among current non-smokers, Reduced nicotine content (RNC) cigarettes have led to smoking fewer cigarettes, withdrawal relief, and facilitation of cessation, Evidence from a number of small smoking cessation studies suggests that the use of cigarettes with reduced nicotine content, in combination with nicotine replacement therapy (NRT), may help reduce withdrawal symptoms and increase quit rates, The concept for a reduced-nicotine cigarette designed to progressively wean smokers from the smoking habit is based on research demonstrating that successful smoking cessation is not only dependent on withdrawal of nicotine, but also on weaning from the habitual sensory and behavioral reinforcement of smoking, These results suggest that use of NRT before a target quit-smoking date deserves further evaluation as a possible smoking cessation treatment. Moreover, while nicotine patches were well tolerated when subjects smoked nicotine-containing cigarettes, the use of nicotine skin patches with reduced-nicotine cigarettes potentially offers the advantage of increased efficacy without introducing concern about toxic effects of excessive nicotine intake., Preliminary studies suggest an extinction-based smoking cessation treatment using reduced nicotine content (RNC) cigarettes decreases self-report craving for cigarettes prior to quitting and may be an effective smoking cessation treatment.", "label": "yes"}
{"id": "converted_147", "sentence1": "Has the protein TIEG1 been associated with apoptosis?", "sentence2": "TGF-beta) inducible early gene 1 (TIEG1) is known to induce apoptosis in TGF-beta sensitive pancreatic cancer cells, yet its effect on TGF-beta resistant cancer cells remains unclear, overexpression of TIEG1, protected ALL cells against chemotherapy-induced cell death,  TIEG1 might be involved in mediating this effect from the microenvironment onto the leukemia cells, We also demonstrate that TIEG-1 ectopic expression in CGNPs induces cell cycle arrest that can lead to apoptosis but fails to promote differentiation, TIEG1 acts as an inducer or repressor of gene transcription to enhance the TGFbeta/Smad pathway, as well at other signaling pathways, to regulate cell proliferation, differentiation, and apoptosis., TGFbeta inducible early gene (TIEG1) mimics TGFbeta action and induces apoptosis, the transforming growth factor-beta- (TGF-beta-) inducible early response 1 gene (TIEG1), which plays a pivotal role in TGF-beta-regulated cell growth control and apoptosis, Induction of mRNA for Smad4 and the TGF-beta1-regulated apoptosis-inducing transcription factor TGF-beta1-inducible early gene (TIEG1) was detected within the first 6 h of doxazosin treatmen, TIEG1 (TGF-beta inducible early gene) is a recently characterized transcription factor regulated by TGF-beta that induces apoptosis when overexpressed in pancreatic adenocarcinoma cell lines, Influence of TIEG1 on apoptosis, the influence of TIEG1 on apoptosis of HL-60 cells and the expression of Bcl-2/Bax, The expression of genes involved in insulin resistance (PDK4, AHSG) is increased, together with expression of TIEG1, a transcription factor that can induce apoptosis via the mitochondrial pathway, the overexpression of TIEG1 mediated growth inhibition and apoptosis in TGF-β1-resistant HCC cell lines,, On the other hand, KLF10 deficient keratinocytes showed increased proliferation and apoptosis, LF10, transforming growth factor-β-inducible early gene 1, IEG1 can induce apoptosis of cancer cells, TGF-β inducible early gene 1) plays a significant role in regulating cell proliferation and apoptosis, TIEG1) is a Krüppel-like transcription factor (KLF10) that was originally cloned from human osteoblasts as an early response gene to TGF-β treatment, Adenoviral delivery of TIEG1 (AdTIEG1) to TIEG1(-/-) cells reversed the RANKL-induced NFATc1 signaling defect in TIEG1(-/-) precursors and eliminated the differentiation and apoptosis defects, (TGF)-β inducible early gene (TIEG)-1 is implicated in the control of cell proliferation, differentiation, and apoptosis in some cell types, TIEG1 has been shown to mimic the effects of TGF-beta in various carcinoma cells and plays a critical role in the apoptotic cascade, (TIEG) is a family of primary response genes induced by TGF-beta, which are well recognized in regulating cellular proliferation and apoptosis, In human and murine tissues it has been shown that TIEG1 and TIEG2 induce apoptosis and inhibit cell growth, overexpression of TIEG1 in OLI-neu cells induced apoptosis, (TGF-beta(1))-inducible transcription factors have recently elicited interest because of their critical role in the regulation of cell proliferation, differentiation, and apoptosis, ectopic overexpression of TIEG is sufficient to trigger the apoptotic cell program in these cells", "label": "yes"}
{"id": "converted_4717", "sentence1": "Can parasite infections by Schistosoma japonicum prevent or improve asthma?", "sentence2": "Helminths and their products can shape immune responses by modulating immune cells, which are dysfunctional in inflammatory diseases such as asthm, Schistosoma japonicum peptide SJMHE1 suppresses airway inflammation of allergic asthma in mice., Schistosoma japonicum infection downregulates house dust mite-induced allergic airway inflammation in mice., To our knowledge, it is the first study to reveal the impact of S. japonicum infection on house dust mite induced severe asthma. More in depth investigation is need to elucidate the underlying mechanisms, Novel T-cell epitopes on Schistosoma japonicum SjP40 protein and their preventive effect on allergic asthma in mice., hese results reveal a novel form of immune protective mechanism, which may play an important role in the modulating effect of helminth infection on allergic asthmatic reactions., Using a panel of overlapping peptides, we identified T-cell epitopes on SjP40 protein of Schistosoma japonicum, which can induce Th1 cytokine and inhibit the production of Th2 cytokines and airway inflammation in a mouse model of allergic asthma., Helminths and their products can regulate immune response and offer new strategies to control and alleviate inflammation, including asthma., SJMHE1 Peptide from Schistosoma japonicum Inhibits Asthma in Mice by Regulating Th17/Treg Cell Balance via miR-155., We previously found that a peptide named as SJMHE1 from Schistosoma japonicum can suppress asthma in mice, el of overlapping peptides, we identified T-cell epitopes on SjP40 protein of Schistosoma japonicum, which can induce Th1 cytokine and inhibit the production of Th2 cytokines and airway inflammation in a mouse model of allergic asthma. These resul, has been shown that helminth infections including Schistosoma mansoni may modulate atopic diseases including asthma. I, Schistosoma japonicum infection downregulates house dust mite-induced allergic airway inflammation in mice, it is the first study to reveal the impact of S. japonicum infection on house dust mite induced severe asthma. More in depth inv, s study, we investigated the impact of Schistosoma japonicum infection on the allergic airway inflammation induced by repeated intracheal inoculations of house dust mites (HDM), which is a Th17 and neutrophils dominant murine asthma model, mimicking severe asthma. We found, Schistosoma japonicum infection showed protective effects against allergic airway inflammation (AAI)., Therefore, we hypothesize that Schistosoma japonicum egg antigens, a type of native antigen, can induce production of CD4(+) CD25(+) T cells with regulatory activity, modulating airway inflammation and inhibiting asthma development., Schistosoma japonicum infection modulates the development of allergen-induced airway inflammation in mice., It has been shown that helminth infections including Schistosoma mansoni may modulate atopic diseases including asthma., Schistosoma japonicum egg antigens stimulate CD4 CD25 T cells and modulate airway inflammation in a murine model of asthma., Most previous studies focused on understanding the preventive effect of S. japonicum infection on asthma (infection before allergen sensitization), whereas the protective effects of S. japonicum infection (allergen sensitization before infection) on asthma were rarely investigated., In conclusion, our data showed that lung-stage S. japonicum infection could relieve OVA-induced asthma in a mouse model., In this study, we investigated the protective effects of S. japonicum infection on AAI using a mouse model of OVA-induced asthma.,  prior to OVA immunization. These results suggest that both bisexual and male S. japonicum infections may modulate the development of allergic asthma., aponicum, which can induce Th1 cytokine and inhibit the production of Th2 cytokines and airway inflammation in a mouse model of allergic asthma. These, ve found that Schistosoma infection or Schistosoma related products can improve or prevent some immune and inflammatory diseases, such as severe asthm, Our findings indicated that S. japonicum infection was able to effectively inhibit host's allergic airway inflammation, which may be related to the upregulated Treg cells upon infection., These results suggest that both bisexual and male S. japonicum infections may modulate the development of allergic asthma., We found that lung-stage S. japonicum infection significantly ameliorated OVA-induced AAI, whereas post-lung-stage infection did not., In a murine model of asthma, S. japonicum egg antigens decreased the expression of Th2 cytokines, relieved antigen-induced airway inflammation, and inhibited asthma development., We found that S. japonicum infection downregulated airway hyperresponsiveness., However, in recent years, studies have found that Schistosoma infection or Schistosoma related products can improve or prevent some immune and inflammatory diseases, such as severe asthma, inflammatory bowel disease, diabetes and so on., In areas where schistosomiasis is endemic, a negative correlation is observed between atopy and helminth infection, associated with a low prevalence of asthma.", "label": "yes"}
{"id": "converted_824", "sentence1": "is pharmacological treatment of subclinical hypothyroidism effective in reducing cardiovascular events?", "sentence2": "The decision to treat elderly people is still an unresolved clinical challenge--first, due to a lack of appropriately powered randomized controlled trials of L-T4 in sHT patients, examining cardiovascular hard endpoints in various classes of age; and second, because of the negative effects of possible overtreatment., The lack of specific randomized trials enrolling either old or very old subjects, aimed at evaluate the efficacy of hormonal replacement on overall survival and cardiovascular risk reduction along with the negative effects of possible over-treatment, makes the decision to treat older people a still unresolved clinical challenge, In patients with type 2 DM, the presence of SH serves as an additional risk factor for endothelial dysfunction., Treatment of SCH with levothyroxine was associated with fewer IHD events in younger individuals, but this was not evident in older people., Subclinical hyperthyroidism seems to be a risk factor of developing major cardiovascular events, especially stroke in older adults from the general population with normal left ventricular function., SCH appears to influence the postoperative outcome for patients by increasing the development of postoperative atrial fibrillation. However, it is still unproven whether preoperative thyroxine replacement therapy for patients with SCH might prevent postoperative atrial fibrillation after CABG., In CHF patients TSH levels even slightly above normal range are independently associated with a greater likelihood of heart failure progression., In current RCTs, levothyroxine replacement therapy for subclinical hypothyroidism did not result in improved survival or decreased cardiovascular morbidity. Data on health-related quality of life and symptoms did not demonstrate significant differences between intervention groups., However, the actual effectiveness of thyroid hormone substitution in reducing the risk of cardiovascular events remains to be elucidated. In conclusion, the multiplicity and the possible reversibility of subclinical hypothyroidism-associated cardiovascular abnormalities suggest that the decision to treat a patient should depend on the presence of risk factors, rather than on a TSH threshold. , However, whether SH confers a high risk for cardiovascular disease, and whether LT4 therapy has a long-term benefit that clearly outweighs the risks of overzealous treatment in these individuals, remain topics of controversy.", "label": "no"}
{"id": "converted_3413", "sentence1": "Is celecoxib effective for amyotrophic lateral sclerosis?", "sentence2": "In conclusion, the celecoxib-creatine combination was selected as preferable to the minocycline-creatine combination for further evaluation. , ESULTS: Celecoxib did not slow the decline in muscle strength, vital capacity, motor unit number estimates, ALS Functional Rating Scale-Revised, or affect survival. , INTERPRETATION: At the dosage studied, celecoxib did not have a beneficial effect on research subjects with ALS, and it was safe. , INTERPRETATION\n\nAt the dosage studied, celecoxib did not have a beneficial effect on research subjects with ALS, and it was safe., RESULTS\n\nCelecoxib did not slow the decline in muscle strength, vital capacity, motor unit number estimates, ALS Functional Rating Scale-Revised, or affect survival., RESULTS\nCelecoxib did not slow the decline in muscle strength, vital capacity, motor unit number estimates, ALS Functional Rating Scale-Revised, or affect survival., INTERPRETATION: At the dosage studied, celecoxib did not have a beneficial effect on research subjects with ALS, and it was safe., RESULTS: Celecoxib did not slow the decline in muscle strength, vital capacity, motor unit number estimates, ALS Functional Rating Scale-Revised, or affect survival., At the dosage studied, celecoxib did not have a beneficial effect on research subjects with ALS, and it was safe., Celecoxib did not slow the decline in muscle strength, vital capacity, motor unit number estimates, ALS Functional Rating Scale-Revised, or affect survival.", "label": "no"}
{"id": "converted_2860", "sentence1": "Can CPX-351 be used for the treatment of tuberculosis?", "sentence2": "CPX-351 is a novel liposomal formulation of cytarabine and daunorubicin which has recently been FDA approved for treatment of acute myeloid leukemia (AML).", "label": "no"}
{"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.", "label": "no"}
{"id": "converted_3387", "sentence1": "Has ZP-PTH been tested in a phase II clinical trial?", "sentence2": "This system was successfully tested in a Phase 2 clinical trial for the treatment of post-menopausal women with osteoporosis.", "label": "yes"}
{"id": "converted_888", "sentence1": "Does replication timing affect the rate of somatic mutations?", "sentence2": "Here we observe that mutation rate, as reflected in recent evolutionary divergence and human nucleotide diversity, is markedly increased in later-replicating regions of the human genome, ll classes of substitutions are affected, suggesting a generalized mechanism involving replication time-dependent DNA damage, We show that mutation rate varies 6-fold across a single chromosome, that this variation is correlated with replication timing, and we propose a model to explain this variation that relies on the temporal separation of two processes for replicating past damaged DNA: error-free DNA damage tolerance and translesion synthesis., Recent studies revealed a long suspected replication-timing effect on mutation rate, but the mechanisms that regulate the increase in mutation rate as the genome is replicated remain unclear. , DNA repair systems, in general, are less efficient in late replicating heterochromatic regions compared to early replicating euchromatic regions of the genome., The mutational profile of the yeast genome is shaped by replication, the mutation rate increases with the replication timing by more than 30% between the earliest and the latest replicating regions., Thus, we show that the leading replicating strands present an excess of C over G and of A over T in the genome of S. cerevisiae (reciprocally an excess of G + T over C + A in lagging strands), Late-replicating domains have higher divergence and diversity in Drosophila melanogaster, Recent evidence also suggests that late replication is associated with high mutability in yeast., Limited evidence from one chromosome arm in Drosophila melanogaster suggests the opposite pattern, with regions overlapping early-firing origins showing increased levels of diversity and divergence, The mutation rate for DNA mismatch repair null strains was approximately 1 mutation per genome per generation, 225-fold greater than the wild-type rate. The mutations were distributed randomly throughout the genome, independent of replication timing., Many single-nucleotide substitutions in cancer genomes arise because of errors in DNA replication, which is spatio-temporally stratified., Here we propose that DNA replication patterns help shape the mutational landscapes of normal and cancer genomes, Using data on five fully sequenced cancer types and two personal genomes, we determined that the frequency of intergenic single-nucleotide substitution is significantly higher in late DNA replication timing regions, even after controlling for a number of genomic features, we found that genomic regions in close spatial proximity to late-replicating domains display similar mutation spectra as the late-replicating regions themselves, In addition, certain chromosome rearrangements found in cancer cells and in cells exposed to ionizing radiation display a significant delay in replication timing of >3 hours that affects the entire chromosome(2,3). Recent work from our lab indicates that disruption of discrete cis-acting autosomal loci result in an extremely late replicating phenotype that affects the entire chromosome(4)., A conservative estimate is that at least 1-2% of new deleterious mutations affect some aspect of DNA replication, repair, or chromosome segregation. Since deleterious mutations can have an effect even as heterozygotes, this mutation accumulation can create an inherited background of late-acting mutations that themselves enhance mutation rate., Drake calculates that lytic RNA viruses display spontaneous mutation rates of approximately one per genome while most have mutation rates that are approximately 0.1 per genome (Drake 1993). This constancy of germline mutation rates among microbial species need not necessarily mean constancy of the somatic mutation rates., A recent flurry of reports correlates replication timing (RT) with mutation rates during both evolution and cancer., DNA replication timing, genome stability and cancer: late and/or delayed DNA replication timing is associated with increased genomic instability., Since deleterious mutations can have an effect even as heterozygotes, this mutation accumulation can create an inherited background of late-acting mutations that themselves enhance mutation rate., In addition, this method allows for the unambiguous identification of chromosomal rearrangements that correlate with changes in replication timing that affect the entire chromosome.", "label": "yes"}
{"id": "converted_1900", "sentence1": "Has \"RNA interference\" been awarded Nobel prize?", "sentence2": "Since the first unequivocal description of RNA interference (RNAi) in 1998, it has remained one of the hottest topics under investigation, culminating in the award of a Nobel Prize to its discoverers in 2006., RNA interference (RNAi) is considered one of the most powerful genomic tools which allows the study of drug discovery and understanding of the complex cellular processes by high-content screens. This field of study, which was the subject of 2006 Nobel Prize of medicine, has drastically changed the conventional methods of analysis of genes.,  Almost 10 years after Fire and Mello received the Nobel Prize for the discovery of this mechanism in flat worms, RNA interference is on the edge of becoming a new class of therapeutics.", "label": "yes"}
{"id": "converted_1427", "sentence1": "Can cffDNA be used for non-invasive testing?", "sentence2": "Non-invasive prenatal testing using cell-free fetal DNA in maternal circulation, The identification of cell-free fetal DNA (cffDNA) in maternal circulation has made non-invasive prenatal testing (NIPT) possible., In recent years, technical advances in the molecular analysis of fetal DNA (e.g., digital PCR and massively parallel sequencing (MPS)) has enabled the successful implementation of noninvasive testing into clinical practice, such as fetal sex assessment, RhD genotyping, and fetal chromosomal aneuploidy detection.With the ability to decipher the entire fetal genome from maternal plasma DNA, we foresee that an increased number of non-invasive prenatal tests will be available for detecting many single-gene disorders in the near future. This review briefly summarizes the technical aspects of the NIPT and application of NIPT in clinical practice., First identified in 1997, cell-free fetal DNA (cffDNA) has just recently been used to detect fetal aneuploidy of chromosomes 13, 18, and 21, showing its potential to revolutionize prenatal genetic testing as a non-invasive screening tool, To determine how adults in the United States view non-invasive prenatal testing using cell-free fetal DNA (cffDNA testing) in order to help estimate uptake, Non-invasive prenatal testing of cell-free fetal DNA (cffDNA) in maternal plasma can predict the fetal RhD type in D negative pregnant women, The identification of cell-free fetal DNA (cffDNA) in maternal circulation has made non-invasive prenatal testing (NIPT) possible, The effectiveness and clinical utility of non-invasive prenatal diagnosis (NIPD) for fetal sex determination using cell-free fetal DNA (cffDNA) was assessed by undertaking a prospective national audit of UK testing, The recent release of new, non-invasive prenatal tests for fetal aneuploidy using cell-free fetal DNA (cffDNA) has been hailed as a revolution in prenatal testing and has triggered significant commercial interest in the field, Non-invasive prenatal aneuploidy testing that utilizes cell-free fetal DNA (cffDNA) circulating in maternal blood is one example of an innovative technology that promises significant benefits for its intended end users; however, it is currently uncertain whether it will achieve widespread clinical implementation, Analysis of cell free fetal (cff) DNA in maternal plasma is used routinely for non invasive prenatal diagnosis (NIPD) of fetal sex determination, fetal rhesus D status and some single gene disorders, Non-invasive prenatal diagnosis (NIPD) using cell-free fetal DNA (cffDNA) in maternal plasma is an alternative to invasive prenatal diagnosis (IPD), which carries a 1% risk of miscarriage. , The recent release of new, non-invasive prenatal tests for fetal aneuploidy using cell-free fetal DNA (cffDNA) has been hailed as a revolution in prenatal testing and has triggered significant commercial interest in the field. , The effectiveness and clinical utility of non-invasive prenatal diagnosis (NIPD) for fetal sex determination using cell-free fetal DNA (cffDNA) was assessed by undertaking a prospective national audit of UK testing. , NIFTY (Non-invasive Fetal Trisomy Test) is a non-invasive prenatal test which is used for diagnosing fetal trisomy. The test is based on the analysis of cell free fetal DNA (cffDNA) present in the plasma and serum of a pregnant woman., Using non-invasive method of cffDNAs in the shortest time possible, as well as avoiding invasive tests for early determination of fetal gender, provides the opportunity of deciding and employing early treatment for fetuses at risk of genetic diseases., The identification of cell-free fetal DNA (cffDNA) in maternal circulation has made non-invasive prenatal testing (NIPT) possible., To determine how adults in the United States view non-invasive prenatal testing using cell-free fetal DNA (cffDNA testing) in order to help estimate uptake., Nowadays, new advances in the use of cell free fetal DNA (cffDNA) in maternal plasma of pregnant women has provided the possibility of applying cffDNA in prenatal diagnosis as a non-invasive method., Non-invasive prenatal testing of cell-free fetal DNA (cffDNA) in maternal plasma can predict the fetal RhD type in D negative pregnant women., Prevention of contamination following our anti-contamination criteria is a good practice for certain non-invasive sex determination, using cffDNA.", "label": "yes"}
{"id": "converted_3527", "sentence1": "Does metformin alleviate atherosclerosis?", "sentence2": "Metformin and rosiglitazone both improve glycemic control in type 2 diabetes mellitus, however may possess different anti-inflammatory and anti-atherosclerotic properties. , Demonstrating antiatherothrombotic properties of dipeptidyl peptidase-4 inhibitors on proven markers is of substantial clinical significance. Coupled with their proven good safety profile these findings could translate into a significant clinical benefit., pleiotropic benefits of metformin in attenuation of atherosclerosis., Pleiotropic effects of metformin ameliorate atherosclerosis and vascular senescence., Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis., Metformin attenuated Ang-II-induced atheromatous plaque formation and aortic aneurysm in ApoE(-/-) mice partly by reducing monocyte infiltration., Metformin, an anti-diabetic drug, was reported to possess anti-atherosclerotic effects. , Combined use of metformin and atorvastatin attenuates atherosclerosis in rabbits fed a high-cholesterol diet.,  In cultured macrophages, co-treatment with metformin and atorvastatin promoted cholesterol efflux and up-regulated expression of ATP-binding cassette transporters A1 and G1. Taken together, our results suggest that atorvastatin/metformin combination therapy may achieve additional anti-atherosclerotic benefits likely through increasing cholesterol efflux in macrophages., Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission., metformin abated the progression of diabetes-accelerated atherosclerosis by inhibiting mitochondrial fission in endothelial cells., metformin attenuated the development of atherosclerosis by reducing Drp1-mediated mitochondrial fission in an AMPK-dependent manner. , metformin's effects on lipids and atherosclerotic vascular disease and/or provide insights into the drug's mechanisms of action on the heart and vasculature., Several recently completed randomized clinical trials have reported effects of metformin on surrogate measures of atherosclerotic vascular disease, Metformin treatment prevents SREBP2-mediated cholesterol uptake and improves lipid homeostasis during oxidative stress-induced atherosclerosis, Metformin ameliorates the progression of atherosclerosis via suppressing macrophage infiltration and inflammatory responses, Our results suggest that metformin impeded the progression of atherosclerosis, possibly by suppressing macrophage infiltration and inflammatory responses.", "label": "yes"}
{"id": "converted_2308", "sentence1": "Is there an RNAi drug being developed to treat amyloidosis?", "sentence2": "Patisiran is an investigational RNA interference (RNAi) therapeutic in development for the treatment of hereditary ATTR (hATTR) amyloidosis, a progressive disease associated with significant disability, morbidity, and mortality.", "label": "yes"}
{"id": "converted_3753", "sentence1": "Is Bcl-2-like protein 1 an pro apoptotic protein?", "sentence2": "Extensively established key effectors of such apoptotic bypass mechanisms, the antiapoptotic BCL-2 (apoptosis regulator BCL-2) proteins, determine the response of cancer cells to chemotherapeutics, decreasing the expression of anti-apoptotic factors, including apoptosis regulator Bcl-2 and Bcl-2-like protein 1 in FaDu cells, Like many cancers, TNBC cells often deregulate programmed cell death by upregulating anti-apoptotic proteins of the B-cell CLL/lymphoma 2 (Bcl-2) family.,  anti-apoptotic Bcl-2-like protein 1 (BCL2L1, Bcl-xL) ", "label": "no"}
{"id": "converted_4419", "sentence1": "Is Sotatercept effective for Pulmonary Arterial Hypertension?", "sentence2": "Sotatercept for the Treatment of Pulmonary Arterial Hypertension., CONCLUSIONS: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension., Sotatercept for the Treatment of Pulmonary Arterial Hypertension, CONCLUSIONS: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertensio, n hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest.CONCLUSIONS: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background t", "label": "yes"}
{"id": "converted_2449", "sentence1": "Is cilengitide effective for treatment of glioblastoma?", "sentence2": "RESULTS: fourteen randomized clinical trials were identified (7 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) including 4330 patients. Antiangiogenic drugs showed no improvement in overall survival with a pooled HR of 1.00, a trend for an inferior outcome, in terms of overall survival, was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR=1.24, p=0.056)., However, we could not conclusively confirm whether cilengitide 2000mg/5/week was the optimum regime, as only one trial using this protocol was included in our study., Cilengitide (CGT) is a cyclic pentapeptide that demonstrated efficacy for GBM treatment by targeting the integrins avβ3 and avβ5 over-expressed on GBM cells., Cilengitide is recently failed in Phase III CENTRIC trial in unselected patients with GBM., In conclusion, we demonstrate that EGFRvIII/integrin β3 complexes promote GBM progression and metastasis in the environment of hypoxia and vitronectin-enrichment, and cilengitide may serve as a promising therapeutics for EGFRvIII-positive GBMs., he addition of molecularly targeted drugs to TEM + RAD did not improve the OS of patients with GBM; however, it did improve PFS in patients treated by cilengitide who could not get improvement in OS. ,  The randomized phase III CENTRIC and phase II CORE trials explored the integrin inhibitor cilengitide in patients with newly diagnosed glioblastoma with versus without O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. These trials failed to meet their primary endpoints, . In CORE, higher αvβ3 levels in tumor cells were associated with improved progression-free survival by central review and with improved overall survival in patients treated with cilengitide., Cilengitide combined with metronomic temozolomide and procarbazine in MGMT-promoter unmethylated glioblastoma did not improve survival compared with historical data and does not warrant further investigation., The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug., Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression., It may be proposed that the combination therapy of NG2 suppression and cilengitide treatment showed no considerable effect on glioblastoma compared to cilengitide therapy alone.", "label": "no"}
{"id": "converted_2430", "sentence1": "Are splicing speckles associated with transcription?", "sentence2": "We show here that RNA splicing speckled domains (splicing speckles) fluctuate in constrained nuclear volumes and remodel their shapes., We present a model where recycling splicing factors return as part of small sub-speckles from distal sites of RNA processing to larger splicing speckles by a directed ATP-driven mechanism through interchromatin spaces., Analysis of a HeLa cell line stably expressing EYFP-NHPX showed that the nucleolar accumulation of NHPX was preceded by its transient accumulation in splicing speckles., In vivo analysis of NHPX reveals a novel nucleolar localization pathway involving a transient accumulation in splicing speckles., \"Splicing speckles\" are major nuclear domains rich in components of the splicing machinery and polyA(+) RNA. Although speckles contain little detectable transcriptional activity, they are found preferentially associated with specific mRNA-coding genes and gene-rich R bands, and they accumulate some unspliced pre-mRNAs, RNA polymerase II transcribes mRNAs and is required for splicing, with some reports suggesting that the inactive complexes are stored in splicing speckle, In normal cell growth conditions GFPeIF4A-III was mainly nucleoplasmic, but in hypoxia stress conditions it moved to the nucleolus and splicing speckles., Localization of eIF4A-III in the nucleolus and splicing speckles is an indicator of plant stress.,  Using antibodies raised against mouse RBM6 to immunostain mammalian cell lines we found that the endogenous protein was both distributed diffusely in the nucleus and concentrated in a small number of nuclear foci that corresponded to splicing speckles/interchromatin granule clusters (IGCs, Subnuclear targeting of the RNA-binding motif protein RBM6 to splicing speckles and nascent transcripts.", "label": "no"}
{"id": "converted_3620", "sentence1": "Are tumour specific antigens originating from known protein coding genes?", "sentence2": "It is well established that MHC class I molecules present peptides from endogenous proteins, such as virus or tumour antigens, to CD8+ T lymphocytes. , So far, human tumour specific antigens that can be presented by HLA molecules have not been identified on the molecular level., These CTLs recognize short peptides derived from tumour-associated antigens in conjunction with class I molecules expressed on tumour cells.,  The focus on cellular immune responses, combined with rapid biotechnological advances, resulted in the identification of tumour specific antigens, such as MART-1 and gp100, that could be recognised by autologous TIL,  Tumour antigens are mostly of weak immunogenicity, because the vast majority are tumour-associated differentiation antigens already 'seen' by the patient's immune system., Tumour-specific antigens, which could be a more potent target for immunotherapy, mostly arise by point mutations and have the disadvantage of being not only tumour-specific, but also individual-specific., The pioneering studies of Srivastava and colleagues led to the proposal that heat-shock proteins (HSPs) function as ubiquitous tumour-specific antigens, with the specificity residing in a population of bound peptides that identify the tissue of origin of the HSP., Therefore, we propose that CD4(+) T cells that recognize secreted TSA may be superior for immunotherapy by T cell transfer, because the local extracellular antigen concentration will be higher for secreted TSA. ,  Here, we wondered whether these frame-shifted peptide (FSP) sequences represent tumour-specific antigens also for MSI(+) leukaemia and lymphomas (L/L)., Data presented here expand the importance of FSPs as shared and general tumour-specific antigens.", "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)", "label": "yes"}
{"id": "converted_836", "sentence1": "Is there any functional association during viral replication between flaviviridae viral RNA depended RNA polymerase and viral helicase?", "sentence2": "Several labs have obtained evidence for a protein complex that involves many of the nonstructural (NS) proteins encoded by the virus. NS3, NS4A, NS4B, NS5A, and NS5B appear to interact structurally and functionally. In this study, we investigated the interaction between the helicase, NS3, and the RNA polymerase, NS5B. Pull-down experiments and surface plasmon resonance data indicate a direct interaction between NS3 and NS5B that is primarily mediated through the protease domain of NS3. This interaction reduces the basal ATPase activity of NS3. However, NS5B stimulates product formation in RNA unwinding experiments under conditions of excess nucleic acid substrate. When the concentrations of NS3 and NS5B are in excess of nucleic acid substrate, NS5B reduces the rate of NS3-catalyzed unwinding. Under pre-steady-state conditions, in which NS3 and substrate concentrations are similar, product formation increased in the presence of NS5B. The increase was consistent with 1:1 complex formed between the two proteins. A fluorescently labeled form of NS3 was used to investigate this interaction through fluorescence polarization binding assays. Results from this assay support interactions that include a 1:1 complex formed between NS3 and NS5B., Contradictory results have been reported regarding NS3 in RNA synthesis. To investigate the effect of NS3 on classical swine fever virus (CSFV) NS5B RNA-dependent RNA polymerase activity (RdRp) activity and NS3-NS5B interaction, RdRp reactions, GST-pull-down assays and co-immunoprecipitation analyses containing NS5B and either of NS3 protein and the different truncated NS3 mutants were performed, respectively. We found that NS3 stimulated NS5B RdRp activity in a dose-dependent manner by binding to NS5 through a NS3 protease domain. Furthermore, mapping important regions of the NS3 protease domain was carried out by deletion mutagenesis, associated with RdRp reactions, GST-pull-down assays and co-immunoprecipitation analyses. Results showed that stimulation of CSFV NS5B RdRp activity was obtained by NS3 binding to NS5B through a 31-amino acid fragment at the N-terminal end of NS3 protease domain, which mediated a specific NS3-NS5B interaction., The protocols detailed in this unit are used to purify three recombinant enzymes that are widely used in HCV research: the HCV NS3 protease domain, the helicase domain as an NS3+NS4A complex, and the NS5B RNA-dependent RNA polymerase. The active enzymes are purified to homogeneity by two-column chromatography to support a screening program for HCV inhibitors., Among potential targets are viral entry factors, including scavenger receptor type B1 (SR-B1) and CD81, as well as neutralizing antibodies against the viral glycoproteins. Popular targets related to translation and replication are the NS3/4A protease (inhibited by telaprevir and boceprevir) and the NS5B polymerase, as well as the NS2/3 autoprotease, the NS3 helicase, and nonenzymatic targets such as NS4B and NS5A proteins. , The NS3 helicase domain competes with NS3 full-length for NS5 RdRp binding, with a K(d.) of 2.5μM. Since NS3 and NS5 are required for DENV replication, this fascile assay could be used to screen for non-nucleoside, allosteric inhibitors that disrupt the interaction between the two proteins.", "label": "yes"}
{"id": "converted_2619", "sentence1": "Does SARM1 deletion cause neurodegeneration?", "sentence2": "Finally, using neurons from two distinct mutant mouse strains whose axons are highly resistant to neurodegeneration (Wld(S) and Sarm1(-/-)), we found that the three different fibrils were secreted by axons after anterograde transport, in the absence of axonal lysis, indicating that trans-neuronal spread can occur in intact healthy neurons.", "label": "no"}
{"id": "converted_2274", "sentence1": "Is autophagy modulated in a circadian fashion?", "sentence2": "TOR signaling pathway and autophagy are involved in the regulation of circadian rhythms in behavior and plasticity of L2 interneurons in the brain of Drosophila melanogaster.,  Our results indicate that the TOR signaling pathway and autophagy are involved in the regulation of circadian rhythms in the behavior and plasticity of neurons in the brain of adult flies., the pathways of autophagy, mTOR, SIRT1, and Wnt that control mammalian circadian rhythm, Metabolic pathways, bile acid synthesis, and autophagic and immune/inflammatory processes are driven by the biological clock. , our findings suggest that the clock geneBmal1is a positive regulator of autophagy through the mTOR signaling pathway and protects cardiomyocytes against high-glucose toxicity., Autophagy is a highly conserved intracellular degradation system, and recently was shown to display circadian rhythms in mice. ", "label": "yes"}
{"id": "converted_2008", "sentence1": "Is Meis1 implicated in microphthalmia?", "sentence2": "Meis1 coordinates a network of genes implicated in eye development and microphthalmia., Here we show that haploinsufficiency of Meis1, which encodes a transcription factor with evolutionarily conserved expression in the embryonic trunk, brain and sensory organs, including the eye, causes microphthalmic traits and visual impairment in adult mice., We propose that Meis1 is at the core of a genetic network implicated in eye patterning/microphthalmia, and represents an additional candidate for syndromic cases of these ocular malformations., We propose that Meis1 is at the core of a genetic network implicated in eye patterning/microphthalmia, and represents an additional candidate for syndromic cases of these ocular malformations., In the eye primordium, Meis1 coordinates, in a dose-dependent manner, retinal proliferation and differentiation by regulating genes responsible for human microphthalmia and components of the Notch signaling pathway., Meis1 coordinates a network of genes implicated in eye development and microphthalmia, We propose that Meis1 is at the core of a genetic network implicated in eye patterning/microphthalmia, and represents an additional candidate for syndromic cases of these ocular malformations. <CopyrightInformation>© 2015, In the eye primordium, Meis1 coordinates, in a dose-dependent manner, retinal proliferation and differentiation by regulating genes responsible for human microphthalmia and components of the Notch signaling pathway, We propose that Meis1 is at the core of a genetic network implicated in eye patterning/microphthalmia, and represents an additional candidate for syndromic cases of these ocular malformations. <CopyrightInformation>© 2015., In the eye primordium, Meis1 coordinates, in a dose-dependent manner, retinal proliferation and differentiation by regulating genes responsible for human microphthalmia and components of the Notch signaling pathway., Meis1 coordinates a network of genes implicated in eye development and microphthalmia.", "label": "yes"}
{"id": "converted_3432", "sentence1": "Is Dexmecamylamine effective for depression?", "sentence2": "At treatment end, no significant differences were seen for change in MADRS total score with TC-5214 versus placebo. Furthermore, there were no significant differences in any of the secondary endpoints. , TC-5214 (dexmecamylamine) is a nicotinic channel modulator that has previously been evaluated for treatment of major depression disorder (MDD) and is currently being evaluated by Targacept as a treatment for overactive bladder. , In these 2 flexibly-dosed studies, no specific therapeutic effects were observed for TC-5214 (1-4 mg BID) adjunct to antidepressant in the primary endpoint or any secondary endpoint; however, TC-5214 was generally well tolerated. In conclusion, no antidepressant effect of TC-5214 was observed in these studies., TC-5214 (dexmecamylamine) is a nicotinic channel modulator that has previously been evaluated for treatment of major depression disorder (MDD) and is currently being evaluated by Targacept as a treatment for overactive bladder., No notable differences were observed between dexmecamylamine and placebo for any secondary end point., TC-5214 ( dexmecamylamine ) is a nicotinic channel modulator that has previously been evaluated for treatment of major depression disorder ( MDD ) and is currently being evaluated by Targacept as a treatment for overactive bladder . , TC-5214 (dexmecamylamine) is a nicotinic channel modulator that has previously been evaluated for treatment of major depression disorder (MDD) and is currently being evaluated by Targacept as a treatment for overactive bladder., At treatment end, no significant differences were seen for change in MADRS total score with TC-5214 versus placebo., In these 2 flexibly-dosed studies, no specific therapeutic effects were observed for TC-5214 (1-4 mg BID) adjunct to antidepressant in the primary endpoint or any secondary endpoint; however, TC-5214 was generally well tolerated.", "label": "no"}
{"id": "converted_2930", "sentence1": "Do raspberries improve postprandial glucose and acute and chronic inflammation in adults with type 2 Diabetes?", "sentence2": "The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays a critical role in insulin resistance and the pathogenesis of type 2 diabetes. Red raspberry (RB) contains high amounts of dietary fibers and polyphenolic compounds, which are known for their anti-oxidative and anti-inflammatory effects. ", "label": "yes"}
{"id": "converted_3335", "sentence1": "Does BNN27 promote memory loss?", "sentence2": "The novel dehydroepiandrosterone (DHEA) derivative BNN27 counteracts delay-dependent and scopolamine-induced recognition memory deficits in rats., BNN27 is a novel 17C spiroepoxy-DHEA derivative, which devoid of steroidogenic activity. The neuroprotective effects of BNN27 have been recently reported. The present study was designed to investigate the effects of BNN27 on recognition memory in rats. For this purpose, the novel object task (NOT), a procedure assessing non-spatial recognition memory and the novel location task (NLT), a procedure evaluating spatial recognition memory were used. Intraperitoneal (i.p.) administration of BNN27 (3 and 10mg/kg) antagonized delay-dependent deficits in the NOT in the normal rat, suggesting that this DHEA derivative affected acquisition, storage and retrieval of information. In addition, BNN27 (3 and 10mg/kg, i.p.) counteracted the scopolamine [0.2mg/kg, subcutaneously (s.c.)]-induced non-spatial and spatial recognition memory deficits. These findings suggest that BNN27 may modulate different aspects of recognition memory, potentially interacting with the cholinergic system, relevant to cognition.", "label": "no"}
{"id": "converted_533", "sentence1": "Can a peptide aptamer be used as protein inhibitor?", "sentence2": "Peptide aptamers of LIM-only protein 2 (Lmo2) were previously used to successfully treat Lmo2-induced tumours in a mouse model of leukaemia., Inhibition of mammalian cell proliferation by genetically selected peptide aptamers that functionally antagonize E2F activity., Accumulating work over the past decade has shown that peptide aptamer screening represents a valid strategy for inhibitor identification that can be applied to a variety of different targets. , . The target of one inhibitor peptide, Pep80, identified in this screen was determined to be Snapin, a protein associated with the soluble N-ethyl maleimide sensitive factor adaptor protein receptor (SNARE) complex that is critical for calcium-dependent exocytosis during neurotransmission. , Use of the genetically selected intracellular aptamer inhibitors allowed us to define unique mechanisms important to HIV-1 replication and T cell biology., This review will describe pre-clinical and clinical data of four major classes of TGF-β inhibitor, namely i) ligand traps, ii) antisense oligonucleotides, iii) receptor kinase inhibitors and iv) peptide aptamers. ,  A peptide aptamer (ID1/3-PA7) has been designed to prevent this interaction and thereby leading to the transcription of p16(INK4a)., A peptide kinase inhibitor (IP(20)) was used as the aptameric peptide , Peptide aptamer mimicking RAD51-binding domain of BRCA2 inhibits DNA damage repair and survival in Trypanosoma brucei.,  peptide aptamer, Id1/3-PA7, targeting Id1 and Id3,, Targeting Id1 and Id3 by a specific peptide aptamer induces E-box promoter activity, cell cycle arrest, and apoptosis in breast cancer cells., Aptamer-derived peptides as potent inhibitors of the oncogenic RhoGEF Tgat., Our approach thus demonstrates that peptide aptamers are potent inhibitors that can be used to interfere with RhoGEF functions in vivo., Development of systemic in vitro evolution and its application to generation of peptide-aptamer-based inhibitors of cathepsin E., he fusion peptide, TA aptamer, was observed within PC12 cytoplasm and maintained both Abeta-binding ability and antioxygenic property similar to TRX., Stable expression of a novel fusion peptide of thioredoxin-1 and ABAD-inhibiting peptide protects PC12 cells from intracellular amyloid-beta., In order to efficiently select aptamers that bind to and inhibit proteins,, Aptamer selection based on inhibitory activity using an evolution-mimicking algorithm., This demonstrates the utility of this strategy for screening aptamers based on their inhibitory actions., Intracellular expression of the DRD-binding peptide aptamer specifically suppressed receptor-mediated extrinsic apoptosis but not intrinsic pathway, which was recapitulated by the antisense oligonucleotides for FLASH. , Peptide aptamers are peptides constrained and presented by a scaffold protein that are used to study protein function in cells. They are able to disrupt protein-protein interactions , Here we have used a genetic screen in yeast to select in vivo peptides coupled to thioredoxin, called aptamers, that could inhibit GEFD2 activity. One aptamer, TRIAPalpha (TRio Inhibitory APtamer), specifically blocks GEFD2-exchange activity on RhoA in vitro., These results show that cell proliferation can be inhibited using genetically-selected synthetic peptides that specifically target protein-protein interaction motifs within cell cycle regulators., These data highlight the utility of peptide aptamers to identify novel binding interfaces and highlight a role for MAP1B in DAPK-1-dependent signaling in autophagy and membrane blebbing.", "label": "yes"}
{"id": "converted_3047", "sentence1": "Is there any approved treatment for NAFLD?", "sentence2": "Non-alcoholic fatty liver disease (NAFLD) is the leading chronic hepatic condition worldwide and new approaches to management and treatment are limited., Non-alcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide, reflecting the epidemic of global obesity. Those with the progressive variant of NAFLD, non-alcoholic steatohepatitis (NASH), are at significantly increased risk of multisystem morbidity and mortality. However, there are currently no approved pharmacologic therapies for NASH., Although much progress has been made in enhancing our understanding of NAFLD pathogenesis, development of pharmacologic treatments has been hindered by challenges in clinical trial enrollment and complexities in clinical trial design. , Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy., Nonalcoholic fatty liver disease (NAFLD) has an increasing prevalence worldwide. At present, no specific pharmacotherapy is approved for NAFLD. ", "label": "no"}
{"id": "converted_1562", "sentence1": "Is abdominal pain a common symptom in autism?", "sentence2": "Participants included 132 children with ASD and 81 with special educational needs (SEN) but no ASD, aged 10-14 years plus 82 typically developing (TD) children, The ASD group had significantly increased past vomiting and diarrhoea compared with the TD group and more abdominal pain than the SEN group, Many children with autism spectrum disorders (ASDs) suffer from gastrointestinal problems such as diarrhoea, constipation and abdominal pain, Children with autism spectrum disorders (ASD) experience high rates of anxiety, sensory processing problems, and gastrointestinal (GI) problems, The results indicate that anxiety, sensory over-responsivity and GI problems are possibly interrelated phenomenon for children with ASD, and may have common underlying mechanisms., Lactase deficiency not associated with intestinal inflammation or injury is common in autistic children and may contribute to abdominal discomfort, pain and observed aberrant behavior., Autistic behavior is often accompanied by numerous disturbing symptoms on the part of gastrointestinal system, such as abdominal pain, constipation or diarrhea., Information on children's stool patterns and gut symptoms collected by questionnaire at 4 weeks and at 6, 18, 30 and 42 months of age were available for 12,984 children from the Avon Longitudinal Study of Parents and Children (ALSPAC), Comparison of the ASD and control group during the first 3.5 years of life showed no major differences in stool colour or consistency, or in frequency of diarrhoea, constipation, bloody stools or abdominal pain., Constipation is a frequent finding in children with gastrointestinal symptoms and autism, particularly in the rectosigmoid colon, often with acquired megarectum. The absence of any correlation between the clinical history and the degree of fecal impaction in autistic children confirms the importance of an abdominal radiograph in the assessment of their degree of constipation., In a sample of 137 children, age 24-96 months, classified as having autism or ASD by the Autism Diagnostic Observation Schedule-Generic, 24 percent had a history of at least one chronic gastrointestinal symptom. The most common symptom was diarrhea, which occurred in 17 percent.", "label": "yes"}
{"id": "converted_227", "sentence1": "Can DNA intercalators function as topoisomerase inhibitors?", "sentence2": "The aporphine alkaloids (+)-dicentrine and (+)-bulbocapnine are non-planar molecules lacking features normally associated with DNA binding by intercalation or minor groove binding. Surprisingly, dicentrine showed significant activity as a topoisomerase II (EC 5.99.1.3) inhibitor and also was active in a DNA unwinding assay., The DNA unwinding suggests DNA intercalation, which could explain the inhibition of topoisomerase II., We found that several agents, including adriamycin (a DNA intercalator and inhibitor of topoisomerase II), Amsacrine, a DNA intercalator and topoisomerase II inhibitor, is efficacious as an antileukemogenic agent., Quinacrine was less effective. (ii) Inhibitors intercalating and binding to the 'cleavable' DNA-topoisomerase complex (m-AMSA, mitoxantrone, doxorubicin and daunorubicin) strongly suppressed reparative DNA incision. , DNA intercalation and inhibition of topoisomerase II., Among its many properties, amiloride is a DNA intercalator and topoisomerase II inhibitor., To determine whether the ability of amiloride to intercalate into DNA and to inhibit DNA topoisomerase II was dependent on the ability to assume a cyclized conformation, we studied the structure-activity relationship for 12 amiloride analogs, Empirical assays consisting of biophysical, biochemical, and cell biological approaches, as well as computational molecular modeling approaches, were used to determine conformational properties for these molecules, and to determine whether they intercalated into DNA and inhibited topoisomerase II. , Results indicated that only those analogs capable of cyclization could intercalate into DNA and inhibit topoisomerase II. Thus, the ability of amiloride and the 12 analogs studied to intercalate into DNA and to inhibit topoisomerase II appears dependent on the ability to exist in a planar, hydrogen-bonded, tricyclic conformation., Abnormal expression of the nuclear-associated enzyme DNA topoisomerase II (topoisomerase II) has been implicated in the in vitro phenotype of radiation hypersensitive ataxia-telangiectasia (A-T) cells and in modifying sensitivity of eukaryotic cells to topoisomerase II-inhibitor drugs [e.g., the DNA intercalator amsacrine (mAMSA)]. , All three tested anthraquinones, emodin, aloe-emodin, and danthron, showed capabilities to inhibit the non-covalent binding of bisbenzimide Hoechst 33342 to isolated DNA and in mouse lymphoma L5178Y cells comparable to the topoisomerase II inhibitor and intercalator m-amsacrine., These studies suggest that AD 288 inhibits topoisomerase II activity by preventing the initial non-covalent binding of topoisomerase II to DNA. Since AD 288 is a potent DNA intercalator, catalytic inhibition is achieved by prohibiting access of the enzyme to DNA binding sites. , AQ4N (1,4-bis[[2-(dimethylamino)ethyl] amino]-5,8-dihydroxyanthracene-9, 10-dione bis-N-oxide dihydrochloride) is a prodrug which is selectively activated within hypoxic tissues to AQ4, a topoisomerase II inhibitor and DNA intercalator., Amonafide is a DNA intercalator and topoisomerase II inhibitor in clinical development for the treatment of neoplastic diseases.,  We found that three compounds had similar cancer cell-selective growth inhibition to amonafide, while retaining similar subcellular localization, DNA intercalation and topoisomerase II inhibition activities., Amonafide is a novel topoisomerase II (Topo II) inhibitor and DNA intercalator that induces apoptotic signaling by blocking the binding of Topo II to DNA., At higher concentrations, inhibition of Top1 catalytic activity and DNA intercalation is observed., Design, synthesis and biological evaluation of new oligopyrrole carboxamides linked with tricyclic DNA-intercalators as potential DNA ligands or topoisomerase inhibitors., It was found that 1) morpholinyldoxorubicin, cyanomorpholinyldoxorubicin, and Actinomycin D (but not doxorubicin) stimulated DNA topoisomerase I-induced cleavage at specific DNA sites; 2) only doxorubicin and Actinomycin D stimulated DNA cleavage by DNA topoisomerase II; 3) at higher drug concentrations, DNA intercalators suppressed enzyme-mediated DNA cleavage induced by DNA topoisomerase I, as well as topoisomerase II; 4) only cyanomorpholinyldoxorubicin produced DNA-DNA cross-links; no DNA unwinding could be observed; and 5) DNA intercalation (unwinding) potency of morpholinyldoxorubicin was about 2-fold less than that of doxorubicin., The data indicate that some DNA intercalators are not only inhibitors of DNA topoisomerase II but act also on DNA topoisomerase I., The screen of cMAP for uncharacterized drugs indicated the signature of Epoxy anthraquinone derivative (EAD) matched the profiles of multiple known DNA targeted agents (topoisomerase I/II inhibitors, DNA intercalators, and DNA alkylation agents) as predicted by its structure., Cytotoxicity of several classes of antitumor DNA intercalators is thought to result from disturbance of DNA metabolism following trapping of the nuclear enzyme DNA topoisomerase II as a covalent complex on DNA., Most DNA intercalators and epipodophyllotoxins inhibit mammalian topoisomerase II by trapping the enzyme within DNA cleavage complexes that can be detected in cells as protein-associated DNA strand breaks., Many compounds capable of inhibiting DNA topoisomerase II are DNA intercalators., Numerous topoisomerase I poisons including DNA minor groove binders such as Hoechst 33258 and DNA intercalators such as benzophenanthridine alkaloids and indolocarbazole derivatives have been discovered and developed., The stabilization of cleavage intermediates by intercalators may have a common mechanism for DNA topoisomerase I and DNA topoisomerase II., Because structurally related antitumor alkaloids such as camptothecin and fagaronine are known to function as intercalative topoisomerase poisons, it is hypothesized that cytotoxic Stauranthus alkaloids may also serve as intercalative topoisomerase inhibitors., Taken together, our results suggest that much of the activity and specificity of m-AMSA as a topoisomerase II poison is embodied in the headgroup, while DNA intercalation is used primarily to increase the affinity of m-AMSA for the topoisomerase II-DNA cleavage complex., The cross-sensitivity patterns of the mutant were examined for covalently (anthramycin) and non-covalently (distamycin A) binding minor groove ligands, and DNA intercalating [adriamycin, mitoxantrone and 4'-(9-acridinylamino)methanesulphon-m-anisidide (mAMSA)] and non-intercalating (VP16-213) topoisomerase II poisons., Quinoline alkaloids as intercalative topoisomerase inhibitors., DNA intercalation and inhibition of topoisomerase II. Structure-activity relationships for a series of amiloride analogs., These include: (i) the production of improved topoisomerase inhibitors (by consideration of drug/protein as well as drug/DNA interactions); (ii) the development of reductively-activated chromophores as hypoxia-selective agents; and (iii) the use of DNA-intercalators of known DNA binding orientation as 'carriers' for the delivery of other reactive functionality specifically (sequence-, regio- and site-specifically) to DNA., Indolo[2,3-b]quinolines are a family of DNA intercalators and inhibitors of topoisomerase II, synthetic analogs of neocryptolepine, an alkaloid traditionally used in African folk medicine., Their ability to function as bis-intercalators was assessed by a novel and convenient topoisomerase fluorescent assay., Structure-activity relationship of polypyridyl ruthenium(II) complexes as DNA intercalators, DNA photocleavage reagents, and DNA topoisomerase and RNA polymerase inhibitors., In addition, fragments of about 900 kbp were detected in the cells treated with a topoisomerase inhibitor, 4'-(9-acridinylamino)methane-sulfon-m-anisidine, and fragments in the broad size range between 700 and 245 kbp in the cells treated with radical producers, bleomycin and neocarzinostatin. , The data indicate that some DNA intercalators are not only inhibitors of DNA topoisomerase II but act also on DNA topoisomerase I. , Long-term inhibition of DNA synthesis and the persistence of trapped topoisomerase II complexes in determining the toxicity of the antitumor DNA intercalators mAMSA and mitoxantrone., Effects of the DNA intercalators 4'-(9-acridinylamino)methanesulfon-m-anisidide and 2-methyl-9-hydroxyellipticinium on topoisomerase II mediated DNA strand cleavage and strand passage., Most DNA intercalators and epipodophyllotoxins inhibit mammalian topoisomerase II by trapping the enzyme within DNA cleavage complexes that can be detected in cells as protein-associated DNA strand breaks. , Here, molecular interactions of the potent antitumor drug amsacrine (m-AMSA), an inhibitor of topoisomerase II, within living K562 cancer cells have been studied using surface-enhanced Raman (SER) spectroscopy. , It has been shown previously that DNA intercalators can inhibit the action of amsacrine and several other topoisomerase II poisons, presumably as a result of interference with the DNA binding sites for the enzyme. , The gadd153 promoter was strongly activated by a broad spectrum of genotoxic agents including UV-mimetic agents, DNA-cross-linking and alkylating agents, DNA intercalators, and topoisomerase inhibitors. , Our study indicates that Epoxy anthraquinone derivative may be a novel DNA topoisomerase inhibitor that can be potentially used for treatment of neuroblastoma or other cancer patients., Organic intercalators can inhibit nucleic acid synthesis in vivo, and they are now common anticancer drugs in clinical therapy. , Because structurally related antitumor alkaloids such as camptothecin and fagaronine are known to function as intercalative topoisomerase poisons, it is hypothesized that cytotoxic Stauranthus alkaloids may also serve as intercalative topoisomerase inhibitors., Specifically, we measured the ability of these compounds to 1) alter the thermal denaturation profile of DNA, 2) modify the hydrodynamic behavior of DNA, 3) inhibit the catalytic activity of purified DNA topoisomerase II in vitro, 4) promote the topoisomerase II-dependent cleavage of DNA, and 5) inhibit functions associated with DNA topoisomerase II in intact cells. Results indicated that only those analogs capable of cyclization could intercalate into DNA and inhibit topoisomerase II., A function for topoisomerases I and II in DNA excision repair can be postulated from the organization of the mammalian chromosome, involving nucleosomal structures and matrix-attached DNA loops. To analyse this function we determined UV-induced DNA incision in confluent human fibroblasts in the presence of 16 inhibitors of topoisomerases I and II which belonged to at least five different drug categories, based on their mechanism of action., In experiments to determine the mechanism of inhibition of DNA synthesis by amiloride, we observed that amiloride inhibited both the catalytic activity of purified DNA topoisomerase II in vitro and DNA topoisomerase II-dependent cell functions in vivo. Many compounds capable of inhibiting DNA topoisomerase II are DNA intercalators., The pyridoacridines&apos; ability to inhibit TOPO II-mediated decatenation of kDNA correlated with their cytotoxic potencies and their ability to intercalate into calf thymus DNA. These results suggest that disruption of the function of TOPO II, subsequent to intercalation, is a probable mechanism by which pyridoacridines inhibit the proliferation of HCT cells., Evidence for DNA intercalation by AD41 is provided by the observation that the drug introduces positive supercoils into covalently closed plasmid DNA. Based on these data, a hypothesis is proposed that would provide a general mechanism whereby intercalating agents and epipodophyllotoxins alter topoisomerase function and presumably exert their antitumor effects., Therefore, to more fully analyze structure-function relationships and the role of DNA binding in the action of m-AMSA, we analyzed a series of derivatives for the ability to enhance DNA cleavage mediated by human topoisomerase IIα and topoisomerase IIβ and to intercalate DNA. Results indicate that the 3&apos;-methoxy (m-AMSA) positively affects drug function, potentially by restricting the rotation of the headgroup in a favorable orientation.", "label": "yes"}
{"id": "converted_1477", "sentence1": "Does HuR protein regulate the splicing process?", "sentence2": "HuR and TIA1/TIAL1 are involved in regulation of alternative splicing of SIRT1 pre-mRNA, Here we describe experiments showing that HuR and TIA1/TIAL1, two kinds of RNA-binding proteins, were involved in the regulation of alternative splicing of SIRT1 pre-mRNA under normal and stress circumstances, HuR increased SIRT1-∆Exon8 by promoting SIRT1 exon 8 exclusion, whereas TIA1/TIAL1 inhibition of the exon 8 exclusion led to a decrease in SIRT1-∆Exon8 mRNA levels. , HuR regulates alternative splicing of the TRA2β gene in human colon cancer cells under oxidative stress, Hu antigen R (HuR) regulates stress responses through stabilizing and/or facilitating the translation of target mRNAs, We show here that the RBP embryonic lethal abnormal vision like 1 (ELAVL1, also know as HuR) regulates the alternative splicing of eukaryotic translation initiation factor 4E nuclear import factor 1 (Eif4enif1), which encodes an eukaryotic translation initiation factor 4E transporter (4E-T) protein and suppresses the expression of capped mRNAs, Further, endothelial-specific Elavl1 knockout mice exhibited reduced revascularization after hind limb ischemia and tumor angiogenesis in oncogene-induced mammary cancer, resulting in attenuated blood flow and tumor growth, respectively. , Changes in cellular mRNA stability, splicing, and polyadenylation through HuR protein sequestration by a cytoplasmic RNA virus, Furthermore, significant changes can be observed in nuclear alternative polyadenylation and splicing events on cellular pre-mRNAs as a result of sequestration of HuR protein by the 3' UTR of transcripts of this cytoplasmic RNA virus., Here we demonstrate that expression of 2A(pro) induces a selective nucleo-cytoplasm translocation of several important RNA binding proteins and splicing factors. Subcellular fractionation studies, together with immunofluorescence microscopy revealed an asymmetric distribution of HuR and TIA1/TIAR in 2A(pro) expressing cells, which modulates splicing of the human Fas exon 6, knockdown of HuR or overexpression of TIA1/TIAR, leads to Fas exon 6 inclusion in 2A(pro)-expressing cells, The differential expression levels of T-cell intracellular antigens (TIA) and Hu antigen R (HuR) are concomitant with a splicing switch in apoptosis receptor Fas in HCT-116 cells, overexpression and knockdown of HuR led to Fas exon 6 skipping and inclusion, respectively. These results suggest that the TIA and HuR cellular ratio influences cell-type specific Fas exon 6 splicing pattern., Hu antigen R (HuR) functions as an alternative pre-mRNA splicing regulator of Fas apoptosis-promoting receptor on exon definition, antiapoptotic regulator Hu antigen R (HuR, ELAVL1), a member of the embryonic lethal, abnormal vision, Drosophila-like (ELAVL) family, promotes Fas exon 6 skipping by binding to an exonic splicing silencer, 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., The HuR protein regulates the expression of thousands of cellular transcripts by modulating mRNA splicing, trafficking, translation, and stability., Hu antigen R (HuR) functions as an alternative pre-mRNA splicing regulator of Fas apoptosis-promoting receptor on exon definition., I report that antiapoptotic regulator Hu antigen R (HuR, ELAVL1), a member of the embryonic lethal, abnormal vision, Drosophila-like (ELAVL) family, promotes Fas exon 6 skipping by binding to an exonic splicing silencer. , Changes in cellular mRNA stability, splicing, and polyadenylation through HuR protein sequestration by a cytoplasmic RNA virus., Further, the silencing capacity of HuR as splicing regulator resides in the RRM1 and hinge-RRM3 domains. , HuR and TIA1/TIAL1 are involved in regulation of alternative splicing of SIRT1 pre-mRNA., HuR regulates alternative splicing of the TRA2β gene in human colon cancer cells under oxidative stress., The HuR protein regulates the expression of thousands of cellular transcripts by modulating mRNA splicing, trafficking, translation, and stability. , Further, the silencing capacity of HuR as splicing regulator resides in the RRM1 and hinge-RRM3 domains. Taken together, these results support a functional link between HuR as repressor of alternative Fas splicing and the molecular mechanisms modulating programmed cell death., We are interested in interactions involving hnRNP proteins participating in several steps of mRNA processing (mainly pre-mRNA splicing) and HuR with an established role in stability/translation of associated mRNAs. hnRNP and HuR proteins have a major nucleoplasmic localization and ability to shuttle between nucleus and cytoplasm. We report here on interactions between hnRNP and HuR proteins that were identified in the context of isolated hnRNP and mRNP complexes. , Despite the fact that HuR sites are observed in intronic regions, our data do not support a role for HuR in regulating splicing.", "label": "yes"}
{"id": "converted_2571", "sentence1": "Can gas vesicles be detected by ultrasound?", "sentence2": "Gas vesicles-genetically encoded protein nanostructures isolated from buoyant photosynthetic microbes-have recently been identified as nanoscale reporters for ultrasound., Here, we demonstrate that genetic engineering of gas vesicles results in nanostructures with new mechanical, acoustic, surface, and functional properties to enable harmonic, multiplexed, and multimodal ultrasound imaging as well as cell-specific molecular targeting. ", "label": "yes"}
{"id": "converted_4011", "sentence1": "Are there small molecule CGRPs under development for the treatment of migraine?", "sentence2": "Meanwhile, 1 small-molecule CGRP receptor antagonist (ubrogepant, MK-1602) is currently in phase 3 studies for the acute treatment of migraine., Several other small-molecular CGRP receptor antagonists are in earlier stages of development for acute migraine treatment or prevention. ", "label": "yes"}
{"id": "converted_2617", "sentence1": "Is there a link between nuclear position and DNA repair pathway choice?", "sentence2": "Nuclear position dictates DNA repair pathway choice., We demonstrate that DSBs induced at the nuclear membrane (but not at nuclear pores or nuclear interior) fail to rapidly activate the DNA damage response (DDR) and repair by homologous recombination (HR). Real-time and superresolution imaging reveal that DNA DSBs within lamina-associated domains do not migrate to more permissive environments for HR, like the nuclear pores or the nuclear interior, but instead are repaired in situ by alternative end-joining. Our results are consistent with a model in which nuclear position dictates the choice of DNA repair pathway, thus revealing a new level of regulation in DSB repair controlled by spatial organization of DNA within the nucleus., Our results are consistent with a model in which nuclear position dictates the choice of DNA repair pathway, thus revealing a new level of regulation in DSB repair controlled by spatial organization of DNA within the nucleus., Nuclear position dictates DNA repair pathway choice., Our results are consistent with a model in which nuclear position dictates the choice of DNA repair pathway, thus revealing a new level of regulation in DSB repair controlled by spatial organization of DNA within the nucleus.", "label": "yes"}
{"id": "converted_996", "sentence1": "Has Revlimid been approved by the US Food and Drug Administration?", "sentence2": "In the past decade, immunomodulatory drugs have been approved by the US Food and Drug Administration for the treatment of multiple myeloma (MM)-and a number of emerging agents that target the cellular pathways or proteins involved in the pathophysiology of MM are currently in development. Lenalidomide (Revlimid) and pomalidomide induce apoptosis and sensitize MM cells while demonstrating superior efficacy and better tolerability than thalidomide (Thalomid)., In the past decade we have seen four new agents approved by the US Food and Drug Administration for treatment of multiple myeloma: the proteasome inhibitor (PI) bortezomib (Velcade), the immunomodulatory agents lenalidomide (Revlimid) and thalidomide (Thalomid), and liposomal doxorubicin. , In the past decade we have seen four new agents approved by the US Food and Drug Administration for treatment of multiple myeloma: the proteasome inhibitor (PI) bortezomib (Velcade), the immunomodulatory agents lenalidomide (Revlimid) and thalidomide (Thalomid), and liposomal doxorubicin., Thalidomide, lenalidomide (Revlimid), and bortezomib (Velcade) are directed not only at MM cells but also at the BM milieu and have moved rapidly from the bench to the bedside and United States Food and Drug Administration approval to treat MM., Lenalidomide (CC-5013, Revlimid; Celgene Corporation, Summit, NJ), a thalidomide analogue, was granted approval by the U.S. Food and Drug Administration (FDA) on June 29, 2006, for use in combination with dexamethasone in patients with multiple myeloma (MM) who have received at least one prior therapy., Lenalidomide, an IMiD drug (a novel type of immunomodulating drug) was recently approved by the US Food and Drug Administration for the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes (MDS) and interstitial deletions of chromosome 5q [del(5q)], Lenalidomide, a second-generation immunomodulatory drug (IMiD), is approved by the US Food and Drug Administration for treatment of transfusion-dependent anemia in lower-risk MDS patients with deletion 5q chromosomal abnormality, In the past decade we have seen four new agents approved by the US Food and Drug Administration for treatment of multiple myeloma: the proteasome inhibitor (PI) bortezomib (Velcade), the immunomodulatory agents lenalidomide (Revlimid) and thalidomide (Thalomid), and liposomal doxorubicin., lenalidomide (CC5103 or revlimid) are recently approved for the treatment of multiple myeloma.,  In the past decade, immunomodulatory drugs have been approved by the US Food and Drug Administration for the treatment of multiple myeloma (MM)-and a number of emerging agents that target the cellular pathways or proteins involved in the pathophysiology of MM are currently in development. Lenalidomide (Revlimid) and pomalidomide induce apoptosis and sensitize MM cells while demonstrating superior efficacy and better tolerability than thalidomide (Thalomid).", "label": "yes"}
{"id": "converted_3060", "sentence1": "Does the interaction of MOV10 and RNASEH2 promote L1 retrotransposition?", "sentence2": "Interplay between RNASEH2 and MOV10 controls LINE-1 retrotransposition., We show that MOV10 interacts with RNASEH2, and their interplay is crucial for restricting L1 retrotransposition. , Furthermore, we show that RNASEH2-MOV10-mediated L1 restriction downregulates expression of the rheumatoid arthritis-associated inflammatory cytokines and matrix-degrading proteinases in synovial cells, implicating a potential causal relationship between them and disease development in terms of disease predisposition.", "label": "no"}
{"id": "converted_3408", "sentence1": "Is cathepsin L active in endosomes?", "sentence2": "Cathepsin L in the Late Endosome/Lysosome, endosomal cathepsin L, Immunofluorescence and immunoblotting investigations revealed the presence of cathepsin L in the nuclear compartment in addition to its expected endo-lysosomal localization in colorectal carcinoma cells., cleavage by the endosomal/lysosomal protease cathepsin L", "label": "yes"}
{"id": "converted_4535", "sentence1": "Is there a way to distinguish COVID-19 clinically from other respiratory illnesses, particularly influenza?", "sentence2": "Findings indicate that clinical symptoms alone would be insufficient to distinguish between coronavirus disease 2019 and other respiratory infections (eg, influenza) and/or to evaluate the effects of preventive interventions (eg, vaccinations)., Our reasoning highlights how challenging a balanced approach to a patient with fever and flu-like symptoms can be. At present, clinical workup of COVID-19 remains a hard task to accomplish., In our retrospective cohort study comparing the clinical presentation of COVID-19 and other respiratory viral infections, we found that anosmia and dysgeusia were symptoms independently associated with COVID-19 and can be important differentiating symptoms in patients presenting with acute respiratory illness. On the other hand, laboratory abnormalities and radiological findings were not statistically different between the two groups., COVID-19 has a similar pattern of infection, clinical symptoms, and chest imaging findings to influenza pneumonia., Here, we hypothesize the order of symptom occurrence could help patients and medical professionals more quickly distinguish COVID-19 from other respiratory diseases, yet such essential information is largely unavailable, It is difficult to distinguish coronavirus disease-2019 (COVID-19) from other viral respiratory tract infections owing to the similarities in clinical and radiological findings.", "label": "no"}
{"id": "converted_1599", "sentence1": "Is there any protein that undergoes both mono-ubiquitination and poly-ubiquitination?", "sentence2": "The yeast G protein alpha subunit Gpa1 represents a rare example of a protein that undergoes both mono- and poly-ubiquitination. , Expression of p34 promotes PTEN poly-ubiquitination, leading to PTEN protein degradation, whereas p34 knockdown results in PTEN mono-ubiquitination., These fingers possess E3 activities of mono-ubiquitination and poly-ubiquitination, respectively, with ubiquitin-conjugating enzyme (E2)-binding capabilities. , Instead of promoting poly-ubiquitination and degradation, we show that Smurf2 actually induces multiple mono-ubiquitination of Smad3 in vivo., mono-ubiquitination of CIITA dramatically increases its transactivity whereas poly-ubiquitination leads to CIITA degradation., This leads to a model in which Lys134 of LDB1 can be either mono-ubiquitinated, leading to stabilization, or poly-ubiquitinated, leading to degradation by the proteasome pathway. ,  mono-ubiquitination of CIITA increases its transactivity, whereas poly-ubiquitination of CIITA leads to its degradation, PS1 ubiquitination after PI3K inhibition is represented by the multiple mono-ubiquitination, instead of poly-ubiquitination, Our observations support a novel functional relationship between parkin and Hsc/Hsp70 and support the notion that parkin is a multi-purpose E3 ubiquitin ligase capable of modifying proteins either via attachment of alternatively linked poly-ubiquitin chains or through multiple mono-ubiquitination to achieve alternate biological outcomes, our results indicate that Hsp70 facilitates CHIP-mediated poly-ubiquitination of Smad1 whereas it attenuates CHIP-meditated mono-ubiquitination of Smad1., Whereas poly-ubiquitination targets protein substrates for proteasomal degradation, mono-ubiquitination is known to regulate protein trafficking in the endosomal system and to target cargo proteins for lysosomal degradation., Our results suggest that oxidative stress induces not only poly-ubiquitination but also mono-ubiquitination of LDH-A, which may be involved in its lysosomal degradation during unloading., wild type Smad4 is a relatively stable protein that undergoes mono- or oligo-ubiquitination, a modification not linked to protein degradation, These data suggest that oligo-ubiquitination positively regulates Smad4 function, whereas poly-ubiquitination primarily occurs in unstable cancer mutants and leads to protein degradation., We found that Ro52 was strongly conjugated by a single molecule of ubiquitin in cells. Although the biological relevance of this mono-ubiquitination was not defined, the function of Ro52 might be modified by the mono-ubiquitination. We also found that Ro52 was conjugated with poly-ubiquitin chain in cells (poly-ubiquitination)", "label": "yes"}
{"id": "converted_47", "sentence1": "Is Weaver syndrome similar to Sotos?", "sentence2": "Overgrowth conditions are a heterogeneous group of disorders characterised by increased growth and variable features, including macrocephaly, distinctive facial appearance and various degrees of learning difficulties and intellectual disability. Among them, Sotos and Weaver syndromes are clinically well defined and due to heterozygous mutations in NSD1 and EZH2, respectively. NSD1 and EZH2 are both histone-modifying enzymes, NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key roles in the regulation of transcription through histone modification and chromatin modeling: NSD1 preferentially methylates lysine residue 36 of histone 3 (H3K36) and is primarily associated with active transcription, while EZH2 shows specificity for lysine residue 27 (H3K27) and is associated with transcriptional repression, Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap, Clinically, Weaver syndrome is closely related to Sotos syndrome, which is frequently caused by mutations in NSD1, Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia., Thus, it is not surprising that prenatal overgrowth occurs in several syndromes, including the Sotos and Weaver syndromes., NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes., We conclude therefore that NSD1 mutations account for most cases of Sotos syndrome and a significant number of Weaver syndrome cases in our series., We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes., Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia, NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes, We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes, Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. , Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes.,  Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia. Two previous cases of neuroblastoma have been reported in children with Weaver syndrome., Weaver syndrome is closely related to Sotos syndrome,, Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia., Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident., Clinically, Weaver syndrome is closely related to Sotos syndrome, which is frequently caused by mutations in NSD1.", "label": "yes"}
{"id": "converted_4219", "sentence1": "Can thiotepa be recommended for treatment of osteosarcoma?", "sentence2": "CONCLUSION: Adjuvant HDTp failed to significantly improve OS and PFS in resectable relapsed osteosarcomas. Despite a trend of prolonged survival and an acceptable toxicity, thiotepa cannot be recommended.KEY MESSAGE: HDTp and autologous transplantation added to SCT did not improve OS and PFS in patients with resectable relapsed osteosarcomas. Despite a trend of prolonged survival, thiotepa cannot be recommended., Conclusion. The use of HD thiotepa and ASCT is feasible in patients with relapsed osteosarcoma. A randomized study for recurrent osteosarcoma between standard salvage chemotherapy and high dose thiotepa with stem cell rescue is ongoing.", "label": "no"}
{"id": "converted_3897", "sentence1": "Can Freund's complete adjuvant induce arthritis?", "sentence2": "complete Freund's adjuvant (CFA) induced RA, The RA model was established using Freund's complete adjuvant, ,  Rheumatoid arthritis (RA) was induced by Freund's Complete Adjuvant (FCA; 1 mg/0.1 ml paraffin oil), injected subcutaneously on days 0, 30 and 40, The rats were made arthritic using a subcutaneous injection with 0.1 ml complete Freund's adjuvant (CFA) into the footpad of the left hind paw.", "label": "yes"}
{"id": "converted_3928", "sentence1": "Is the Apis mellifera genome available?", "sentence2": " Mining Apis mellifera sequences made it possible to identify the honey bee subspecies both at the mitochondrial and nuclear genome levels., Honey bee research is believed to be influenced dramatically by colony collapse disorder (CCD) and the sequenced genome release in 2006, but this assertion has never been tested.,  The genome release and CCD had quantitively only minor effects, mainly on honey bee health-related topics post-2006. , We show that the honeybee genome is structured with respect to plasticity; genes that respond to an environmental trigger are colocated in the honeybee genome in a series of gene clusters, many of which have been assembled in the last 80 My during the evolution of the Apidae. , we have mined histone methyltransferases and demethylases from the whole genome sequence of Aedes aegypti (Diptera), the pea aphid Acyrthosiphon pisum, the triatomid bug Rhodnius prolixus (Hemiptera), the honeybee Apis mellifera (Hymenoptera),", "label": "yes"}
{"id": "converted_3198", "sentence1": "Can therapeutic levels of  Vedolizumab be found in the breast milk of nursing mothers following treatment for Inflammatory bowel disease?", "sentence2": "Vedolizumab can be detected in the breast milk of nursing mothers. Although more data are imperative, the concentrations of vedolizumab in breast milk are minute and are therefore unlikely to result in systemic or gastro-intestinal immune-suppression of the infant., Although more data are imperative, the concentrations of vedolizumab in breast milk are minute and are therefore unlikely to result in systemic or gastro-intestinal immune-suppression of the infant., Results\nVedolizumab was undetectable in breast milk in IBD patients before the first infusion of vedolizumab [n = 3] and in all of the healthy controls [n = 5]., However, on serial measurements in breast milk after an infusion, drug levels did not surpass 480 ng/ml, which was roughly 1/100 of the comparable serum levels., However, on serial measurements in breast milk after an infusion, drug levels did not surpass 480 ng/ml, which was roughly 1/100 of the comparable serum levels.<br><b>Conclusions</b>: Vedolizumab can be detected in the breast milk of nursing mothers., However, on serial measurements in breast milk after an infusion, drug levels did not surpass 480 ng/ml, which was roughly 1/100 of the comparable serum levels.", "label": "no"}
{"id": "converted_4499", "sentence1": "Does Amblyopia affect the eye?", "sentence2": "The main goal of our study is to assess the effect of transcranial magnetic stimulation, specifically theta burst stimulation (TBS), in a group of amblyopic volunteers measuring several visual parameters: visual acuity, suppressive imbalance, and stereoacuity, This study was undertaken to determine if optometrists in Ghana screen, diagnose and manage paediatric ocular conditions (for example, strabismus, amblyopia), and further assessed if optometrists in Ghana have the requisite paediatric instrumentation in their practices., Many bilateral amblyopia patients have asymmetric visual acuity (VA)., LTS: In patients with persistent amblyopia and in those with recovered amblyopia, the affected eyes were significantly more hyperopic than the fellow eyes. The, e RNFLT was compared between the affected and fellow eyes in patients with persistent amblyopia and in those with recovered amblyopia, and between the amblyopic eyes of patients with persistent amblyopia and the previously amblyopic eyes of patients with recovered amblyopia.RE, We compared the optic nerve head topography and retinal nerve fiber layer (RNFL) thickness of the strabismic and anisometropic amblyopic eyes with the normal fellow eyes and age-matched controls and concluded that, although amblyopia is a functional visual loss, RNFL thickness and optic nerve head topographic changes in strabismic and anisometropic amblyopic eyes may be affected by amblyopia., ODS: Four consecutive infants between 7 and 19 months of age with unilateral periocular vascular lesions that intermittently obstructed vision in the affected eye and no clinical evidence of amblyopia were evaluated. No , Histologic study of the LGNs from a patient with ophthalmologically confirmed anisometropic amblyopia shows a decrease of cell sizes in the parvocellular layers innervated by the amblyopic eye., S: Neutral density filters affect eyes with strabismic amblyopia differently than they do non-amblyopic eyes. A signifi, Together with recent advances in our theoretical understanding of amblyopia and technological advances in amblyopia treatment, we anticipate improved visual outcomes for children affected by this very common eye condition., OBJECTIVE: Amblyopia or lazy eye is a common visual problem affecting children that cannot correct with lenses., Experimental amblyopia in animal models causes a reduction of cell sizes in lateral geniculate nucleus (LGN) laminae connected with the amblyopic eye., Amblyopia cannot be cured by treating the cause alone; the weaker eye must be made stronger in order to see normally., To correct amblyopia, a child must be made to use the weak eye., Similarly, decreased activation of the LGN as well as the visual cortex by the affected eye was demonstrated in the patient with anisometropic amblyopia., Amblyopia is defined as a loss of letter recognition visual acuity in the affected eye; however, studies in both nonhuman primates and man have shown that other important aspects of vision, including color, motion, and contour perception, are also abnormal. The, Amblyopia is a developmental disorder that affects the spatial vision of one or both eyes in the absence of an obvious organic cause; it is associated with a history of abnormal visual experience during childhood, Amblyopia is defined as the reduction of best-corrected visual acuity of one or both eyes caused by conditions that affect normal visual development, Amblyopia is a reduced best-corrected visual acuity of one or both eyes that cannot be attributed to a structural abnormality; it is a functional reduction in the vision of an eye caused by disuse during a critical period of visual development, Amblyopia is defined as reduced and uncorrectable vision in a structurally normal eye, Amblyopia or \"lazy eye\" represents a disorder of the visual system characterized by poor vision in an eye that is otherwise physically normal. , Amblyopia is a common visual disorder that results in a spatial acuity deficit in the affected eye, Amblyopia is a common deficit in spatial vision that could be based on either unreliable local estimates of image structure, irregularities in global image integration or a combination of errors at both these stages., Amblyopia is a disorder of visual acuity in one eye, thought to arise from suppression by the other eye during development of the visual cortex., Amblyopia is characterised by decrease in vision in one or both eyes as a result of processing defect in the visual pathways of the brain, Amblyopia is defined as a loss of letter recognition visual acuity in the affected eye; however, studies in both nonhuman primates and man have shown that other important aspects of vision, including color, motion, and contour perception, are also abnormal, Amblyopia, commonly known as \"lazy eye,\" is a frequent but preventable cause of decreased vision, Here, we consider four explanations that may account for decreased fellow eye sensitivity: the fellow eye is adversely impacted by treatment for amblyopia; the maturation of the fellow eye is delayed by amblyopia; fellow eye sensitivity is impacted for visual functions that rely on binocular cortex; and fellow eye deficits reflect an adaptive mechanism that works to equalize the sensitivity of the two eyes, Therefore, the aim of this review paper is to provide a comprehensive review of current knowledge about the effects of amblyopia on eye movements, upper limb reaching and grasping movements, as well as balance and gait, Atropine occlusion in the treatment of strabismic amblyopia and its effect upon the non-amblyopic eye., Amblyopia is the most common cause of monocular visual impairment in children, with a prevalence of 2-3%, Amblyopia is a neurodevelopmental disorder of the visual system, as a result of discordant visual experience during infancy or early childhood, By its nature, however, amblyopia has an adverse effect on the development of a binocular visual system and the interactions between signals from two eyes., Unilateral Amblyopia Affects Two Eyes: Fellow Eye Deficits in Amblyopia., PURPOSE: Impairment of spatiotemporal visual processing is the hallmark of amblyopia, but its effects on eye movements during visuomotor tasks have rarely been, Amblyopia is defined as a loss of letter recognition visual acuity in the affected eye; however, studies in both nonhuman primates and man have shown that other important aspects of vision, including color, motion, and contour perception, are also abnormal., Further research targeted at exploring fellow eye deficits in amblyopia will provide us with a broader understanding of normal visual development and how amblyopia impacts the developing visual system., While these fellow eye deficits have been noted, no overarching theory has been proposed to describe why and under what conditions the fellow eye is impacted by amblyopia., Here, we consider four explanations that may account for decreased fellow eye sensitivity: the fellow eye is adversely impacted by treatment for amblyopia; the maturation of the fellow eye is delayed by amblyopia; fellow eye sensitivity is impacted for visual functions that rely on binocular cortex; and fellow eye deficits reflect an adaptive mechanism that works to equalize the sensitivity of the two eyes., In anisometropes, the amblyopic eye influenced a relatively small proportion of cortical neurons; in strabismics, the influence of the two eyes was more nearly equal., studied. Here the authors investigate how visual deficits in anisometropic amblyopia affect saccadic eye movements.METHODS: Thirteen patients with anisometropic amblyopia and 13 control subj, Unilateral amblyopia is a visual disorder that arises after selective disruption of visual input to one eye during critical periods of development., Amblyopia is a developmental disorder resulting in poor vision in one eye., In the clinic, amblyopia is understood as poor visual acuity in an eye that was deprived of pattern vision early in life., Ocular misalignment or unilateral blur often causes amblyopia, a disorder that has become a standard for understanding developmental plasticity., Amblyopia is a developmental disorder of pattern vision.,  amblyopia are associated with poor PS. PS of amblyopic and fellow eyes is differentially , The contrast sensitivity function of both eyes of subjects with functional amblyopia has been measured. A clinically significant difference was found between the amblyopic and the normal eye., t appears that the functionally amblyopic eye takes more information from the peripheral parts of the stimulus than does the normal eye, Previous studies focused on the differences between amblyopic patients and normal controls without evaluating amblyopic eyes after patching. To evaluate differences in the superficial vascular density of amblyopic eyes, normal eyes, and amblyopic eyes reaching normal BCVA after patch therapy,", "label": "yes"}
{"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.", "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.", "label": "yes"}
{"id": "converted_728", "sentence1": "Is the Prostate- Specific Antigen (PSA) test relevant only for prostate cancer?", "sentence2": "rostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer death in men, PSA is known to be prostate specific, but not PCa specific, deficiencies of serum PSA as a prostate-cancer-specific diagnostic test are well recognized., medical debate surrounding the use of the prostate-specific antigen (PSA) test for prostate cancer screening, The clinical relevance of this surprisingly high rate of prostate cancer in men with a normal PSA is yet to be determined , Rapid uptake of prostate-specific antigen (PSA) testing has occurred in the United States despite inconclusive evidence regarding mortality benefit, Routine cancer screening with prostate-specific antigen (PSA) is controversial, and practice guidelines recommend that men be counseled about its risks and benefits, Prostate carcinoma was histologically confirmed in 14 (0.66%) of the men, nine times in the early stage (T2) and five times in the clinical stage (T3), corresponding to an incidence of circa 650 cases per 100,000 men in the target age group, This newly developed PSA test system can enhance the acceptance rate and effectiveness of medical check-ups for prostate cancer,, PSA can be used reliably as a unique tool in the follow-up of patients for the early detection of progressive disease, PSA showed negative predictive values of 82 and 77%, respectively, using 4 and 10 ng/ml as cutoff points, have assessed the feasibility of using fixed-limit criteria based on medical relevance and biological variation for evaluating the analytical performance of the prostate-specific antigen (PSA) test", "label": "no"}
{"id": "converted_3237", "sentence1": "Is the crystal structure of Pim-1 available?", "sentence2": "Recent crystallographic studies of Pim-1 have identified unique structural features but have not provided insight into how the kinase recognizes its target substrates. , a co-crystal structure of lead molecule (HS38) in complex with DAPK3, a dual Pim/DAPK3 inhibitor (HS56), The crystal structure of this compound with PIM1 confirmed the predicted binding mode and protein-ligand interactions except those in the acidic ribose pocket. , Using the determined X-ray crystal structure of PIM1 complexed to the compound 1-R as a control, we discuss the importance of including the protein flexibility inherent in the ensemble docking protocol, for the accuracy of the structure prediction of the bound state. , Here, we describe the crystal structure of Pim1 in complex with a newly developed pyrido[4,3-d]pyrimidine-derivative inhibitor (SKI-O-068)., Crystallographic and docking data analyses have been undertaken using inhibitor complexes , The crystal structures of Pim1 in apo form and bound with AMPPNP have been solved", "label": "yes"}
{"id": "converted_815", "sentence1": "Is indicated the use of antioxidant supplements in patients at risk for coronary artery disease?", "sentence2": "We and others have published observational epidemiologic studies in support of vitamins in the primary prevention of CVD, but the results from intervention studies are mixed., For vitamin E, observational data suggest benefit at doses of 100 to 400 IU/d. Results from recent large-scale trials are mixed, with some showing modest benefit but others suggesting no benefit, especially for secondary prevention. Results for B vitamins are also mixed and further complicated by the recent folate fortification of the flour supply. If greater B vitamin intake does reduce CVD, the benefits are likely to be greatest for primary prevention and in populations with intake below dietary reference standards. , In the dose-response meta-analysis, each 30 mg/day increase in vitamin C, 30 IU/day increase in vitamin E, and 1 mg/day increase in beta-carotene yielded the estimated overall relative risk for CHD of 1.01 (95% CI, 0.99-1.02), 0.96 (95% CI, 0.94-0.99), and 1.00 (95% CI, 0.88-1.14), respectively. CONCLUSIONS: Our findings in this meta-analysis suggest that an increase in dietary intake of antioxidant vitamins has encouraging prospects for possible CHD prevention., High levels of α-tocopherol in serum were associated with 30% lower CAD risk in another study (HR 0.71; 95%CI 0.53-0.94). Among minerals (zinc, selenium, and chromium), an inverse association between zinc and CAD was observed; levels lower than 14.1 µmol/L were associated with an increased risk for CAD (RR 1.70; 95%CI 1.21-2.38)., The information available on this issue is scarce. Further prospective studies are needed to elucidate the role of these nutrients in the cardiovascular risk of patients with diabetes., Coenzyme Q10 supplementation at a dosage of 150 mg appears to decrease the inflammatory marker IL-6 in patients with CAD.,  Coenzyme Q10 supplements at a dose of 150 mg can decrease oxidative stress and increase antioxidant enzyme activity in patients with CAD. A higher dose of coenzyme Q10 supplements (>150 mg/d) might promote rapid and sustainable antioxidation in patients with CAD., Alpha-tocopherol or beta-carotene supplementation has no protective effect on macrovascular outcomes or total mortality of diabetic male smokers., Sodium selenite supplementation increases GPx-1 activity in endothelial cells and in CAD patients. Future studies have to demonstrate whether long-term CAD outcome can be improved., After 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6, and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering.,  In this population-based study, vitamin E use was unrelated to mortality, but this apparently null finding seems to represent a combination of increased mortality in those with severe cardiovascular disease and a possible protective effect in those without.,  In this large cohort of apparently healthy US male physicians, self-selected supplementation with vitamin E, vitamin C, or multivitamins was not associated with a significant decrease in total CVD or CHD mortality. , The American Heart Association has recommended consumption of a balanced diet with emphasis on antioxidant-rich fruits and vegetables but has made no recommendations regarding vitamin E supplementation for the general population. Although vitamin E supplementation seems to be safe for most people, recommendations from health care professionals should reflect the uncertainty of established benefit as demonstrated in clinical trials, Recent studies show that supplementation with antioxidant vitamins E and C have benefits in CHD prevention; however, supplementation with beta-carotene may have deleterious effects and is not recommended. Current evidence suggests that patients with CHD would probably benefit from taking vitamin E in a dosage of 400 IU per day and vitamin C in a dosage of 500 to 1,000 mg per day. Clinicians may also want to consider vitamin supplementation for CHD prevention in high-risk patients. Folate lowers elevated homocysteine levels, but evidence for routine supplemental use does not yet exist. , In patients at high risk for cardiovascular events, treatment with vitamin E for a mean of 4.5 years had no apparent effect on cardiovascular outcomes.", "label": "no"}
{"id": "converted_1489", "sentence1": "Is there any role for long noncoding RNAs in adipogenesis?", "sentence2": "Long noncoding RNAs regulate adipogenesis., Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). RNAi-mediated loss of function screens identified functional lncRNAs with varying impact on adipogenesis. Collectively, we have identified numerous lncRNAs that are functionally required for proper adipogenesis., Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). ", "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.", "label": "yes"}
{"id": "converted_742", "sentence1": "Can mutations in Calmodulin cause ventricular fibrillation?", "sentence2": "We characterized a family presenting with a history of ventricular fibrillation (VF) and sudden death without ECG or echocardiographic abnormalities at rest. Two siblings died suddenly at the ages of 9 and 10 years, and another two were resuscitated from out-of-hospital cardiac arrest with documented VF at age 10 and 16, respectively. Exome sequencing identified a missense mutation affecting a highly conserved residue (p.Phe90Leu) in the CALM1 gene encoding calmodulin. This mutation was also carried by one of the sibs who died suddenly, for whom DNA was available. The mutation was present in the mother and in an sibling, both asymptomatic but displaying a marginally prolonged QT-interval during exercise. CONCLUSIONS: We identified a mutation in CALM1 underlying IVF manifesting in childhood and adolescence. The causality of the mutation is supported by previous studies demonstrating that Phe90 mediates the direct interaction of CaM with target peptides, Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted CaM binding and eliminated Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM were restored by intracellular application of a peptide modelled after the IQ domain. ", "label": "yes"}
{"id": "converted_2451", "sentence1": "Can multiple myeloma patients develop hyperviscosity syndrome?", "sentence2": "Multiple myeloma (MM) is an immedicable malignancy of the human plasma cells producing abnormal antibodies (also referred to as paraproteins) leading to kidney problems and hyperviscosity syndrome. , This skin condition may be observed in patients with the following condtions, such as primary polycythemic hyperviscosity (polycythemia, thrombocytemia) treated with hydroxyurea, primary plasma hyperviscosity (multiple myeloma, cryoglobulinemia, cryofibrinogenemia, dysfibrinogenemia, and connective tissue diseases), primary sclerocythemic hyperviscosity (hereditary spherocytosis, thalassemia, and sickle cell disease). ,  A 73-year-old woman with known MM who received little treatment for several years, presented secondary to dysarthria and at first was thought to have hyperviscosity syndrome. ,  After a comprehensive evaluation ruled out common causes of acute renal failure, the patient underwent testing with a bone survey, urine protein electrophoresis (UPEP), serum protein electrophoresis (SPEP), and immunoelectrophoresis for suspected plasma cell dyscrasia and received plasmapheresis for hyperviscosity syndrome and nephrotoxicity, which resulted in improved renal function. Lab results showed monoclonal gammopathy, elevated serum free light chains, and Bence Jones protein in the urine with a follow-up bone marrow biopsy indicating plasma cell dyscrasia. The patient received a diagnosis of multiple myeloma (MM) and was started on chemotherapy and immunosuppression. , Plasmapheresis (PE) is recommended for patients with hyperviscosity syndrome or cast nephropathy presented with AKI, which may help to increase the dialysis-independency., Multiple myeloma is a neoplastic plasma-cell disorder resulting from malignant plasma cells in the bone marrow. It can cause a hyperviscosity syndrome secondary to the paraproteinaemia associated with the disease. The increased hyperviscosity can lead to retinal vein occlusions and other ocular problems that may challenge clinicians. , Etiologies are various but symptomatic hyperviscosity is more common in Waldenström's macroglobulinemia and multiple myeloma. , Double filtration plasmapheresis in a dog with multiple myeloma and hyperviscosity syndrome., A 12 year old, 38 kg, mix-breed, intact male dog presented with a 20 day history of clinical signs consistent with hyperviscosity syndrome secondary to multiple myeloma. , The present study reported for the first time the use of double filtration plasmapheresis to reduce clinical signs of hyperviscosity syndrome in a dog with multiple myeloma., An otherwise healthy young man presents with bilateral CRVO as the first sign of hyperviscosity syndrome in the setting of new multiple myeloma.,  In haematology the most common indication for plasmapheresis is the supportive treatment of multiple myeloma. The procedure is performed in patients with high protein levels endangered with hyperviscosity syndrome., Five to 10 percent of patients with multiple myeloma are suffered from the hyperviscosity syndrome because of increased serum viscosity due to the presence of myeloma protein., Plasmapheresis is known as an efficient method for rapid improvement of the hyperviscosity syndrome, and double filtration plasmapheresis is most commonly used for plasma exchange of multiple myeloma patients in our country., PE is the most effective method in the treatment of hyperviscosity syndrome often seen with multiple myeloma and Waldenström's macroglobulinemia, and it is therapy of choice for this complication., Patients with multiple myeloma who have complications secondary to hyperviscosity are treated by chemotherapy and/or plasmapheresis.", "label": "yes"}
{"id": "converted_1899", "sentence1": "Have the promoter regions of the genes implicated in Rett Syndrome been characterized with CAGE?", "sentence2": "CAGE-defined promoter regions of the genes implicated in Rett Syndrome., Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other with respect to expression levels and regulatory regions. Here we analyzed data from hundreds of mouse and human samples included in the FANTOM5 project, to identify transcript initiation sites, expression levels, expression correlations and regulatory regions of the three genes.RESULTS: Our investigations reveal the predominantly used transcription start sites (TSSs) for each gene including novel transcription start sites for FOXG1. We show that FOXG1 expression is poorly correlated with the expression of MECP2 and CDKL5. We identify promoter shapes for each TSS, the predicted location of enhancers for each gene and the common transcription factors likely to regulate the three genes. Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum.CONCLUSIONS: Our analyses provide a comprehensive picture of the regulatory regions of the three genes involved in Rett Syndrome., CAGE-defined promoter regions of the genes implicated in Rett Syndrome, CAGE-defined promoter regions of the genes implicated in Rett Syndrome.", "label": "yes"}
{"id": "converted_3006", "sentence1": "Is galcanezumab effective for treatment of migraine?", "sentence2": "Importance: Galcanezumab (LY2951742), a monoclonal antibody against calcitonin gene-related peptide (CGRP), is one of a novel class of new medicines for migraine prevention., Conclusions and Relevance: Monthly subcutaneous injections of galcanezumab, both 120 mg and 300 mg, demonstrated efficacy (repeated-measures analysis) for the preventive treatment of migraine and support further development in larger phase 3 studies. , PURPOSE OF REVIEW: Monoclonal antibodies (mAbs) targeting the calcitonin-gene-related peptide (CGRP) pathway have been developed for episodic and chronic migraine prevention, either through binding the CGRP ligand (eptinezumab, fremanezumab, galcanezumab) or the CGRP receptor (erenumab)., Background Safety findings from a Phase 2b study of galcanezumab, a humanized monoclonal antibody against calcitonin gene-related peptide, for prevention of migraine (NCT02163993) are reported here., Safety of galcanezumab in patients with episodic migraine: A randomized placebo-controlled dose-ranging Phase 2b study., Currently, there is considerable excitement regarding monoclonal antibodies against calcitonin gene-related peptide (eptinezumab, galcanezumab, fremanezumab) and the calcitonin gene-related peptide receptor (erenumab). To date, these monoclonal antibodies have shown promising efficacy in clinical trials, with no major safety concerns. If ongoing long-term studies show that their efficacy can be maintained, this may herald a new era for effective antimigraine therapies., CGRP receptor antagonists such as ubrogepant are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine attacks. , Four monoclonal antibodies (mAbs) targeting the CGRP pathway are currently under evaluation for the prevention of episodic and chronic migraine: eptinezumab (ALD403), fremanezumab (TEV-48125), galcanezumab (LY2951742), and erenumab (AMG334). , Introduction Galcanezumab is a humanized monoclonal antibody binding calcitonin gene-related peptide, used for migraine prevention., Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial., Galcanezumab induced a robust, dose-dependent, and durable inhibition of capsaicin-induced increase in DBF, supporting the continued clinical development of galcanezumab for prophylaxis in migraine patients., The efficacy and safety of calcitonin gene-related peptide monoclonal antibody for episodic migraine: a meta-analysis.Based on the results of this meta-analysis, CGRP monoclonal antibodies significantly reduced the monthly migraine days and acute migraine-specific medication. , Importance\nGalcanezumab (LY2951742), a monoclonal antibody against calcitonin gene-related peptide (CGRP), is one of a novel class of new medicines for migraine prevention., Galcanezumab appears efficacious, safe, and well tolerated for the preventive treatment of chronic migraine., BACKGROUND\nGalcanezumab is a humanized monoclonal antibody that selectively binds to the calcitonin gene-related peptide (CGRP) and has demonstrated efficacy in reducing migraine headache days (MHD) in patients with episodic and chronic migraine., BACKGROUND\nGalcanezumab, a humanized monoclonal antibody that selectively binds to the calcitonin gene-related peptide, has demonstrated in previous Phase 2 and Phase 3 clinical studies (≤6-month of treatment) a reduction in the number of migraine headache days and improved patients' functioning., CONCLUSION\nTwelve months of treatment with self-administered injections of galcanezumab was safe and associated with a reduction in the number of monthly migraine headache days., CGRP receptor antagonists such as ubrogepant are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine attacks., Conclusions and Relevance\nMonthly subcutaneous injections of galcanezumab, both 120 mg and 300 mg, demonstrated efficacy (repeated-measures analysis) for the preventive treatment of migraine and support further development in larger phase 3 studies., Importance Galcanezumab (LY2951742), a monoclonal antibody against calcitonin gene-related peptide (CGRP), is one of a novel class of new medicines for migraine prevention., BACKGROUND Galcanezumab, a humanized monoclonal antibody that selectively binds to the calcitonin gene-related peptide, has demonstrated in previous Phase 2 and Phase 3 clinical studies (≤6-month of treatment) a reduction in the number of migraine headache days and improved patients' functioning., BACKGROUND Galcanezumab is a humanized monoclonal antibody that selectively binds to the calcitonin gene-related peptide (CGRP) and has demonstrated efficacy in reducing migraine headache days (MHD) in patients with episodic and chronic migraine., Both galcanezumab dose groups demonstrated greater overall mean reduction in the number of monthly MHDs compared to placebo (placebo -2.7, galcanezumab 120 mg -4.8, galcanezumab 240 mg -4.6) (<br><b>CONCLUSIONS</b>: Both doses of galcanezumab were superior to placebo in reducing the number of monthly MHDs., Galcanezumab appears efficacious, safe, and well tolerated for the preventive treatment of chronic migraine.<br><b>CLINICALTRIALSGOV IDENTIFIER</b>: NCT02614261.<br><b>CLASSIFICATION OF EVIDENCE</b>: This interventional study provides Class I evidence that galcanezumab is superior to placebo in the reduction of the number of monthly MHDs.<br>, In September 2018, the US FDA approved galcanezumab as a once-monthly subcutaneous injection for the preventive treatment of migraine in adults., This article summarizes the milestones in the development of galcanezumab leading to its first approval for the preventive treatment of migraine in adults.<br>, Galcanezumab appears efficacious, safe, and well tolerated for the preventive treatment of chronic migraine., This article summarizes the milestones in the development of galcanezumab leading to its first approval for the preventive treatment of migraine in adults., Twelve months of treatment with self-administered injections of galcanezumab was safe and associated with a reduction in the number of monthly migraine headache days.", "label": "yes"}
{"id": "converted_4261", "sentence1": "Is Lysozyme abundant in human tears?", "sentence2": "lysozyme present in the natural tear, Lysozyme (Lyz) is a naturally occurring enzyme that operates against Gram-positive bacteria and leads to cell death. This antimicrobial enzyme forms the part of the innate defense system of nearly all animals and exists in their somatic discharges such as milk, tears, saliva and urine., tear lysozyme, lysozyme in tears, saliva, sweat, and other body fluids, , In this study we quantify lysozyme, the most prevalent protein in tear fluid, , Lysozyme (LZM) is a natural anti-bacterial protein that is found in the saliva, tears and milk of all mammals including humans. ", "label": "yes"}
{"id": "converted_1959", "sentence1": "Are Ultra-conserved elements (UCEs) enriched in segmental duplications?", "sentence2": "Here we address the process by which CNVs become depleted of UCEs., We begin by showing that depletion for UCEs characterizes the most recent large-scale human CNV datasets and then find that even newly formed de novo CNVs, which have passed through meiosis at most once, are significantly depleted for UCEs., In striking contrast, CNVs arising specifically in cancer cells are, as a rule, not depleted for UCEs and can even become significantly enriched., Alternatively, lack of depletion for UCEs from cancer CNVs may reflect the diseased state. , ULEs are located in intergenic or intronic regions and are depleted from segmental duplications., Interestingly, human UCEs have been reported to be strongly depleted among segmental duplications and benign copy number variants (CNVs)., In addition, here we show that these elements are preferentially found in pathogenic deletions (enrichment ratio 3.6 vs. 0.5 in duplications), and that this association is not related with a higher content of genes., In contrast, pathogenic CNVs lacking UCEs showed almost a threefold higher content in genes, 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., Mammalian ultraconserved elements are strongly depleted among segmental duplications and copy number variants., Here, we show that UCEs are significantly depleted among segmental duplications and copy number variants. Notably, of the UCEs that are found in segmental duplications or copy number variants, the majority overlap exons, indicating, along with other findings presented, that UCEs overlapping exons represent a distinct subset., 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., Here, we show that UCEs are significantly depleted among segmental duplications and copy number variants., 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 show that UCEs are significantly 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, melanogaster genome revealed depletion of the P-element and piggyBac insertions in and around the Sophophora UCEs., Mammalian ultraconserved elements are strongly depleted among segmental duplications and copy number variants., Here, we show that UCEs are significantly depleted among segmental duplications and copy number variants., Interestingly, human UCEs have been reported to be strongly depleted among segmental duplications and benign copy number variants (CNVs).", "label": "no"}
{"id": "converted_3583", "sentence1": "Has amantadine ER been approved by the FDA?", "sentence2": "ADS-5102 (amantadine) extended-release (ER) capsules (GOCOVRITM) is a recent US FDA-approved treatment for dyskinesia in PD patients. ", "label": "yes"}
{"id": "converted_3188", "sentence1": "Are artificial blood cells available?", "sentence2": "The critical point for the break through for artificial blood products did not come yet but could be ahead-, We suggest a novel method that uses artificial blood cells (hemoglobin vesicles, Hb-Vs) as photosensitizers in dye laser treatment (at 595-nm wavelength) for port-wine stains (i.e., capillary malformations presenting as red birthmarks) based on the results of animal experiments. ", "label": "no"}
{"id": "converted_1285", "sentence1": "Are EDNRB mutations involved in the development of Hirschsprung disease?", "sentence2": "QTL analysis identifies a modifier locus of aganglionosis in the rat model of Hirschsprung disease carrying Ednrb(sl) mutations, As reported previously, when the same null mutation of the Ednrb gene, Ednrb(sl), was introgressed into the F344 strain, almost 60% of F344-Ednrb(sl/sl) pups did not show any symptoms of aganglionosis, appearing healthy and normally fertile., Genetic background strongly modifies the severity of symptoms of Hirschsprung disease, but not hearing loss in rats carrying Ednrb(sl) mutations, In this study, we found that the null mutation of the Ednrb gene, thought indispensable for enteric neuron development, is insufficient to result in HSCR disease when bred onto a different genetic background in rats carrying Ednrb(sl) mutations., New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease., The aim of this study was to evaluate the implication of the EDN3 and EDNRB genes in a series of patients with Hirschsprung disease from Spain and determinate their mutational spectrum., A De Novo novel mutation of the EDNRB gene in a Taiwanese boy with Hirschsprung disease, Although mutations in eight different genes (EDNRB, EDN3, ECE1, SOX10, RET, GDNF, NTN, SIP1) have been identified in affected individuals, it is now clear that RET and EDNRB are the primary genes implicated in the etiology of HSCR., Mutations in genes of the RET receptor tyrosine kinase and endothelin receptor B (EDNRB) signaling pathways have been shown to be associated in HSCR patients. , Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10Dom mouse model of Hirschsprung disease, Molecular genetic analyses have revealed that interactions between mutations in the genes encoding the RET receptor tyrosine kinase and the endothelin receptor type B (EDNRB) are central to the genesis of HSCR, Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease, Thus, genetic interaction between mutations in RET and EDNRB is an underlying mechanism for this complex disorder., EDNRB/EDN3 and Hirschsprung disease type II., Analysis of the RET, GDNF, EDN3, and EDNRB genes in patients with intestinal neuronal dysplasia and Hirschsprung disease, wo susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene and the endothelin B receptor (EDNRB) gene., We conclude that Ednrb loss only in neural crest cells is sufficient to produce the Hirschsprungs disease phenotype observed with genomic Ednrb mutations, EDNRB mutations were detected in 2 of the 13 short-segment HD, The mutations of EDNRB gene and EDN-3 gene are found in the short-segment HD of sporadic Hirschsprung's disease in Chinese population, which suggests that the EDNRB gene and EDN-3 gene play important roles in the pathogenesis of HD, Functional characterization of three mutations of the endothelin B receptor gene in patients with Hirschsprung's disease, Hirschsprung's disease (HSCR) is one the most common congenital intestinal disease. It leads to aganglionic megacolon in the early childhood. Several susceptibility genes have been identified : RET protooncogene and its ligand, glial cell derived neutrophic factor (GDNF), Sox 10, Endothelin-3 (EDN3) and its receptor B (EDNRB). EDNRB mutations are found in 5% of familial or sporadic HSCR, Enteric aganglionosis in Hirschsprung disease has been linked to genes coding for endothelin-3 (EDN3) and the endothelin B receptor (EDNRB), To date, three genes have been identified as susceptibility genes for Hirschsprung's disease (HSCR), the RET proto-oncogene, the endothelin-B receptor gene (EDNRB) and the endothelin-3 gene (EDN3), Our data indicate that RET and EDNRB mutations have a role in the aetiology of some sporadically occurring HSCR, Mutations of the endothelin-B receptor and endothelin-3 genes in Hirschsprung's disease, The endothelin-B receptor gene (EDNRB) and the endothelin-3 gene (EDN3) have recently been recognized as susceptibility genes for Hirschsprung's disease (HD), These observations confirm that impaired function of the endothelin-B receptor or endothelin-3 is involved in the aetiology of some human HD cases. EDNRB mutations appear to be associated with short-segment HD, in contrast to RET mutations, which are found mainly in long-segment aganglionosis, In addition to mutations in the RET and EDNRB genes, embryonic environmental factors and/or other genetic factors appear to be involved in the development of Hirschsprung disease., Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease., QTL analysis identifies a modifier locus of aganglionosis in the rat model of Hirschsprung disease carrying Ednrb(sl) mutations., Homozygous mutations in the endothelin-B receptor gene (EDNRB) on 13q22 have been identified in humans and mice with Hirschsprung disease type 2 (HSCR2)., A De Novo novel mutation of the EDNRB gene in a Taiwanese boy with Hirschsprung disease., Hitherto however, homozygosity for EDNRB mutations accounted for the HSCR-Waardenburg syndrome (WS) association., These data might suggest that EDNRB mutations could be dosage sensitive: heterozygosity would predispose to isolated HSCR with incomplete penetrance, while homozygosity would result in more complex neurocristopathies associating HSCR and WS features., Highly recurrent RET mutations and novel mutations in genes of the receptor tyrosine kinase and endothelin receptor B pathways in Chinese patients with sporadic Hirschsprung disease., Mutations in genes encoding the RET receptor tyrosine kinase and endothelin receptor type B (EDNRB) are involved in HSCR pathogenesis; however, also important in ENS development are molecules that mediate events that are more restricted than those of RET and EDNRB, act later in development and which might not be HSCR-associated., Several missense mutations of the endothelin-B receptor (EDNRB) associated with Hirschsprung disease have recently been identified., These findings indicate that these missense mutations result in loss of function of EDNRB, and may provide the molecular pathological basis of Hirschsprung disease in some individuals., Manifestation of the disease has been linked to mutations in genes that encode the crucial signals for the development of the enteric nervous system-the RET and EDNRB signalling pathways., In addition to mutations in the RET and EDNRB genes, embryonic environmental factors and/or other genetic factors appear to be involved in the development of Hirschsprung disease, In this study, we investigated whether germline mutations of endothelin receptor B (EDNRB), a gene involved in Hirschsprung disease (HSCR), could also predispose for malignant melanoma (MM), However, the similarity between the distal colonic aganglionosis in Hirschsprung disease and that due to EDN3 or EDNRB mutations led to the hypothesis that levels of expression of these genes might be affected in the absence of mutation, thus causing the Hirschsprung disease phenotype, Our data strongly suggest that EDNRB is involved in predisposition for two different multigenic disorders, HSCR and melanoma.", "label": "yes"}
{"id": "converted_436", "sentence1": "Is progesterone effective for treatment of patients with traumatic brain injury based on clinical trial data?", "sentence2": "BACKGROUND: Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized, controlled trials. , The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo. CONCLUSIONS: Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials., BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI. , There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). , CONCLUSIONS: This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. , Numerous studies, however, show that progesterone has substantial pleiotropic properties as a neuroprotective agent in both animal models and humans., RESULTS: There was a better recovery rate and GOS score for the patients who were given progesterone than for those in the control group in a 3-months follow-up period (50% vs. 21%); subgroup analysis showed a significant difference in the percentage of favorable outcome between the two groups with GCS of 5-8 (p=0.03). CONCLUSION: The use of progesterone may significantly improve neurologic outcome of patients suffering severe TBI up to 3 months after injury, especially those with 5≤GCS≤8, providing a potential benefit to the treatment of acute severe TBI patients. Considering this drug had no significant side effects, so progesterone could be used in patients with severe TBI as a neuro-protective drug., While progesterone and ciclosporin have shown promise in phase II studies, success in larger phase III, randomized, multicentre, clinical trials is pending.,  All three studies reported the effects of progesterone on mortality. The pooled risk ratio (RR) for mortality at end of follow-up was 0.61, 95% confidence interval (CI) 0.40 to 0.93. Three studies measured disability and found the RR of death or severe disability in patients treated with progesterone to be 0.77, 95% CI 0.62 to 0.96., AUTHORS' CONCLUSIONS: Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required., GOS was classified to 2 main categories of favorable and unfavorable recovery, of which, favorable recovery in placebo, progesterone, and progesterone-vitamin D was 25%, 45%, and 60%, respectively which showed a statistical significant difference among the groups (P-value = 0.03). CONCLUSION: The results showed that recovery rate in patients with severe brain trauma in the group receiving progesterone and vitamin D together was significantly higher than that of progesterone group, which was in turn higher than that of placebo group.,  The pooled relative risk (RR) for mortality at end of follow-up is 0.61, 95% confidence interval (CI) 0.40 to 0.93. Three studies measured disability and found the RR of death or severe disability in patients treated with progesterone was 0.77, 95% confidence interval (CI) 0.62 to 0.96., AUTHORS' CONCLUSIONS: Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required., Clinical trials have shown that short-and long-term progesterone treatment induces a significant improvement in the level of disability among patients with brain injury. , Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial., CONCLUSION: Our data suggest that acute severe TBI patients with administration of progesterone hold improved neurologic outcomes for up to 6 months. These results provide information important for further large and multicenter clinical trials on progesterone as a promising neuroprotective drug. , The modified Functional Independence Measure scores in the progesterone group were higher than those in the placebo group at both 3-month and 6-month follow-up (P < 0.05 and P < 0.01). The mortality rate of the progesterone group was significantly lower than that of the placebo group at 6-month follow-up (P < 0.05). , CONCLUSION: Our data suggest that acute severe TBI patients with administration of progesterone hold improved neurologic outcomes for up to 6 months. These results provide information important for further large and multicenter clinical trials on progesterone as a promising neuroprotective drug. , These data, combined with the results of the previously published ProTECT trial, show progesterone to be safe and potentially efficacious in the treatment of TBI. Larger phase III trials will be necessary to verify results prior to clinical implementation., CONCLUSION: It indicated that successive early application of PG will benefit the patients with acute severe head injury by improving the recovery and reducing the disability, which may be related to its alleviating inflammatory and lipid peroxidation response., Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). , However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo. CONCLUSION: In this small study, progesterone caused no discernible harm and showed possible signs of benefit., After more than 30 years of research and 30 failed clinical trials with as many different treatments, progesterone is the first agent to demonstrate robust clinical efficacy as a treatment for traumatic brain injuries., After more than 30 years of research and 30 failed clinical trials with as many different treatments, progesterone is the first agent to demonstrate robust clinical efficacy as a treatment for traumatic brain injuries, A US National Institutes of Health-sponsored, nationwide Phase III clinical trial is now evaluating progesterone for moderate-to-severe TBI in 1200 patients, An industry-sponsored Phase III international trial is also under way, and planning for a trial using progesterone to treat pediatric brain injury has begun, More than two decades of pre-clinical research and two recent clinical trials have shown that progesterone (PROG) and its metabolites exert beneficial effects after traumatic brain injury (TBI) through a number of metabolic and physiological pathways that can reduce damage in many different tissues and organ systems, After more than 30 years of research and 30 failed clinical trials with as many different treatments, progesterone is the first agent to demonstrate robust clinical efficacy as a treatment for traumatic brain injuries, RESULTS: Analysis of these reviews yielded meanfuling observations: (1) The effectiveness of most ordinary treatments in TBI is inconclusive except that corticosteroids are likely to be ineffective or harmful, and tranexamic acid, nimodipine and progesterone show a promising effect in bleeding trauma, traumatic subarachnoid hemorrhage, TBI or severe TBI., Laboratory data strongly show that progesterone treatment after TBI reduces edema, improves outcomes, and restores blood-brain barrier function. Clinical studies to date agree with these data, and there are ongoing human trials for progesterone treatment after TBI.", "label": "no"}
{"id": "converted_3470", "sentence1": "Is overexpression of LY6K associated with better prognosis for non-small cell lung cancer patients?", "sentence2": "Gene expression profile analyses of non-small cell lung carcinomas (NSCLC) and esophageal squamous cell carcinomas (ESCC) revealed that lymphocyte antigen 6 complex locus K (LY6K) was specifically expressed in testis and transactivated in a majority of NSCLCs and ESCCs. Immunohistochemical staining using 406 NSCLC and 265 ESCC specimens confirmed that LY6K overexpression was associated with poor prognosis for patients with NSCLC (P = 0.0003), as well as ESCC (P = 0.0278), and multivariate analysis confirmed its independent prognostic value for NSCLC (P = 0.0035). , Immunohistochemical staining using 406 NSCLC and 265 ESCC specimens confirmed that LY6K overexpression was associated with poor prognosis for patients with NSCLC (P = 0.0003), as well as ESCC (P = 0.0278), and multivariate analysis confirmed its independent prognostic value for NSCLC (P = 0.0035)., Immunohistochemical staining using 406 NSCLC and 265 ESCC specimens confirmed that LY6K overexpression was associated with poor prognosis for patients with NSCLC (P = 0.0003), as well as ESCC (P = 0.0278), and multivariate analysis confirmed its independent prognostic value for NSCLC (P = 0.0035).", "label": "no"}
{"id": "converted_3501", "sentence1": "Do MAIT cells have a role in multiple myeloma?", "sentence2": "hus, MAIT cells are reduced in MM patients, which may contribute to disease in these individuals, and moreover, MAIT cells may represent new immunotherapeutic targets for treatment of MM and other malignancies., Here we have analysed the frequency and function of MAIT cells in multiple myeloma (MM) patients. We show that MAIT cell frequency in blood is reduced compared to healthy adult donors, but comparable to elderly healthy control donors, Newly diagnosed MM patient MAIT cells had reduced IFNγ production and CD27 expression, suggesting an exhausted phenotype, although IFNγ-producing capacity is restored in relapsed/refractory patient samples. , We describe recent observations with regard to functional exhaustion of iNKT and MAIT cells in MM pathology and discuss the potential application of checkpoint inhibition as an attractive target for prolonged activation of these immunomodulatory T cells in the treatment of MM., Enumeration, functional responses and cytotoxic capacity of MAIT cells in newly diagnosed and relapsed multiple myeloma., Thus, MAIT cells are reduced in MM patients, which may contribute to disease in these individuals, and moreover, MAIT cells may represent new immunotherapeutic targets for treatment of MM and other malignancies.", "label": "yes"}
{"id": "converted_1497", "sentence1": "Is depression associated with poor prognosis of brain tumor patients?", "sentence2": "Before surgery 27 patients (35%) had BDI scores indicating the presence of depression. These scores were significantly higher in patients with a history of depression (p = 0.017) and in those with a lower functional outcome (p = 0.015)., A lower functional status (KPS score < or = 70) in patients was significantly associated with high depression scores at the 3-month (p = 0.000) and 1-year (p = 0.005) assessments., At all follow-ups, depressed low-grade glioma patients had a significantly shorter survival time, 3.3-5.8 years, compared to non-depressed low-grade glioma patients, 10.0-11.7 years., The results suggest that depression and decreased QOL among low-grade glioma patients is related to shorter survival at long-term follow-up., The adverse impact of depression in relation to survival among cancer patients is currently a subject of great interest in research., In the subgroup of patients with low-grade gliomas, depressive patients had a significantly shorter survival time compared with nondepressive subjects (P = 0.031, Kaplan-Meier survival analysis)., Preoperative depression seemed to be a significant prognostic factor for worse survival in low-grade glioma patients., Major depressive disorder was marginally associated with outcomes, while surgical interventions and radiotherapy did not show strong associations with test performances.", "label": "yes"}
{"id": "converted_3584", "sentence1": "Can PRL3-zumab inhibit PRL3+ cancer cells in vitro and in vivo?", "sentence2": "Here we show that PRL3-zumab specifically inhibits PRL3+ cancer cells in vivo, but not in vitro.", "label": "no"}
{"id": "converted_3744", "sentence1": "Has tocilizumab been assessed against Covid-19?", "sentence2": "Preliminary clinical results have indicated that antagonism of the IL-6 receptor (IL-6R), including with the FDA-approved humanized monoclonal antibody tocilizumab, can improve the outcomes of patients with severe or critical COVID-19 while maintaining a good safety profile.", "label": "yes"}
{"id": "converted_4138", "sentence1": "Is methotrexate used for the treatment of Rheumatoid Arthritis (RA)?", "sentence2": "The use of methotrexate in rheumatoid arthritis., Historical perspective on the use of methotrexate for the treatment of rheumatoid arthritis., Aminopterin, a folic acid analogue was first reported in 1948 to produce temporary remission of acute leukemia of children, was also reported in 1951 to produce an important and rapid improvement in patients with rheumatoid arthritis (RA) and psoriasis, The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis., Methotrexate (MTX) is currently under study for use in juvenile rheumatoid arthritis. , The rational use of methotrexate in rheumatoid arthritis and other rheumatic diseases., Methotrexate-induced hepatic cirrhosis is less common in rheumatoid arthritis than previously thought, although its occurrence in psoriasis is probably higher than in rheumatoid arthritis. , Methotrexate is clearly effective in the treatment of rheumatoid arthritis and may be able to decrease the rate of formation of new bony erosions. , The use of methotrexate in rheumatoid arthritis., Review of the international literature on the clinical use of MTX in rheumatoid arthritis (RA) disease., MTX has emerged as a relatively safe and effective treatment for RA that compares favorably with other therapies, particularly because of its considerably longer median drug survival., The objective of this review is to update the recommendations of the 2010 Italian Consensus on the use of methotrexate (MTX) in rheumatoid arthritis (RA) and other rheumatic diseases, A new recommendation for patients with RA who are in MTX-induced clinical remission was also proposed and approved by the panel. Updated recommendations for the use of MTX in patients with RA or other rheumatologic disease are proposed., Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1980s and to this day is often the first line medication for RA treatment., OBJECTIVE: Most recommendations for the use of methotrexate (MTX) in rheumatoid arthritis (RA) are issued by developed countries., Low dose pulse methotrexate (MTX) has become a widely used therapy for rheumatoid arthritis (RA) because of its good response rate profile. With, Treatment with methotrexate (MTX) in rheumatoid arthritis (RA) can lead to severe side-effects, especially pulmonary and haematological complications. The ai, Patients having rheumatoid arthritis (RA) treated with methotrexate (MTX) are at an increased risk of developing lymphoproliferative disorder (LPD). Epstei, Increasingly, methotrexate (MTX) and sulphasalazine (SASP) are used initially for second-line therapy of rheumatoid arthritis (RA). Althoug, OBJECTIVES: The folate antagonist methotrexate (MTX) has become established as the most commonly used disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA) but is commonly discontinued due to adverse effe, e suspected methotrexate (MTX)-associated lymphoproliferative disorder (LPD) induced by MTX treatment for rheumatoid arthritis (RA). About , BACKGROUND: Treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) leads to decreased total immunoglobulin (Ig) levels and impairs vaccine-specific IgG antibody levels following pneumococcal vaccinat, In rheumatoid arthritis (RA) treatment, the concomitant use of methotrexate has been shown to reduce the incidence of antibodies to infliximab (ATI), on the other hand, it is unclear whether azathioprine can reduce ATI production. We enro, Methotrexate (MTX) is known as a first-line synthetic disease-modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA)., Biological treatments are expensive and using SC methotrexate can improve disease control in RA patients, thus potentially avoiding or delaying the requirement for future biological treatment., Most recommendations for the use of methotrexate (MTX) in rheumatoid arthritis (RA) are issued by developed countries., We reviewed existing recommendations on the use of MTX for the treatment of RA and summarized areas of agreement that could be relevant for least developed countries (LDCs).M, st covered some but not all of the following areas: baseline \"pre-MTX\" assessment (7/12;58%), prescription of MTX (10/12;83.3%), management of MTX side effects (6/12;50%), and special considerations (e.g., peri-operative management) (8/12; 66.7%). R, lectronic databases and registries were searched for recommendations on MTX use in RA, duplicates were eliminated, and the most updated version adopted when there were several versions on the same recommendation. , MTX must at the present time be used only in severe RA, refractory to more than one classical slow acting drug., MTX is as effective in treating RA as the other second line drugs and always more rapidly effective, perhaps because of anti-inflammatory properties., For the low doses used in RA (less than 15 mg/week), MTX is completely and rapidly absorbed with an active process membrane transport., Methotrexate, which is used for RA treatment, causes thrombocytopenia., Methorexate therapy in a patient with rheumatoid arthritis complicated by idiopathic thrombocytopenic purpura., This case shows that methotrexate may be used in patients diagnosed with RA that is associated with ITP under strict monitoring., Here, we report an RA case that also had ITP, which did not decrease in platelet count after methotrexate therapy., We started methotrexate therapy 10 mg per week for treatment of RA, and hydroxychloroquine therapy was stopped due to nonresponse., Methotrexate (MTX) is the anchor treatment for rheumatoid arthritis (RA) and has been very thoroughly studied in many different patient populations, as monotherapy and in combination with various other disease modifying antirheumatic drugs and biologic agents, as they became available., Although rheumatologists have been using methotrexate in the treatment of RA for some time, controlled studies have been needed to establish the safety and efficacy of this agent., Methotrexate is generally the first-line drug for the treatment of RA, psoriatic arthritis and other forms of inflammatory arthritis, and it enhances the effect of most biologic agents in RA., Despite the introduction of numerous biologic agents for the treatment of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, low-dose methotrexate therapy remains the gold standard in RA therapy., A number of studies show the efficacy of methotrexate (MTX) for rheumatoid arthritis (RA) in general., Methotrexate (MTX) is currently the most frequently used drugs in the treatment of rheumatoid arthritis (RA)., Methotrexate (MTX) has been the anchor treatment in rheumatoid arthritis (RA) over the last 15 years, and is used in combination with biologic agents to enhance efficacy over the last decade or so.", "label": "yes"}
{"id": "converted_1898", "sentence1": "Is Stat4 a transcription factor?", "sentence2": "transcription factors T-bet and STAT4, STAT4 is a member of the signal transducer and activator of transcription (STAT) family of molecules that localizes to the cytoplasm. STAT4 regulates various genes expression as a transcription factor after it is phosphorylated, dimerizes and translocates to the nucleus. , STAT4 is a latent cytosolic factor that encodes a transcription factor transmitting signals stimulated by cytokines. ,  To investigate the role of signal transduction and activation of transcription 4 (STAT4) in the development and progression of human hepatocellular carcinoma (HCC)", "label": "yes"}
{"id": "converted_4546", "sentence1": "Is METTL1 overexpression associated with better patient survival?", "sentence2": " Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of m7G-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. ", "label": "no"}
{"id": "converted_2862", "sentence1": "Does lucatumumab bind to CD140?", "sentence2": "Lucatumumab is a fully humanized anti-CD40 antibody that blocks interaction of CD40L with CD40 and also mediates antibody-dependent cell-mediated cytotoxicity (ADCC). , Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia., Saturation of CD40 receptor on CLL cells was uniform at all doses post-treatment but also persisted at trough time points in the 3.0 mg/kg or greater cohorts.", "label": "no"}
{"id": "converted_1751", "sentence1": "Is Thalidomide currently a marketed drug?", "sentence2": "In this retrospective study, pharmacy claims were analyzed for those patients with a diagnosis of MM who received thalidomide,, The Japanese POEMS syndrome with Thalidomide (J-POST) Trial is a phase II/III multicentre, double-blinded, randomised, controlled trial that aims to evaluate the efficacy and safety of a 24-week treatment with thalidomide in POEMS syndrome,, Thalidomide could relieve clinical symptoms and intestinal mucosal lesions effectively in children with refractory inflammatory bowel disease (IBD) from the pre-clinical study., Thalidomide is now available as an investigational drug in the USA., The STEPStrade mark (System for Thalidomide Education and Prescribing Safety) Program has been developed by Celgene, the commercial manufacturer of thalidomide, to ensure compliance with prescription and usage protocols., New uses of thalidomide., Thalidomide is an anti-angiogenesis agent that currently is being evaluated in the treatment of various types of cancer., The comeback of thalidomide to the legitimate status of a marketed drug came in 1998 when it received FDA approval for the treatment of erythema nodosum leprosum (ENL), Thalidomide is considered the drug of choice for the treatment of ENL, but for other conditions, it is recommended only when resistance to the currently available form of therapy is encountered, Thalidomide is an anti-inflammatory and anti-angiogenic drug currently used for the treatment of several diseases, including erythema nodosum leprosum, which occurs in patients with lepromatous leprosy, Thalidomide, once banned, has returned to the center of controversy with the Food and Drug Administration's (FDA's) announcement that thalidomide will be placed on the market for the treatment of erythema nodosum leprosum, a severe dermatological complication of Hansen's disease. , In 1998, FDA approved the marketing of thalidomide (Thalomid, Celgene). , In 1998 the US Food and Drug Administration approved thalidomide exclusively for the treatment of ENL, and strict conditions were stipulated for its use in order to prevent teratogenic adverse effects., BACKGROUND: The use of thalidomide during the 1950s resulted in teratogenic effects in thousands of infants. Although thalidomide is currently approved for the treatment of a complication of leprosy, it is commercially available to treat other diseases through a controlled distribution system., The comeback of thalidomide to the legitimate status of a marketed drug came in 1998 when it received FDA approval for the treatment of erythema nodosum leprosum (ENL).", "label": "yes"}
{"id": "converted_2512", "sentence1": "Is celiac disease caused by gliadin-induced transglutaminase-2 (TG2)-dependent events ?", "sentence2": "Celiac disease (CD) is a frequent inflammatory intestinal disease, with a genetic background, caused by gliadin-containing food. , Celiac disease (CD) is an autoimmune enteropathy initiated and sustained by the ingestion of gluten in genetically susceptible individuals. It is caused by a dysregulated immune response toward both dietary antigens, the gluten proteins of wheat, rye, and barley, and autoantigens, the enzyme tissue transglutaminase (TG2), Celiac disease (CD) is an autoimmune gastrointestinal disorder characterized by the presence of anti-transglutaminase 2 (TG2) and anti-gliadin antibodies, Transglutaminase 2 (TG2) catalyzes cross-linking or deamidation of glutamine residues in peptides and proteins. The in vivo deamidation of gliadin peptides plays an important role in the immunopathogenesis of celiac disease (CD)., Tissue transglutaminase (TG2) modifies proteins and peptides by transamidation or deamidation of specific glutamine residues. TG2 also has a central role in the pathogenesis of celiac disease. The enzyme is both the target of disease-specific autoantibodies and generates deamidated gliadin peptides recognized by intestinal T cells from patients.", "label": "yes"}
{"id": "converted_4578", "sentence1": "Is the protein HOXA11 associated with endometrial disease?", "sentence2": " Both CD10 and HOXA11 have been implicated in regulation of endometrial homeostasis., Combined expression of HOXA11 and CD10 identifies endometriosis versus normal tissue and tumors., The combination of HOXA11 and CD10 expression profiles provides a useful tool to identify ectopic endometrial tissue and for distinguishing endometriosis from various types of gynecological malignancies and metastases., Downregulation of HOXA11 enhances endometrial cancer malignancy, Low HOXA11 expression may promote the proliferation, migration, invasion of endometrial cancer cells, and increase their resistance to cisplatin through activating PTEN/AKT pathway., Endometrial mRNA and protein expression levels of HOXA10 and HOXA11 were significantly lower in patients with AM than in control patients.", "label": "yes"}
{"id": "converted_1768", "sentence1": "Is there a role of regorafenib for sarcoma treatment?", "sentence2": "Regorafenib has been approved for third-line therapy., Study protocol of REGOSARC trial: activity and safety of regorafenib in advanced soft tissue sarcoma: a multinational, randomized, placebo-controlled, phase II trial., DISCUSSION: The design of this trial allows an assessment of regorafenib activity over placebo in four sarcoma strata and might provide evidence for launching a phase III trial., This case provides rationale for adding a Ewing sarcoma arm to SARC024, a phase II study of regorafenib, another multi-targeted kinase inhibitor, in patients with liposarcoma, osteosarcoma and Ewing and Ewing-like sarcomas (NCT02048371)., Thus, the Phase III studies with pazopanib, regorafenib, muramyl tripeptide (MTP) and ridaforolimus are extensively discussed as well as the biological rationale for the use of these compounds., Currently, regorafenib is examined in several clinical trials (mostly phase II) in different tumor entities, including renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and soft tissue sarcoma (STS)., Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P<0.05)., Parametric and non-parametric statistical analyses were performed as appropriate.RESULTS: After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P<0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P<0.05)., We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.RESULTS: After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P<0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P<0.05)., We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.RESULTS: After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P<0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P<0.05)., We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.RESULTS: After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P<0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P<0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib., After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05).", "label": "yes"}
{"id": "converted_1567", "sentence1": "Does low T3 negatively affect prognosis of patients after cardiac surgery?", "sentence2": "ur findings suggest that the development of LCOS after congenital heart surgery is associated with decreased total and free T3, and increased IL-8 levels at 48 hours, and preoperative tT4 level is an independent predictor of LCOS., Low basal fT3 concentration can reliably predict the occurrence of postoperative AF in CABG patients., A relevant finding was that the days of post-operative hospitalization (10+/-3 days, means+/-S.D.) was inversely correlated with the slope of the recovery of T3 concentration (P<0.001) or with the area under the plasma curves of T3 (P=0.024, time range 72-144 h) and the FT3/FT4 ratio (P=0.037, time range 72-144 h) during the post-operative period. ", "label": "yes"}
{"id": "converted_4585", "sentence1": "Are Tregs CD4(+)CD25(+) regulatory T cells a positive regulator of the immune response?", "sentence2": "The immunosuppressive effects of CD4+ CD25 high regulatory T cells (Tregs) interfere with antitumor immune responses in cancer patients., Alteration of regulatory T cells (Tregs) may contribute to ineffective suppression of proinflammatory cytokines in type 1 diabetes.AIM, Regulatory T cells (Tregs) suppress excessive immune responses in IRI, CD4(+)CD25(+) regulatory T cells (Tregs) are negative regulators of the immune system that induce and maintain immune tolerance., lar to chronic patients, Treg from patients with PHI inhibited the proliferation of purified tuberculin (PPD) and HIV p24 activated CD4CD25 T cells. CD4,  demonstrate that aTregs are necessary for tolerance, DBA/2 skin was transplanted onto C57BL/6-RAG-1-deficient recipients adoptively transferred with purified sorted CD4CD25 T cells; half of the recipients undergo tolerance induction treatment.RE, It is well established that CD4CD25 regulatory T cells (Tregs) downregulate inflammatory immune responses and help to maintain immune homeostasis., In vitro expanded human CD4+CD25+ regulatory T cells are potent suppressors of T-cell-mediated xenogeneic responses., BACKGROUND: Regulatory T cells (Tregs) are essential in the control of tolerance., CD4(+)CD25(+) regulatory T cells (Tregs) are critical for the peripheral immune tolerance., T regulatory cells (Tregs) have a role in immunosuppression and control of autoimmunity, and are currently an important topic in the study of immune response to tumor cells., CD4+CD25+ regulatory T cells attenuate lipopolysaccharide-induced systemic inflammatory responses and promotes survival in murine Escherichia coli infection., OBJECTIVES: CD4CD25 regulatory T cells (Tregs) play a key role in the prevention of various inflammatory and autoimmune disorders by suppressing immune responses., CD25(High) CD4+ regulatory T cells (Treg cells) have been described as key players in immune regulation, preventing infection-induced immune pathology and limiting collateral tissue damage caused by vigorous anti-parasite immune response. In t, ic subset of T cells, currently recognized as FOXP3(+) CD25(+) CD4(+) regulatory T cells (Tregs), are pivotal in suppressing autoimmunity and maintaining immune homeostasis by mediating self-tolerance at the periphery as shown in autoimmune diseases and cancers. A growing body of , CD4+CD25+ regulatory T cells (Tregs) are essential negative regulators of immune responses. , Accumulating evidence has demonstrated that naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) are critical for maintenance of immunological tolerance and have been shown to be important in regulating the immune responses in many diseases. Curcu, 4+CD25+ Foxp3+ regulatory T cells (Tregs) are recognized as one of the major regulatory factors in immune tolerance and inflammatory responses. Si, lly occurring CD4(+)CD25(+) regulatory T cells (Tregs) have a key role in the prevention of various inflammatory and autoimmune disorders by suppressing immune responses. We tested t, CD4(+)CD25(+) regulatory T cells (Tregs) are considered to play a key role as suppressors of immune mediated reactions. The a, CD4+ CD25+ T regulatory cells (Tregs) are classified as a subset of T cells whose role is the suppression and regulation of immune responses to self and non-self. , CD4(+)CD25(+) regulatory T cells (Tregs) are potent modulators of immune responses., CD4+ T cells naturally expressing CD25 molecules (natural T regulatory cells (Tregs)) have a role in maintaining self tolerance and in regulating responses to infectious agents, transplantation Ags, and tumor Ags., Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) are essential for the active suppression of autoimmunity., Amongst these, naturally occurring CD4(+)CD25(+) Treg cells (nTreg) represent a major lymphocyte population engaged in the dominant control of self-reactive T responses and maintaining tolerance in several models of autoimmunity., CD4+CD25+ regulatory T cells (Tregs) are essential negative regulators of immune responses., Naturally occurring CD4(+)CD25(+)FoxP3(+) regulatory T cells (CD25(+) Tregs) constitute a specialized population of T cells that is essential for the maintenance of peripheral self-tolerance., One of the subpopulations of CD4+ T cells that express CD25+ and the transcription factor FOXP3, known as Regulator T cells (TReg), plays an essential role in maintaining tolerance and immune homeostasis preventing autoimmune diseases, minimalize chronic inflammatory diseases by enlisting various immunoregulatory mechanisms., Regulatory T cells (Tregs) are CD4(+)CD25(bright)CD62L(high) cells that actively down-regulate immune responses., CD4(+)CD25(+) regulatory T cells (Treg) play a central role in the prevention of autoimmunity and in the control of immune responses by down-regulating the function of effector CD4(+) or CD8(+) T cells., FoxP3(+)CD25(+)CD4(+) regulatory T cells (Tregs) suppress a variety of normal physiological and pathological immune responses via several pathways, such as inhibitory cytokine secretion, direct cytolysis induction, and antigen-presenting cell functional modulation., Regulatory CD4(+) CD25(+) T (Treg) cells with the ability to suppress host immune responses against self- or non-self antigens play important roles in the processes of autoimmunity, transplant rejection, infectious diseases and cancers., BACKGROUND: Evidence indicating that CD4+CD25+ regulatory T (Treg) cells play a crucial role in the maintenance of peripheral T cell tolerance to allergens has been ", "label": "no"}
{"id": "converted_4609", "sentence1": "Do the proteins Talin and Amot interact?", "sentence2": "we show that Amot binds Talin and is essential for relaying forces between fibronectin and the cytoskeleton", "label": "yes"}
{"id": "converted_2391", "sentence1": "Does the association of PARP1 and CTCF follow a circadian rhythm?", "sentence2": "here we uncovered an inter-chromosomal network connecting active loci enriched in circadian genes to repressed lamina-associated domains (LADs)., Synchronization of the circadian rhythm by serum shock induces oscillations in PARP1-CTCF interactions, which is accompanied by oscillating recruitment of circadian loci to the lamina, followed by the acquisition of repressive H3K9me2 marks and transcriptional attenuation, PARP1- and CTCF-regulated contacts between circadian loci and the repressive chromatin environment at the lamina therefore mediate circadian transcriptional plasticity., Synchronization of the circadian rhythm by serum shock induces oscillations in PARP1-CTCF interactions, which is accompanied by oscillating recruitment of circadian loci to the lamina, followed by the acquisition of repressive H3K9me2 marks and transcriptional attenuation. Furthermore, depletion of H3K9me2/3, inhibition of PARP activity by olaparib, or downregulation of PARP1 or CTCF expression counteracts both recruitment to the envelope and circadian transcription. PARP1- and CTCF-regulated contacts between circadian loci and the repressive chromatin environment at the lamina therefore mediate circadian transcriptional plasticity., transcriptionally active and inactive chromatin domains tend to segregate into separate sub nuclear compartments to maintain stable expression patterns however here we uncovered an inter chromosomal network connecting active loci enriched in circadian genes to repressed lamina associated domains lads the interactome is regulated by parp1 and its co factor ctcf they not only mediate chromatin fiber interactions but also promote the recruitment of circadian genes to the lamina synchronization of the circadian rhythm by serum shock induces oscillations in parp1 ctcf interactions which is accompanied by oscillating recruitment of circadian loci to the lamina followed by the acquisition of repressive h3k9me2 marks and transcriptional attenuation furthermore depletion of h3k9me2 3 inhibition of parp activity by olaparib or downregulation of parp1 or ctcf expression counteracts both recruitment to the envelope and circadian transcription parp1 and ctcf regulated contacts between circadian loci and the repressive chromatin environment at the lamina therefore mediate circadian transcriptional plasticity., Synchronization of the circadian rhythm by serum shock induces oscillations in PARP1-CTCF interactions, which is accompanied by oscillating recruitment of circadian loci to the lamina, followed by the acquisition of repressive H3K9me2 marks and transcriptional attenuation.", "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. ", "label": "yes"}
{"id": "converted_3479", "sentence1": "Is modified vaccinia Ankara effective for smallpox?", "sentence2": "BACKGROUND: Modified Vaccinia Ankara (MVA) is a live, viral vaccine under advanced development as a non-replicating smallpox vaccine. , The three MVA lots induced equivalent antibody titers two weeks after the second vaccination, with seroconversion rates of 99·8% (PRNT) and 99·7% (ELISA). , INTRODUCTION: To guide the use of modified vaccinia Ankara (MVA) vaccine in response to a release of smallpox virus, the immunogenicity and safety of shorter vaccination intervals, and administration by jet injector (JI), were compared to the standard schedule of administration on Days 1 and 29 by syringe and needle (S&N)., Erratum: Safety and Immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic Smallpox Vaccine in Vaccinia-Naive and Experienced Human Immunodeficiency Virus-Infected Individuals: An Open-Label, Controlled Clinical Phase II Trial., Modified vaccinia Ankara virus (MVA) is a smallpox vaccine candidate. , A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN®) in 56-80-Year-Old Subjects., BACKGROUND: Modified Vaccinia Ankara MVA-BN® is a live, highly attenuated, viral vaccine under advanced development as a non-replicating smallpox vaccine. , CONCLUSIONS: One or two doses of MVA were safe and immunogenic in a 56-80 years old vaccinia-experienced population. , The results suggest that a single dose of MVA in a 56-80 years old population was well tolerated and sufficient to rapidly boost the long-term B cell memory response induced by a prior vaccination with a traditional smallpox vaccine., Modified Vaccinia Ankara (MVA) poxvirus has been assessed for cardiac safety in a large placebo-controlled clinical trial., BACKGROUND: Modified vaccinia Ankara (MVA) is being developed as a safer smallpox vaccine and is being placed in the US Strategic National Stockpile (SNS) as a liquid formulation for subcutaneous (SC) administration at a dose of 1×10(8) TCID50 in a volume of 0.5mL. , IMVAMUNE, an attenuated modified vaccinia Ankara virus vaccine for smallpox infection., Bavarian Nordic is developing IMVAMUNE, which is based on a live attenuated modified vaccinia Ankara virus, for the potential prevention of smallpox infection, particularly in those patients contraindicated to traditional smallpox vaccines, such as the immunocompromised and those with eczema or dermatitis., IMVAMUNE: modified vaccinia Ankara strain as an attenuated smallpox vaccine., Modified vaccinia Ankara: potential as an alternative smallpox vaccine., Evaluation of modified vaccinia virus Ankara as an alternative vaccine against smallpox in chronically HIV type 1-infected individuals undergoing HAART., Modified vaccinia Ankara: potential as an alternative smallpox vaccine, Modified vaccinia Ankara ( MVA ) is being developed as a safer smallpox vaccine and is being placed in the US Strategic National Stockpile ( SNS ) as a liquid formulation for subcutaneous ( SC ) administration at a dose of 1×10 ( 8 ) TCID50 in a volume of 0.5mL, Modified vaccinia Ankara was safe and immunogenic in subjects infected with HIV and represents a promising smallpox vaccine candidate for use in immunocompromised populations, Bavarian Nordic is developing IMVAMUNE , which is based on a live attenuated modified vaccinia Ankara virus , for the potential prevention of smallpox infection , particularly in those patients contraindicated to traditional smallpox vaccines , such as the immunocompromised and those with eczema or dermatitis, One of the most advanced and most promising vectors is the attenuated , non-replicating poxvirus MVA ( modified vaccinia virus Ankara) , a safer derivative of the uniquely successful smallpox vaccine, Modified vaccinia virus Ankara ( MVA ) is a highly attenuated vaccinia virus that is under consideration as an alternative to the conventional smallpox vaccine Dryvax, Modified Vaccinia virus Ankara ( MVA ) is an attenuated derivative , also used in the smallpox eradication campaign and now being developed as a recombinant viral vector to produce vaccines against infectious diseases and cancer, While modified vaccinia virus Ankara ( MVA ) is currently in clinical development as a safe vaccine against smallpox and heterologous infectious diseases , its immunogenicity is likely limited due to the inability of the virus to replicate productively in mammalian hosts, Modified vaccinia Ankara was safe and immunogenic in subjects infected with HIV and represents a promising smallpox vaccine candidate for use in immunocompromised populations., Modified Vaccinia virus Ankara (MVA) is a replication-deficient and attenuated derivative, also used in the smallpox eradication campaign and now being developed as a recombinant viral vector to produce vaccines against infectious diseases and cancer.,  Modified vaccinia Ankara was safe and immunogenic in subjects infected with HIV and represents a promising smallpox vaccine candidate for use in immunocompromised populations.", "label": "yes"}
{"id": "converted_2587", "sentence1": "Are sleep apnea and snoring associated with cardiac arrhythmias?", "sentence2": "Atrial fibrillation (AF) is the commonest arrhythmia in clinical practice and is associated with increased cardiovascular morbidity and mortality. Obstructive sleep apnea (OSA), a common breathing disorder, is an independent risk factor for AF., There is a growing consensus in the scientific community that suggests a strong association between obstructive sleep apnea (OSA) and cardiovascular (CVD) conditions and events, including coronary artery disease, hypertension, arrhythmia, heart failure, and sudden cardiac death. , part from well-established risk factors that increase the odds for the development of AF, e.g. age or arterial hypertension, recent analyses indicate that obstructive sleep apnoea (OSA) may independently, negatively modify the arrhythmia occur-rence profile. , Evidence supports a causal association of sleep apnea with the incidence and morbidity of hypertension, coronary heart disease, arrhythmia, heart failure, and stroke., Severe snoring may be associated with pulmonary and systemic hypertension, secondary polycythemia, and cardiac arrhythmias.<br>, Severe snoring may be associated with pulmonary and systemic hypertension, secondary polycythemia, and cardiac arrhythmias., BACKGROUND AND PURPOSE Nocturnal cardiac arrhythmias occur in patients with obstructive sleep apnea (OSA), reportedly as a consequence of the autonomic effects of recurrent apnea with subsequent oxygen desaturation., Obstructive apnea is associated with myocardial ischemia (silent or symptomatic), acute coronary events, stroke and transient ischemic attacks, cardiac arrhythmia, pulmonary hypertension and heart failure., Obstructive sleep apnea (OSA) is the most common form of sleep-disordered breathing, affecting 5-15% of the population. It is characterized by intermittent episodes of partial or complete obstruction of the upper airway during sleep that disrupts normal ventilation and sleep architecture, and is typically associated with excessive daytime sleepiness, snoring, and witnessed apneas. Patients with obstructive sleep apnea present risk to the general public safety by causing 8-fold increase in vehicle accidents, and they may themselves also suffer from the physiologic consequences of OSA; these include hypertension, coronary artery disease, stroke, congestive heart failure, pulmonary hypertension, and cardiac arrhythmias, Obstructive sleep apnea and central sleep apnea with Cheyne-Stokes respiration                     are associated with an increased risk of cardiac arrhythmia. , Obstructive sleep apnea (OSA) affects approximately 4% of middle-aged men and 2% of middle-aged women. Cardiac arrhythmias are common problems in patients with OSA, even though the true prevalence and clinical relevance of cardiac arrhythmias remains to be determined. , Cardiac arrhythmias during wakefulness and sleep in 15 patients with sleep-induced obstructive apnea, and the effect of atropine and tracheostomy on these arrhythmias were studied by continuous overnight Holter electrocardiographic, respiratory and electroencephalographic recordings., obstructive sleep apnea (OSA) as its most extreme variant, is characterized by intermittent episodes of partial or complete obstruction of the upper airway, leading to cessation of breathing while asleep. Cardiac arrhythmias are common problems in OSA patients, although the true prevalence and clinical relevance of cardiac arrhythmias remains to be determined, The mechanisms associated with the cardiovascular consequences of obstructive sleep apnea include abrupt changes in autonomic tone, which can trigger cardiac arrhythmias. ,  Recent studies have shown that cardiac arrhythmias and conduction disorders are common in patients with SA. Sleep apnea, Severity of nocturnal cardiac arrhythmias correlates with intensity of sleep apnea in men, Patients affected with OSA are frequently hypertensive and can have dangerous cardiac arrhythmias., Patients with stable cardiac failure who snore may present sleep hypopnea and cardiac arrhythmias. ,  Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality. Cardiac arrhythmias are common in patients with OSA. , Nocturnal hypoxia has been associated with serious ventricular tachyarrhythmias as well as life-threatening bradyarrhythmias. Obesity and snoring, both of which increase with age, have been identified as risk factors for sleep-related breathing disorders, as have hypertension and heart disease., Obstructive sleep apnea syndrome is associated with excess daytime sleepiness, depression, and an increased incidence of ischemic cardiopathy, cardiac arrhythmias, systemic hypertension and brain infarction., We found 58 percent prevalence of arrhythmias in patients with sleep apnea (apnea/hypopnea index = AHI>10), vs 42 percent in nonapneic controls (chi 2 = 16.7, p<0.0001)", "label": "yes"}
{"id": "converted_3111", "sentence1": "Does Axitinib prolong survival of Pancreatic Cancer patients?", "sentence2": "CONCLUSIONS: Axitinib/gemcitabine, while tolerated, did not provide survival benefit over gemcitabine alone in patients with advanced pancreatic cancer from Japan or other regions., RESULTS: Among Japanese patients, median overall survival was not estimable (95% confidence interval, 7.4 months-not estimable) with axitinib/gemcitabine (n = 58) and 9.9 months (95% confidence interval, 7.4-10.5) with placebo/gemcitabine (n = 56) (hazard ratio 1.093 [95% confidence interval, 0.525-2.274]). Median survival follow-up (range) was 5.1 months (0.02-12.3) with axitinib/gemcitabine vs. 5.4 months (1.8-10.5) with placebo/gemcitabine. Similarly, no difference was detected in overall survival between axitinib/gemcitabine and placebo/gemcitabine in patients from North America or the European Union. , At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9-9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9-10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786-1·309; one-sided p=0·5436). , INTERPRETATION: The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. , INTERPRETATION\nThe addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer., However, as with other tyrosine kinase inhibitors of the same class, axitinib does not prolong overall survival; therefore, selection of second-line tyrosine kinase inhibitor therapy, including axitinib, must be carefully considered to maximize outcomes for each patient., CONCLUSIONS\nAxitinib/gemcitabine, while tolerated, did not provide survival benefit over gemcitabine alone in patients with advanced pancreatic cancer from Japan or other regions., Similarly, no difference was detected in overall survival between axitinib/gemcitabine and placebo/gemcitabine in patients from North America or the European Union., Axitinib/gemcitabine, while tolerated, did not provide survival benefit over gemcitabine alone in patients with advanced pancreatic cancer from Japan or other regions., The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer.", "label": "no"}
{"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.", "label": "yes"}
{"id": "converted_388", "sentence1": "Is there an association between borna virus and brain tumor?", "sentence2": "Borna disease virus (BDV), a nonsegmented, negative-strand RNA virus, infects a wide variety of mammalian species and readily establishes a long-lasting, persistent infection in brain cells. , To investigate the biological characteristics of field isolates of Borna disease virus (BDV), as well as to understand BDV infections outside endemic countries, we isolated the virus from brain samples of a heifer with Borna disease in Japan., Neonatal Borna disease virus (BDV) infection of the rat brain is associated with microglial activation and damage to the certain neuronal populations., In addition, compared to uninfected mixed cultures, activation of microglia in BDV-infected mixed cultures was associated with a significantly greater lipopolysaccharide-induced release of tumor necrosis factor alpha, interleukin 1beta, and interleukin 10. Taken together, the present data are the first in vitro evidence that persistent BDV infection of neurons and astrocytes rather than direct exposure to the virus or dying neurons is critical for activating microglia., Usually, Borna disease virus is not cleared from the brain but rather persists in neural cells., Varied persistent life cycles of Borna disease virus in a human oligodendroglioma cell line., Borna disease virus (BDV) establishes a persistent infection in the central nervous system of vertebrate animal species as well as in tissue cultures. , Thus, our findings show that BDV may have established a persistent infection at low levels of viral expression in OL cells with the possibility of a latent infection., These results suggested that BDV infection may cause direct damage in the developing brain by inhibiting the function of amphoterin due to binding by the p24 phosphoprotein., We describe a model for investigating disorders of central nervous system development based on neonatal rat infection with Borna disease virus, a neurotropic noncytolytic RNA virus. , Borna disease virus (BDV) replicates in brain cells. The neonatally infected rat with BDV exhibits developmental-neuromorphological abnormalities, neuronal cytolysis, and multiple behavioral and physiological alterations. , Borna disease virus (BDV) causes central nervous system (CNS) disease in several vertebrate species, which is frequently accompanied by behavioral abnormalities., Intrinsic responses to Borna disease virus infection of the central nervous system., Immune cells invading the central nervous system (CNS) in response to Borna disease virus (BDV) antigens are central to the pathogenesis of Borna disease (BD). , We report here the partial purification and characterization of cell-free BDV from the tissue culture supernatant of infected human neuroblastoma SKNSH cells., We have used the reverse transcriptase-polymerase chain reaction technique to gain insight into the pathogenesis of encephalitis caused by Borna disease virus (BDV). , In contrast, in the BDV-infected primary mixed cultures, we observed proliferation of microglia cells that acquired the round morphology and expressed major histocompatibility complex molecules of classes I and II.", "label": "no"}
{"id": "converted_214", "sentence1": "Are there focused databases from which you can retrieve gene expression data on renal disease?", "sentence2": "Proteomics database in chronic kidney disease, Naturally occurring human urinary peptides for use in diagnosis of chronic kidney disease", "label": "yes"}
{"id": "converted_1166", "sentence1": "Are CpG islands located close to housekeeping genes?", "sentence2": "our analysis indicates that the association of CGIs with housekeeping genes is not as strong as previously estimated, CpG islands are preferentially located at the start of transcription of housekeeping genes and are associated with tissue-specific genes, It has been envisaged that CpG islands are often observed near the transcriptional start sites (TSS) of housekeeping genes., These regions represent about 1% of genomic DNA and are generally found in the promoter region of housekeeping genes., CpG islands are stretches of DNA sequence that are enriched in the (CpG)n repeat and are present in close association with all housekeeping genes as well as some tissue-specific genes in the mammalian genome., CpG islands, which are found almost exclusively at the 5'-end of housekeeping genes, In housekeeping and many tissue-specific genes, the promoter is embedded in a so-called CpG island., All housekeeping and widely expressed genes have a CpG island covering the transcription start, whereas 40% of the genes with a tissue-specific or limited expression are associated with islands, Methylation-free CpG clusters, so-called HTF islands, are most often associated with the promoter regions of housekeeping genes, whereas genes expressed in a single-cell type are usually deficient in these sequences., Unmethylated CpG rich islands are a feature of vertebrate DNA: they are associated with housekeeping and many tissue specific genes., CpG islands were associated with the 5' ends of all housekeeping genes and many tissue-specific genes, and with the 3' ends of some tissue-specific genes.", "label": "yes"}
{"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.", "label": "yes"}
{"id": "converted_2779", "sentence1": "Are there microbes in human breast milk?", "sentence2": "Contrary to long-held dogma, human milk is not sterile. Instead, it provides infants a rich source of diverse bacteria, particularly microbes belonging to the Staphylococcus, Streptococcus, and Pseudomonas genera., The origins of the bacteria in milk are thought to include the maternal gastrointestinal tract (via an entero-mammary pathway) and through bacterial exposure of the breast during nursing.", "label": "yes"}
{"id": "converted_1340", "sentence1": "Are there enhancer RNAs (eRNAs)?", "sentence2": "active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription,  eRNAs may then facilitate enhancer-promoter interaction or activate promoter-driven transcription, Enhancer RNAs: a class of long noncoding RNAs synthesized at enhancers, Enhancer RNAs and regulated transcriptional programs, enhancers have been found to be broadly transcribed, resulting in the production of enhancer-derived RNAs, or eRNAs, The emerging roles of eRNAs in transcriptional regulatory networks, we found certain enhancer RNAs (eRNAs) regulate chromatin accessibility of the transcriptional machinery at loci encoding master regulators of myogenesis (i.e., MyoD/MyoG), thus suggesting their significance and site-specific impact in cellular programming, Enhancer RNAs: the new molecules of transcription,  the discovery that distal regulatory elements known as enhancers are transcribed and such enhancer-derived transcripts (eRNAs) serve a critical function in transcriptional activation has added a new dimension to transcriptional regulation, eRNAs reach the heart of transcription, Recent studies have disclosed the function of enhancer RNAs (eRNAs), which are long non-coding RNAs transcribed from gene enhancer regions, in transcriptional regulation., Since the discovery that many transcriptional enhancers are transcribed into long noncoding RNAs termed \"enhancer RNAs\" (eRNAs), their putative role in enhancer function has been debated., Recent studies have revealed that active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs)., Enhancer RNAs (eRNAs) are a class of long noncoding RNAs (lncRNA) expressed from active enhancers, whose function and action mechanism are yet to be firmly established., In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs)., In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs). , A subset of enhancers are occupied by RNA polymerase II (RNAP II) and transcribed to produce long non-coding RNAs termed eRNAs. , Very recent evidence has indicted that some eRNAs play a role in initiating or activating transcription, possibly by helping recruit and/or stabilize binding of the general transcription machinery to the proximal promoter of their target genes. , In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs). However, it has remained unclear whether these eRNAs are functional or merely a reflection of enhancer activation. , Notably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 monomethylated at lysine 4. The level of eRNA expression at neuronal enhancers positively correlates with the level of messenger RNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis., A function of CBP at enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of enhancers. Notably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 monomethylated at lysine 4.,  Enhancer RNAs (eRNAs) are a class of long noncoding RNAs (lncRNA) expressed from active enhancers, whose function and action mechanism are yet to be firmly established. Here we show that eRNAs facilitate the transition of paused RNA polymerase II (RNAPII) into productive elongation by acting as a decoy for the negative elongation factor (NELF) complex upon induction of immediate early genes (IEGs) in neurons., Recent studies have disclosed the function of enhancer RNAs (eRNAs), which are long non-coding RNAs transcribed from gene enhancer regions, in transcriptional regulation., Recent studies have revealed that active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription., Enhancer RNAs (eRNAs) are a class of long noncoding RNAs (lncRNA) expressed from active enhancers,, In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs). However, it has remained unclear whether these eRNAs are functional or merely a reflection of enhancer activation.,  Recent studies have revealed that active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription.", "label": "yes"}
{"id": "converted_1491", "sentence1": "Is there any research that relates the function of Notch Signaling with Alzheimer Disease?", "sentence2": "RIP regulates signaling pathways by abrogating or releasing signaling molecules. Since the discovery, already >15 years ago, of its catalytic component, presenilin, and even much earlier with the identification of amyloid precursor protein as its first substrate, γ-secretase has been commonly associated with Alzheimer's disease. However, starting with Notch and thereafter a continuously increasing number of novel substrates, γ-secretase is becoming linked to an equally broader range of biological processes., In the last decade, increasing evidence has pointed out an important role of this pathway beyond embryonic development, indicating that Notch also displays a critical function in the mature brain of vertebrates and invertebrates. This pathway appears to be involved in neural progenitor regulation, neuronal connectivity, synaptic plasticity and learning/memory. In addition, Notch appears to be aberrantly regulated in neurodegenerative diseases, including Alzheimer's disease and ischemic injury, Along with β-secretase, this enzyme produces the amyloid β-protein of Alzheimer's disease (AD) from the amyloid β-protein precursor. Because of its key role in the pathogenesis of AD, γ-secretase has been a prime target for drug discovery, and many inhibitors of this protease have been developed. The therapeutic potential of these inhibitors is virtually negated by the fact that γ-secretase is an essential part of the Notch signaling pathway, rendering the compounds unacceptably toxic upon chronic exposure, High physiological concentrations of Aβ monomer induced angiogenesis by a conserved mechanism that blocks γ-secretase processing of a Notch intermediate, NEXT, and reduces the expression of downstream Notch target genes. Our findings allude to an integration of signaling pathways that utilize γ-secretase activity, which may have significant implications for our understanding of Alzheimer's pathogenesis vis-à-vis vascular changes that set the stage for ensuing neurodegeneration., Aggregated forms of Aβ have a pathogenic role in Alzheimer disease and, thus, reducing the Aβ levels by inhibiting γ-secretase is a possible treatment strategy for Alzheimer disease. Regrettably, clinical trials have shown that inhibition of γ-secretase results in Notch-related side effects. Therefore, it is of great importance to find ways to inhibit amyloid precursor protein (APP) processing without disturbing vital signaling pathways such as Notch. Nicastrin (Nct) is part of the γ-secretase complex and has been proposed to be involved in substrate recognition and selection", "label": "yes"}
{"id": "converted_4587", "sentence1": "Does atemoya juice inhibit the CYP1A2 enzyme?", "sentence2": "Atemoya juice significantly inhibited CYP1A2 activity in human liver microsomes, but not the activities of CYP2C9 and CYP3A., This suggests that the intake of an excess amount of atemoya juice is necessary to cause a change in the pharmacokinetics of phenacetin when the IC50 values for CYP1A2 inhibition by atemoya and fluvoxamine are taken into account", "label": "yes"}
{"id": "converted_3904", "sentence1": "Is Ixodes a species of tick?", "sentence2": "ixodid ticks, ixodid ticks ,  ixodid ticks, tick, Ixodes ricinus, hard ticks (family Ixodidae), The two enzootic tick vectors, Ixodes affinis and Ixodes minor, rarely bite humans but are more important than the human biting \"bridge\" vector, Ixodes scapularis, in maintaining the enzootic spirochete cycle in nature., is more common in coastal habitats, where a greater diversity of Ixodes species ticks are found feeding on small mammal hosts (four species when compared with only I. pacificus in other sampled habitats)., We found three of five previously reported tick species as well as a tick resembling the eastern North American tick Ixodes minor Neumann (which we here designate Ixodes \"Mojave morphotype\") on isolated Amargosa voles and Owens Valley voles (Microtus californicus vallicola Bailey) in Inyo County in 2012 and 2014., THODS: We focused on the well-studied tick genus Ixodes from which many species are known to transmit zoonotic diseases to humans. W, Ectoparasites of Microtus californicus and Possible Emergence of an Exotic Ixodes Species Tick in California., Since 2007, non-native tick species have been documented in the state every year, including Amblyomma americanum, Dermacentor andersoni, Dermacentor occidentalis, Dermacentor variabilis, Ixodes pacificus, Ixodes ricinus, Ixodes scapularis, Ixodes texanus, and Rhipicephalus sanguineus sensu lato (s.l.)., in 1.5% of Ixodes species ticks and 3.6% of small mammals., Data-driven predictions and novel hypotheses about zoonotic tick vectors from the genus Ixodes., spirochetes and transmitted by Ixodes species ticks., In this study, cutaneous bite-site lesions were analyzed using Affymetrix mouse genome 430A 2.0 arrays and histopathology at 1, 3, 6, and 12 hours after uninfected Ixodes scapularis nymphal tick attachment., The minimally vegetated, extremely arid desert surrounding the pools is essentially uninhabitable for Ixodes species ticks., Biology of Ixodes species ticks in relation to tick-borne zoonoses., Borrelia miyamotoi is a newly described emerging pathogen transmitted to people by Ixodes species ticks and found in temperate regions of North America, Europe, and Asia., Rickettsia conorii was found in virtually all non- Ixodes tick species from Albania and Turkey., Ixodes anatis is a species of endophilic (nidicolous) tick species parasitizing brown kiwi (Apteryx mantelli). Even, Ixodes ariadnae is a tick species of bats so far reported only in Central Europe, with its description based on the female and nymph. Th, BACKGROUND: Ixodes collaris Hornok, 2016 is a recently discovered tick species associated with bats, Ixodes holocyclus (Acarina: Ixodidae) and Ixodes cornuatus (Acarina: Ixodidae) are two tick species found in the more densely populated areas of Australia and are known to be the cause of the neurotoxic disease tick paralysis in humans and mammals. Borre, Ixodes affinis Neumann (Acari: Ixodidae) is a hard-bodied tick species distributed throughout much of the southeastern United States. Alt, ixodid tick fauna consists of 241 species in the genus Ixodes and 442 species in the genera Amblyomma, Anomalohimalaya, Bothriocroton, Cosmiomma, Dermacentor, Haemaphysalis, Hyalomma, Margaropus, Nosomma, Rhipicentor and Rhipicephalus in the family Ixodidae, with the genus Boophilus becoming a subgenus of the genus Rhipicephalus. The family Nutt, e following 16 ixodid tick species were identified: Ixodes fuscipes, Amblyomma auricularium, Amblyomma coelebs, Amblyomma dubitatum, Amblyomma geayi, Amblyomma humerale, Amblyomma latepunctatum, Amblyomma longirostre, Amblyomma naponense, Amblyomma nodosum, Amblyomma oblongoguttatum, Amblyomma ovale, Amblyomma romitii, Amblyomma rotundatum, Amblyomma scalpturatum, and Amblyomma varium. From these, A. aur, In 2014, a new tick species, Ixodes inopinatus, was described, which is closely related to Ixodes ricinus. So fa, ontinent. Zoonotic Babesia is vectored by Ixodes ticks and is commonly transmitted in North America by Ixodes scapularis, the tick species responsible for transmitting the pathogens that also cause Lyme disease, Powassan virus, and anaplasmosis in hu, In addition to identifying novel, testable hypotheses about intrinsic features driving vectorial capacity across Ixodes tick species, our model identifies particular Ixodes species with the highest probability of carrying zoonotic diseases, offering specific targets for increased zoonotic investigation and surveillance., To date, the tick fauna of this area consists of 117 species in the following families: Argasidae-Argas (7 species), Carios (4 species) and Ornithodoros (2 species); Ixodidae-Amblyomma (8 species), Anomalohimalaya (2 species), Dermacentor (12 species), Haemaphysalis (44 species), Hyalomma (6 species), Ixodes (24 species) and Rhipicephalus (8 species)., During a 3-yr comprehensive study, 196 ixodid ticks (9 species) were collected from 89 passerine birds (32 species) from 25 localities across Canada to determine the distribution of avian-associated tick species and endogenous Lyme disease spirochetes, Borrelia burgdorferi Johnson, Schmid, Hyde, Steigerwalt, and Brenner., In the Polish fauna there are 19 species of ticks (Ixodida) recognized as existing permanently in our country: Argas reflexus, Argas polonicus, Carios vespertilionis, Ixodes trianguliceps, Ixodes arboricola, Ixodes crenulatus, Ixodes hexagonus, Ixodes lividus, Ixodes rugicollis, Ixodes caledonicus, Ixodes frontalis, Ixodes simplex, Ixodes vespertilionis, Ixodes apronophorus, Ixodes persulcatus, Ixodes ricinus, Haemaphysalis punctata, Haemaphysalis concinna, Dermacentor reticulatus., Occasionally, alien species of ticks transferred to the territory of Poland are recorded: Amblyomma sphenodonti, Amblyomma exornatum, Amblyomma flavomaculatum, Amblyomma latum, Amblyomma nuttalli, Amblyomma quadricavum, Amblyomma transversale, Amblyomma varanensis, Amblyomma spp., Dermacentor marginatus, Hyalomma aegyptium, Hyalomma marginatum, Ixodes eldaricus, Ixodes festai, Rhipicephalus rossicus, Rhipicephalus sanguineus., Haemaphysalis leporispalustris (Packard) (one nymph, 14 larvae); the bird tick Ixodes brunneus Koch (two larvae); the American dog tick, Dermacentor variabilis (Say) (one nymph); and Ixodes affinis Neumann (one larva)., Four members of the Ixodes ricinus species complex, Ixodes pacificus, Ixodes persulcatus, Ixodes ricinus and Ixodes scapularis, have, between them, a worldwide distribution within the northern hemisphere., Diapause in ticks of the medically important Ixodes ricinus species complex., Herein, we report these ticks to represent three different species: Ixodes catarinensis n. sp., We found that 430 endemic ticks were from 3 Ixodes species: Ixodes pacificus, Ixodes spinipalpis, and Ixodes angustus, whereas Ixodes scapularis (n = 111) was the most common species among the 119 nonendemic ticks., In total, 549 human-biting Ixodes ticks were submitted comprising both endemic and nonendemic species., Human-Biting Ixodes Ticks and Pathogen Prevalence from California, Oregon, and Washington., In this study, we show that many nonendemic Ixodes ticks (119/549) are most likely acquired from travel to a different geographic region., The Ixodes ricinus species complex is a group of ticks distributed in almost all geographic regions of the world., We report a tick associated with the enhancement of mammalian meat anaphylaxis after tick bite which is novel for both Australia and the world and establishes Ixodes (Endopalpiger) australiensis as a second tick species associated with mammalian meat allergy in Australia., Among the various species of hard ticks, Ixodes ricinus is the most frequently found tick throughout Europe.,  in humans. We aimed to identify intrinsic traits that predict which Ixodes tick species are confirmed or strongly suspected to be vectors of zoonotic pathogens.METHODS: We focused on the well-studied tick genus Ixodes from which many species are known to transmit zoonoti, A list of the 70 species of Australian ticks; diagnostic guides to and species accounts of Ixodes holocyclus (paralysis tick), Ixodes cornuatus (southern paralysis tick) and Rhipicephalus australis (Australian cattle tick); and consideration of the place of Australia in the evolution of ticks with comments on four controversial ideas., Differentiation of medically important Euro-Asian tick species Ixodes ricinus, Ixodes persulcatus, Ixodes hexagonus, and Dermacentor reticulatus by polymerase chain reaction., All these I. granulatus ticks collected from Taiwan and Japan were genetically affiliated to a monophyletic group with highly homogeneous sequences (95.8-99.5% similarity), and can be discriminated from other species and subgenera of Ixodes ticks with a sequence divergence ranging from 13.6% to 62.9%., The phylogenetic relationships were analyzed by comparing the sequences of mitochondrial 16S ribosomal DNA gene obtained from 19 strains of ticks representing seven species of Ixodes and two outgroup species (Rhipicephalus sanguineus and Haemaphysalis inermis)., e, I. woyliei n. sp. was only found on two I. o. fusciventer.CONCLUSIONS: Morphological and molecular data have confirmed the first new Australian Ixodes tick species described in ov, More than 800 tick species have been reported world-wide however only about 30 tick species feed on humans, among them Ixodes ricinus, which is the most frequent tick species biting humans in Europe., Description of a new tick species, Ixodes collaris n. sp. (Acari: Ixodidae), from bats (Chiroptera: Hipposideridae, Rhinolophidae) in Vietnam.", "label": "yes"}
{"id": "converted_2205", "sentence1": "Does the Abelson-related gene (ARG) gene encode for a serine kinase?", "sentence2": "One isoform of Arg/Abl2 tyrosine kinase is nuclear and the other seven cytosolic isoforms differently modulate cell morphology, motility and the cytoskeleton., The non-receptor tyrosine kinase Abelson related gene (Arg/Abl2) regulates cell migration and morphogenesis by modulating the cytoskeleton. , The human Arg (Abl2) nonreceptor tyrosine kinase has a role in cytoskeletal rearrangements by its C-terminal F-actin- and microtubule-binding sequences. , The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts.,  The ARG gene encodes for a nonreceptor tyrosine kinase characterized by high homology with c-Abl in the TK, SH2, and SH3 domains. This is the first report on ARG involvement in a human malignancy., Ultraviolet-A and -B differentially modify the tyrosine-kinase profile of human keratinocytes and induce the expression of Arg+., Arg (Abelson-related gene, Abl2) was the PTK with the highest prevalence (30% of all PTKs) and UVA led to a further induction of Arg expression reaching nine-fold mRNA baseline expression at 17 h after irradiation., To investigate the expression profile of protein tyrosine kinases (PTKs) in normal human epidermal keratinocytes (NHEK) in response to UVA and UVB we employed a reversed transcriptase polymerase chain reaction (PCR) approach using degenerate primers derived from the conserved catalytic domain of PTKs. , By 3'rapid amplification of cDNA ends-polymerase chain reaction (3'RACE-PCR), a novel fusion transcript was identified between the ETV6 and the Abelson-related gene (ARG) at 1q25, resulting in a chimeric protein consisting of the HLH oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine kinase (PTK) domains of ARG., The non-receptor tyrosine kinase Abelson related gene (Arg/Abl2) regulates cell migration and morphogenesis by modulating the cytoskeleton., Arg (Abelson-related gene, Abl2) was the PTK with the highest prevalence (30% of all PTKs) and UVA led to a further induction of Arg expression reaching nine-fold mRNA baseline expression at 17 h after irradiation., We studied the relationship of direct karyotypes, determined at diagnosis and remission, to Abelson-related tyrosine kinase activity and the cytogenetic features of erythroid and myeloid colonies derived from remission marrow of six children with acute lymphoblastic leukemia (ALL)., ABL2/ARG (ABL-related gene) belongs to the ABL (Abelson tyrosine-protein kinase) family of tyrosine kinases, The non-receptor tyrosine kinase Abelson related gene (Arg/Abl2) regulates cell migration and morphogenesis by modulating the cytoskeleton, The ARG gene encodes for a nonreceptor tyrosine kinase characterized by high homology with c-Abl in the TK, SH2, and SH3 domains., ABL2/ARG (ABL-related gene) belongs to the ABL (Abelson tyrosine-protein kinase) family of tyrosine kinases., We report that the Abelson (Abl) and Abl-related gene (Arg) nonreceptor tyrosine kinases are required for maintenance of cortical dendrites in the mouse brain., The products of the human ARG gene and the human ABL gene characterize the Abelson family of non-receptor tyrosine protein kinases., The products of the human Arg gene and human, mouse, Drosophila, and nematode Abl genes characterize the Abelson family of nonreceptor tyrosine protein kinase., By 3'rapid amplification of cDNA ends-polymerase chain reaction (3'RACE-PCR), a novel fusion transcript was identified between the ETV6 and the Abelson-related gene (ARG) at 1q25, resulting in a chimeric protein consisting of the HLH oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine kinase (PTK) domains of ARG., The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts.", "label": "no"}
{"id": "converted_4604", "sentence1": "Is Daprodustat effective for anemia?", "sentence2": "CONCLUSIONS: Oral daprodustat was noninferior to CERA in achieving and maintaining target hemoglobin levels in Japanese ND patients. , BACKGROUND: The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor (PHI) Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is non-inferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: haemoglobin efficacy and cardiovascular safety., Daprodustat is one of the orally administrated small-molecule HIF-PH inhibitors, leading to an increase in erythropoietin production, which is regulated by HIF. Also, daprodustat is expected to improve iron metabolism. Recently, several clinical trials showed its efficacy and safety in both hemodialysis- and non-hemodialysis- dependent CKD patients. , Once-daily oral daprodustat treatment was generally well tolerated and mean hemoglobin was achieved and maintained within the target range in Japanese peritoneal dialysis participants., Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia of chronic kidney disease. , Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated for treatment of anemia in chronic kidney disease., Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis., ONCLUSIONS: Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. , Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis., CONCLUSIONS: Among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes., Daprodustat (GSK1278863) is a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor in development for treatment of anemia of chronic kidney disease., BACKGROUND: Daprodustat (GSK1278863) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for treatment of anemia associated with chronic kidney disease (CKD)., Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed for treating anemia of chronic kidney disease., Daprodustat is under development as an emerging new class of agents for the treatment of anemia associated with chronic kidney disease (CKD)., Conclusion: Daprodustat was efficacious and well tolerated for anemia in both NDD and DD patients in the short term based on current RCTs., And daprodustat may become an effective alternative for treatment of anemia with CKD.", "label": "yes"}
{"id": "converted_3115", "sentence1": "Is lactotransferrin a tumour suppressor?", "sentence2": "LTF (lactotransferrin, or lactoferrin) plays important role in innate immunity, and its anti-tumor function has also been reported in multiple cancers., We previously reported that LTF is significantly down-regulated in nasopharyngeal carcinoma (NPC) and acts as a tumor suppressor by suppressing AKT signaling., The tumor suppressor function of lactotransferrin (LTF) has been reported in a variety of tumors, including GC, nasopharyngeal carcinoma (NPC) and prostate cancer., Lactotransferrin (LTF) has been confirmed to act as a tumor suppressor in multiple cancers, Lactotransferrin acts as a tumor suppressor in nasopharyngeal carcinoma by repressing AKT through multiple mechanisms., LTF is likely to be a candidate tumor suppressor and downregulates the development of NPC by inhibiting NPC proliferation through induction of cell cycle arrest and modulation of the MAPK signaling pathway.", "label": "yes"}
{"id": "converted_1664", "sentence1": "Is the protein FAK (Focal Adhesion Kinase) phosphorylated?", "sentence2": "Overexpression of NEDD9 led to tyrosine phosphorylation of FAK and SRC oncoproteins, , yrosine phosphorylated FAK, TNFα contributes for attenuating both Y397FAK and Y416Src phosphorylations in osteoblasts.,  It was possible to show that TNFα provokes attenuation at Y-phosphorylation of both FAK (at Y397 ), ownregulation of G3BP significantly inhibited the phosphorylation of Src, FAK, Periodic mechanical stress significantly induced sustained phosphorylation of FAK at Tyr(397) and Tyr(576/577). , oss of αSNAP impaired Golgi-dependent glycosylation and trafficking of β1 integrin and decreased phosphorylation of focal adhesion kinase (FAK) and paxillin resulting in FA disassembly., functional characterization of many of today's best-known Src substrates (for example, p85-Cortactin, p110-AFAP1, p130Cas, p125FAK and p120-catenin), Western blots were used for P-FAK, e first time, that the EGF-dependent EGFR activation led to increased P-FAKSer732, . P-FAKSer732 presence was crucial for the maintenance of the proliferation rate and its levels were inversely related to the levels of acetylated α-tubulin. P-FAKSer732 localized at the microtubules (MTs) of the spindle, biochemically associated with MTs and contributed to MT depolymerization., specially, phosphorylation of Tyr925-FAK that is required for full activation of FAK was nearly completely suppressed even with 1nM of methyl violet 2B in A375P cancer cells. ,  The protein expression of PTPN13, focal adhesion kinase (FAK) and phosphorylated FAK (P-FAK) was evaluated using immunohistochemical staining and western blotting., Curcumin inhibits focal adhesion kinase (FAK) phosphorylation and enhances the expressions of several extracellular matrix components which play a critical role in invasion and metastasis. , uppressed both the phosphorylation of FAK ,  A GEF-inactive Rgnef mutant rescues FAK-Y397 phosphorylation ", "label": "yes"}
{"id": "converted_2277", "sentence1": "Are TAD boundaries in Drosophila depleted in highly-expressed genes?", "sentence2": "Furthermore, we find that these TAD boundaries are present irrespective of the expression and looping of genes located between them., In particular, Hi-C revealed that chromosomes of animals are organized into topologically associating domains (TADs), evolutionary conserved compact chromatin domains that influence gene expression., Drosophila inter-TADs harbor active chromatin and constitutively transcribed (housekeeping) genes. , The insulator-like, TAD-boundary-like, and TAD-interior-like regions are each enriched for distinct epigenetic marks and are each correlated with different gene expression levels, We conclude that epigenetic modifications, gene density, and transcriptional activity combine to shape the local packing of the A. thaliana nuclear genome., Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions., Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome., The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure., Ectopically expressed roX1 and roX2 RNAs target HAS on the X chromosome in trans and, via spatial proximity, induce spreading of the MSL complex in cis, leading to increased expression of neighboring autosomal genes. , Collectively, our results suggest that TADs are condensed chromatin domains depleted in active chromatin marks, separated by regions of active chromatin., However, Drosophila inter-TADs harbor active chromatin and constitutively transcribed (housekeeping) genes.", "label": "no"}
{"id": "converted_1854", "sentence1": "Is vortioxetine effective for treatment of depression?", "sentence2": "Vortioxetine is the most recently approved medication for the treatment of major depressive disorder (MDD). , [Vortioxetine: a new antidepressant to treat depressive episodes]., Vortioxetine is a new antidepressant, which mechanism of action is multimodal, targeting the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT3, 5-HT7 receptors and the serotonin transporter (5-HTT). , In short-term studies (8 weeks), vortioxetine is more efficacious than placebo in decreasing depressive symptoms as measured by the MADRS total score, response rate (vortioxetine: 53.2% vs placebo: 35.2%) and remission rate (vortioxetine: 29.2% vs placebo: 19.3%). In a long-term study (52 weeks), vortioxetine is also superior to placebo in preventing relapses and recurrences. Moreover, in second line treatment, after failure of a first line selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrin reuptake inhibitor (SNRI), vortioxetine is superior to agomelatine in improving depressive symptoms and achieving response and remission. , Against this background, we feature the novel antidepressants vortioxetine, vilazodone and milnacipran/levomilnacipran with regard to their serotonin receptor targets such as the 5-HT1A, 5-HT3 and 5-HT7 which may account for their specific effects on certain symptoms of depression (e.g. cognition and anxiety) as well as a characteristic side-effect profile., CONCLUSION: Vortioxetine dominated venlafaxine XR in South Korea and is a relevant treatment option for MDD patients initiating or switching therapy., Vortioxetine: a New Treatment for Major Depressive Disorder., INTRODUCTION: Vortioxetine is a structurally novel medication that has recently been approved for treatment of major depressive disorder (MDD)., EXPERT OPINION: Results of placebo-controlled trials suggest efficacy and an overall safety profile comparable to existing first-line antidepressants. , The authors suggest that vortioxetine is currently a good second-line antidepressant option and shows promise, pending additional long-term data, to become a first-line antidepressant option., Clinical studies indicate that vortioxetine is effective in the treatment of major depression, though there is no suggestion of superiority over active comparators., Vortioxetine has been effective in various animal models of depression and anxiety and clinical studies have shown the antidepressant and antianxiety properties of vortioxetine in a dose range of 5-20 mg/day., Vortioxetine was significantly more effective than was placebo, with a standardized mean difference (SMD) of -0.118 (95% CIs, -0.203 to -0.033, P = 0.007)., Vortioxetine for the treatment of depression., Vortioxetine for the treatment of major depression., Vortioxetine (Lu-AA-21004; 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine hydrobromide) is a novel orally active molecule that is being investigated by Lundbeck and Takeda for the treatment of major depression and generalized anxiety disorders., Vortioxetine (Lu AA21004) is a multi-modal antidepressant in clinical development for the treatment of major depressive disorder (MDD)., A randomized, double-blind, fixed-dose study comparing the efficacy and tolerability of vortioxetine 2.5 and 10 mg in acute treatment of adults with generalized anxiety disorder., Vortioxetine has been effective in various animal models of depression and anxiety and clinical studies have shown the antidepressant and antianxiety properties of vortioxetine in a dose range of 5-20 mg/day., Secondary endpoints included response and remission rates, anxiety symptoms(Hamilton Anxiety Rating Scale), Clinical Global Impression, overall functioning (Sheehan Disability Scale), health-related quality of life(EuroQol 5 Dimensions), productivity (work limitation questionnaire) and family functioning (Depression and Family Functioning Scale).RESULTS: Primary endpoint noninferiority was established and vortioxetine (n = 252) was superior to agomelatine (n = 241) by 2.2 MADRS points (p<0.01)., Vortioxetine (Lu AA21004) is an antidepressant with a mechanism of action thought to be related to a combination of 2 pharmacologic actions: direct modulation of several receptors and inhibition of the serotonin transporter.To evaluate the efficacy of vortioxetine 10 and 20 mg once daily in outpatients with major depressive disorder.This 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted from July 2010 to January 2012 among adults with a primary diagnosis of recurrent major depressive disorder (DSM-IV-TR).Eligible subjects were randomized in 1:1:1 ratio to 1 of 3 treatment arms: vortioxetine 10 mg, vortioxetine 20 mg, or placebo once daily for 8 weeks., Vortioxetine (Lu AA21004) is a new antidepressant that combines a number of neurotransmitter reuptake and receptor effects that have been thought to predict efficacy as a treatment for depressive and anxiety disorders.This review summarizes the pharmacology and neurobiology of vortioxetine, In the study of elderly patients, vortioxetine 5 mg (n = 136) improved 12-item Health Status Questionnaire scores significantly more than placebo (n = 148) for the domains of health perception (10.4, P &lt; 0.0001, SES of 0.54), mental health (7.9, P &lt; 0.001, SES of 0.44), and energy (6.4, P &lt; 0.05, SES of 0.28) (FAS, mixed model for repeated measures).Vortioxetine yielded significant, meaningful HRQoL improvements in 6 MDD studies of 6 to 8 weeks duration., All references included were published between 1999 and 2014.All studies that included humans and were published in English, with data describing vortioxetine for the treatment of MDD, were reviewed.Vortioxetine is a novel multimodal antidepressant agent, which inhibits the 5-HT transporter protein, acts as a 5-HT3 antagonist, 5-HT1A receptor agonist, 5-HT7 receptor antagonist, and a partial agonist of the 5-HT1B receptor, Vortioxetine has been effective in various animal models of depression and anxiety and clinical studies have shown the antidepressant and antianxiety properties of vortioxetine in a dose range of 5-20 mg/day, Vortioxetine is an antidepressant with multimodal activity which has shown efficacy in major depressive disorder (MDD) patients in six of ten short-term, randomized, placebo-controlled trials (completed end 2012).We performed meta-regression analyses to indirectly compare vortioxetine to seven marketed antidepressants with different mechanisms of action, Data were available from 51 human trials involving vortioxetine, and included a total of 7,666 healthy volunteers and patients with a diagnosis of major depressive disorder (MDD) or generalized anxiety disorder who were exposed to at least 1 dose of vortioxetine for a total of 2,743 patient-years.Vortioxetine was effective in treating MDD in the United States at a dose of 20 mg/d, Vortioxetine is a recently approved multimodal antidepressant with anxiolytic properties in preclinical studies.This double-blind, placebo-controlled study assessed the efficacy and tolerability of vortioxetine in subjects with a primary diagnosis of generalized anxiety disorder.Subjects (n = 457) were randomized 1:1:1 to treatment with placebo or vortioxetine 2.5 or 10 mg once daily, There was a significant difference for nausea between the two groups (OR=3.01, 95 % CI=2.22-4.09, Z=7.08, P=0.00001), but no significant differences were observed for the other four adverse effects.CONCLUSIONS: For the treatment of major depressive disorder, our results show that a dose of 5 mg/day vortioxetine was more effective, but more easily induced nausea, compared to placebo., The efficacy and safety of 5 mg/d Vortioxetine compared to placebo for major depressive disorder: A meta-analysis., Vortioxetine: a meta-analysis of 12 short-term, randomized, placebo-controlled clinical trials for the treatment of major depressive disorder., Vortioxetine in the treatment of adult patients with major depressive disorder: a meta-analysis of randomized double-blind controlled trials., Vortioxetine has been effective in various animal models of depression and anxiety and clinical studies have shown the antidepressant and antianxiety properties of vortioxetine in a dose range of 5-20 mg/day. , Clinical studies indicate that vortioxetine is effective in the treatment of major depression, though there is no suggestion of superiority over active comparators., The incidence of treatment-emergent adverse events was significantly higher in the duloxetine group than in the vortioxetine group.Duloxetine was more effective but less well-tolerated than vortioxetine in MDD., There was no significant difference in discontinuation rates between vortioxetine and comparators owing to inefficacy (OR 0.983, 95% CI 0.585 to 1.650), whereas discontinuation owing to AEs was significantly less common in the vortioxetine than in the comparator group (OR 0.728, 95% CI 0.554 to 0.957).Studies examining the role of vortioxetine in the treatment of MDD are limited.Although our results suggest that vortioxetine may be an effective treatment option for MDD, they should be interpreted and translated into clinical practice with caution, as the meta-analysis was based on a l, We performed a meta-analysis to increase the statistical power of these studies and enhance our current understanding of the role of vortioxetine in the treatment of MDD.We performed an extensive search of databases and the clinical trial registry., BACKGROUND: Vortioxetine is a recently approved multimodal antidepressant with anxiolytic properties in preclinical studies.OBJECTIVE: This double-blind, placebo-controlled study assessed the efficacy and tolerability of vortioxetine in subjects with a primary diagnosis of generalized anxiety disorder.METHODS: Subjects (n = 457) were randomized 1:1:1 to treatment with placebo or vortioxetine 2.5 or 10 mg once daily., Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent MDD and these effects were largely independent of its effect on improving depressive symptoms., Furthermore, a statistically significant number of patients with MDD who were on vortioxetine have achieved a greater than or equal to 50% reduction in depression symptoms from baseline., BACKGROUND: Vortioxetine is a novel multimodal compound that has recently been approved by the FDA for the treatment of major depressive disorder (MDD)., Although our results suggest that vortioxetine may be an effective treatment option for MDD, they should be interpreted and translated into clinical practice with caution, as the meta-analysis was based on a limited number of heterogeneous RCTs.., Vortioxetine is an effective agent for the treatment of MDD, but it does not have any clear advantages over other available treatment options.., Vortioxetine was significantly more effective than placebo for acute treatment of major depressive disorder (MDD)., Duloxetine was more effective but less well-tolerated than vortioxetine in MDD., Vortioxetine is an orally administered small molecule developed by Lundbeck A/S for the once-daily treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). Vortioxetine received its first global approval for MDD in the USA in September 2013 and regulatory approval for its use in this indication in the EU (where it has received a positive opinion) and Canada is awaited. , This article summarizes the milestones in the development of vortioxetine leading to this first approval for MDD., Vortioxetine was efficacious and well tolerated in the treatment of patients with major depressive disorder., On the primary efficacy endpoint, both vortioxetine doses were statistically significantly superior to placebo, with a mean difference to placebo (n=158) of -5.5 (vortioxetine 15 mg, P<0.0001, n=149) and -7.1 MADRS points (vortioxetine 20 mg, P<0.0001, n=151)., The change in the severity of depressive and anxiety symptoms was maintained throughout the study as reflected by a 24-item Hamilton Depression Scale total score of 8.2 at week 52 (from 17.6 at open-label baseline) in the observed case data set., Vortioxetine is a multi-modal antidepressant that functions as a human 5-HT3A and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist, and inhibitor of the serotonin transporter. , Approval for the treatment of MDD was based on a clinical development programme that included six positive 6-8 week studies, including one study in elderly people, and one positive maintenance study in adults., Vortioxetine represents another option for the treatment of MDD. , The multimodal compounds vortioxetine and vilazodone are examples of this approach with diverse mechanisms, and their different clinical effects will provide valuable insights into serotonergic modulation of glutamate transmission for the potential treatment of depression and associated cognitive dysfunction., Two new antidepressant drugs, vilazodone (marketed in the USA) and vortioxetine (in development) incorporate partial 5-HT1A-R agonist properties with SERT blockade., Novel drugs in development include those that combine multiple simultaneous pharmacologic mechanisms in addition to SERT inhibition within the same molecule, such as vilazodone (combining 5HT1A partial agonism with SERT inhibition), triple reuptake inhibitors (combining norepinephrine and dopamine reuptake inhibition with SERT inhibition), and vortioxetine, a multimodal antidepressant combining actions at the G protein receptor mode (5HT1A and 5HT1B partial agonism and 5HT7 antagonism), at the ion channel mode (5HT3 antagonism) as well as the neurotransmitter transporter mode (SERT inhibition). , In this study of adults with MDD treated for 8 weeks with vortioxetine 2.5 mg or 5 mg per day, reductions in depression symptoms were not statistically significant compared with placebo. , However, on the basis of these findings, vortioxetine (2.5, 5, 10 mg/day) demonstrated a favourable safety and tolerability profile and maintained effectiveness over 12 months of treatment. , In this study of adults with MDD, 5 mg vortioxetine did not differ significantly from placebo in reducing depression symptoms after 6 wk of treatment., After 8 weeks of treatment with Lu AA21004 10 mg, there was a significant reduction in HDRS-24 total score compared with placebo in adults with MDD., In conclusion, Lu AA21004 was efficacious and well tolerated in the treatment of elderly patients with recurrent major depressive disorder., Thus, Lu AA21004 was effective in preventing relapse of MDD and was well tolerated as maintenance treatment.,  Findings on secondary outcome measures, using MMRM instead of LOCF, were supportive of likely efficacy for Lu AA21004 5mg and 10mg and duloxetine. , In this study, treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD., Results from phase II clinical trials have reported improvement in depression and anxiety symptoms after 6 weeks of treatment. ", "label": "yes"}
{"id": "converted_352", "sentence1": "Are there studies representing the involvement of Notch mutations in neurodegenerative diseases such as Down syndrome, Pick's and Prion's disease, and cadasil syndrome?", "sentence2": "he Notch signaling pathway plays a critical role in maintaining the balance between cell proliferation, differentiation and apoptosis, and is a highly conserved signaling pathway that regulates normal development in a context- and dose-dependent manner. Dysregulation of Notch signaling has been suggested to be key events in a variety of hematological malignancies. Notch1 signaling appears to be the central oncogenic trigger in T cell acute lymphoblastic leukemia (T-ALL), in which the majority of human malignancies have acquired mutations that lead to constitutive activation of Notch1 signaling., In a forward genetic screen for mutations that alter intracellular Notch receptor trafficking in Drosophila melanogaster, we recovered mutants that disrupt genes encoding serine palmitoyltransferase and acetyl-CoA carboxylase., Signaling pathways have become a major source of targets for novel therapies in hepatocellular carcinoma (HCC). Survival benefits achieved with sorafenib, a multikinase inhibitor, are unprecedented and underscore the importance of improving our understanding of how signaling networks interact in transformed cells., Notch-1 immunoexpression is increased in Alzheimer's and Pick's disease, (PSEN1) is the major locus for mutations causing familial Alzheimer's disease (FAD) and is also mutated in Pick disease of brain, familial acne inversa and dilated cardiomyopathy. It is a critical facilitator of Notch signalling and many other signalling pathways and protein cleavage events including production of the Amyloidβ (Aβ) peptide from the AMYLOID BETA A4 PRECURSOR PROTEIN (APP, As beta-APP and Notch are both processed by gamma-secretase, we analyzed expression of the Notch signaling pathway in the adult DS brain and in a model system for DS, human trisomy 21 fibroblasts by quantitative PCR. In adult DS cortex we found that Notch1, Dll1 and Hes1 expression is up-regulated. Moreover, DS fibroblasts and Alzheimer disease cortex also show overexpression of Notch1 and Dll1, indicating that enhanced beta-APP processing found in both DS and AD could be instrumental in these changes, A systems biology approach to Down syndrome: identification of Notch/Wnt dysregulation in a model of stem cells aging, Notch3 gene has been recently identified as a causative gene for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)", "label": "yes"}
{"id": "converted_2433", "sentence1": "Does Enzastaurin improve survival of glioblastoma patients?", "sentence2": "RESULTS: fourteen randomized clinical trials were identified (7 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) including 4330 patients. Antiangiogenic drugs showed no improvement in overall survival with a pooled HR of 1.00, a trend for an inferior outcome, in terms of overall survival, was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR=1.24, p=0.056). , Enzastaurin (LY317615) in combination with bevacizumab for recurrent malignant gliomas is well-tolerated, with response and progression-free survival similar to bevacizumab monotherapy., So far, inhibition of angiogenesis by compounds such as bevacizumab, cediranib, enzastaurin or cilengitide as well as alternative dosing schedules of temozolomide did not prolong survival, neither at primary diagnosis nor at recurrent disease., Despite promising phase II clinical trial results and patient benefit in terms of clinical improvement and longer progression-free survival, an overall survival benefit has not been demonstrated in four randomized phase III trials of bevacizumab or cilengitide in newly diagnosed glioblastoma or cediranib or enzastaurin in recurrent glioblastoma., EXPERT OPINION: Enzastaurin and cediranib failed in randomized Phase III trials in recurrent glioblastoma, aflibercept in Phase II. , Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma., Grade 3 to 4 hematologic toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P < or = .001).<br><b>CONCLUSION</b>: Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma.<br>, Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma., Enzastaurin has anti-glioma activity in patients with recurrent high-grade glioma, but does not appear to have enough single-agent activity to be useful as monotherapy., Enzastaurin (LY317615) in combination with bevacizumab for recurrent malignant gliomas is well-tolerated, with response and progression-free survival similar to bevacizumab monotherapy., CONCLUSION Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma., glioblastomas are highly vascularized tumors and various antiangiogenic drugs have been investigated in clinical trials showing unclear results we performed a systematic review and a meta analysis to clarify and evaluate their effectiveness in glioblastoma patients we searched relevant published and unpublished randomized clinical trials analyzing antiangiogenic drugs versus chemotherapy in glioblastoma patients from january 2006 to january 2016 in medline web of science asco esmo and sno databases fourteen randomized clinical trials were identified 7 with bevacizumab 2 cilengitide 1 enzastaurin 1 dasatinib 1 vandetanib 1 temsirolimus 1 cediranib including 4330 patients antiangiogenic drugs showed no improvement in overall survival with a pooled hr of 1 00 a trend for an inferior outcome in terms of overall survival was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone hr 1 24 p 0 056 bevacizumab did not improve overall survival twelve trials 4113 patients were analyzed for progression free survival among antiangiogenic drugs only bevacizumab demonstrated an improvement of progression free survival hr 0 63 p 0 001 both alone hr 0 60 p 0 003 or in combination to chemotherapy hr 0 63 p 0 001 both as first line treatment hr 0 70 p 0 001 or in recurrent disease hr 0 52 p 0 001 antiangiogenic drugs did not improve overall survival in glioblastoma patients either as first or second line treatment and either as single agent or in combination with chemotherapy among antiangiogenic drugs only bevacizumab improved progression free survival regardless of treatment line both as single agent or in combination with chemotherapy., glioblastoma is characterized by high expression levels of proangiogenic cytokines and microvascular proliferation highlighting the potential value of treatments targeting angiogenesis antiangiogenic treatment likely achieves a beneficial impact through multiple mechanisms of action ultimately however alternative proangiogenic signal transduction pathways are activated leading to the development of resistance even in tumors that initially respond the identification of biomarkers or imaging parameters to predict response and to herald resistance is of high priority despite promising phase ii clinical trial results and patient benefit in terms of clinical improvement and longer progression free survival an overall survival benefit has not been demonstrated in four randomized phase iii trials of bevacizumab or cilengitide in newly diagnosed glioblastoma or cediranib or enzastaurin in recurrent glioblastoma however future studies are warranted predictive markers may allow appropriate patient enrichment combination with chemotherapy may ultimately prove successful in improving overall survival and novel agents targeting multiple proangiogenic pathways may prove effective., this phase iii open label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma who grade 4 patients were randomly assigned 2 1 to receive 6 week cycles of enzastaurin 500 mg d 1 125 mg loading dose day 1 or lomustine 100 to 130 mg m 2 day 1 assuming a 45 improvement in progression free survival pfs 397 patients were required to provide 80 power to achieve statistical significance at a one sided level of 025 enrollment was terminated at 266 patients enzastaurin n 174 lomustine n 92 after a planned interim analysis for futility patient characteristics were balanced between arms median pfs 1 5 v 1 6 months hazard ratio hr 1 28 95 ci 0 97 to 1 70 overall survival 6 6 v 7 1 months hr 1 20 95 ci 0 88 to 1 65 and 6 month pfs rate p 13 did not differ significantly between enzastaurin and lomustine respectively stable disease occurred in 38 5 and 35 9 of patients and objective response occurred in 2 9 and 4 3 of patients respectively time to deterioration of physical and functional well being and symptoms did not differ between arms hr 1 12 p 54 four patients discontinued enzastaurin because of drug related serious adverse events aes eleven patients treated with enzastaurin died on study four because of aes one was drug related all four deaths that occurred in patients receiving lomustine were disease related grade 3 to 4 hematologic toxicities were significantly higher with lomustine 46 events than with enzastaurin one event p or 001 enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma., this study s primary objective was evaluation of the progression free survival rate at 6 months pfs 6 in patients with newly diagnosed glioblastoma without o 6 methylguanine dna methyltransferase mgmt promoter hypermethylation postsurgically treated with enzastaurin before and concomitantly with radiation therapy followed by enzastaurin maintenance therapy pfs 6 of at least 55 was set to be relevant compared with the data of the eortc 26981 22981 ncic ce 3 trial adult patients with a life expectancy of at least 12 weeks who were newly diagnosed with a histologically proven supratentorial glioblastoma without mgmt promoter hypermethylation were eligible patients were treated with enzastaurin prior to concomitantly with and after standard partial brain radiotherapy here we report on a multicenter open label uncontrolled phase ii study of patients with newly diagnosed glioblastoma without mgmt promoter hypermethylation treated with enzastaurin and radiation therapy within 4 study periods pfs 6 was 53 6 95 confidence interval ci 39 8 65 6 the median overall survival was 15 0 months 95 ci 11 9 17 9 for all patients 3 9 months 95 ci 0 8 9 0 for patients with biopsy 15 4 months 95 ci 10 1 17 9 for patients with partial resection and 18 9 months 95 ci 13 9 28 5 for patients with complete resection the safety profile in this study was as expected from previous trials and the therapy was well tolerated pfs 6 missed the primary planned outcome of 55 the secondary exploratory analysis according to resection status of the different subgroups of patients with biopsies partial resection and complete resection demonstrates the strong prognostic influence of resection on overall survival., we evaluated the efficacy of combination enzastaurin ly317615 and bevacizumab for recurrent malignant gliomas and explored serologic correlates we enrolled 81 patients with glioblastomas gbm n 40 and anaplastic gliomas ag n 41 patients received enzastaurin as a loading dose of 1125 mg followed by 500 or 875 mg daily for patients on non enzyme inducing or enzyme inducing antiepileptics respectively patients received bevacizumab 10 mg kg intravenously biweekly clinical evaluations were repeated every 4 weeks magnetic resonance imaging was obtained at baseline and every 8 weeks from treatment onset phosphorylated glycogen synthase kinase gsk 3 levels from peripheral blood mononuclear cells pbmcs were checked with each mri median overall survival was 7 5 and 12 4 months for glioblastomas and anaplastic glioma cohorts with median progression free survivals of 2 0 and 4 4 months respectively of gbm patients 3 40 7 5 were not evaluable while 8 37 22 had partial or complete response and 20 37 54 had stable disease for 2 months of the 39 evaluable ag patients 18 46 had an objective response and 16 41 had stable disease for 2 months the most common grade 3 toxicities were lymphopenia 15 hypophosphatemia 8 8 and thrombotic events 7 5 two 2 5 gbm patients died suddenly another death 1 3 occurred from intractable seizures phosphorylated gsk 3 levels from pbmcs did not correlate with treatment response a minimally important improvement in health related quality of life was self reported in 7 9 24 29 2 37 5 early response based on levin criteria was significantly associated with significantly longer progression free survival for glioblastomas enzastaurin ly317615 in combination with bevacizumab for recurrent malignant gliomas is well tolerated with response and progression free survival similar to bevacizumab monotherapy.", "label": "no"}
{"id": "converted_3733", "sentence1": "Has saracatinib been tested in clinical trials?", "sentence2": "Saracatinib as a metastasis inhibitor in metastatic castration-resistant prostate cancer: A University of Chicago Phase 2 Consortium and DOD/PCF Prostate Cancer Clinical Trials Consortium Study., A phase II study of saracatinib (AZD0530), a Src inhibitor, administered orally daily to patients with advanced thymic malignancies., Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer., Metastatic colorectal cancer patients who had received one prior treatment and had measurable disease were enrolled in this phase 2 study., A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease., Herein, we present a Phase Ib trial of the repurposed investigational drug AZD0530, a Src family kinase inhibitor specific for Fyn and Src kinase, for the treatment of patients with mild-to-moderate AD., The study was a 4-week Phase Ib multiple ascending dose, randomized, double-blind, placebo-controlled trial of AZD0530 in AD patients with Mini-Mental State Examination (MMSE) scores ranging from 16 to 26.", "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.", "label": "no"}
{"id": "converted_2796", "sentence1": "Does vesatolimod inhibit TLR7?", "sentence2": "Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. ", "label": "no"}
{"id": "converted_3459", "sentence1": "Is the protein ABCG2 transmembrane?", "sentence2": "the transmembrane ATP-binding cassette transporter G2, ATP-binding cassette (ABC) transporters are transmembrane efflux transporters mediating the extrusion of an array of substrates ranging from amino acids and lipids to xenobiotics, and many therapeutic compounds, including anticancer drugs., The ATP-binding cassette (ABC) transporter family is a large class of ATP energy-dependent transmembrane proteins", "label": "yes"}
{"id": "converted_4359", "sentence1": "Is proton beam therapy used for treatment of craniopharyngioma?", "sentence2": " The majority of children had adjuvant therapy comprising proton beam therapy (18/59; 30.5%) or conventional radiotherapy (16/59; 27.1%)., Proton Therapy for Craniopharyngioma - An Early Report from a Single European Centre., AIMS: Proton beam therapy (PBT) is being increasingly used for craniopharyngioma. , MATERIALS AND METHODS: Between August 2013 and July 2016, 18 patients with craniopharyngiomas were treated with 54 Cobalt Gray Equivalent (CGE) in 30 fractions over 6 weeks at our centre., CONCLUSIONS: Our early results are encouraging and comparable with the limited literature on PBT for craniopharyngioma., All of the other patients underwent proton-beam radiotherapy with no documented tumor growth (median follow-up: 20 months; range 5.1-29.9 months)., Where aggressive subtotal resection is achieved, patients should be closely followed, with radiation initiated at the time of progression or recurrence-ideally via proton beam therapy, although three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and stereotactic radiosurgery are very appropriate in a range of circumstances, governed by access, patient age, disease architecture, and character of the recurrence.,  This study examined parental distress in a sample of families of patients with Cp treated with proton beam therapy to identify factors for targeting psychological intervention.PROCEDURE: Prior to (n = 96) and 1 year after (n = 73) proton therapy, parents of children diagnosed with Cp (9.81 ± 4.42 years at baseline; 49% male) completed a self-report measure of distress, the Brief Symptom Inventory (BSI)., Diagnoses included medulloblastoma, craniopharyngioma, ependymoma, glial tumors, germ cell tumors, and others., Initial experience with proton beam therapy in childhood-onset craniopharyngioma patients shows promising results in terms of more protective radiological treatment. , Monte Carlo simulations were used to assess secondary neutron doses received by patients treated with proton therapy for ocular melanoma and craniopharyngioma., Secondary neutron doses in proton therapy treatments of ocular melanoma and craniopharyngioma., AIMS: Proton beam therapy (PBT) is being increasingly used for craniopharyngioma., LTS: Published reports suggest a benefit to proton beam therapy for use in tumors of the skull base, including craniopharyngiomas, chordomas, skull-base sarcomas, and unresectable meningiomas.CONC, In recent years, proton therapy (PT), with its physical properties of heavy ion beam, that is, Prague peak phenomenon, has been more frequently used in patients with craniopharyngioma., Proton beam therapy versus conformal photon radiation therapy for childhood craniopharyngioma: multi-institutional analysis of outcomes, cyst dynamics, and toxicity., PURPOSE: We compared proton beam therapy (PBT) with intensity modulated radiation therapy (IMRT) for pediatric craniopharyngioma in terms of disease control, cyst dynamics, and toxicity., Proton therapy for craniopharyngioma in adults: a protocol for systematic review and meta-analysis., We hereby report a case of a 7-year-old boy with a craniopharyngioma which had been subtotally resected and was subsequently treated with modern pencil beam proton therapy under high-precision image guidance., Pencil beam scanning proton therapy for the treatment of craniopharyngioma complicated with radiation-induced cerebral vasculopathies: A dosimetric and linear energy transfer (LET) evaluation., tial experience with proton beam therapy in childhood-onset craniopharyngioma patients shows promising results in terms of more protective radiological treatment. R, PURPOSE: We compared proton beam therapy (PBT) with intensity modulated radiation therapy (IMRT) for pediatric craniopharyngioma in terms of disease control, cyst dynamics, and toxic, BACKGROUND AND PURPOSE: This study analyses the dosimetric and dose averaged Linear Energy transfer (LETd) correlation in paediatric craniopharyngioma (CP) patients with and without radiation-induced cerebral vasculopathies (RICVs) treated with pencil beam scanning (PBS) pro, OBJECTIVE: The authors compared survival and multiple comorbidities in children diagnosed with craniopharyngioma who underwent gross-total resection (GTR) versus subtotal resection (STR) with radiation therapy (RT), either intensity-modulated radiation therapy (IMRT) or proton beam therapy (P, Proton Therapy for Craniopharyngioma - An Early Report from a Single European Centre, s. Some studies have shown that PT has advantages in the treatment of craniopharyngioma in adu, Postoperative cerebral glucose metabolism in pediatric patients receiving proton therapy for craniopharyngioma, Clinical equipoise: Protons and the child with craniopharyngioma., skull base. More public attention has been given to proton beam therapy due to the increasing number of centers now in operation or in the planning stages for offering this treatment option.METHODS: We reviewed the physical properties of protons and the clinical studies performed to justify their use in the management of skull-base tumors and determine the benefits of proton beam therapy.RESULTS: Published reports suggest a benefit to proton beam therapy for use in tumors of the skull base, including craniopharyngiomas, chordomas, skull-base sarcomas, and unresectable meningiomas.CONCLUSIONS: Use of proton beam th, PURPOSE: We report the results of the early cohort of patients treated for craniopharyngioma with combined proton-photon irradiation at the Massachusetts General Hospital and the Harvard Cyclotron Laboratory.METHODS AND MATERIALS: Between 1981 and 1988, 15 patients with craniopharyngioma were treated in part or entirely with fractiona, UNLABELLED: This retrospective preliminary review evaluated the efficacy and toxicity of fractionated proton radiotherapy in the management of pediatric craniopharyngioma.METHODS: Sixteen patients, aged 7-34 years, were treated with p, population. We evaluated the outcomes of all adult craniopharyngioma patients treated at our institution using proton therapy to report outcomes for disease control, treatment-related toxicity, and tumor response.METHODS: We analyzed 14 adult patie, Proton radiation has been used safely and effectively for medulloblastoma, primitive neuro-ectodermal tumors, craniopharyngioma, ependymoma, germ cell intracranial tumors, low-grade glioma, retinoblastoma, rhabdomyosarcoma and other soft tissue sarcomas, Ewing's sarcoma and other bone sarcomas., ontroversial. The purpose of this study was to evaluate the efficacy and safety of PT for craniopharyngioma in adults.METHODS AND ANALYSIS: We will search six databases (MEDLINE, EMBASE, Web of Science, the Cochrane Library, Amed, Scopus), clinical research registration websites and grey literature, aiming to identify randomised controlled trials (RCTs) on PT for craniopharyngioma in adults between 1", "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", "label": "yes"}
{"id": "converted_885", "sentence1": "Does  thyroid hormone receptor beta1 affect insulin secretion?", "sentence2": "We demonstrated that thyroid hormone T3 rapidly induces Akt activation in pancreatic beta cells rRINm5F and hCM via thyroid hormone receptor (TR) beta1., The silencing of TRbeta1 expression through RNAi confirmed this receptor to be crucial for the T3-induced activation of Akt., T3 is able to specifically activate Akt in the islet beta cells rRINm5F and hCM through the interaction between TRbeta1 and PI3K p85alpha, demonstrating the involvement of TRbeta1 in this novel T3 non-genomic action in islet beta cells.", "label": "no"}
{"id": "converted_300", "sentence1": "Is alternative splicing of apoptotic genes playing a role in the response to DNA or mitochondrial damage?", "sentence2": "Apoptosis promoted by UV in cells lacking p53 is prevented when the change in AS of the apoptotic gene bcl-x is reverted, confirming the relevance of this mechanism., We demonstrate that E2F1 requires SC35 to switch the alternative splicing profile of various apoptotic genes such as c-flip, caspases-8 and -9 and Bcl-x, towards the expression of pro-apoptotic splice variants. Finally, we provide evidence that E2F1 upregulates SC35 in response to DNA-damaging agents and show that SC35 is required for apoptosis in response to these drugs., This analysis revealed that DNA damage resulted in changes in splicing activity that modified the splicing pattern of Fas, a key pro-apoptotic, p53-inducible death receptor., Bortezomib induces mitochondrial damage in native cells and also activates the UPR by splicing of Xbp-1 and induction of CHOP, which is significantly reduced by silencing of MUC4., The tumour-suppressor protein p53 is an important activator of apoptosis. Although p53-deficient cancer cells are less responsive to chemotherapy, their resistance is not complete, which suggests that other apoptotic pathways may exist. A p53-related gene, p73, which encodes several proteins as a result of alternative splicing, can also induce apoptosis., Induction of apoptosis was significantly reduced in P388/SPR cells, as indicated by minimal DNA fragmentation. Analysis of oncogenes regulating apoptotic cell death revealed a marked decrease of bcl-2 in combination with a moderate reduction of bax protein, but a striking overexpression of the long form of the bcl-X protein.", "label": "yes"}
{"id": "converted_4001", "sentence1": "Should nerinetide be used for treatment of ischaemic stroke?", "sentence2": "337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups., INTERPRETATION: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo.", "label": "no"}
{"id": "converted_4331", "sentence1": "Are Epoxyeicosatrienoic acids (EETs) synthesized by cytochrome P450 epoxygenases from arachidonic acid?", "sentence2": "Biologically active epoxyeicosatrienoic acid (EET) regioisomers are synthesized from arachidonic acid by cytochrome P450 epoxygenases of endothelial, myocardial, and renal tubular cells., epoxyeicosatrienoic acids (EETs), synthesized by cytochrome P450 epoxygenases from arachidonic acid. , Epoxyeicosatrienoic acids (EETs), synthesized from arachidonic acid by cytochrome P450 epoxygenases, Epoxyeicosatrienoic acids (EETs), which are synthesized from arachidonic acid by cytochrome P450 epoxygenases, function primarily as autocrine and paracrine effectors in the cardiovascular system and kidney. , Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid by cytochrome P450 epoxygenases in endothelial cells. I, Epoxyeicosatrienoic acids (EETs), the eicosanoid biomediators synthesized from arachidonic acid by cytochrome P450 epoxygenases,, Epoxyeicosatrienoic acids (EETs) are bioactive eicosanoids produced from arachidonic acid by cytochrome P450 epoxygenases., Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by cytochrome (CYP) P450 epoxygenases, and to ω-terminal hydroxyeicosatetraenoic acids (HETEs) by ω-hydroxylases., Epoxyeicosatrienoic acids (EETs), synthesized from arachidonic acid by cytochrome P450 epoxygenases, are converted to dihydroxyeicosatrienoic acids by soluble epoxide hydrolase., Epoxyeicosatrienoic acids (EETs), which are synthesized from arachidonic acid by cytochrome P450 epoxygenases, function primarily as autocrine and paracrine effectors in the cardiovascular system and kidney., Epoxygenases metabolize arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs) and selected monohydroxyeicosatetraenoic acids (HETEs)., Epoxyeicosatrienoic acids (EETs) are potent lipid mediators formed by cytochrome P450 epoxygenases from arachidonic acid. , Epoxyeicosatrienoic acids (EETs) are bioactive eicosanoids produced from arachidonic acid by cytochrome P450 epoxygenases. , Epoxyeicosatrienoic acids (EETs), derived from arachidonic acid by cytochrome P450 epoxygenases, are potent vasodilators that function as endothelium-derived hyperpolarizing factors in some vascular beds. E, Epoxyeicosatrienoic acids (EETs), which are synthesized from arachidonic acid by cytochrome P450 epoxygenases, function primarily as autocrine and paracrine effectors in the cardiovascular system and kidney. T, poxyeicosatrienoic acids (EETs) are epoxy lipids derived from metabolism of arachidonic acid by cytochrome P450 epoxygenases. W, he vascular endothelium metabolizes arachidonic acid by cytochrome P450 epoxygenases to epoxyeicosatrienoic acids or EETs., Epoxyeicosatrienoic acids (EETs) are the epoxidation products of arachidonic acid catalyzed by cytochrome P450 (CYP) epoxygenases, which possess multiple biological activities. In , OBJECTIVE: Arachidonic acid metabolism by cytochrome P450 (CYP) epoxygenases leads to epoxyeicosatrienoic acids (EETs), which are eicosanoids with vasodilator and anti-inflammatory pro, Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which play important and diverse roles in the cardiovascular system. Th, Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites produced by cytochrome P450 epoxygenases which are highly expressed in hepatocytes. , Epoxyeicosatrienoic acids (EETs) are epoxides of arachidonic acid generated by cytochrome P450 (CYP) epoxygenases., Although eicosanoids, including prostaglandins and leukotrienes, are best known as products of arachidonic acid metabolism by cyclooxygenases and lipoxygenases, arachidonic acid is also a substrate for another enzymatic pathway, the cytochrome P450 (CYP) system., Epoxyeicosatrienoic acids (EETs), lipid mediators synthesized from arachidonic acid by cytochrome P-450 epoxygenases, are converted by soluble epoxide hydrolase (SEH) to the corresponding dihydroxyeicosatrienoic acids (DHETs)., Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid by cytochrome P450 epoxygenases in endothelial cells., Epoxyeicosatrienoic acids (EETs), the eicosanoid biomediators synthesized from arachidonic acid by cytochrome P450 epoxygenases, are inactivated in many tissues by conversion to dihydroxyeicosatrienoic acids (DHETs)., Epoxyeicosatrienoic acids (EETs) are potent lipid mediators formed by cytochrome P450 epoxygenases from arachidonic acid., Recent studies show that mouse epidermis expresses CYP2B19, a keratinocyte-specific epoxygenase that generates 11,12- and 14,15-epoxyeicosatrienoic (EET) acids from arachidonate., Identification of rabbit cytochromes P450 2C1 and 2C2 as arachidonic acid epoxygenases., Epoxyeicosatrienoic acids (EETs) are formed from arachidonic acid by the action of P450 epoxygenases (CYP2C and CYP2J)., Epoxyeicosatrienoic acids (EETs) are generated from arachidonic acid by cytochrome P450 (CYP) epoxygenases.", "label": "yes"}
{"id": "converted_4061", "sentence1": "Is acupotomy used to treat muscle stiffness?", "sentence2": "All the included studies reviewed musculoskeletal disorders and reported a significantly higher total effective and cure rates in the acupotomy group for frozen shoulder, cervical spondylosis, third lumbar vertebrae transverse process syndrome, trigger finger, knee osteoarthritis, and lumbar spinal stenosis, compared to the other active control groups, Acupotomy showed promising results for some musculoskeletal disorders; however, additional high-quality evidence is required to make clinical recommendations regarding this procedure., Acupotomy has been widely used to treat nerve entrapment syndrome, To evaluate the clinical efficacy and safety of acupotomy in treatment of knee osteoarthritis , Effect and safety of acupotomy in treatment of knee osteoarthritis, Acupotomy Therapy for Knee Osteoarthritis Pain: Systematic Review and Meta-Analysis., We included only randomized controlled trials (RCTs) that used acupotomy therapy as the major intervention in adults with knee OA,, Acupotomy, which involves the addition of a scalpel function to the conventional acupuncture treatment, has recently been applied as a conservative treatment method for lumbar disc herniation (LDH), LTS: The systematic review will provide high-quality evidence to assess the efficacy and safety of acupotomy for KOA by pain, stiffness, and dysfunction of knee joint, and quality of life, as well as adverse events.CONC, Acupotomy has been widely used to treat KOA., Acupotomy, a biomechanical therapy guided by traditional Chinese medicine theory, alleviates cartilage degradation and is widely used in the clinic to treat KOA by correcting abnormal mechanics., BACKGROUND: Acupotomy has been widely used to treat nerve entrapment syndrome., Acupotomy has been widely used to treat calcaneodynia., The aim of this study is to evaluate the efficacy and safety of the acupotomy treatment in patients with calcaneodynia., otomy combined with rehabilitation was associated with significantly higher TER (RR 1.24, 95% CI 1.01-1.52, I = 77%) and gross motor function measure score (MD 12.62, 95% CI 11.75-13.49, I = 54%), and significantly lower muscle tone of gastrocnemius measured by the Ashworth scale or the modified Ashworth scale (MD -0.97, 95% CI -1.07 to -0.88, I = 0%) compared with rehabilitation alone. No , Both acupotomy and acupuncture have been widely used clinically to treat CSR in China with satisfied efficacy., GN AND METHODS: Total 75 patients were participated in acupotomy therapy and ultrasonic drug penetration to treat joint osteoarthritis. The, Acupotomy Alleviates Energy Crisis at Rat Myofascial Trigger Points, its in the acupotomy and EA groups underwent bilateral acupotomylysis intervention; those in the acupotomy-EA group underwent acupotomylysis and EA interventions. On the, LTS: The systematic review will provide high-quality evidence to assess the efficacy and safety of acupotomy for KOA by pain, stiffness, and dysfunction of knee joint, and quality of life, as well as adverse events.CON, Acupotomy for knee osteoarthritis: A systematic review protocol.,  The aim of this study is to evaluate the efficacy and safety of acupotomy for the treatment of patients with KOA, SION: The systematic review will provide evidence to assess the effectiveness and safety of acupotomy therapy for KOA patients.PROSP, e systematic review will provide high-quality evidence to assess the efficacy and safety of acupotomy for KOA by pain, stiffness, and dysfunction of knee joint, and quality of life, as well as adverse events.CON, The aim of this study is to evaluate the efficacy and safety of acupotomy for the treatment of patients with KOA.M,  systematic review will provide evidence to assess the effectiveness and safety of acupotomy therapy for KOA patients.PROS, To observe the clinical efficacy of minimally invasive acupotomy-injection technique with targeted three-point in the treatment of frozen shoulder.M, [Percutaneous dynamic release in stress position by acupotomy in treating severe scapulohumeral periarthritis]., To investigate the clinical efficacy of acupotomy stress position percutaneous dynamic release for severe shoulder periarthritis.M, l sequelae. Acupotomy, a modernized acupuncture form combining the effects of microsurgery and conventional acupuncture, may show specific benefits in the treatment of CP, especially with respect to, Background: Acupotomy, which involves the addition of a scalpel function to the conventional acupuncture treatment, has recently been applied as a conservative treatment method for lumbar disc herni, he methodological quality was medium-to-high in AMSTAR. All the included studies reviewed musculoskeletal disorders and reported a significantly higher total effective and cure rates in the acupotomy group for frozen shoulder, cervical spondylosis, third lumbar vertebrae transverse process syndrome, trigger finger, knee osteoarthritis, and lumbar spinal stenosis, compared to the other active control groups.CONCLUSION: Acupotomy showed promising results for some musculoskeletal disorders; however, additional high-quality evidence is", "label": "no"}
{"id": "converted_2342", "sentence1": "Does DDX54 play a role in DNA damage response?", "sentence2": "DDX54 regulates transcriptome dynamics during DNA damage response., The contribution of post-transcriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. Here, we systematically identified RNA-binding proteins differentially interacting with polyadenylated transcripts upon exposure of human breast carcinoma cells to ionizing radiation (IR). Interestingly, more than 260 proteins, including many nucleolar proteins, showed increased binding to poly(A)+RNA in IR-exposed cells. The functional analysis of DDX54, a candidate genotoxic stress responsive RNA helicase, revealed that this protein is an immediate-to-early DDR regulator required for the splicing efficacy of its target IR-induced pre-mRNAs. Upon IR exposure, DDX54 acts by increased interaction with a well-defined class of pre-mRNAs that harbor introns with weak acceptor splice sites, as well as by protein-protein contacts within components of U2 snRNP and spliceosomal B complex, resulting in lower intron retention and higher processing rates of its target transcripts. Because DDX54 promotes survival after exposure to IR, its expression and/or mutation rate may impact DDR-related pathologies. Our work indicates the relevance of many uncharacterized RBPs potentially involved in the DDR., The functional analysis of DDX54, a candidate genotoxic stress responsive RNA helicase, revealed that this protein is an immediate-to-early DDR regulator required for the splicing efficacy of its target IR-induced pre-mRNAs.", "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. ", "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.", "label": "yes"}
{"id": "converted_374", "sentence1": "Is desmin an intermediate filament protein involved in Dilated Cardiomyopathy (DCM)?", "sentence2": "Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal muscle disease caused by mutations in the desmin (DES) gene. Mutations in the central 2B domain of DES cause skeletal muscle disease that typically precedes cardiac involvement. However, the prevalence of DES mutations in dilated cardiomyopathy (DCM) without skeletal muscle disease is not known., The lack of severe disruption of cytoskeletal desmin network formation seen with mutations in the 1A and tail domains suggests that dysfunction of seemingly intact desmin networks is sufficient to cause DCM., According to the predominant view, desmin mutations cause dilated cardiomyopathy (DCM). We evaluated a family with restrictive cardiomyopathy (RCM) associated with a novel desmin mutation and reviewed recent reports regarding the frequency of RCM in patients with desmin myopathy., Dilated cardiomyopathy (DCM) is characterized by enlargement and dilation of all heart compartments associated with serious decrease of its contractile function. DCM hallmark is the combination of dystrophic and hypertrophic alterations of cardiomyocytes. Since the power output of cardiac cells is directly related to remodeling of their contractile machinery we investigated expression of selected contractile and cytoskeletal proteins in the left ventricle of DCM patients using immunoblotting. The content of the recognized protein markers of cardiomyocyte hypertrophy such as tubulin, desmin and slow skeletal myosin heavy chain isoform, MHCbeta, was significantly elevated in DCM compared to normal myocardium., In contrast, overexpression of desmin filaments by itself is not detrimental to the heart. Although loss-of-function studies have been more limited, ablation of the desmin gene causes mitochondrial dysfunction and apoptosis, resulting in cardiomyopathy in mice. From function studies, abnormal desmin aggregation and disruption of the desmin networks resulting from expression of either mutant desmin or mutant CryAB have been shown to remodel the heart and compromise cardiac function, suggesting their synergistic roles in disease pathogenesis., A missense mutation in the desmin gene (DES) causes DCM in a human family., Mice deficient in desmin, the muscle-specific member of the intermediate filament gene family, display defects in all muscle types and particularly in the myocardium. Desmin null hearts develop cardiomyocyte hypertrophy and dilated cardiomyopathy (DCM) characterized by extensive myocyte cell death, calcific fibrosis and multiple ultrastructural defects. Several lines of evidence suggest impaired vascular function in desmin null animals., Familial DCM is commonly inherited as autosomal dominant trait; less frequently it is autosomal recessive, X-linked or matrilinear. The disease is clinically and genetically heterogeneous. Genes causally linked to this phenotype include dystrophin, dystrophin-associated glycoproteins, actin, desmin, beta-miosin heavy chain, cardiac troponin T, and mitochondrial DNA genes, mostly transfer RNAs., Examination of families has identified so far eight disease genes, namely the dystrophin, tafazzin, cardiac actin, desmin, lamin A/C, delta- sarcoglycan, cardiac beta-myosin heavy chain, and cardiac troponin T gene., Mutations of the desmin,   delta-sarcoglycan, the cardiac actin and beta-myosin heavy chain as well as the troponin T gene are known to cause autosomal dominant-dilated cardiomyopathy without other abnormalities., Autosomal dominant DCM is the most frequent form (56% of our cases), and several candidate disease loci have been identified by linkage analysis. Three disease genes are presently known: the cardiac actin gene, the desmin gene, and the lamin A/C gene., Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), whereas three other genes (actin, lamin A/C, and desmin) cause autosomal dominant DCM;, Desmin defects were also recently identified in 1 familial dilated cardiomyopathy., By candidate gene screening, the molecular diagnosis can be provided for dystrophin, DAG, mitochondrial DNA, actin and desmin gene defects., Desmin (z-bands) are partly destroyed in DCM. Anti-desmin antibody titers as indicators of a possible secondary immune response are found high in patients with acute myocarditis declining during reconvalescence and are also elevated in DCM. , Desmin, the muscle-specific intermediate filament protein, is a major target in dilated cardiomyopathy and heart failure in humans and mice, Desmin, the muscle-specific intermediate filament, is involved in myofibrillar myopathies, dilated cardiomyopathy and muscle wasting", "label": "yes"}
{"id": "converted_607", "sentence1": "Is microRNA(miRNA) 30 involved in post-ischemic cardiac remodeling?", "sentence2": "The myocardium of the failing heart undergoes a number of structural alterations, most notably hypertrophy of cardiac myocytes and an increase in extracellular matrix proteins, often seen as primary fibrosi, Connective tissue growth factor (CTGF) is a key molecule in the process of fibrosis and therefore seems an attractive therapeutic target, CTGF is importantly regulated by 2 major cardiac microRNAs (miRNAs), miR-133 and miR-30., the expression of both miRNAs was inversely related to the amount of CTGF in 2 rodent models of heart disease and in human pathological left ventricular hypertrophy. Second, in cultured cardiomyocytes and fibroblasts, knockdown of these miRNAs increased CTGF levels. Third, overexpression of miR-133 or miR-30c decreased CTGF levels, which was accompanied by decreased production of collagens., miR-30 importantly limit the production of CTGF, miR-30 directly downregulate CTGF, a key profibrotic protein, and thereby establish an important role for these miRNAs in the control of structural changes in the extracellular matrix of the myocardium.", "label": "yes"}
{"id": "converted_2271", "sentence1": "Is davunetide being considered for the treatment of progressive supranuclear palsy?", "sentence2": "Critical appraisal of the role of davunetide in the treatment of progressive supranuclear palsy., Davunetide's efficacy and tolerability are being tested in a placebo-controlled study in PSP patients, making it the most advanced drug candidate in this indication. This review examines the disease characteristics of PSP, the rationale for treating PSP with davunetide and assesses some of the challenges of clinical trials in this patient population.", "label": "yes"}
{"id": "converted_3792", "sentence1": "Is tocilizumab a csDMARD?", "sentence2": "The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). ", "label": "no"}
{"id": "converted_3377", "sentence1": "Is KAT2A involved in Acute myeloid leukemia (AML)?", "sentence2": "Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies., Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies., KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells., Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies., KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells.", "label": "yes"}
{"id": "converted_2349", "sentence1": "Do chromatin features predict genes associated with eQTLs?", "sentence2": "Using the random forest classifier, we found that genomic proximity plus five TF and chromatin features are able to predict>90% of target genes within 1 megabase of eQTLs, Using the random forest classifier, we found that genomic proximity plus five TF and chromatin features are able to predict >90% of target genes within 1 megabase of eQTLs., Cell type-specific gene expression in humans involves complex interactions between regulatory factors and DNA at enhancers and promoters. Mapping studies for expression quantitative trait loci (eQTLs), transcription factors (TFs) and chromatin markers have become widely used tools for identifying gene regulatory elements, but prediction of target genes remains a major challenge. Here, we integrate genome-wide data on TF-binding sites, chromatin markers and functional annotations to predict genes associated with human eQTLs. Using the random forest classifier, we found that genomic proximity plus five TF and chromatin features are able to predict >90% of target genes within 1 megabase of eQTLs. Despite being regularly used to map target genes, proximity is not a good indicator of eQTL targets for genes 150 kilobases away, but insulators, TF co-occurrence, open chromatin and functional similarities between TFs and genes are better indicators. Using all six features in the classifier achieved an area under the specificity and sensitivity curve of 0.91, much better compared with at most 0.75 for using any single feature. We hope this study will not only provide validation of eQTL-mapping studies, but also provide insight into the molecular mechanisms explaining how genetic variation can influence gene expression.", "label": "yes"}
{"id": "converted_653", "sentence1": "Is delayed enhancement documented in patients with non-ischemic dilated cardiomyopathy?", "sentence2": "Myocardial fibrosis was present in 30% of patients, the majority of which was mid-myocardial (63%). ,  DCM patients frequently have myocardial fibrosis detected on CE-CMR, the majority of which is mid-myocardial., Fifty (40%) patients showed myocardial DE, representing 12±7% of LV mass., one case was dilated cardiomyopathy, in which the delayed enhancement was diffuse small midwall spots , In the dilated cardiomyopathy group, only seven (29%) patients showed delayed enhancement and its pattern was characterized by mid-wall, patchy or diffuse location., Patterns of delayed enhancement are different in dilated cardiomyopathy and ischemic cardiomyopathy, reflecting the presence of scarring or various degrees of fibrosis in left ventricular myocardium. The presence of subendocardial or transmural delayed enhancement at contrast-enhanced cardiovascular magnetic resonance allowed distinction between dilated cardiomyopathy and ischemic cardiomyopathy with high sensitivity (88%) and specificity (100%).", "label": "yes"}
{"id": "converted_2197", "sentence1": "Is Pfh1 a component of the replisome?", "sentence2": "Pfh1 Is an Accessory Replicative Helicase that Interacts with the Replisome to Facilitate Fork Progression and Preserve Genome Integrity, Although the Schizosaccharomyces pombe 5'-to-3' DNA helicase Pfh1 is known to promote fork progression, its genomic targets, dynamics, and mechanisms of action are largely unknown. Here we address these questions by integrating genome-wide identification of Pfh1 binding sites, comprehensive analysis of the effects of Pfh1 depletion on replication and DNA damage, and proteomic analysis of Pfh1 interaction partners by immunoaffinity purification mass spectrometry., DNA replication through hard-to-replicate sites, including both highly transcribed RNA Pol II and Pol III genes, requires the S. pombe Pfh1 helicase., Here, we show that Pfh1 is required for efficient fork movement in the ribosomal DNA, the mating type locus, tRNA, 5S ribosomal RNA genes, and genes that are highly transcribed by RNA polymerase II. ,  Thus, Pfh1 promotes DNA replication and separation of converged replication forks and suppresses DNA damage at hard-to-replicate sites., Cells depleted of Pfh1 were inviable if they also lacked the human TIMELESS homolog Swi1, a replisome component that stabilizes stalled forks., Pfh1 Is an Accessory Replicative Helicase that Interacts with the Replisome to Facilitate Fork Progression and Preserve Genome Integrity., Thus, we conclude that Pfh1 is an accessory DNA helicase that interacts with the replisome and promotes replication and suppresses DNA damage at hard-to-replicate sites., Consistent with this interpretation, Pfh1 co-purified with many key replisome components, including the hexameric MCM helicase, replicative DNA polymerases, RPA, and the processivity clamp PCNA in an S phase dependent manner., Although Pfh1 affected replication and suppressed DNA damage at discrete sites throughout the genome, Pfh1 and the replicative DNA polymerase bound to similar extents to both Pfh1-dependent and independent sites, suggesting that Pfh1 is proximal to the replication machinery during S phase., Cells depleted of Pfh1 were inviable if they also lacked the human TIMELESS homolog Swi1, a replisome component that stabilizes stalled forks, Here, we show that Pfh1 is required for efficient fork movement in the ribosomal DNA, the mating type locus, tRNA, 5S ribosomal RNA genes, and genes that are highly transcribed by RNA polymerase II, Thus, Pfh1 promotes DNA replication and separation of converged replication forks and suppresses DNA damage at hard-to-replicate sites, Cells depleted of Pfh1 were inviable if they also lacked the human TIMELESS homolog Swi1, a replisome component that stabilizes stalled forks., Thus, we conclude that Pfh1 is an accessory DNA helicase that interacts with the replisome and promotes replication and suppresses DNA damage at hard-to-replicate sites., Consistent with this interpretation, Pfh1 co-purified with many key replisome components, including the hexameric MCM helicase, replicative DNA polymerases, RPA, and the processivity clamp PCNA in an S phase dependent manner., Pfh1 Is an Accessory Replicative Helicase that Interacts with the Replisome to Facilitate Fork Progression and Preserve Genome Integrity.", "label": "no"}
{"id": "converted_771", "sentence1": "Can PLN mutations lead to dilated cardiomyopathy?", "sentence2": "A PLN founder mutation (43 cases) and LMNA mutations (19 cases, 16 different mutations) were most prevalent and often demonstrated a specific phenotype., PLN mutation R14del was identified in 12 (12 %) ARVC patients and in 39 (15 %) DCM patients, The PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC, Arg(9) → Cys (R9C) and Arg(14) deletion (R14del) mutations in PLN are associated with lethal dilated cardiomyopathy in humans, We previously reported the deletion of the highly conserved amino acid residue arginine 14 (nucleic acids 39, 40 and 41) in DCM patients., Mutations in the gene encoding PLN have been associated with idiopathic dilated cardiomyopathy;, Mutations in the PLN gene are a rare cause of heart failure, present almost exclusively in patients with dilated cardiomyopathy etiology, A missense mutation in PLN cytoplasmic domain (R9C) triggers dilated cardiomyopathy in humans, leading to premature death., Complete genetic and clinical analyses were performed in a family with familial dilated cardiomyopathy due to the PLN-R14Del mutation., A candidate gene approach resulted in identification of a heterozygous deletion of arginine 14 in the gene encoding phospholamban (PLN-R14Del) segregating with dilated cardiomyopathy in the family pedigree. Mutation carriers suffered from familial dilated cardiomyopathy associated with cardiac death between the ages of 26 and 50 years., a family with familial dilated cardiomyopathy due to the PLN-R14Del mutation., For the phospholamban (PLN) and titin cap (TTN) genes, a direct mutation screening approach was used. DNA sequence analysis of all exons showed no evidence that these genes are involved in DCM in the Newfoundland dog., two human PLN mutations, associated with either absence or sustained dephosphorylation of PLN, were linked to dilated cardiomyopathy., Mutations in the gene encoding PLN have been associated with dilated cardiomyopathy characterized by early onset and the presence of lethal ventricular arrhythmias., The identical PLN mutation can be associated with both mild and severe forms of dilated cardiomyopathy. Additionally, PLN mutations should be considered in late onset cardiomyopathy, Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure., No PLN gene mutation was found in patients with DCM in Chengdu. This result indicated that PLN gene mutation may not be a common cause for DCM in the Chinese population in Chengdu., none in PLN, the recent discoveries of human PLN mutations leading to disease states., Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27., humans lacking PLN develop lethal dilated cardiomyopathy., Here we report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban (PLN)", "label": "yes"}
{"id": "converted_860", "sentence1": "Is hypersensitivity to DNA crosslinking agents a hallmark of Fanconi anemia?", "sentence2": "The Fanconi anemia (FA) core complex plays a central role in the DNA damage response network, FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability., Fanconi anemia (FA) is a rare genetic disorder characterized by aplastic anemia, cancer/leukemia susceptibility and cellular hypersensitivity to DNA crosslinking agents, such as cisplatin., Fanconi anemia (FA) is an inherited chromosomal recessive syndrome characterized by cellular hypersensitivity to DNA crosslinking agents and bone marrow failure, which cause aplastic anemia, and an increased incidence of malignancy., Features of chromosomal aberrations, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy have suggested a fundamental anomaly of DNA repair in Fanconi anemia., Fanconi anemia (FA) is one of several genetic diseases with characteristic cellular hypersensitivity to DNA crosslinking agents which suggest that FA proteins may function as part of DNA repair processes., Fanconi anemia (FA) is characterized by cellular hypersensitivity to DNA crosslinking agents, but how the Fanconi pathway protects cells from DNA crosslinks and whether FA proteins act directly on crosslinks remain unclear., Fanconi Anemia (FA) is a rare genetic disorder associated with a bone-marrow failure, cancer predisposition and hypersensitivity to DNA crosslinking agents., Fanconi anemia (FA) is a heterogeneous disease associated with a bone marrow failure, cancer predisposition and hypersensitivity to DNA crosslinking agents., Fanconi anemia (FA) is an inherited disorder characterized by defective DNA repair and cellular sensitivity to DNA crosslinking agents., Fanconi anemia (FA) is an inherited disease characterized by bone marrow failure, increased cancer risk and hypersensitivity to DNA cross-linking agents, implying a role for this pathway in the maintenance of genomic stability., Genetic or epigenetic inactivation of the pathway formed by the Fanconi Anemia (FA) proteins occurs in several cancer types, including head and neck squamous cell carcinomas (HNSCC), rendering the affected tumors potentially hypersensitive to DNA crosslinking agents., Fanconi Anemia (FA) is a rare autosomic recessive and X-linked disease with chromosomal instability after exposure to crosslinking agents as the hallmark., Fanconi Anemia (FA) is an autosomal recessive disease characterized by chromosome instability, cellular hypersensitivity to DNA cross-linking agents, and increased predisposition to malignancies., The Bloom protein (BLM) and Topoisomerase IIIalpha are found in association with proteins of the Fanconi anemia (FA) pathway, a disorder manifesting increased cellular sensitivity to DNA crosslinking agents., Using siRNA depletion and gene knockout techniques, we show that FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability., Fanconi anemia (FA) is a recessive human cancer prone syndrome featuring bone marrow failure, developmental abnormalities and hypersensitivity to DNA crosslinking agents exposure., FA is a chromosome instability syndrome characterized by childhood-onset aplastic anemia, cancer or leukemia susceptibility, and cellular hypersensitivity to DNA crosslinking agents., Functional defects in the Fanconi pathway can result in a marked hypersensitivity to interstrand crosslinking agents, such as mitomycin C., At the cellular level, hypersensitivity to DNA interstrand crosslinks is the defining feature in Fanconi anemia., DNA crosslinking agents may led to DNA cross-linking lesion, and Fanconi anemia pathway plays a key role in repairing its cross-linking., Fanconi anemia (FA), an autosomal recessive disorder of children, is characterized by congenital or childhood aplastic anemia, multiple developmental anomalies, increased incidence of myeloid leukemia, increased spontaneous chromosome breakage, and cellular and chromosomal hypersensitivity to DNA bifunctional crosslinking and alkylating agents., elegans provides an excellent model system for the study of the Fanconi Anemia (FA), one of the hallmarks of which is sensitivity to interstrand crosslinking agents, Using siRNA depletion and gene knockout techniques, we show that FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability, One of the hallmark phenotypes of FA is cellular hypersensitivity to agents that induce DNA interstrand crosslinks (ICLs), such as mitomycin C (MMC), Furthermore, the cytological hallmark of FA, the DNA crosslink-induced radial chromosome formation, exemplifies an innate impairment in the repair of these particularly cytotoxic DNA lesions [A.D, Fanconi anemia (FA) is characterized by cellular hypersensitivity to DNA crosslinking agents, but how the Fanconi pathway protects cells from DNA crosslinks and whether FA proteins act directly on crosslinks remain unclear, Features of chromosomal aberrations, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy have suggested a fundamental anomaly of DNA repair in Fanconi anemia, Fanconi anemia (FA) is an inherited chromosomal recessive syndrome characterized by cellular hypersensitivity to DNA crosslinking agents and bone marrow failure, which cause aplastic anemia, and an increased incidence of malignancy, Genetic or epigenetic inactivation of the pathway formed by the Fanconi Anemia (FA) proteins occurs in several cancer types, including head and neck squamous cell carcinomas (HNSCC), rendering the affected tumors potentially hypersensitive to DNA crosslinking agents, Fanconi anemia (FA) is a human autosomal disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinking agents such as mitomycin C and diepoxybutane, The Fanconi anemia pathway promotes DNA glycosylase-dependent excision of interstrand DNA crosslinks., DNA crosslinking agents may led to DNA cross-linking lesion, and Fanconi anemia pathway plays a key role in repairing its cross-linking, FA is a chromosome instability syndrome characterized by childhood-onset aplastic anemia, cancer or leukemia susceptibility, and cellular hypersensitivity to DNA crosslinking agents, The disease is manifested by defects in DNA repair, hypersensitivity to DNA crosslinking agents, and a high degree of chromosomal aberrations", "label": "yes"}
{"id": "converted_949", "sentence1": "Do R-loops tend to form at sites of DNA replication?", "sentence2": "Escherichia coli rnhA mutants devoid of RNase HI exhibit constitutive stable DNA replication, cSDR, which is thought to be initiated from R-loops stabilized in the absence of RNase HI., We propose that the organized structure of the R-loop is critical for primer RNA function in vivo with important implications for the RNA processing and DNA replication machinery., The precursor primer RNA exists as a persistent RNA-DNA hybrid, known as an R-loop, formed during transcription through the replication origin (Xu, B., and Clayton, D. A. (1996) EMBO J. 15, 3135-3143)., We found that overproduction of RecG protein drastically decreased copy numbers of ColE1-type plasmids, which require R-loop formation between the template DNA and a primer RNA transcript (RNA II) for the initiation of replication., These results suggest that overproduced RecG inhibits the initiation of replication by prematurely resolving the R-loops formed at the replication origin region of these plasmids with its unique helicase activity. The possibility that RecG regulates the initiation of a unique mode of DNA replication, oriC-independent constitutive stable DNA replication, by its activity in resolving R-loops is discussed., We propose that downstream of a replication block, RNA at R-loops is extended by DNA polymerase I, opening up the DNA duplex and leading to the recruitment of the replisome. This would allow replication to proceed while the original block is repaired or bypassed, Furthermore, increased RNaseH expression significantly alleviated genomic instability in deficient fibroblasts suggesting that cotranscriptional R-loops formation contributes to the genesis of replication-dependent DSBs in these cells., Transcription is an important source of replicative stress and consequently, maintenance of genome integrity requires the protection of chromosomes from the deleterious effects arising from the interaction between nascent RNAs and template DNA, leading to stable DNA-RNA hybrids (R-loop) formation., Strikingly, we found that attenuation of replication strongly suppresses R-loop-mediated DNA rearrangements in both E. coli and HeLa cells., More importantly, we then show that R-loop formation causes DNA replication fork stalling, and that this in fact underlies the effects of R loops on genomic stabilit, R-loop-mediated genomic instability is caused by impairment of replication fork progression, When any of these processes are not properly coordinated, aberrant outcomes such as fork reversal and R-loop formation arise and trigger unscheduled recombinogenic events and genome rearrangements. , Many studies show that cells can manage R loop formation with efficiency, and can also process the R-loops already formed in the cell, and by which, the bad effects of R-loops on DNA replication, gene mutation and homologous recombination can be regulated., Here we propose that physiological R-loop formation at CpG island promoters can contribute to DNA replication origin specification at these regions, the most efficient replication initiation sites in mammalian cells. , In agreement with this, we found that R-loops co-localize with the ORC within the same CpG island region in a significant fraction of these efficient replication origins, precisely at the position displaying the highest density of G4 motifs. , connection between transcription and replication in human cells and suggests that R-loop dysregulation at CpG island promoter-origins might contribute to the phenotype of DNA replication abnormalities and loss of genome integrity detected in cancer cells., We show that RNA:DNA hybrids (R-loops) form at sites of transcription/replication collisions and that RNase H1 functions to suppress CFS instability., R-loops and initiation of DNA replication in human cells: a missing link?, Stable RNA-DNA hybrids (R-loops) prime the initiation of replication in Escherichia coli cells., We propose that downstream of a replication block, RNA at R-loops is extended by DNA polymerase I, opening up the DNA duplex and leading to the recruitment of the replisome., Immediately after infection, RNA-DNA hybrids (R-loops) occur on (at least some) replication origins, with the annealed RNA serving as a primer for leading-strand synthesis in one direction., Here we propose that physiological R-loop formation at CpG island promoters can contribute to DNA replication origin specification at these regions, the most efficient replication initiation sites in mammalian cells., ColE1 plasmid origins of replication and oriK sites initiate primosome assembly by an RNA-DNA hybrid structure known as R-loop., This scenario builds on the connection between transcription and replication in human cells and suggests that R-loop dysregulation at CpG island promoter-origins might contribute to the phenotype of DNA replication abnormalities and loss of genome integrity detected in cancer cells., The multiple cleavage sites on the R-loop substrate match the priming sites observed in vivo, suggesting that RNase MRP alone is capable of generating virtually all of the leading-strand replication primers., Mechanisms of primer RNA synthesis and D-loop/R-loop-dependent DNA replication in Escherichia coli., Alternative oriC-independent modes of replication initiation are possible, one of which is constitutive stable DNA replication (cSDR) from transcription-associated RNA-DNA hybrids or R-loops., Our results suggest that Top1 execute this function by suppressing the formation of DNA-RNA hybrids during transcription, these so-called R-loops interfering with the progression of replication forks., Critical role of R-loops in processing replication blocks., The possibility that RecG regulates the initiation of a unique mode of DNA replication, oriC-independent constitutive stable DNA replication, by its activity in resolving R-loops is discussed., Competition between the RNA transcript and the nontemplate DNA strand during R-loop formation in vitro: a nick can serve as a strong R-loop initiation site., More importantly, we then show that R-loop formation causes DNA replication fork stalling, and that this in fact underlies the effects of R loops on genomic stability. , Consistent with this hypothesis, the 3' ends of the mitochondrial R-loop formed by in vitro transcription are located close to the initiation sites of the mitochondrial DNA replication. , A hybrid G-quadruplex structure formed between RNA and DNA explains the extraordinary stability of the mitochondrial R-loop., Previous studies have shown that the newly synthesized primers form a stable and persistent RNA-DNA hybrid, a R-loop, near the leading-strand origin of DNA replication. , Escherichia coli rnhA mutants devoid of RNase HI exhibit constitutive stable DNA replication, cSDR, which is thought to be initiated from R-loops stabilized in the absence of RNase HI. ", "label": "yes"}
{"id": "converted_2236", "sentence1": "Is sonidegib effective for basal cell carcinoma?", "sentence2": "This review of the literature aims to describe previous and current treatment options for oral therapy in locally advanced and metastatic NMSC otherwise unamenable to standard treatment. Oral Smoothened (Smo) inhibitors Vismodegib, Sonidegib, and Taladegib have shown to be effective in several trials. , Sonidegib is a new smoothened inhibitor currently under investigation for treatment of laBCC, which demonstrates a comparable safety profile to vismodegib. , The recent development of novel hedgehog pathway inhibitors for high-risk BCC (including oral vismodegib and sonidegib) may represent a paradigm shift towards medical management of NMSC., Sonidegib (Odomzo®), an oral smoothened (SMO) antagonist, is indicated for the treatment of adults with locally advanced basal cell carcinoma (laBCC) who are not candidates for surgery or radiation therapy, or adults with recurrent laBCC following surgery or radiation therapy. , The acceptable benefit-risk profile of sonidegib, along with a paucity of treatment options and the seriousness of the condition, makes sonidegib an emerging option for the treatment of adults with laBCC that has recurred following surgery or radiation therapy, or in those who are not candidates for surgery or radiation therapy., Sonidegib phosphate: new approval for basal cell carcinoma., Sonidegib, a novel smoothened inhibitor for the treatment of advanced basal cell carcinoma., Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group.The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat.Novartis Pharmaceuticals Corporation.<CopyrightInformation>Copyright © 2015 Elsevier Ltd. All rights reserved.</, However, to date, Hh inhibitors, specifically those targeting Smoothened [such as vismodegib, BMS-833923, saridegib (IPI-926), sonidegib/erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506, and TAK-441], have demonstrated good efficacy as monotherapy in patients with basal cell carcinoma and medulloblastoma, but have shown limited activity in other tumor types., The hedgehog pathway inhibitor sonidegib demonstrated meaningful tumor shrinkage in more than 90% of patients with locally advanced basal cell carcinoma (BCC) or metastatic BCC in the BCC Outcomes with LDE225 Treatment study.This report provides long-term follow-up data collected up to 12 months after the last patient was randomized.In this multicenter, randomized, double-blind phase II study, patients were randomized 1:2 to sonidegib 200 or 800 mg. The primary end point was objective response rate assessed by central review.Objective response rates in the 200- and 800-mg arms were 57.6% and 43.8% in locally advanced B, Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group.The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat.Novartis Pharmaceuticals Corporation.<CopyrightInformation>Copyright © 2015 Elsevier Ltd. All rights reserved.</C, Oral sonidegib is approved in Switzerland for the treatment of adult patients with advanced basal cell carcinoma (BCC) and in the US and EU for the treatment of adult patients with locally advanced BCC that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy., Sonidegib phosphate: new approval for basal cell carcinoma.", "label": "yes"}
{"id": "converted_2055", "sentence1": "Does Jarid2 play a role in early embryo development?", "sentence2": "Jarid2 Coordinates Nanog Expression and PCP/Wnt Signaling Required for Efficient ESC Differentiation and Early Embryo Development, Unlike other PRC2-deficient embryonic stem cells (ESCs), however, Jarid2-deficient ESCs show a severe differentiation block, altered colony morphology, and distinctive patterns of deregulated gene expression. Here, we show that Jarid2(-/-) ESCs express constitutively high levels of Nanog but reduced PCP signaling components Wnt9a, Prickle1, and Fzd2 and lowered β-catenin activity. Depletion of Wnt9a/Prickle1/Fzd2 from wild-type ESCs or overexpression of Nanog largely phenocopies these cellular defects. Co-culture of Jarid2(-/-) with wild-type ESCs restores variable Nanog expression and β-catenin activity and can partially rescue the differentiation block of mutant cells. In addition, we show that ESCs lacking Jarid2 or Wnt9a/Prickle1/Fzd2 or overexpressing Nanog induce multiple ICM formation when injected into normal E3.5 blastocysts. These data describe a previously unrecognized role for Jarid2 in regulating a core pluripotency and Wnt/PCP signaling circuit that is important for ESC differentiation and for pre-implantation development., Jarid2 Coordinates Nanog Expression and PCP/Wnt Signaling Required for Efficient ESC Differentiation and Early Embryo Development., Consistent with an essential role for PcG proteins in early development, we demonstrate that JARID2 is required for the differentiation of mouse embryonic stem cells., Jumonij (JMJ)/Jarid2 plays important roles in embryonic development and functions as a transcriptional repressor., Thus, these results demonstrate that JARID2 is essential for the binding of PcG proteins to target genes and, consistent with this, for the proper differentiation of embryonic stem cells and normal development., JARID2 is an accessory component of Polycomb repressive complex-2 (PRC2) required for the differentiation of embryonic stem cells (ESCs)., Jarid2 Coordinates Nanog Expression and PCP/Wnt Signaling Required for Efficient ESC Differentiation and Early Embryo Development., These data describe a previously unrecognized role for Jarid2 in regulating a core pluripotency and Wnt/PCP signaling circuit that is important for ESC differentiation and for pre-implantation development..", "label": "yes"}
{"id": "converted_2483", "sentence1": "Are the human bombesin receptors, GRPR and NMBR, frequently overexpressed G-protein-coupled-receptors by lung-cancers?", "sentence2": "Members of the gastrin-releasing peptide (GRP) family and its analogs bombesin (BBN) have been implicated in the biology of several human cancers including prostate, breast, colon and lung., All 3 bombesin receptor subtypes (GRPR, NMBR, and BRS-3) were present on pulmonary and intestinal carcinoids by immunohistochemistry, There is increased interest in the Bn-receptor family because they are frequently over/ectopically expressed by tumors and thus useful as targets for imaging or receptor-targeted-cytotoxicity. , ML-18 is a non-peptide bombesin receptor subtype-3 antagonist which inhibits lung cancer growth., Gastrin-releasing peptide (GRP), a member of the bombesin family of peptides, has been shown to have mitogenic activity in small cell lung carcinoma (SCLC), and to be produced by SCLC in an autocrine fashion.", "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", "label": "yes"}
{"id": "converted_3662", "sentence1": "Should Lubeluzole be used for treatment of ischemic stroke?", "sentence2": "Lubeluzole showed promising neuroprotective effects in animal stroke models, but failed to show benefits in acute ischemic stroke in humans. , However, clinical research on lubeluzole is now at a standstill, since lubeluzole seems to be associated with the acquired long QT syndrome and ventricular arrhythmias. , Ten classes of neuroprotective agents have reached phase III efficacy trials but have shown mixed results. They included calcium channel antagonists, NMDA receptor antagonists, lubeluzole, CDP-choline, the free radical scavenger tirilazad and ebselen, enlimomab, GABA agonist clomethiazole, the sodium channel antagonist fosphenytoin, magnesium, glycine site antagonist GV150526 and piracetam. , CONCLUSIONS: This study failed to show an efficacy of lubeluzole in the treatment of acute stroke. , Overall, of all treated patients, 401 (22.5%) died: 203 (22.5%) in the lubeluzole group and 198 (22.4%) with placebo. Of all subjects treated, 853 (95%) on lubeluzole and 826 (93%) on placebo reported an adverse event during their treatment period or within the next 2 days after discontinuation of treatment., CONCLUSIONS: Treatment with lubeluzole within 6 hours of the onset of ischemic stroke had a nonsignificant effect on mortality and resulted in improved clinical outcome compared with placebo, with no safety concerns., RESULTS: The overall mortality rate at 12 weeks for lubeluzole-treated patients was 20.7% compared to 25.2% for placebo-treated patients (NS). Controlling for relevant covariates, the degree of neurological recovery (NIHSS) at week 12 significantly favored lubeluzole over placebo (P = .033). Lubeluzole treatment similarly resulted in significantly greater improvements in functional status (Barthel Index) (P = .038) and overall disability (Rankin Scale) (P = .034) after 12 weeks. A global test statistic confirmed that lubeluzole-treated patients had a more favorable clinical outcome at 12 weeks (P = .041)., CONCLUSIONS: In patients with acute ischemic stroke, the dosage regimen of 7.5 mg over 1 hour followed by 10 mg/d of intravenous lubeluzole is safe and statistically significantly reduced mortality. , CONCLUSIONS\n\nTreatment with lubeluzole within 6 hours of the onset of ischemic stroke had a nonsignificant effect on mortality and resulted in improved clinical outcome compared with placebo, with no safety concerns., CONCLUSIONS: Lubeluzole, given in the acute phase of ischaemic stroke, is not associated with a significant reduction of death or dependency at the end of scheduled follow-up period but seems to be associated with a significant increase of heart-conduction disorders (Q-T prolonged >450 msec)., Treatment with lubeluzole within 6 hours of the onset of ischemic stroke had a nonsignificant effect on mortality and resulted in improved clinical outcome compared with placebo, with no safety concerns., In the overall study population, treatment with intravenous lubeluzole within 6 h of the onset of ischaemic stroke did not affect mortality or clinical outcome.", "label": "no"}
{"id": "converted_1333", "sentence1": "Can cognitive behavioral therapy improve fatigue in cancer patients?", "sentence2": "Physical activity, educational interventions, and cognitive-behavioral therapy have the most supportive data and can be recommended to patients with confidence. , For women undergoing radiotherapy (3 RCTs), hypnosis combined with cognitive-behavioral therapy improved distress and fatigue., Patients in the CBT group reported a significantly larger decrease in fatigue scores than patients in the waiting list group., However, relative to VCBT-I, PCBT-I was associated with significantly greater improvements of insomnia severity, early morning awakenings, depression, fatigue, and dysfunctional beliefs about sleep. , CBT-I may also improve mood, fatigue, and overall quality of life, and can be successfully delivered through a variety of treatment modalities, making it possible to reach a broader range of patients who may not have access to more traditional programs. , No group differences in improvement were noted relative to QOL, fatigue, or mood. , In case of persistent fatigue, personalized cognitive behavioral therapy can be considered., ONCLUSION: The results support CBTH as an evidence-based intervention to control fatigue in patients undergoing radiotherapy for breast cancer. , Severe fatigue after cancer treatment can be treated effectively with cognitive behavioral therapy (CBT), but it is unclear whether CBT has an effect on cognitive functioning., CONCLUSION: CBT for post-cancer fatigue has already been shown to be an effective therapy. , Frequently reported side effects include cancer-related fatigue, peripheral neuropathy, and psychological distress. Exercise and cognitive behavioral therapy interventions have counteracted such adverse effects in other cancer populations. , There is evidence from methodologically rigorous controlled trials that exercise, psycho-educational interventions, and cognitive-behavioral therapy for insomnia are effective in the treatment of CRF, and a wide range of pharmacologic and nonpharmacologic interventions has shown initial promise in single-arm pilot studies with small, heterogeneous samples. , CONCLUSIONS: Physical training combined with cognitive-behavioral therapy and physical training alone had significant and beneficial effects on fatigue compared with no intervention. Physical training was equally effective as or more effective than physical training combined with cognitive-behavioral therapy in reducing cancer-related fatigue, suggesting that cognitive-behavioral therapy did not have additional beneficial effects beyond the benefits of physical training., RESULTS: Imagery/hypnosis and CBT/CST interventions have produced improvement in all the three cancer-related symptoms individually: pain, fatigue, and sleep disturbance., RESULTS: Multilevel modeling indicated that for weekly FACIT fatigue data, there was a significant effect of the CBTH intervention on the rate of change in fatigue (p < .05), such that on average, CBTH participants' fatigue did not increase over the course of treatment, whereas control group participants' fatigue increased linearly., ONCLUSION: The results suggest that CBTH is an effective means for controlling and potentially preventing fatigue in breast cancer radiotherapy patients., Results were consistent with the view that CBTH was effective in managing fatigue and skin discomfort, and increasing relaxation., RESULTS: Participants in the Internet group showed significant improvements at post-assessment compared with those in the control group in overall insomnia severity (F(1,26) = 22.8; p<0.001), sleep efficiency (F(1,24) = 11.45; P = 0.002), sleep onset latency (F(1,24) = 5.18; P = 0.03), soundness of sleep (F(1,24) = 9.34; P = 0.005), restored feeling upon awakening (F(1,24) = 11.95; P = 0.002), and general fatigue (F(1,26) = 13.88; P = 0.001). , Cognitive-behavior therapy (CBT) has alleviated fatigue and improved QOL of cancer patients; however, little is known about the effects of nurse-led CBT on breast cancer patients undergoing radiotherapy., Physical training was equally effective as or more effective than physical training combined with cognitive-behavioral therapy in reducing cancer-related fatigue, suggesting that cognitive-behavioral therapy did not have additional beneficial effects beyond the benefits of physical training., Cognitive-behavior therapy (CBT) has alleviated fatigue and improved QOL of cancer patients; however, little is known about the effects of nurse-led CBT on breast cancer patients undergoing radiotherapy., Physical training was equally effective as or more effective than physical training combined with cognitive-behavioral therapy in reducing cancer-related fatigue, suggesting that cognitive-behavioral therapy did not have additional beneficial effects beyond the benefits of physical training., The positive effects of cognitive behavioral therapy in adolescents with chronic fatigue syndrome are sustained after cognitive behavioral therapy", "label": "yes"}
{"id": "converted_573", "sentence1": "Are there telemedicine applications for chronic pain management?", "sentence2": "An integrated cognitive-behavioral and physical therapy group protocol has been developed and then implemented at remote sites using videoconferencing technology to provide pain management for veterans. , Tele-pain management: use of videoconferencing technology in the delivery of an integrated cognitive-behavioral and physical therapy group intervention., It is feasible to provide treatment to women veterans living in rural areas by utilizing video-teleconferencing technology between larger VA medical centers and facilities at CBOCs in more rural settings, The results suggest that a smartphone-delivered intervention with diaries and personalized feedback can reduce catastrophizing and prevent increases in functional impairment and symptom levels in women with chronic widespread pain following inpatient rehabilitation.,  Of the studies available, there are very few randomized trials of telehealth pain care and only one general overview of e-health and chronic pain, which dedicates just a few paragraphs to telehealth., therapy adaptation and the resultant specification for the SMART2 project-a technology-based self-management system for assisting long-term health conditions, including chronic pain, Results showed the use of videoconferencing for this group of patients is useable and satisfactory for both patients and staff, that the patients save time and money, and that for a system where videoconferencing equipment is already in use, it is also cost effective. Staff were able to identify new patient problems. , This pilot study indicates that telemedicine follow-up consultations for chronic pain patients are feasible and cost-saving. Patients and anesthesiologists were highly satisfied with telemedicine consultation.", "label": "yes"}
{"id": "converted_4422", "sentence1": "Is pRETRO-SUPER an adenoviral vector?", "sentence2": " In this study, we investigated the effect of small interfering RNA (siRNA) of connective tissue growth factor (CTGF) by pRetro-Super (PRS) retrovirus vector on the expression of CTGF and related extracellular matrix molecules in human renal proximal tubular cells (HKCs) induced by high glucose, to provide help for renal tubulointerstitial fibrosis therapy.", "label": "no"}
{"id": "converted_4450", "sentence1": "Is SOX10 expressed in melanoma cells?", "sentence2": "Our study confirmed that SOX10 is an oncogene and activate Notch signaling pathway, which suggests the potential treatment for melanoma patients by target SOX10/Notch axis., The most commonly used melanocytic markers include S100, Melan-A, HMB45 and SOX10, melanocytic markers melan-A and SOX10 ", "label": "yes"}
{"id": "converted_1215", "sentence1": "Is zolpidem an antibiotic?", "sentence2": "Zolpidem is a short-acting imidazopyridine hypnotic drug that is metabolized mainly by CYP3A4., FGIN-1-27 and alpidem, like the neurosteroid 3 alpha,21-dehydroxy-5 alpha-pregnane-20-one (THDOC), clonazepam and zolpidem (the direct allosteric modulators of gamma-aminobutyric acidA receptors) delay the onset of isoniazid and metrazol-induced convulsions., olpidem is a new, short-acting hypnotic of imidazopyridine structure which binds selectively to a subpopulation of receptors involved in the action of benzodiazepines [omega 1 (BZ1) sites of the gamma-aminobutyric acidA receptors], lpidem is a new, short-acting hypnotic of imidazopyridine structure which binds selectively to a subpopulation of receptors involved in the action of benzodiazepines [omega 1 (BZ1) sites of the gamma-aminobutyric acidA receptors], In contrast, after repeated treatment with zolpidem, there was no change in its ability to produce sedative and anticonvulsant effects., Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects., Zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide hemitartrate] is reported to be a rapid onset, short duration hypnotic that interacts at the benzodiazepine recognition site., The imidazopyridine zolpidem is a short-acting hypnotic chemically distinct from benzodiazepines (BZs)., According to its peculiar neuropharmacologic activity (selectivity for the omega 1-BZ receptors), zolpidem is expected to be a pure hypnotic, without the other effects of BZs.", "label": "no"}
{"id": "converted_2129", "sentence1": "Is diphosphatidylglycerol (cardiolipin) a phospholipid of the mitochondrial membranes?", "sentence2": "A unique organelle for studying membrane biochemistry is the mitochondrion whose functionality depends on a coordinated supply of proteins and lipids. Mitochondria are capable of synthesizing several lipids autonomously such as phosphatidylglycerol, cardiolipin and in part phosphatidylethanolamine, phosphatidic acid and CDP-diacylglycerol., A small decrease of diphosphatidylglycerol also occurred in the hepatoma mitochondria inner membrane. , Diphosphatidylglycerol was confined to the mitochondrial fraction, where it represented about 7% of the total phosphoacylglycerols. , Mitochondrial membranes were isolated from the myocardium of young (4-month-old) and aged (33-month-old) male Long-Evans rats and compared in terms of cholesterol content and phospholipid and fatty acid composition. In aged rats, as compared to young, the major observations include: markedly higher cholesterol content; increased percentage of sphingomyelin and diphosphatidylglycerol (cardiolipin); , The polyglycerophosphatides (typified by diphosphatidylglycerol) were apparently synthesized in situ by intramitochondrial membrane-bound enzymes using CDP-diglycerides as intermediates. , Both the mitochondrial and microsomal fractions contained significant proportions of solvent front phospholipid (SFP) and whereas the mitochondrial SFP displayed the relatively unsaturated fatty acid composition characteristic of diphosphatidylglycerol (cardiolipin), the fatty acids of the microsomal SFP were distinctly more saturated., Ten to 15% of microsomal radioactive CDP-diglycerides was transferred to mitochondrial membranes and incorporated into mitochondrial radioactive lipids identified as phosphatidylglycerol, phosphatidylglycerophosphate, and, when [14C]linoleoyl CDP-diglycerides were used, diphosphatidylglycerol (cardiolipin)., The enzyme responsible for the conversion of phosphatidylglycerol to diphosphatidylglycerol (cardiolipin) in the presence of cytidine diphosphate diacylglycerol is firmly associated with mitochondrial membranes and is not extracted with hypotonic or hypertonic media or with nonionic detergents., The mechanism of cardiolipin (diphosphatidylglycerol) biosynthesis was examined in mitochondria and outer and inner mitochondrial membranes prepared from guinea pig and rat livers to determine whether this formation from phosphatidylglycerol was absolutely dependent on cytidinediphosphodiglyceride, as previously reported for intact mitochondria., In isolated mitochondrial outer membranes, cardiolipin (diphosphatidylglycerol) increased CPT1 activity 4-fold and the Km for carnitine 6-fold., Ten to 15% of microsomal radioactive CDP-diglycerides was transferred to mitochondrial membranes and incorporated into mitochondrial radioactive lipids identified as phosphatidylglycerol, phosphatidylglycerophosphate, and, when [14C]linoleoyl CDP-diglycerides were used, diphosphatidylglycerol (cardiolipin)., 90% or more of the phospholipid, cardiolipin was found in the mitochondrial membranes of wild type and petite yeast., Furthermore, the same mechanism for the biosynthesis of cardiolipin was operational in the outer and inner mitochondrial membranes., The mechanism of cardiolipin (diphosphatidylglycerol) biosynthesis was examined in mitochondria and outer and inner mitochondrial membranes prepared from guinea pig and rat livers to determine whether this formation from phosphatidylglycerol was absolutely dependent on cytidinediphosphodiglyceride, as previously reported for intact mitochondria, Cardiolipin (CL) is a key phospholipid in mitochondrial membranes, playing important roles in maintaining the functional integrity and dynamics of mitochondria in animals and yeasts, Cardiolipin, the specific phospholipid of mitochondria, is involved in the biogenesis, the dynamics, and the supramolecular organization of mitochondrial membranes, Cardiolipin (CL), the signature phospholipid of mitochondrial membranes, is crucial for both mitochondrial function and cellular processes outside of the mitochondria, Since it has been recognized that mitochondria are crucial not only for energy metabolism but also for other cellular functions, there has been a growing interest in cardiolipin, the specific phospholipid of mitochondrial membranes, Cardiolipin, the main anionic phospholipid in mitochondrial membranes, is expected to be a determinant in this adaptive mechanism since it modulates the activity of most membrane proteins, Ten to 15% of microsomal radioactive CDP-diglycerides was transferred to mitochondrial membranes and incorporated into mitochondrial radioactive lipids identified as phosphatidylglycerol, phosphatidylglycerophosphate, and, when [14C]linoleoyl CDP-diglycerides were used, diphosphatidylglycerol (cardiolipin), Cardiolipin is normally localized to the inner mitochondrial membrane; however, when cardiolipin becomes externalized to the surface of dysregulated mitochondria, it promotes inflammasome activation and stimulates the elimination of damaged or nonfunctional mitochondria by mitophagy, In isolated mitochondrial outer membranes, cardiolipin (diphosphatidylglycerol) increased CPT1 activity 4-fold and the Km for carnitine 6-fold. , Increasing levels of cardiolipin differentially influence packing of phospholipids found in the mitochondrial inner membrane., Here, we used Saccharomyces cerevisiae subjected to conditions that affect mitochondrial metabolism as a model to determine the possible role of cardiolipin in stress adaptation. , This decline of respiration was attributed to a progressive diminution of the number of mitochondria in copper-treated cells, based on the demonstration of the concomitant decline of (1) cardiolipin (diphosphatidylglycerol) and cytochrome aa3 (cytochrome oxidase), two specific markers of mitochondrial inner membrane, and (2) fumarase activity, a specific marker of mitochondrial matrix space., Diphosphatidylglycerol (DPG) or cardiolipin, a specific component of the inner mitochondrial membrane, represents about 4% of the total lipid content., Experimental results confirmed that the biosynthesis of cardiolipin, from the membrane-bound radioactive phosphatidylglycerol in intact mitochondria isolated from guinea pig and rat liver, was absolutely dependent on CDP-diglycerides and required the addition of divalent cations., We have shown that decrease of cardiolipin in mitochondrial membrane occurs early during ischemia, and only during the irreversible phase of ischemia are phosphatidylethanolamine and phosphatidylcholine broken down., Partial purification of diphosphatidylglycerol synthetase from liver mitochondrial membranes., A small decrease of diphosphatidylglycerol also occurred in the hepatoma mitochondria inner membrane.", "label": "yes"}
{"id": "converted_1452", "sentence1": "Does dronedarone  affect  T3 and T4 levels?", "sentence2": "Amiodarone resulted in increased T4, T4/T3 and rT3, whereas dronedarone did not alter the thyroid hormone profile in normal animals., Fifty-five Wistar rats were randomly allocated to a 2-week oral treatment with either vehicle (n=18), amiodarone (30 mg/kg, n=20), or dronedarone (30 mg/kg, n=17)., Thyroid function was similar in the 3 groups., Plasma levels of T3, T4, and rT3 were changed after SR 33589 treatment except a decrease in T4 level at the highest dose whilst the T4 T3 ratio and the level of rT3 were dose-dependently increased by amiodarone treatment.", "label": "no"}
{"id": "converted_366", "sentence1": "Is there an association between TERT promoter mutation and survival of glioblastoma patients?", "sentence2": "Glioblastoma patients with TERT mutations showed a shorter survival than those without TERT mutations in univariate analysis (median, 9.3 vs. 10.5 months; P = 0.015) and multivariate analysis after adjusting for age and gender (HR 1.38, 95 % CI 1.01-1.88, P = 0.041). However, TERT mutations had no significant impact on patients' survival in multivariate analysis after further adjusting for other genetic alterations, or when primary and secondary glioblastomas were separately analysed. These results suggest that the prognostic value of TERT mutations for poor survival is largely due to their inverse correlation with IDH1 mutations, which are a significant prognostic marker of better survival in patients with secondary glioblastomas., Patients with tumors lacking hTERT expression/TA showed a significant survival benefit (Kaplan-Meier test, both P < .01), which, however, was based exclusively on the younger patient subgroup (≤60 y, both P < .005; >60 y, both ns). , Glioblastoma patients with TERT mutations showed a shorter survival than those without TERT mutations in univariate analysis (median, 9.3 vs", "label": "yes"}
{"id": "converted_3010", "sentence1": "In clinical trials, the H3 R antagonist CEP-26401 has a positive effect on cognition, yes or no?", "sentence2": "CEP-26401 is a novel orally active, brain-penetrant, high-affinity histamine H3 receptor (H3R) antagonist, with potential therapeutic utility in cognition enhancement, hese results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H₃R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders, CEP-26401 is a novel orally active, brain-penetrant, high-affinity histamine H3 receptor (H3R) antagonist, with potential therapeutic utility in cognition enhancement., CEP-26401 (irdabisant), a potent and selective histamine H₃ receptor antagonist/inverse agonist with cognition-enhancing and wake-promoting activities., However, although a number of clinical studies examining the efficacy of H3 receptor antagonists for a variety of cognitive disorders are currently underway, no clinical proof of concept for an H3 receptor antagonist has been reported to date., Further clinical studies are required to establish the potential of low-dose CEP-26401 in cognition enhancement.<br>", "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).", "label": "yes"}
{"id": "converted_1099", "sentence1": "Are there any HCV replication inhibitors available?", "sentence2": "We report here the discovery of the first small-molecule HCV infectivity inhibitor, GS-563253, also called HCV infectivity inhibitor 1 (HCV II-1). , Resistance to mericitabine (prodrug of HCV NS5B polymerase inhibitor PSI-6130) is rare and conferred by the NS5B S282T mutation., We tested the ability of NA808 to inhibit SPT's enzymatic activity in FLR3-1 replicon cells, The SPT inhibitor NA808 prevents replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in cultured hepatocytes and in mice with humanized livers., Vaniprevir (phase III clinical trials) and MK-5172 (phase II clinical trials) are two potent antiviral compounds that target NS3/4A protease, treatment for hepatitis C virus (HCV) infection has been significantly improved with the approval of the first two HCV NS3/4A protease inhibitors, telaprevir (Incivek) and boceprevir (Victrelis). , Combination therapy with telaprevir and BMS-788329 (NS5A inhibitor) reduced serum HCV RNA to undetectable levels. The presence of an NS3-V36A telaprevir resistance mutation resulted in poor response to telaprevir monotherapy but showed significant HCV reduction when telaprevir was combined with BMS-788329. However, a BMS-788329-resistant strain emerged at low frequency. Infection with a BMS-788329-resistant NS5A-L31V mutation rapidly resulted in gain of an additional NS5A-Y93A mutation that conferred telaprevir resistance during combination therapy, HCV NS5A replication complex inhibitors, exemplified by Daclatasvir (BMS-790052), represent a new class of DAA, ACH-806 (or GS-9132) is a novel, small-molecule inhibitor specific for hepatitis C virus (HCV). , Telaprevir and boceprevir are the first two protease inhibitor (PI) DAAs to be approved for combination therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV). , symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed, In vitro, boceprevir is more active than telaprevir against the HCV G3 NS3/4A enzyme in cell-based and biochemical assays and against G3 isolates in replicon assays, Alisporivir is the most advanced host-targeting antiviral in clinical development. Alisporivir blocks HCV replication by neutralizing the peptidyl-prolyl isomerase activity of the abundant host cytosolic protein, cyclophilin A, Interestingly, the NS5A inhibitor daclatasvir (BMS-790052) caused a decrease in serum HCV RNA levels by about two orders of magnitude within 6 h of administration", "label": "yes"}
{"id": "converted_42", "sentence1": "Is irritable bowel syndrome more common in women with endometriosis?", "sentence2": "CONCLUSIONS: Comorbid pain syndromes, mood conditions and asthma are common in adolescents and young women with endometriosis., There are many etiologies of pelvic pain that present with symptoms resembling those of endometriosis-associated pelvic pain that are not diagnosable with laparoscopy, such as interstitial cystitis and irritable bowel syndrome., Often, such patients are labelled with irritable bowel syndrome. , Irritable bowel syndrome (IBS) is also common in this setting, and it was speculated that the visceral hypersensitivity associated with this condition might be amplifying the symptoms of endometriosis. , RESULTS: Compared with controls, patients with minimal to mild and moderate to severe endometriosis had a higher prevalence of symptoms consistent with IBS (0% vs 65% and 50%, respectively, p<0.001) with significantly lower mean pain thresholds (39.5 mm Hg (95% CI 36.0 to 43.0) vs 28.1 mm Hg (95% CI 24.5 to 31.6), p=0.001 and 28.8 mm Hg (95% CI 24.9 to 32.6), p=0.002) not explained by differences in rectal compliance. , Similarly, women with a history of irritable bowel syndrome were twice as likely to develop endometriosis [AOR=1.9, 95% CI (1.03-3.87)]., A weak association between reported family history of endometriosis and history of irritable bowel syndrome and the development of endometriosis was also observed. , Irritable bowel syndrome and chronic constipation in patients with endometriosis., Fifteen per cent of the patients with endometriosis also had IBS and 14% of the patients with endometriosis had functional constipation without IBS., CONCLUSION: In patients with endometriosis, 29% also had IBS or constipation. , Seventy-six women (21.4%) had previously been diagnosed with irritable bowel syndrome and 79% of them had endometriosis confirmed., Compared with controls, women with endometriosis had increased risks of abdominopelvic pain (OR 5.2 [95% CI: 4.7-5.7]), dysmenorrhoea (OR 8.1 [95% CI: 7.2-9.3]), menorrhagia (OR 4.0 [95% CI: 3.5-4.5]), subfertility (OR 8.2 [95% CI: 6.9-9.9]), dyspareunia and/or postcoital bleeding (OR 6.8 [95% CI: 5.7-8.2]), and ovarian cysts (OR 7.3 [95% CI: 5.7-9.4]), and of being diagnosed with irritable bowel syndrome (IBS) (OR 1.6 [95% CI: 1.3-1.8]) or pelvic inflammatory disease (OR 3.0 [95% CI: 2.5-3.6])., Endometriosis may coexist with or be misdiagnosed as pelvic inflammatory disease or IBS., RESULTS: Compared with the controls, women with endometriosis were 3.5 times more likely to have received a diagnosis of IBS (OR 3.5 [95% CI: 3.1-3.9]). Even after women had been diagnosed with endometriosis, they were still two and a half times more likely to receive a new diagnosis of IBS when compared with the controls (OR 2.5 [95% CI: 2.2-2.8])., CONCLUSIONS: Women with endometriosis are more likely to be diagnosed with IBS and PID than controls, even after a definitive diagnosis of endometriosis has been reached., In women, clinical studies suggest that functional pain syndromes such as irritable bowel syndrome, interstitial cystitis, and fibromyalgia, are co-morbid with endometriosis, chronic pelvic pain, and others diseases., In women, clinical studies suggest that pain syndromes such as irritable bowel syndrome and interstitial cystitis, which are associated with visceral hyperalgesia, are often comorbid with endometriosis and chronic pelvic pain. , Depression, anxiety, IBS, FM, CFS, and IC were more common in migraine with EM group than in controls., Intestinal endometriosis can mimic many gastrointestinal diseases, such as irritable bowel syndrome, inflammatory bowel disease, infections and neoplasms., Endometriosis is often associated with other painful conditions such as irritable bowel syndrome, interstitial cystitis and fibromyalgia. , CONCLUSIONS: Diagnosis of endometriosis should be considered in women with recurrent monthly abdominal pain and bowel symptoms, especially if accompanied by gynaecologic complaints, even because the significant symptoms overlap with the irritable bowel syndrome (IBS) and makes the differentiation extremely difficult., Intestinal endometriosis is typically asymptomatic; however, when symptoms occur, they can mimic those of irritable bowel syndrome.,  Similarly, women with a history of irritable bowel syndrome were twice as likely to develop endometriosis [AOR=1., Irritable bowel syndrome (IBS) is also common in this setting, and it was speculated that the visceral hypersensitivity associated with this condition might be amplifying the symptoms of endometriosis., Irritable bowel syndrome (IBS) is also common in this setting, and it was speculated that the visceral hypersensitivity associated with this condition might be amplifying the symptoms of endometriosis.", "label": "yes"}
{"id": "converted_3080", "sentence1": "Is treatment with Bacillus Calmette Guerin used for bladder cancer?", "sentence2": "Intravesical Bacillus Calmette-Guerin (BCG) is the best treatment modality for progression of non-muscle invasive bladder cancer. , this result indicates that they may be used as putative biomarkers for monitoring changes in bladder carcinogenesis in response to BCG immunotherapy., response of urothelial precancerous lesions to intravesical BCG treatment, bladder cancer (BC) is a major clinical issue.METHODS: We performed immunohistochemistry to assess the role of human epidermal growth factor receptor-2 (HER-2) and microsatellite instability (MSI) factors MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in predicting recurrence and progression of T1 high-grade BCs having undergone transurethral resection of bladder tumor (TURBT) alone or TURBT + intravesical instillations of bacillus Calmette-Guerin (BCG)., To evaluate the efficacy and safety of a tailored endovesical immunotherapy protocol with biweekly BCG for elderly Patients with high risk non muscle invasive bladder cancer , Bacillus of Calmette-Guerin (BCG) therapy for high risk non muscle invasive bladder cancer treatment in older patients., BCG (Bacillus of Calmette Guerin) has been used for more than 20 years and is currently the most active agent for superficial bladder cancer therapy., BCG (Bacillus of Calmette Guerin) therapy of high-risk superficial bladder cancer., Production of IL-5, a classical T(H)2 cytokine, following bacillus Calmette guerin immunotherapy of bladder cancer., Intravesical Bacillus Calmette-Guerin is used to treat patients with superficial bladder cancer., There is some evidence that BCG therapy improves survival and progression rates of patients with high-risk superficial bladder cancer decreasing the proportion who require radical cystectomy., Local immunotherapy with bacillus Calmette-Guerin (BCG) is an effective and frequently used treatment for superficial bladder cancer., CONCLUSIONS\nIntravesical bacillus Calmette-Guerin is a viable therapeutic option in patients with high risk superficial bladder cancer and concomitant lymphoma or chronic lymphocytic leukemia, treatment with low dose oral steroids or treatment with inhaled steroids., PURPOSE\nBacillus Calmette-Guerin is the most effective therapy for nonmuscle invasive bladder cancer., INTRODUCTION\nBacillus Calmette-Guerin (BCG) is a live attenuated strain of Mycobacterium bovis that has been used to treat urothelial carcinoma since 1976, and has been reported to eradicate disease in more than 70% of patients with in situ and stage I disease., Intravesical administration of bacillus Calmette-Guerin has been shown to be highly effective treatment of superficial bladder cancer., Intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results., We describe a 53 year- old man with a disseminated bacillus Calmette-Guerin (BCG) infection after intravescical instillation for bladder carcinoma., We tested the hypothesis that tumor expression of natural cytotoxicity receptor ligands can serve as a predictive factor for the response to intravesical bacillus Calmette-Guerin in patients with nonmuscle invasive, high grade bladder cancer., Bacillus Calmette-Guerin immunotherapy has been found by a number of investigators to be effective in the treatment and prevention of superficial bladder cancer., Pancreatic and psoas abscesses as a late complication of intravesical administration of bacillus Calmette-Guerin for bladder cancer: a case report and review of the literature.This case illustrates the fact that although intravesical administration of bacillus Calmette-Guerin is generally considered to be safe, it is not exempt from complications and these could appear immediately after treatment or as a delayed complication many years later., Effects of local bacillus Calmette-Guerin therapy in patients with bladder carcinoma on immunocompetent cells of the bladder wall.The antitumoral effects of intravesical bacillus Calmette-Guerin against recurrent superficial urothelial bladder cancer seem to be linked to immunological effector mechanisms. , Fatal sepsis following intravesical bacillus Calmette-Guerin administration for bladder cancer.Intravesical administration of bacillus Calmette-Guerin has been shown to be highly effective treatment of superficial bladder cancer. , Intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results.We treated 40 patients with superficial bladder cancer via intravesical bacillus Calmette-Guerin for 1) prophylaxis against tumor recurrence, 2) residual carcinoma or 3) flat carcinoma in situ. , Bacillus Calmette-Guerin immunotherapy for bladder cancer.Bacillus Calmette-Guerin immunotherapy has been found by a number of investigators to be effective in the treatment and prevention of superficial bladder cancer. , Safety and efficacy of intravesical bacillus Calmette-Guerin instillations in steroid treated and immunocompromised patients.Intravesical bacillus Calmette-Guerin is a viable therapeutic option in patients with high risk superficial bladder cancer and concomitant lymphoma or chronic lymphocytic leukemia, treatment with low dose oral steroids or treatment with inhaled steroids. , Our results suggest that intralesional bacillus Calmette-Guerin immunotherapy can afford long term protection from transplanted bladder cancer, and that live bacillus Calmette-Guerin is superior to levamisole and P3 + Re-glycolipid + bacillus Calmette-Guerin cell walls in the treatment of bladder cancer., A randomized controlled prospective evaluation of intravesical and percutaneous bacillus Calmette-Guerin immunotherapy was done in 57 patients with transitional cell carcinoma of the bladder., Up to 90% of patients with high grade superficial bladder tumors experience tumor recurrence and up to 50% have progression despite bacillus Calmette-Guerin treatment., We review how the bacillus Calmette-Guerin vaccine evolved to become standard therapy for superficial bladder cancer., We reviewed the historical literature describing the origin of the bacillus Calmette-Guerin vaccine as an anticancer agent and its singular success as the most effective immunotherapy used against a human neoplasm.", "label": "yes"}
{"id": "converted_3046", "sentence1": "Does Rhamnose have any effect on aging?", "sentence2": "The monosaccharide analysis showed that rhamnose (Rha) and glucose (Glu) may play vital roles in maintaining the antioxidant and anti-aging activities. , Some of these mechanisms will be reviewed as well as the capacity of fucose- and rhamnose-rich oligo- and polysaccharides (FROP and RROP) to counteract several of the mechanisms involved in skin aging.", "label": "yes"}
{"id": "converted_3970", "sentence1": "Does erenumab target the calcitonin gene-related peptide?", "sentence2": "Four monoclonal antibodies have been developed: one targeting the calcitonin gene-related peptide receptor (erenumab) and three targeting the calcitonin gene-related peptide (eptinezumab, fremanezumab, and galcanezumab).", "label": "no"}
{"id": "converted_142", "sentence1": "Is amiodarone a class I anti-arrhythmic drug?", "sentence2": "Common class I agents are excluded due to the inherent abnormal cardiac structure and function in the setting of cardiogenic shock. Class III drug options include dofetilide and amiodarone., Amiodarone has been used as an anti-arrhythmic drug since the 1970s and has an established role in the treatment of ventricular tachyarrhythmias. Although considered to be a class III anti-arrhythmic, amiodarone also has class I, II and IV actions, which gives it a unique pharmacological and anti-arrhythmic profile. , Amiodarone, an iodinated benzofuran derivative, introduced in 1960's as an anti-anginal agent, emerged as a potent anti-arrhythmic agent by 1970's and is currently one of the most commonly prescribed drugs in US for ventricular and atrial arrhythmias. Although amiodarone is considered a class III anti-arrhythmic agent, it also has class I, II, IV actions, making it a unique and effective anti-arrhythmic agent., Amiodarone, a representative class III agent, exerts negative dromotropism by suppressing the fast sodium current responsible for conduction in acute administration (class I effects). Chronic amiodarone causes prolongation of ERP (class III effects), which is sometimes associated with negative dromotropism based on the alteration of passive or active membrane properties., Amiodarone, an iodinated benzofuran derivative with predominantly class III anti-arrhythmic effects, is used to treat supraventricular and ventricular arrhythmias., Although amiodarone is considered a class III anti-arrhythmic agent, it also has class I, II, IV actions, making it a unique and effective anti-arrhythmic agent, Amiodarone, a class III antiarrhythmic drug, is one of the most effective drugs used in the treatment of ventricular and paroxysmal supraventricular tachyarrhythmia, Although amiodarone is considered a class III anti-arrhythmic agent, it also has class I, II, IV actions, making it a unique and effective anti-arrhythmic agent, Although considered to be a class III anti-arrhythmic, amiodarone also has class I, II and IV actions, which gives it a unique pharmacological and anti-arrhythmic profile, Amiodarone is a potent class III anti-arrhythmic drug that also possesses beta-blocking properties", "label": "no"}
{"id": "converted_944", "sentence1": "Has protein citrullination been implicated in rheumatoid arthritis?", "sentence2": ": Citrullination has become a hot topic within recent years due to its involvement in diseases such as rheumatoid arthritis (RA), multiple sclerosis and fibrosis. , Current literature suggests that increased levels of citrullinated proteins are found in several if not all inflammatory diseases. , Antibodies directed against citrullinated proteins and peptides (ACPAs) are the most specific serological markers available for diagnosing RA. , Citrullination of proteins is well described in rheumatoid arthritis (RA), and hypercitrullination of proteins may be related to inflammation in general. , Some ACPA are remarkably effective as diagnostics in autoimmune disorders, most notably rheumatoid arthritis (RA). Several ACPA can be observed before other clinical RA manifestations are apparent. , Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein/peptide autoantibodies (ACPAs). , Anti-citrullinated peptides as autoantigens in rheumatoid arthritis-relevance to treatment., The implications of citrullination affecting integrin binding in disease open up a new area of study and might have implications for the pathogenesis of inflammatory diseases like rheumatoid arthritis and periodontitis., In this paper, we will review the three of the main classes of PTMs already associated with RA: citrullination, carbamylation, and oxidation., Citrullinated collagen II (CII) is a well-known autoantigen in rheumatoid arthritis (RA). , Among the RA-associated autoantibodies, especially anti-citrullinated protein antibodies (ACPAs) have been studied intensively in the last decade., Protein citrullination is a posttranslational modification that has attracted increased attention, especially for its involvement in rheumatoid arthritis (RA)., Identification of citrullinated cellular fibronectin in synovial fluid from patients with rheumatoid arthritis., Cellular fibronectin (cFn) has been implicated in the pathogenesis of rheumatoid arthritis (RA), and we previously demonstrated the presence of citrullinated cFn in rheumatoid synovial tissues. , . In rheumatoid arthritis, PAD4 and protein citrullination are increased in inflamed joints, and anti-citrullinated protein antibodies (ACPAs) form against citrullinated antigens are formed. ", "label": "yes"}
{"id": "converted_855", "sentence1": "Do carmustine wafers improve survival of glioblastoma patients?", "sentence2": "At recurrence, treatment options include repeat surgery (with or without Gliadel wafer placement), reirradiation or systemic therapy. , DISCUSSION: Carmustine wafers for primary HGG surgery in accordance with the NICE TA121 were associated with a median survival of 15.3 months; this is improved compared with previously reported randomised trials. Multimodal treatment with carmustine wafers, radical radiotherapy and concomitant temozolomide was associated with improved survival., Gliadel wafer is a new approach to the treatment of glioblastoma, which involves controlled release delivery of carmustine from biodegradable polymer wafers. It has shown promising results and provides a silver lining for glioblastoma patients., For patient with and without Gliadel, median and 1-year RFS were 12.9 months and 52% vs. 14 months and 42%, respectively (p = 0.89)., According to pathology, Gliadel did not influence OS of patients with Grade III or glioblastoma, CONCLUSION: In patients with high-grade gliomas, adding Gliadel before performing a Stupp protocol did not improve survival., Randomized phase III trials have shown significant improvement of survival 1, 2, and 3 years after implantation of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers for patients with newly diagnosed malignant glioma. , CONCLUSIONS: The combination of aggressive resection, Gliadel wafer implantation, and GKS in addition to standard fractionated RT in selected patients resulted in increased local control and increased survival compared with a historical control group treated with surgery and involved-field RT alone., OBJECT: Gliadel (BCNU) wafer and concomitant temozolomide (TMZ) therapy, when used individually as adjuvant therapies, extend survival from that achieved by resection and radiation therapy (XRT) for glioblastoma multiforme (GBM). , BACKGROUND: Gliadel (polifeprosan 20 with carmustine [BCNU] implant) is commonly used for local delivery of BCNU to high-grade gliomas after resection and is associated with increased survival., Temozolomide administered according to this protocol produced a median survival benefit of 2 months in glioblastomas, and carmustine a similar benefit in high-grade gliomas., Analysis of a large trial by Westphal and colleagues (n = 240) showed a 29% risk reduction (P = 0.03) in the BCNU wafer-treated group over the course of the 30-month trial., Median survival of patients treated with BCNU wafers was 13.8 months vs 11.6 months in placebo-treated patients (P = 0.017) with a hazard ratio of 0.73 (P = 0.018), representing a 27% significant risk reduction. This survival advantage was maintained at 1, 2, and 3 years and was statistically significant (P = 0.01) at 3 years., CONCLUSION: Malignant glioma patients treated with BCNU wafers at the time of initial surgery in combination with radiation therapy demonstrated a survival advantage at 2 and 3 years follow-up compared with placebo., OBJECTIVE: Recently a randomized placebo-controlled phase III trial of biodegradable polymers containing carmustine has demonstrated a significant survival benefit for patients treated with local chemotherapy. , CONCLUSION: In this subgroup analysis of a phase III trial population both the clinical progression and radiological progression were significantly delayed in patients treated with local chemotherapy, resulting in an increased survival time., A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme. A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers., Median survival in the intent-to-treat group was 13.9 months for the BCNU wafer-treated group and 11.6 months for the placebo-treated group (log-rank P -value stratified by country = 0.03), with a 29% reduction in the risk of death in the treatment group. When adjusted for factors affecting survival, the treatment effect remained positive with a risk reduction of 28% ( P = 0.03). , Controlled release delivery of carmustine from biodegradable polymer wafers was approved as an adjunct to surgical resection in the treatment of recurrent glioblastoma multiforme after it was shown in clinical trials to be well tolerated and effective. , Clinical trials have demonstrated significant improvements in survival and quality of life for patients after complete tumour resection and BCNU wafer implantation., BCNU wafers are an effective means of increasing survival and quality of life in patients diagnosed with malignant glioma, and are a valuable addition to the overall multimodal treatment strategy for these tumours., CONCLUSIONS: Carmustine wafer with concurrent TMZ and radiation followed by rotational chemotherapy is a well tolerated, effective therapy, and has a survival benefit compared with radiation alone., Median overall survival in 14 studies of newly-diagnosed patients suggested a modest improvement versus resection followed by Stupp protocol or resection with BCNU wafers, with an acceptable and manageable safety profile., The efficacy of carmustine wafers for older patients with glioblastoma multiforme: prolonging survival., DISCUSSION: Older patients with GBM may benefit from carmustine wafers. The survival for older patients who received carmustine wafers is significantly longer than matched patients who did not receive carmustine wafers., For glioblastoma patients who received ≥90% resection in the BCNU wafer study, median survival increased for BCNU wafer versus placebo (14.5 versus 12.4 months, respectively; P = 0.02), but no survival increase was found for <90% resection (11.7 versus 10.6 months, respectively; P = 0.98)., A wafer impregnated with carmustine, for use as an implant after surgical removal of recurrent GBM showed a prolongation in the median survival time of only 2 mo, from 20 to 28 wk in a study with a total of 222 patients. , No clear survival benefit associated with wafer implantation was identified., In three of the trials, patients with GBM who received carmustine wafers had significantly longer median survival than patients who did not receive wafers. , TMZ and carmustine (BCNU) biodegradable wafer (Gliadel) are the only adjuvant chemotherapies that have improved survival in randomised GB clinical trials . , The carmustine implant wafer was demonstrated to improve survival in blinded placebo-controlled trials in selected patients with newly diagnosed or recurrent malignant glioma, with little increased risk of adverse events. , For patients undergoing repeat resection for malignant glioma, a randomized, blinded, placebo-controlled trial demonstrated a median survival for 110 patients who received carmustine polymers of 31 weeks compared with 23 weeks for 122 patients who only received placebo polymers., Median survival was improved from 11.6 to 13.9 months (P = 0.03), with a 29% reduction in the risk of death. When patients with glioblastoma multiforme alone were analyzed, the median survival improved from 11.4 to 13.5 months, but this improvement was not statistically significant. , OBJECT: Locoregional chemotherapy with carmustine wafers, positioned at surgery and followed by radiation therapy, has been shown to prolong survival in patients with newly diagnosed glioblastoma, as has concomitant radiochemotherapy with temozolomide., Following the resection of newly diagnosed or recurrent glioblastomas, local implantation of carmustine-impregnated biodegradable wafers (Gliadel) in the resection cavity constitutes an adjuvant therapy that can improve the possibilities of survival., The carmustine implant wafer was demonstrated to improve survival in blinded placebo-controlled trials in selected patients with newly diagnosed or recurrent malignant glioma, with little increased risk of adverse events., However, patients with carmustine wafers demonstrated prolonged survival as compared to patients without wafers., The median survival for patients with carmustine wafers was 8.7 months, while median survival for patients without wafers was 5.5 months (P=0.007)., Likewise, in subgroup analysis, patients older than 70 years (P=0.0003) and 75 years (P=0.04) who had carmustine wafers had significantly longer survival than matched patients without wafers., Implantation of carmustine wafers did not significantly improve progression-free survival, In three of the trials, patients with GBM who received carmustine wafers had significantly longer median survival than patients who did not receive wafers, A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme, A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers, Following the resection of newly diagnosed or recurrent glioblastomas, local implantation of carmustine-impregnated biodegradable wafers (Gliadel) in the resection cavity constitutes an adjuvant therapy that can improve the possibilities of survival, Multimodal treatment with carmustine wafers, radical radiotherapy and concomitant temozolomide was associated with improved survival, The carmustine implant wafer was demonstrated to improve survival in blinded placebo-controlled trials in selected patients with newly diagnosed or recurrent malignant glioma, with little increased risk of adverse events, TMZ and carmustine (BCNU) biodegradable wafer (Gliadel) are the only adjuvant chemotherapies that have improved survival in randomised GB clinical trials ", "label": "yes"}
{"id": "converted_2088", "sentence1": "Are cutaneous porphyrias inherited with a recessive pattern?", "sentence2": "Five of the porphyrias are low-penetrance autosomal dominant conditions in which clinical expression results from additional factors that act by increasing demand for haem or by causing an additional decrease in enzyme activity or by a combination of these effects, Molecular mechanisms of dominant expression in porphyria., Variegate porphyria (VP) is an autosomal-dominant disorder that is caused by inheritance of a partial deficiency of the enzyme protoporphyrinogen oxidase (EC 1.3.3.4). It is characterized by cutaneous photosensitivity and/or various neurological manifestations. , The acute porphyrias constitute a group of metabolic disorders engaging enzymes in the haem synthetic chain and generally following dominant inheritance patterns.", "label": "no"}
{"id": "converted_3396", "sentence1": "Autophagy is the process where a virus obtains nutrients from it's host, yes or no?", "sentence2": "In this study, we demonstrate that autophagy is a critical mediator of the viral degradation pathway and that this pathway is not HIV-1 specific., Autophagy is important in cellular homeostasis for the cell survival mechanism., Autophagy is a cellular survival pathway that is necessary for the degradation of cellular constituents such as long-lived proteins and damaged organelles., Autophagy-related genes (ATGs) regulate the autophagy and also control the crosstalk with autophagy-associated cell death and apoptosis in some condition. , Autophagy is an evolutionarily conserved cellular process in which intracellular components are eliminated via lysosomal degradation to supply nutrients for organelle biogenesis and metabolic homeostasis., Autophagy is a lysosome-associated, degradative process that catabolizes cytosolic components to recycle nutrients for further use and maintain cell homeostasis., Autophagy is a self-eating process, in which the damaged or excessed cell organelles and misfolded protein aggregates are removed from the cellular microenvironment., Autophagy is a lysosome-associated, degradative process that catabolizes cytosolic components to recycle nutrients for further use and maintain cell homeostasis., Autophagy is an evolutionarily conserved cellular process in which intracellular components are eliminated via lysosomal degradation to supply nutrients for organelle biogenesis and metabolic homeostasis., Autophagy is a homeostatic process involved in the turnover or elimination of cytoplasmic components, damaged organelles, and protein aggregates via a lysosomal degradation mechanism., Autophagy is known as a catabolic process for the recycling of the cytoplasmic macromolecules.", "label": "no"}
{"id": "converted_67", "sentence1": "Is TENS machine effective in pain?", "sentence2": "Transcutaneous electrical nerve stimulation is widely used in pain management but its effectiveness depends on the stimulation being targeted appropriately, hypoalgesic effects of transcutaneous electrical nerve stimulation upon experimentally induced ischaemic pain., The results of this study have provided evidence of the hypoalgesic effects of TENS upon experimental ischaemic pain which were found to be frequency specific with the lower frequency used here (4 Hz) demonstrating the only significant effect", "label": "yes"}
{"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.", "label": "yes"}
{"id": "converted_4439", "sentence1": "Are circular RNAs implicated in diseases of the eye?", "sentence2": "n this review, we summarized the function of circRNAs and indicated their roles in the pathogenesis of DR, which may provide new therapeutic targets for clinical treatment., This study aimed to determine whether circular RNAs (circRNAs) in whole blood could be served as novel non-invasive biomarkers for proliferative diabetic retinopathy (PDR).M, Discovery and validation of hsa_circ_0001953 as a potential biomarker for proliferative diabetic retinopathy in human blood., Circular RNA hsa_circ_0000034 (circ_0000034) was reported to be upregulated in RB tissues., We recently identified a circular RNA transcript (circGRM4) that is significantly upregulated in the eye of cystathionine β-synthase-deficient mice., Circular and long non-coding RNAs and their role in ophthalmologic diseases., In this review, we summarize current knowledge about gene expression regulators - long non-coding and circular RNA molecules in eye diseases., fied a circular RNA transcript (circGRM4) that is significantly upregulated in the eye of cystathionine β-synthase-deficient mice. We also discovered, NAs (circRNAs) are dominant players regulating their parental genes' expression dynamics, their importance in ocular biology has not been appreciated. Progress in gene-cent, Circular RNA Expression Profiling Identifies Glaucoma-Related Circular RNAs in Various Chronic Ocular Hypertension Rat Models, Circular RNAs profiling in the cystathionine-β-synthase mutant mouse reveals novel gene targets for hyperhomocysteinemia induced ocular disorders, Circular and long non-coding RNAs and their role in ophthalmologic diseases, Comprehensive circular RNA profiling of proliferative vitreoretinopathy and its clinical significance,  these findings, we completed the first in-depth study of rat retinal circular RNA expression profiling to identify probable biomarkers for the diagnosis of glaucoma. Two ocu, Circular RNAs profiling in the cystathionine-β-synthase mutant mouse reveals novel gene targets for hyperhomocysteinemia induced ocular disorders., Although, increasing evidence suggests that circRNAs may also contribute in different ocular diseases, the outline of circRNAs in ocular diseases remains obscure, In this review, we summarize current knowledge about gene expression regulators - long non-coding and circular RNA molecules in eye diseases, Recent studies recognized the vital roles that circRNAs played in the pathogenesis of various eye diseases, highlighting circRNAs as promising biomarkers for diagnosis and assessment of progression and prognosis, Partly because their circularity makes them resistant to degradation, they hold great promise as unique biomarkers for ocular and central nervous system (CNS) disorders, In this review we consider the current state of knowledge regarding the potential role and underlying mechanism of circRNAs in ocular diseases including pterygium, age-related cataract, glaucoma, diabetic retinopathy, retinoblastoma, retinal vascular dysfunction and hyperhomocysteinemia induced ocular diseases, emphasizing that circRNAs could be promising biomarkers for the diagnosis and prognosis evaluation., Recent studies recognized the vital roles that circRNAs played in the pathogenesis of various eye diseases, highlighting circRNAs as promising biomarkers for diagnosis and assessment of progression and prognosis., Although, increasing evidence suggests that circRNAs may also contribute in different ocular diseases, the outline of circRNAs in ocular diseases remains obscure., Circular RNAs: Novel Promising Biomarkers in Ocular Diseases., This review summarizes our current perception of the properties, biogenesis, and functions of circRNAs and the development of circRNA researches related to ophthalmologic diseases, including diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, glaucoma, corneal neovascularization, cataract, pterygium, proliferative vitreoretinopathy, retinoblastoma, and ocular melanoma., CircRNA Is a Rising Star in Researches of Ocular Diseases., Interventions targeting circRNAs provide insights for developing novel treatments for these ocular diseases., Future circRNAs-targeted intervention may become a novel therapeutic tool for the treatment of ocular diseases., Findings also revealed several microRNAs that are specific to each circRNA suggesting their roles in HHcy induced ocular disorders., Therefore, circRNAs may serve as potential regulators of corneal LG., Expression profiling of circular RNAs in glaucoma, which is a form of optic neuropathy, has not been performed to date., Although circular RNAs (circRNAs) are dominant players regulating their parental genes' expression dynamics, their importance in ocular biology has not been appreciated., Progress in gene-centered analytics via improved microarray and bioinformatics are enabling dissection of genomic pathways however there is an acute under-representation of circular RNAs in ocular disorders., Circular RNAs constitute an inherent gene regulatory axis in the mammalian eye and brain 1., Together with the target microRNAs underlying the top differentially expressed circular RNAs, a new target of hsa_circ_0023826 and its host gene TENM4 were identified and further verified in the aqueous humor of glaucoma patients, indicating a promising biomarker for the disease., Recent studies suggest that they are differentially expressed both in healthy ocular tissues as well as in eye pathologies, such as neovascularization, proliferative vitreoretinopathy, glaucoma, cataract, ocular malignancy or even strabismus.", "label": "yes"}
{"id": "converted_1045", "sentence1": "Is clathrin involved in E-cadherin endocytosis?", "sentence2": "We demonstrated that GnT-III induced a stabilizing effect on E-cadherin at the cell membrane by inducing a delay in the turnover rate of the protein, contributing for the formation of stable and functional adherens-junctions, and further preventing clathrin-dependent E-cadherin endocytosis., Conversely, GnT-V promotes the destabilization of E-cadherin, leading to its mislocalization and unstable adherens-junctions with impairment of cell-cell adhesion., Here we show that E-cadherin polarity is controlled by the polarized regulation of clathrin- and dynamin-mediated endocytosis., We delineate a pathway that controls the initiation of E-cadherin endocytosis through the regulation of AP2 and clathrin coat recruitment by E-cadherin., Clathrin dependent endocytosis of E-cadherin is regulated by the Arf6GAP isoform SMAP1, E-cadherin is a central component of the adherens junction in epithelial cells and continuously undergoes endocytosis via clathrin-coated vesicles and/or caveolae depending on the cell type., Collectively, SMAP1 likely represents a key Arf6GAP in clathrin dependent endocytosis of E-cadherin in MDCK cells., Consistent with these observations, we found that selective uncoupling of p120 from E-cadherin by introduction of amino acid substitutions in the p120-binding site increased the level of E-cadherin endocytosis. The increased endocytosis was clathrin-dependent, because it was blocked by expression of a dominant-negative form of dynamin or by hypertonic shock., We found that in this experimental system E-cadherin entered a transferrin-negative compartment before transport to the early endosomal compartment, where it merged with classical clathrin-mediated uptake pathways.", "label": "yes"}
{"id": "converted_1206", "sentence1": "Is the SDHAF2 gene encoding a protein necessary for flavination of SDHA?", "sentence2": "Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. , At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes., the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), SDHAF2, required for flavination of SDHA, At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes., Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA., In a recent issue of Science, Rutter and coworkers showed that SDH5 is required for the flavination of SDHA, which is necessary for SDH assembly and function., At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes, Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA, CONTEXT: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. , This gene is co-expressed with a number of genes encoding mitochondrial proteins, including SDH1-1, and has low partial sequence similarity to human SDHAF2, a protein required for flavin-adenine dinucleotide (FAD) insertion into SDH. , At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes., Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA.", "label": "yes"}
{"id": "converted_847", "sentence1": "Is transcription-associated mutagenesis (TAM) related to gene expression levels?", "sentence2": "These mutations were frequent in plasmid-borne lacS expressed at a high level but not in single-copy lacS in the chromosome or at lower levels of expression in a plasmid., The results suggest that important DNA repair or replication fidelity functions are impaired or overwhelmed in pJlacS, with results analogous to those of the \"transcription-associated mutagenesis\" seen in bacteria and eukaryotes., the rate of point mutation in a gene increases with the expression level of the gene. Transcription induces mutagenesis on both DNA strands, indicating simultaneous actions of several TAM mechanisms., High-levels of transcription through a gene stimulate spontaneous mutation rate, a phenomenon termed transcription-associated mutation (TAM)., High levels of transcription in Saccharomyces cerevisiae are associated with increased genetic instability, which has been linked to DNA damage. Here, we describe a pGAL-CAN1 forward mutation assay for studying transcription-associated mutagenesis (TAM) in yeast., The acquisition of mutations was directly correlated to the level of transcription, Our results demonstrate that the level of Leu(+) reversions increased significantly in parallel with the induced increase in transcription levels., Transcription-associated mutagenesis in yeast is directly proportional to the level of gene expression, spontaneous mutation rate is directly proportional to the transcription level, suggesting that movement of RNA polymerase through the target initiates a mutagenic process(es), High transcription is associated with genetic instability, notably increased spontaneous mutation rates, which is a phenomenon termed Transcription-Associated-Mutagenesis (TAM)., Using this system, we also investigated two hypotheses that have been proposed to explain transcription-associated mutagenesis (TAM): (1) transcription impairs replication fork progression in a directional manner and (2) DNA lesions accumulate under high-transcription conditions., Transcription-associated mutagenesis in yeast is directly proportional to the level of gene expression and influenced by the direction of DNA replication., High levels of transcription in Saccharomyces cerevisiae are associated with increased genetic instability, which has been linked to DNA damage., Using this system, we also investigated two hypotheses that have been proposed to explain transcription-associated mutagenesis (TAM): (1) transcription impairs replication fork progression in a directional manner and (2) DNA lesions accumulate under high-transcription conditions., Using comparative genomics of related species as well as mutation accumulation lines, we show in yeast that the rate of point mutation in a gene increases with the expression level of the gene, High transcription is associated with genetic instability, notably increased spontaneous mutation rates, which is a phenomenon termed Transcription-Associated-Mutagenesis (TAM), Using this system, we also investigated two hypotheses that have been proposed to explain transcription-associated mutagenesis (TAM): (1) transcription impairs replication fork progression in a directional manner and (2) DNA lesions accumulate under high-transcription conditions, High-levels of transcription through a gene stimulate spontaneous mutation rate, a phenomenon termed transcription-associated mutation (TAM)", "label": "yes"}
{"id": "converted_1550", "sentence1": "Is macitentan an ET agonist?", "sentence2": "Administration of an ET receptor antagonist, either bosentan or macitentan, markedly attenuated PD-induced MMT, fibrosis, angiogenesis, and peritoneal functional decline. , Macitentan is an oral, once-daily, dual endothelin (ET)A and ETB receptor antagonist with high affinity and sustained receptor binding that was approved in the USA, Europe, Canada, and Switzerland for the treatment of PAH., Macitentan (Opsumit®) is a novel dual endothelin receptor antagonist (ERA) with sustained receptor binding properties developed by Actelion Pharmaceuticals Ltd., Macitentan, also called Actelion-1 or ACT-064992 [N-[5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-N'-propylaminosulfonamide], is a new dual ET(A)/ET(B) endothelin (ET) receptor antagonist designed for tissue targeting. Selection of macitentan was based on inhibitory potency on both ET receptors and optimization of physicochemical properties to achieve high affinity for lipophilic milieu. In vivo, macitentan is metabolized into a major and pharmacologically active metabolite, ACT-132577. , Macitentan and its metabolite antagonized the specific binding of ET-1 on membranes of cells overexpressing ET(A) and ET(B) receptors and blunted ET-1-induced calcium mobilization in various natural cell lines, with inhibitory constants within the nanomolar range. In functional assays, macitentan and ACT-132577 inhibited ET-1-induced contractions in isolated endothelium-denuded rat aorta (ET(A) receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ET(B) receptors). In rats with pulmonary hypertension, macitentan prevented both the increase of pulmonary pressure and the right ventricle hypertrophy, and it markedly improved survival. , In conclusion, macitentan, by its tissue-targeting properties and dual antagonism of ET receptors, protects against end-organ damage in diabetes and improves survival in pulmonary hypertensive rats. This profile makes macitentan a new agent to treat cardiovascular disorders associated with chronic tissue ET system activation., Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist., Renal, retinal and cardiac changes in type 2 diabetes are attenuated by macitentan, a dual endothelin receptor antagonist., Here we investigated the effects of macitentan, an orally-active, tissue-targeting dual ET receptor antagonist on chronic complications in type 2 diabetes.MAIN METHODS: db/db mice and their age- and sex-matched controls were examined after 2 and 4 months of diabetes. , Macitentan is a novel dual ETA/ETB receptor antagonist with enhanced tissue distribution and sustained receptor binding properties designed to achieve a more efficacious ET receptor blockade. , Recently oral prostacyclin receptor agonists have shown encouraging results. Many clinical studies targeting the vasoconstrictor ET-1 pathway with receptor antagonists like bosentan and ambrisentan have shown strong results, even more optimism coming from macitentan, the newest drug.", "label": "no"}
{"id": "converted_391", "sentence1": "Does the majority of the mitochondrial genomes abide to the second parity rule (PR2)?", "sentence2": "a large number of mitochondrial genomes significantly deviate from the 2nd parity rule in contrast to the eubacterial ones, mitochondria may be divided into three distinct sub-groups according to their overall deviation from the aforementioned parity rule., The behaviour of the large majority of the mitochondrial genomes may be attributed to their distinct mode of replication, which is fundamentally different from the one of the eubacteria., We tested all available organellar genomes and found that a large number of mitochondrial genomes significantly deviate from the 2nd parity rule in contrast to the eubacterial ones, although mitochondria are believed to have evolved from proteobacteria., The behaviour of the large majority of the mitochondrial genomes may be attributed to their distinct mode of replication, which is fundamentally different from the one of the eubacteria., We tested all available organellar genomes and found that a large number of mitochondrial genomes significantly deviate from the 2nd parity rule in contrast to the eubacterial ones, although mitochondria are believed to have evolved from proteobacteria., The behaviour of the large majority of the mitochondrial genomes may be attributed to their distinct mode of replication, which is fundamentally different from the one of the eubacteria, We tested all available organellar genomes and found that a large number of mitochondrial genomes significantly deviate from the 2nd parity rule in contrast to the eubacterial ones, although mitochondria are believed to have evolved from proteobacteria", "label": "no"}
{"id": "converted_3545", "sentence1": "Does the BRAFV600E mutation have an effect on clinical response to radioiodine therapy?", "sentence2": "Preclinical studies showed that BRAF mutation significantly reduced radioiodine uptake and decreased the sensitivity to radioactive iodine (RAI) therapy., The status of BRAF mutation may not affect the clinical response to RAI therapy for patients with PTMC with intermediate-risk to high-risk features. More trials examining the role of BRAF mutation in guiding postoperative RAI therapy are needed., our results suggest that the combination of BRAFV600E+ve mutation and MIBI-ve scintigraphy may be considered a negative prognostic clue, which predicts the absence of radioiodine uptake at pT-WBS in DTC patients with incomplete bio-chemical response to first RAIT, The results indicate that BRAF(V600E) mutation is correlated with a lower expression of NIS in PTCs without HT, suggesting the radioiodine-refractory effects during RIA therapy in these patients.", "label": "yes"}
{"id": "converted_2085", "sentence1": "Is Musclin a secretory peptide?", "sentence2": "Musclin is a novel skeletal muscle-derived secretory factor,, Musclin has been described as a muscle-derived secretory peptide, responsive to insulin in vivo, and inducing insulin resistance in vitro., Musclin is a type of muscle-secreted cytokine and its increased gene expression induces insulin resistance in type 2 diabetes. , Musclin is a novel skeletal muscle-derived factor found in the signal sequence trap of mouse skeletal muscle cDNAs., Musclin is a novel skeletal muscle-derived secretory factor found in the signal sequence trap of mouse skeletal muscle cDNAs. , Musclin is a novel skeletal muscle-derived secretory factor that was isolated by our group. ", "label": "yes"}
{"id": "converted_2284", "sentence1": "Has IVIG been tested in clinical trials for the treatment of Alzheimer's disease?", "sentence2": "Clinical trials of intravenous immunoglobulin for Alzheimer's disease., Preclinical and clinical studies have shown that IVIG has anti-amyloid and immune modulatory properties relevant to treating neurodegenerative disorders. In early stage AD clinical trials, IVIG was found to reduce cognitive decline and increase brain glucose metabolism. Unfortunately, IVIG failed to meet primary outcome objectives in the North American Phase 3 clinical trial in mild to moderate AD., While the results of clinical trials to date do not provide support for the use of IVIG to treat AD at the doses tested, additional studies of IVIG's mechanisms are warranted and may guide the development of more effective therapies for AD in the future.", "label": "yes"}
{"id": "converted_1953", "sentence1": "Is ABCE1 involved in ribosomal recycling?", "sentence2": "Ribosome recycling orchestrated by the ATP binding cassette (ABC) protein ABCE1 can be considered as the final-or the first-step within the cyclic process of protein synthesis, connecting translation termination and mRNA surveillance with re-initiation.,  Recent studies have identified ABCE1 as a ribosome-recycling factor important for translation termination in mammalian cells, yeast and also archaea., d a termination/prerecycling complex containing eRF1-ABCE1, ABCE1, a eukaryotic ribosome recycling factor", "label": "yes"}
{"id": "converted_3854", "sentence1": "Are super enhancers structurally insulated in chromatin loops?", "sentence2": "Dissecting super-enhancer hierarchy based on chromatin interactions, Genetic ablation of hub enhancers results in profound defects in gene activation and local chromatin landscape., We also demonstrate that the Wap super-enhancer, which is built on STAT5 and other common transcription factors, retains its exquisite mammary specificity when placed into globally permissive chromatin, suggesting a limited role of chromatin in controlling cell specificity. , Although there is evidence that chromatin neighbourhoods, formed by the zinc-finger protein CTCF, can sequester enhancers and their target genes, there is limited in vivo evidence for CTCF demarcating super-enhancers and preventing cross talk between distinct regulatory elements., CTCF sites are porous borders, allowing a super-enhancer to activate a secondary target., Transcription factors and chromatin-remodeling complexes are key determinants of embryonic stem cell (ESC) identity. ", "label": "no"}
{"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.", "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.", "label": "yes"}
{"id": "converted_4221", "sentence1": "Does a comet assay measure radiation induced mutations?", "sentence2": "Evaluation of primary DNA-damage is one way to identify potential genotoxic agents and for this purpose the Comet assay has, for the last decades, been used to monitor DNA single strand and double strand breaks in individual cells, DNA strand-break frequency was examined by means of the comet assay i, . The comet assay (as this method was subsequently named) was able to measure, for the first time, the fraction of radiobiologically hypoxic cells in mouse and human tumors. It was used to determine that the rate of rejoining of DNA breaks was relatively homogenous within an irradiated population of cells, The comet assay is frequently used to measure DNA damage in individual cells. , Thus a complete repair of DNA damage induced by gamma-irradiation and measurable by the Comet assay was observed, whereas the yield of somatic mutations increased in relation to the radiation dose., xanthi) mutagenicity assay is the ability to analyze and compare on the same plants under identical treatment conditions both the induced acute DNA damage in somatic cells as measured by the Comet assay and the yield of induced leaf somatic mutations., The present study reveals that gamma radiation induces single strand breaks in DNA as measured by alkaline comet assay in bivalves and comet assay serves as a sensitive and rapid method to detect genotoxicity of gamma radiation., The present study is aimed (a) to know the genotoxic effect of gamma radiation on aquatic fauna employing two species of selected bivalves, (b) to evaluate the possible use of 'Comet assay' for detecting genetic damage in haemocytes of bivalves as a biomarker for environmental biomonitoring and also (c) to compare the relative sensitivity of two species of bivalves viz., The single cell gel electrophoresis (SCGE) assay, more commonly known as the comet assay, due to the \"comet-like\" appearance of the cells, was originally developed as a technique to measure the presence of DNA single-strand breaks., BACKGROUND: The neutral comet assay was devised to measure double-stranded DNA breaks, but it has also been used to measure apoptosis based on its characteristic DNA fragmentation patterns., 2, 4, 6, 8 and 10 Gy) of gamma radiation and their genotoxic effects on the haemocytes were studied using the comet assay., PURPOSE: The Deoxyribonucleic Acid (DNA) Comet assay, being a quick, simple, sensitive, reliable and fairly inexpensive method for measuring DNA strand breaks, has been used to assess DNA damage caused by gamma radiation in developmental stages of maize weevil Sitophilus zeamais Motschulsky., This paper attempts a correlation between the induction and repair of DNA damage measured in the comet assay and the clinical observed reaction in order to evaluate the suitability of the comet assay for prediction of radiation sensitivity., gle cell gel electrophoresis (e.g., Comet Assay) and immunofluoresence microscopy to detect the presence of gamma-H2AX foci, we find that Cr[VI] induces DNA double-strand breaks similar to ionizing radiation (IR). We also demo, ir of DNA damage induced by gamma-irradiation and measurable by the Comet assay was observed, whereas the yield of somatic mutations increased in relation to the radiation dose. Data on the kinetic, eased yield of somatic mutations was highly correlated (r = 0.996) with the increased DNA damage measured by the Comet assay immediately after irradiation. With inc, rther assess potential co-mutagenic effects of FA, we exposed A549 human lung cells to FA in combination with various mutagens and measured the induction and removal of DNA damage by the comet assay and the production of chromosomal mutations by the cytokinesis-block micronucleus assay (CBMN assay). The , DNA effects were analysed in leukocytes using the alkaline Comet assay, gene mutations and chromosome aberrations were measured in erythrocytes using the flow cytometric Pig-a gene mutation assay and the micronucleus test (applying both microscopic and flow cytometric evaluation), respectively., A wide variety of mutagens have been shown to cause DNA alterations detectable with the comet assay, but it is not yet clear whether a relationship exists between the DNA effects and the induction of mutations., The transgenerational changes in mutation rates were attributed to the presence of a persistent subset of endogenous DNA lesions (double- and single-strand breaks), measured by the phosphorylated form of histone H2AX (gamma-H2AX) and alkaline Comet assays., The single-cell electrophoresis (comet) assay is an established method for measuring radiation-induced strand breaks in DNA., The COMET assay is recognized as a rapid and sensitive method in quantifying radiation induced DNA damage., The relationship between cellular radiosensitivity and radiation-induced DNA damage measured by the comet assay., Reliable Comet assay measurements for detecting DNA damage induced by ionising radiation and chemicals., Radiation sensitivity of lymphocytes from healthy individuals and cancer patients as measured by the comet assay., The comet assay is a potential tool for use in neutron therapy, as well as a method for the rapid screening of samples from individuals accidentally exposed to radiation., Induction and repair of DNA damage as measured by the Comet assay and the yield of somatic mutations in gamma-irradiated tobacco seedlings., The increased yield of somatic mutations was highly correlated (r = 0.996) with the increased DNA damage measured by the Comet assay immediately after irradiation., The alkaline version of single cell gel electrophoresis (comet) assay is widely used for evaluating DNA damage at the individual cell level., Induction (2 and 5 Gy) of gamma-ray-induced DNA damage and its repair (during 60 min after irradiation) was measured with the alkaline and neutral comet assay., The alkaline single-cell gel electrophoresis (SCGE or Comet) assay appears to be a promising tool for measuring DNA damage at the individual cell level in both in vitro and in vivo studies., Considering our previous studies showing significant increases in the frequency of cytogenetic damage (when measured as micronuclei) in patients treated with relatively low doses of 131I, the results obtained in the present work by using the Comet assay could indicate that 1 week after the exposure most of the radioiodine-induced DNA lesions, that can be detected with this assay, have already been repaired., Hence, we are using the single-cell gel electrophoresis (comet assay) to detect mouse mutants that display a genetic susceptibility to ionizing radiation., We have established the analysis parameters in the comet assay which are currently used to detect radiation-sensitive mouse mutants and to control the variance within the mouse population in the ENU screen., Comet assay as a tool to screen for mouse models with inherited radiation sensitivity.", "label": "yes"}