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Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells. Several anti-PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti-PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity. | What molecule is targeted by Avelumab? | 5884c72fe56acf517600000f_015 | {
"answer_start": [
1603
],
"text": [
"PD-L1"
]
} |
Cloning and expression of cDNA encoding human galactocerebrosidase, the enzyme deficient in globoid cell leukodystrophy. Globoid cell leukodystrophy (Krabbe disease) is an autosomal recessive disorder resulting from the deficiency of galactocerebrosidase (GALC) activity. GALC is responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon. We describe the molecular cloning of human GALC cDNA and its expression in COS-1 cells. Degenerate PCR primers, derived from N-terminal amino acid sequence from the 51 kDa band from human brain, were used to amplify cat testes RNA, and the resulting product was used to screen human testes and brain libraries. Two overlapping clones contained the total protein coding region, while additional clones and PCR amplification were needed to obtain the complete 3' end of the cDNA. The 3795 bp obtained include 47 bp 5' to the initiation start site, 2007 bp of open reading frame (coding for 669 amino acids), and 1741 bp of 3' untranslated sequence. Modification of the sequence surrounding the initiation codon to one more favorable for expression, resulted in a 6-fold increase in GALC activity in transfected COS-1 cells. The isolation of this clone will permit investigations into the causes for GALC deficiency in humans and available animal models, development of more accurate tests for patient and carrier identification, and evaluation of methods for effectively treating GALC deficiency, initially using the animal models. | Which enzyme is deficient in Krabbe disease? | 5147c8a6d24251bc05000027_012 | {
"answer_start": [
234
],
"text": [
"galactocerebrosidase"
]
} |
Evaluation of three chromogenic media (MRSA-ID, MRSA-Select and CHROMagar MRSA) and ORSAB for surveillance cultures of methicillin-resistant Staphylococcus aureus. Screening specimens were homogenised in saline 0.9% w/v before either direct inoculation or following enrichment in broth on three chromogenic media (MRSA-ID, CHROMagar MRSA and MRSA Select) and ORSAB medium for the detection of methicillin-resistant Staphylococcus aureus (MRSA). In total, 102 of 466 specimens yielded MRSA on at least one medium. After incubation for 16-18 h, the sensitivity was 51%, 59%, 47% and 65% on MRSA-ID, CHROMagar MRSA, ORSAB and MRSA Select, respectively, compared with 82%, 75%, 67% and 80%, respectively, after 42 h, and 93%, 95%, 79% and not tested, respectively, following broth enrichment. There were significantly more MRSA colonies on MRSA-Select after 16-18 h than on ORSAB or MRSA ID (p 0.001 and 0.0022, respectively), whereas there were more MRSA colonies after 42 h on MRSA-ID and MRSA-Select than on ORSAB (p 0.0004 and 0.012, respectively). The specificity of the media for identifying MRSA based on the colour of colonies after incubation for 16-18 h was 100%, 99%, 99% and 100%, respectively, compared with 98%, 97%, 98% and 98%, respectively, after 42 h, and 100%, 99%, 100% and not tested, respectively, following broth enrichment. The speed of detection (mean time to report a positive result) was 1.65, 1.72, 2.31 and 1.35 days, respectively. For each of the three media tested following enrichment, the use of an enrichment broth increased the detection rate of MRSA by 16-24%. | What is MRSA? | 58a32efe60087bc10a000013_083 | {
"answer_start": [
438
],
"text": [
"MRSA"
]
} |
Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD. Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused by decreased epigenetic repression of the D4Z4 macrosatellite repeats and ectopic expression of DUX4, a retrogene encoding a germline transcription factor encoded in each repeat. Unaffected individuals generally have more than 10 repeats arrayed in the subtelomeric region of chromosome 4, whereas the most common form of FSHD (FSHD1) is caused by a contraction of the array to fewer than 10 repeats, associated with decreased epigenetic repression and variegated expression of DUX4 in skeletal muscle. We have generated transgenic mice carrying D4Z4 arrays from an FSHD1 allele and from a control allele. These mice recapitulate important epigenetic and DUX4 expression attributes seen in patients and controls, respectively, including high DUX4 expression levels in the germline, (incomplete) epigenetic repression in somatic tissue, and FSHD-specific variegated DUX4 expression in sporadic muscle nuclei associated with D4Z4 chromatin relaxation. In addition we show that DUX4 is able to activate similar functional gene groups in mouse muscle cells as it does in human muscle cells. These transgenic mice therefore represent a valuable animal model for FSHD and will be a useful resource to study the molecular mechanisms underlying FSHD and to test new therapeutic intervention strategies. | Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4? | 550f0e4c6a8cde6b72000003_047 | {
"answer_start": [
135
],
"text": [
"FSHD"
]
} |
SECISaln, a web-based tool for the creation of structure-based alignments of eukaryotic SECIS elements. SUMMARY: Selenoproteins contain the 21st amino acid selenocysteine which is encoded by an inframe UGA codon, usually read as a stop. In eukaryotes, its co-translational recoding requires the presence of an RNA stem-loop structure, the SECIS element in the 3 untranslated region of (UTR) selenoprotein mRNAs. Despite little sequence conservation, SECIS elements share the same overall secondary structure. Until recently, the lack of a significantly high number of selenoprotein mRNA sequences hampered the identification of other potential sequence conservation. In this work, the web-based tool SECISaln provides for the first time an extensive structure-based sequence alignment of SECIS elements resulting from the well-defined secondary structure of the SECIS RNA and the increased size of the eukaryotic selenoproteome. We have used SECISaln to improve our knowledge of SECIS secondary structure and to discover novel, conserved nucleotide positions and we believe it will be a useful tool for the selenoprotein and RNA scientific communities. AVAILABILITY: SECISaln is freely available as a web-based tool at http://genome.crg.es/software/secisaln/. | What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins? | 533ea8fcc45e133714000010_009 | {
"answer_start": [
339
],
"text": [
"SECIS"
]
} |
[Therapeutic monoclonal antibodies against multiple myeloma]. Multiple myeloma (MM) remains mostly incurable despite the recent progress in the treatment strategy. One of novel fields for anti-MM therapeutic strategy is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This article focuses on the basic and clinical aspects of several emerging and promising novel MoAbs for MM, such as elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are highly expressed in more than 90% of MM patients, and the clinical trials have shown promising anti-MM effects, especially in combination with immunomodulatory agent lenalidomide. We also discuss the characteristics and the results of clinical trials of other MoAbs, such as tabalumab against B cell activating factor or dacetuzumab against CD40, being developed for MM. | What is the target of daratumumab? | 5880aef4c872c95565000001_034 | {
"answer_start": [
500
],
"text": [
"CD38"
]
} |
Should we conduct a trial of distributing naloxone to heroin users for peer administration to prevent fatal overdose? Heroin overdose is a major cause of death among heroin users, and often occurs in the company of other users. However, sudden death after injection is rare, giving ample opportunity for intervention. Naloxone hydrochloride, an injectable opioid antagonist which reverses the respiratory depression, sedation and hypotension associated with opioids, has long been used to treat opioid overdose. Experts have suggested that, as part of a comprehensive overdose prevention strategy, naloxone should be provided to heroin users for peer administration after an overdose. A trial could be conducted to determine whether this intervention improves the management of overdose or results in a net increase in harm (by undermining existing prevention strategies, precipitating naloxone-related complications, or resulting in riskier heroin use). | Which medication should be administered when managing patients with suspected acute opioid overdose? | 5149f494d24251bc0500004c_005 | {
"answer_start": [
598
],
"text": [
"naloxone"
]
} |
LepChorionDB, a database of Lepidopteran chorion proteins and a set of tools useful for the identification of chorion proteins in Lepidopteran proteomes. Chorion proteins of Lepidoptera have a tripartite structure, which consists of a central domain and two, more variable, flanking arms. The central domain is highly conserved and it is used for the classification of chorion proteins into two major classes, A and B. Annotated and unreviewed Lepidopteran chorion protein sequences are available in various databases. A database, named LepChorionDB, was constructed by searching 5 different protein databases using class A and B central domain-specific profile Hidden Markov Models (pHMMs), developed in this work. A total of 413 Lepidopteran chorion proteins from 9 moths and 1 butterfly species were retrieved. These data were enriched and organised in order to populate LepChorionDB, the first relational database, available on the web, containing Lepidopteran chorion proteins grouped in A and B classes. LepChorionDB may provide insights in future functional and evolutionary studies of Lepidopteran chorion proteins and thus, it will be a useful tool for the Lepidopteran scientific community and Lepidopteran genome annotators, since it also provides access to the two pHMMs developed in this work, which may be used to discriminate A and B class chorion proteins. LepChorionDB is freely available at http://bioinformatics.biol.uoa.gr/LepChorionDB. | Which database is available for the identification of chorion proteins in Lepidopteran proteomes? | 554148c23f2354b713000001_005 | {
"answer_start": [
0
],
"text": [
"LepChorionDB"
]
} |
DNA 5-methylcytosine demethylation activities of the mammalian DNA methyltransferases. Methylation at the 5-position of DNA cytosine on the vertebrate genomes is accomplished by the combined catalytic actions of three DNA methyltransferases (DNMTs), the de novo enzymes DNMT3A and DNMT3B and the maintenance enzyme DNMT1. Although several metabolic routes have been suggested for demethylation of the vertebrate DNA, whether active DNA demethylase(s) exist has remained elusive. Surprisingly, we have found that the mammalian DNMTs, and likely the vertebrates DNMTs in general, can also act as Ca(2+) ion- and redox state-dependent active DNA demethylases. This finding suggests new directions for reinvestigation of the structures and functions of these DNMTs, in particular their roles in Ca(2+) ion-dependent biological processes, including the genome-wide/local DNA demethylation during early embryogenesis, cell differentiation, neuronal activity-regulated gene expression, and carcinogenesis. | Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation? | 51585b28d24251bc0500008d_039 | {
"answer_start": [
315
],
"text": [
"DNMT1"
]
} |
About three cases of ulceroglandular tularemia, is this the re-emergence of Francisella tularensis in Belgium? Tularemia is a zoonosis caused by Francisella tularensis that can be transmitted by several ways to human being and cause different clinical manifestations. We report three clinical cases of tularemia with ulceroglandular presentation in young males acquired during outdoor activities in Southern Belgium. Confirmation of the diagnosis was established by serology. Only three cases of tularemia have been reported in Belgium between 1950 and 2012 by the National Reference Laboratory CODA-CERVA (Ref Lab CODA-CERVA) but re-emergence of tularemia is established in several European countries and F. tularensis is also well known to be present in animal reservoirs and vectors in Belgium. The diagnosis of tularemia has to be considered in case of suggestive clinical presentation associated with epidemiological risk factors. | What organism causes tularemia? | 58f4b9d470f9fc6f0f000016_002 | {
"answer_start": [
145
],
"text": [
"Francisella tularensis"
]
} |
Role of orally available antagonists of factor Xa in the treatment and prevention of thromboembolic disease: focus on rivaroxaban. Interpatient variability in the safety and efficacy of oral anticoagulation with warfarin presents several challenges to clinicians, thus underscoring the emergent need for new orally available anticoagulants with predictable pharmacokinetic and pharmacodynamic profiles and ability to target circulating clotting factors. Seven compounds including rivaroxaban, apixaban, betrixaban, and eribaxaban are orally available direct inhibitors of activated factor X currently in development for the prevention and treatment of venous thromboembolism and for thromboprophylaxis in patients with atrial fibrillation or following an acute coronary syndrome. At doses used in phase 2 and 3 clinical trials, rivaroxaban and apixaban demonstrated a predictable onset of effect, maximal plasma concentration, and half-life that was unaffected by age, renal, or hepatic disease. In clinical trials for the treatment and prevention of venous thromboembolism, rivaroxaban and apixaban produced equivalent or superior reductions in the development or progression of venous thromboembolism compared with either low molecular weight heparin or warfarin. Trials comparing the efficacy of rivaroxaban or apixaban to standard therapy for stroke prophylaxis in patients with atrial fibrillation are in process. Rivaroxaban, the sentinel compound in this class, is already approved in the European Union and Canada. It is likely to be approved for use in the United States in 2010. | Which clotting factor is inhibited by betrixaban? | 55200c606b348bb82c000013_127 | {
"answer_start": [
508
],
"text": [
"xa"
]
} |
Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Immunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies. | What is the target of daratumumab? | 5880aef4c872c95565000001_054 | {
"answer_start": [
1600
],
"text": [
"CD38"
]
} |
FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. BACKGROUND: The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury. METHODS AND RESULTS: Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts. CONCLUSIONS: During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure. | The drug JTV519 is derivative of which group of chemical compounds? | 54f9b74306d9727f76000004_042 | {
"answer_start": [
366
],
"text": [
"1,4-benzothiazepine"
]
} |
Molecular and cellular effects of NEDD8-activating enzyme inhibition in myeloma. The NEDD8-activating enzyme is upstream of the 20S proteasome in the ubiquitin/proteasome pathway and catalyzes the first step in the neddylation pathway. NEDD8 modification of cullins is required for ubiquitination of cullin-ring ligases that regulate degradation of a distinct subset of proteins. The more targeted impact of NEDD8-activating enzyme on protein degradation prompted us to study MLN4924, an investigational NEDD8-activating enzyme inhibitor, in preclinical multiple myeloma models. In vitro treatment with MLN4924 led to dose-dependent decrease of viability (EC(50) = 25-150 nmol/L) in a panel of human multiple myeloma cell lines. MLN4924 was similarly active against a bortezomib-resistant ANBL-6 subline and its bortezomib-sensitive parental cells. MLN4924 had submicromolar activity (EC(50) values <500 nmol/L) against primary CD138(+) multiple myeloma patient cells and exhibited at least additive effect when combined with dexamethasone, doxorubicin, and bortezomib against MM.1S cells. The bortezomib-induced compensatory upregulation of transcripts for ubiquitin/proteasome was not observed with MLN4924 treatment, suggesting distinct functional roles of NEDD8-activating enzyme versus 20S proteasome. MLN4924 was well tolerated at doses up to 60 mg/kg 2× daily and significantly reduced tumor burden in both a subcutaneous and an orthotopic mouse model of multiple myeloma. These studies provide the framework for the clinical investigation of MLN4924 in multiple myeloma. | Which enzyme does MLN4924 inhibit? | 56ed03862ac5ed1459000004_003 | {
"answer_start": [
504
],
"text": [
"NEDD8-activating enzyme"
]
} |
Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor. Ubiquitination, endocytosis, and lysosomal degradation of the IFNAR1 (interferon alpha receptor 1) subunit of the type I interferon (IFN) receptor is mediated by the SCFbeta-Trcp (Skp1-Cullin1-F-box protein beta transducin repeat-containing protein) E3 ubiquitin ligase in a phosphorylation-dependent manner. In addition, stability of IFNAR1 is regulated by its binding to Tyk2 kinase. Here we characterize the determinants of IFNAR1 ubiquitination and degradation. We found that the integrity of two Ser residues at positions 535 and 539 within the specific destruction motif present in the cytoplasmic tail of IFNAR1 is essential for the ability of IFNAR1 to recruit beta-Trcp as well as to undergo efficient ubiquitination and degradation. Using an antibody that specifically recognizes IFNAR1 phosphorylated on Ser535 we found that IFNAR1 is phosphorylated on this residue in cells. This phosphorylation is promoted by treatment of cells with IFNalpha. Although the cytoplasmic tail of IFNAR1 contains seven Lys residues that could function as potential ubiquitin acceptor sites, we found that only three (Lys501, Lys525, and Lys526), all located proximal to the destruction motif, are essential for ubiquitination and degradation of IFNAR1. Expression of Tyk2 stabilized IFNAR1 in a manner that was dependent neither on its binding to beta-Trcp nor IFNAR1 ubiquitination. We discuss the complexities and specifics of the ubiquitination and degradation of IFNAR1, which is a beta-Trcp substrate that undergoes degradation via a lysosomal pathway. | Which E3 ubiquitin ligase mediates the ubiquitination and degradation of the interferon receptor type 1 (IFNAR1)? | 55192892622b194345000012_004 | {
"answer_start": [
324
],
"text": [
"beta-Trcp"
]
} |
Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial. BACKGROUND: The RTS,S/AS01(E) candidate malaria vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01(E) when integrated into the EPI. We report extended follow-up to 19 months, including efficacy results. METHODS: We did a randomised, open-label, phase 2 trial of safety and efficacy of the RTS,S/AS01(E) candidate malaria vaccine given with EPI vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6-10 weeks of age at first vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus influenzae type b vaccine, and oral polio vaccine at study months 0, 1, and 2, and measles vaccine and yellow fever vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01(E) at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefined block list with a computer-generated randomisation code. Detection of serious adverse events and malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007. FINDINGS: 511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01(E) 0, 1, 2 month group (34%, 95% CI 27-41), 47 in the 0, 1, 7 month group (28%, 21-35), and 49 (29%, 22-36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were significantly higher in the RTS,S/AS01(E) groups than in the control group. Vaccine efficacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site-adjusted according-to-protocol analysis) was 53% (95% CI 26-70; p=0·0012) against first malaria episodes and 59% (36-74; p=0·0001) against all malaria episodes. For the entire study period, (total vaccinated cohort) vaccine efficacy against all malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33-73; p=0·0002) than with the 0, 1, 7 month schedule (32% CI 16-45; p=0·0003). 1 year after dose three, vaccine efficacy against first malaria episodes was similar for both schedules (0, 1, 2 month group, 61·6% [95% CI 35·6-77·1], p<0·001; 0, 1, 7 month group, 63·8% [40·4-78·0], p<0·001, according-to-protocol cohort). INTERPRETATION: Vaccine efficacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a first-generation malaria vaccine. The 0, 1, 2 month vaccine schedule has been selected for phase 3 candidate vaccine assessment. FUNDING: Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals. | RTS S AS01 vaccine was developed to prevent which disease? | 56bc77a3ac7ad10019000015_019 | {
"answer_start": [
49
],
"text": [
"malaria"
]
} |
Combined transcranial-orbital approach for resection of optic nerve gliomas: a clinical and anatomical study. PURPOSE: To describe a combined transcranial-orbital approach for en bloc resection of optic nerve gliomas with preservation of the annulus of Zinn that minimizes recurrence and prevents postoperative paralytic ptosis. DESIGN: A retrospective, noncomparative, interventional case series. STUDY POPULATION: All patients who underwent optic nerve glioma resections using this technique with the authors between 1994 and 2010. PROCEDURE: A transcranial-orbital approach is used to resect the intracranial segment of the optic nerve glioma from 2 mm anterior to the chiasm to the posterior extent of annulus of Zinn. The proximal transected edge of the nerve is examined intraoperatively for tumor margin clearance. Through a superior orbitotomy exposure, the entire retrobulbar segment of the tumor is transected from the globe to the annulus of Zinn. A simulation of the procedure in a cadaver and en bloc resection of the orbital apex are performed to demonstrate the subdural plane of dissection within the annulus of Zinn. MAIN OUTCOME MEASURES: Postoperative outcome measures include: health of the ipsilateral globe, paralytic ptosis, postoperative complications, and tumor recurrence. RESULTS: Eleven patients underwent resection of optic nerve gliomas using this technique. No patients had tumor recurrence or developed postoperative paralytic ptosis. CONCLUSIONS: The combined transcranial-orbital approach with preservation of the annulus of Zinn is a safe and effective way to remove optic nerve gliomas and ensure tumor clearance while avoiding paralytic ptosis. | Where can you find the annulus of Zinn? | 58917c88621ea6ff7e00000a_006 | {
"answer_start": [
155
],
"text": [
"orbit"
]
} |
Explaining intermediate filament accumulation in giant axonal neuropathy. Giant axonal neuropathy (GAN)(1) is a rare autosomal recessive neurological disorder caused by mutations in the GAN gene that encodes gigaxonin, a member of the BTB/Kelch family of E3 ligase adaptor proteins.(1) This disease is characterized by the aggregation of Intermediate Filaments (IF)-cytoskeletal elements that play important roles in cell physiology including the regulation of cell shape, motility, mechanics and intra-cellular signaling. Although a range of cell types are affected in GAN, neurons display the most severe pathology, with neuronal intermediate filament accumulation and aggregation; this in turn causes axonal swellings or "giant axons." A mechanistic understanding of GAN IF pathology has eluded researchers for many years. In a recent study(1) we demonstrate that the normal function of gigaxonin is to regulate the degradation of IF proteins via the proteasome. Our findings present the first direct link between GAN mutations and IF pathology; moreover, given the importance of IF aggregations in a wide range of disease conditions, our findings could have wider ramifications. | Which gene is involved in Giant Axonal Neuropathy? | 572096c90fd6f91b6800000e_012 | {
"answer_start": [
186
],
"text": [
"GAN gene"
]
} |
Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation. PURPOSE OF REVIEW: In recent years, we have seen remarkable progress in our understanding of the disease mechanism underlying facioscapulohumeral muscular dystrophy (FSHD). The purpose of this review is to provide a comprehensive overview of our current understanding of the disease mechanism and to discuss the observations supporting the possibility of a developmental defect in this disorder. RECENT FINDINGS: In the majority of cases, FSHD is caused by contraction of the D4Z4 repeat array (FSHD1). This results in local chromatin relaxation and stable expression of the DUX4 retrogene in skeletal muscle, but only when a polymorphic DUX4 polyadenylation signal is present. In some cases (FSHD2), D4Z4 chromatin relaxation and stable DUX4 expression occur in the absence of D4Z4 array contraction. DUX4 is a germline transcription factor and its expression in skeletal muscle leads to activation of early stem cell and germline programs and transcriptional activation of retroelements. SUMMARY: Recent studies have provided a plausible disease mechanism for FSHD in which FSHD results from inappropriate expression of the germline transcription factor DUX4. The genes regulated by DUX4 suggest several mechanisms of muscle damage, and provide potential biomarkers and therapeutic targets that should be investigated in future studies. | Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4? | 550f0e4c6a8cde6b72000003_010 | {
"answer_start": [
1154
],
"text": [
"FSHD"
]
} |
Focal cortical dysplasia in meningioangiomatosis. Meningioangiomatosis is a rare, benign, developmental, or hamartomatous lesion which may involve the leptomeninges and underlying brain parenchyma. Histologically, meningioangiomatosis is marked by a proliferation of blood vessels in the parenchyma, rimmed by collars of spindled meningothelial cells. There are anecdotal reports of an association of meningioangiomatosis with focal cortical dysplasia. We retrospectively analyzed the clinical, histopathologic, and treatment outcomes of 16 patients with a diagnosis of meningioangiomatosis, specifically investigating these cases for evidence of adjacent focal cortical dysplasia. Patients ranged in age from 1 to 34 years (median 18), 12 of whom had medically-intractable epilepsy as their presenting symptom. No patients in this study had a confirmed diagnosis of neurofibromatosis type II. Four patients (25%) were found to have fibrous meningiomas associated with the meningioangiomatosis. Ten of the 12 patients (83%) who had adequate tissue excised adjacent to the meningioangiomatosis demonstrated evidence of focal cortical dysplasia, with 6 of those (60%) classified as Palmini type IA, and 4 patients (40%) classified as Palmini type IIA. Seven of the patients (44%) had no post-operative seizures, and were off anti-epileptic drugs, while 2 patients relapsed, and required pharmacologic treatment for seizure control. This study therefore presents evidence to support inclusion of meningioangiomatosis as a focal cortical dysplasia-associated entity, as suggested by the ILAE classification (type IIIc). As focal cortical dysplasia is a developmental malformation, its association with meningioangiomatosis supports a developmental etiology of sporadic meningioangiomatosis. | Which disorder is rated by Palmini classification? | 56c1f020ef6e394741000047_025 | {
"answer_start": [
1118
],
"text": [
"focal cortical dysplasia"
]
} |
Coeliac disease presenting as dermatitis herpetiformis in infancy. The incidence of reporting and diagnosis of coeliac disease (CD) in children is increasing with the improvement in sensitivity and specificity of screening markers. This in turn has led to an increasing awareness of gluten-sensitive enteropathy and associated disorders. We report the unusual case of an 8-month-old child presenting to his general practitioner with pruritic skin lesions, subsequently proven to be dermatitis herpetiformis (DH) as the first sign of gluten-sensitive disease. This infant is the youngest child presenting with DH who could be identified from published report dating from 1966 onwards. Dermatitis herpetiformis is the commonest associated pathology of CD, although rare in infancy, it should be considered in any child presenting with failure to thrive and atypical, chronic rash not responding to simple measures. | What is the typical rash associated with gluten ? | 55180ef46487737b43000006_005 | {
"answer_start": [
482
],
"text": [
"dermatitis herpetiformis"
]
} |
Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD. Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused by decreased epigenetic repression of the D4Z4 macrosatellite repeats and ectopic expression of DUX4, a retrogene encoding a germline transcription factor encoded in each repeat. Unaffected individuals generally have more than 10 repeats arrayed in the subtelomeric region of chromosome 4, whereas the most common form of FSHD (FSHD1) is caused by a contraction of the array to fewer than 10 repeats, associated with decreased epigenetic repression and variegated expression of DUX4 in skeletal muscle. We have generated transgenic mice carrying D4Z4 arrays from an FSHD1 allele and from a control allele. These mice recapitulate important epigenetic and DUX4 expression attributes seen in patients and controls, respectively, including high DUX4 expression levels in the germline, (incomplete) epigenetic repression in somatic tissue, and FSHD-specific variegated DUX4 expression in sporadic muscle nuclei associated with D4Z4 chromatin relaxation. In addition we show that DUX4 is able to activate similar functional gene groups in mouse muscle cells as it does in human muscle cells. These transgenic mice therefore represent a valuable animal model for FSHD and will be a useful resource to study the molecular mechanisms underlying FSHD and to test new therapeutic intervention strategies. | Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4? | 550f0e4c6a8cde6b72000003_046 | {
"answer_start": [
104
],
"text": [
"Facioscapulohumeral dystrophy"
]
} |
Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific agents used in a DOAC associated bleeding but with limited success. Idarucizumab, the first novel antidote against direct thrombin inhibitor dabigatran was approved by US FDA in October 2015. It comprehensively reversed dabigatran-induced anticoagulation in a phase I study. A phase III trial on Idarucizumab also complete reversal of anticoagulant effect of dabigatran. Andexanet alfa (PRT064445), a specific reversal agent against factor Xa inhibitors, showed a complete reversal of anticoagulant activity of apixaban and rivaroxaban within minutes after administration without adverse effects in two recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. It is currently being studied in ANNEXA-4, a phase IV study. Aripazine (PER-977), the third reversal agent, has shown promising activity against dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH. This review article summarizes pharmacological characteristics of these novel antidotes, coagulation's tests affected, available clinical and preclinical data, and the need for phase III and IV studies. | Andexanet Alfa is an antidote of which clotting factor inhibitors? | 5880b073c872c95565000003_072 | {
"answer_start": [
1184
],
"text": [
"xa"
]
} |
Acrokeratosis paraneoplastica (Bazex syndrome): report of a case associated with small cell lung carcinoma and review of the literature. Acrokeratosis paraneoplastic (Bazex syndrome) is a rare, but distinctive paraneoplastic dermatosis characterized by erythematosquamous lesions located at the acral sites and is most commonly associated with carcinomas of the upper aerodigestive tract. We report a 58-year-old female with a history of a pigmented rash on her extremities, thick keratotic plaques on her hands, and brittle nails. Chest imaging revealed a right upper lobe mass that was proven to be small cell lung carcinoma. While Bazex syndrome has been described in the dermatology literature, it is also important for the radiologist to be aware of this entity and its common presentations. | Name synonym of Acrokeratosis paraneoplastica. | 56bc751eac7ad10019000013_001 | {
"answer_start": [
31
],
"text": [
"Bazex syndrome"
]
} |
Methicillin-resistant Staphylococcus aureus (MRSA) detection: comparison of two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) with three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA) for use with infection-control swabs. Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem. Rapid detection of MRSA-colonized patients has the potential to limit spread of the organism. We evaluated the sensitivities and specificities of MRSA detection by two molecular methods (IDI-MRSA PCR assay and GenoType MRSA Direct PCR assay) and three selective MRSA agars (MRSA ID, MRSASelect, and CHROMagar MRSA), using 205 (101 nasal, 52 groin, and 52 axillary samples) samples from consecutive known MRSA-infected and/or -colonized patients. All detection methods had higher MRSA detection rates for nasal swabs than for axillary and groin swabs. Detection of MRSA by IDI-MRSA was the most sensitive method, independent of the site (94% for nasal samples, 80% for nonnasal samples, and 90% overall). The sensitivities of the GenoType MRSA Direct assay and the MRSA ID, MRSASelect, and CHROMagar MRSA agars with nasal swabs were 70%, 72%, 68%, and 75%, respectively. All detection methods had high specificities (95 to 99%), independent of the swab site. Extended incubation for a further 24 h with selective MRSA agars increased the detection of MRSA, with a corresponding decline in specificity secondary to a significant increase in false-positive results. There was a noticeable difference in test performance of the GenoType MRSA Direct assay in detection of MRSA (28/38 samples [74%]) compared with detection of nonmultiresistant MRSA (17/31 samples [55%]) (susceptible to two or more non-beta-lactam antibiotics). This was not observed with selective MRSA agar plates or IDI-MRSA. Although it is more expensive, in addition to rapid turnaround times of 2 to 4 h, IDI-MRSA offers greater detection of MRSA colonization, independent of the swab site, than do conventional selective agars and GenoType MRSA Direct. | What is MRSA? | 58a32efe60087bc10a000013_054 | {
"answer_start": [
175
],
"text": [
"MRSA"
]
} |
[SENSITIVITY OF THE NEW SKIN TEST DIASKINTEST® FOR THE DIAGNOSIS OF TUBERCULOSIS INFECTION IN CHILDREN AND ADOLESCENTS]. In Russia, an intradermal Diaskintest® drug has been designed, which is a recombinant tuberculosis allergen based on M. tuberculosis-- specific proteins: ESAT-6 and CFP-10 produced by a genetically modified Escherichia coli culture. Diaskintest® test and Mantoux test with 2TE PPD-L were concurrently carried out in 300 children and adolescents with tuberculosis and followed up in risk groups at a tuberculosis dispensary to determine the sensitivity of the new skin test in active tuberculosis infection. Diaskintest® showed a high sensitivity not only in active tuberculosis, but also in occult, the so-called latent, tuberculosis infection. This is suggested by the following evidence. The high percentage (83.8%) of positive responses to Diaskintest® is noted in children and adolescents with tuberculosis, receiving an intensive course of chemotherapy. Negative tests were observed only in minor forms at the resolution stage. In the children who had completed treatment, positive tests were seen in 78.3%, moreover in those with prior tuberculosis of intrathoracic lymph nodes; negative tests were observed not earlier than 18 months after start of treatment. The highest sensitivity of Diaskintest® was shown in children with early primary tuberculosis infection and through family contact with bacteria-excreting subjects (91.7%). These children may be judged with the highest assurance to have latent tuberculosis infection, the population of which is in an active state at the moment of the study. The children with early primary tuberculosis infection, but in no family contact with bacteria-excreting individuals, showed a lower percentage of positive responses to Diaskintest® both before (37.5%) and after (10%) treatment, which suggests that there must be a lower bacterial burden in the child. A high percentage of positive responses to Diaskintest® (76.2%) were found in subjects with hyperergic reactions to tuberculin. These were in only 16.7% in the group of patients receiving preventive therapy. In children and adolescents with a persistent positive Mantoux test (for more than 3 years), the response to Diaskintest® was negative in most cases since in early infection when mycobacteria propagated, the reaction to the drug was positive, but as 3 years pass the probability of the infection transition to the persistence stage is high--at that time the response to Diaskintest® becomes negative. Diaskintest® induces no delayed hypersensitivity associated with BCG vaccination, suggesting its high specificity. There were no positive reactions in patients with nonspecific lung diseases. | The Mantoux test detects what latent infection/disease? | 5ab147edfcf4565872000013_002 | {
"answer_start": [
520
],
"text": [
"tuberculosis"
]
} |
Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Dot1 is an evolutionarily conserved histone methyltransferase that methylates lysine-79 of histone H3 in the core domain. Unlike other histone methyltransferases, Dot1 does not contain a SET domain, and it specifically methylates nucleosomal histone H3. We have solved a 2.5 A resolution structure of the catalytic domain of human Dot1, hDOT1L, in complex with S-adenosyl-L-methionine (SAM). The structure reveals a unique organization of a mainly alpha-helical N-terminal domain and a central open alpha/beta structure, an active site consisting of a SAM binding pocket, and a potential lysine binding channel. We also show that a flexible, positively charged region at the C terminus of the catalytic domain is critical for nucleosome binding and enzymatic activity. These structural and biochemical analyses, combined with molecular modeling, provide mechanistic insights into the catalytic mechanism and nucleosomal specificity of Dot1 proteins. | What is the characteristic domain of histone methyltransferases? | 532dcfc9d6d3ac6a34000021_021 | {
"answer_start": [
293
],
"text": [
"SET domain"
]
} |
Emerging anticoagulants. Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease. | Which clotting factor is inhibited by betrixaban? | 55200c606b348bb82c000013_039 | {
"answer_start": [
935
],
"text": [
"Xa"
]
} |
Inhibition of CaM kinase II activation and force maintenance by KN-93 in arterial smooth muscle. Ca(+)/calmodulin-dependent protein kinase II (CaM kinase II) has been implicated in the regulation of smooth muscle contractility. The goals of this study were to determine: 1) to what extent CaM kinase II is activated by contractile stimuli in intact arterial smooth muscle, and 2) the effect of a CaM kinase II inhibitor (KN-93) on CaM kinase II activation, phosphorylation of myosin regulatory light chains (MLC(20)), and force. Both histamine (1 microM) and KCl depolarization activated CaM kinase II with a time course preceding maximal force development, and suprabasal CaM kinase II activation was sustained during tonic contractions. CaM kinase II activation was inhibited by KN-93 pretreatment (IC(50) approximately 1 microM). KN-93 inhibited histamine-induced tonic force maintenance, whereas early force development and MLC(20) phosphorylation responses during the entire time course were unaffected. Both force development and maintenance in response to KCl were inhibited by KN-93. Rapid increases in KCl-induced MLC(20) phosphorylation were also inhibited by KN-93, whereas steady-state MLC(20) phosphorylation responses were unaffected. In contrast, phorbol 12,13-dibutyrate (PDBu) did not activate CaM kinase II and PDBu-stimulated force development was unaffected by KN-93. Thus KN-93 appears to target a step(s) essential for force maintenance in response to physiological stimuli, suggesting a role for CaM kinase II in regulating tonic contractile responses in arterial smooth muscle. Pharmacological activation of protein kinase C bypasses the KN-93 sensitive step. | Which kinase is inhibited by the small molecule KN-93? | 54f89e1a06d9727f76000001_004 | {
"answer_start": [
739
],
"text": [
"CaM kinase II"
]
} |
GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-β family, is a secreted protein that circulates as a 25-kDa dimer. In humans, elevated GDF15 correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor α-like (GFRAL), a distant relative of receptors for a distinct class of the TGF-β superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity. | How does increased GDF15 affect body weight? | 5a7d5ce0faa1ab7d2e00001b_001 | {
"answer_start": [
373
],
"text": [
"reduces body weight"
]
} |
[Dermatoglyphics of homo- and heterozygotes for Wilson's disease (hepatolenticular degeneration) (author's transl)]. Dermatoglyphics of 11 patients with Wilson's disease and 16 of their clinically asymptomatic relatives of first degree were investigated; 11 of the latter ones were heterozygous in agreement with the turn over rates of Cu-67, 12 under the assumption of autosomal recessive inheritance. On the finger tips the Mb. Wilson patients showed 52.7% whorls, their heterozygous relatives about 40%; compared with our controls (males 33.16%, females 28.82%, Aue-Hauser, 1970) that means a strong increase of this pattern type. On the palm the high frequency of hypothenar patterns in homo- and heterozygotes for Wilson's disease and of loops with accessory triradius in the 4th interdigitum of the patients with Wilson's disease was striking. | What is the mode of inheritance of Wilson's disease? | 52bf1b0a03868f1b06000009_013 | {
"answer_start": [
370
],
"text": [
"autosomal recessive"
]
} |
Clinics in diagnostic imaging (175). Corpus callosum glioblastoma multiforme (GBM): butterfly glioma. A 54-year-old man presented with change in behaviour, nocturnal enuresis, abnormal limb movement and headache of one week's duration. The diagnosis of butterfly glioma (glioblastoma multiforme) was made based on imaging characteristics and was further confirmed by biopsy findings. As the corpus callosum is usually resistant to infiltration by tumours, a mass that involves and crosses the corpus callosum is suggestive of an aggressive neoplasm. Other neoplastic and non-neoplastic conditions that may involve the corpus callosum and mimic a butterfly glioma, as well as associated imaging features, are discussed. | What is the most common histological diagnosis of "butterfly glioma"? | 5a7234352dc08e987e000007_007 | {
"answer_start": [
53
],
"text": [
"glioblastoma multiforme"
]
} |
CAGEr: precise TSS data retrieval and high-resolution promoterome mining for integrative analyses. Cap analysis of gene expression (CAGE) is a high-throughput method for transcriptome analysis that provides a single base-pair resolution map of transcription start sites (TSS) and their relative usage. Despite their high resolution and functional significance, published CAGE data are still underused in promoter analysis due to the absence of tools that enable its efficient manipulation and integration with other genome data types. Here we present CAGEr, an R implementation of novel methods for the analysis of differential TSS usage and promoter dynamics, integrated with CAGE data processing and promoterome mining into a first comprehensive CAGE toolbox on a common analysis platform. Crucially, we provide collections of TSSs derived from most published CAGE datasets, as well as direct access to FANTOM5 resource of TSSs for numerous human and mouse cell/tissue types from within R, greatly increasing the accessibility of precise context-specific TSS data for integrative analyses. The CAGEr package is freely available from Bioconductor at http://www.bioconductor.org/packages/release/bioc/html/CAGEr.html. | Which tool is used for promoterome mining using CAGE data? | 56afe6d40a360a5e45000017_004 | {
"answer_start": [
1206
],
"text": [
"CAGEr"
]
} |
Phospholamban phosphorylation by CaMKII under pathophysiological conditions. Sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) transports Ca2+ into the SR, decreasing the cytosolic Ca2+ during relaxation and increasing the SR Ca2+ available for contraction. SERCA2a activity is regulated by phosphorylation of another SR protein: Phospholamban (PLN). Dephosphorylated PLN inhibits SERCA2a. Phosphorylation of PLN by either cAMP or cGMP-dependent protein kinase at Ser16 or the Ca2+-calmodulin-dependent protein kinase (CaMKII), at Thr17, relieves this inhibition, increasing SR Ca2+ uptake and SR Ca2+ load. Thus, PLN is a major player in the regulation of myocardial relaxation and contractility. This review will examine the main aspects of the role of CaMKII and Thr17 site of PLN, on different pathophysiological conditions: acidosis, ischemia/reperfusion (I/R) and heart failure (HF). Whereas CaMKII-activation and PLN phosphorylation contribute to the functional recovery during acidosis and stunning, CaMKII results detrimental in the irreversible I/R injury, producing apoptosis and necrosis. Phosphorylation of Thr17 residue of PLN and CaMKII activity vary in the different models of HF. The possible role of these changes in the depressed cardiac function of HF will be discussed. | Which is the main regulatory molecule of SERCA2A function in the cardiac muscle? | 54cb9c94f693c3b16b000005_020 | {
"answer_start": [
409
],
"text": [
"PLN"
]
} |
The melanocortin 1 receptor (MC1R): more than just red hair. The melanocortin 1 receptor, a seven pass transmembrane G protein coupled receptor, is a key control point in melanogenesis. Loss-of-function mutations at the MC1R are associated with a switch from eumelanin to phaeomelanin production, resulting in a red or yellow coat colour. Activating mutations, in animals at least, lead to enhanced eumelanin synthesis. In man, a number of loss-of-function mutations in the MC1R have been described. The majority of red-heads (red-haired persons) are compound heterozygotes or homozygotes for up to five frequent loss-of-function mutations. A minority of redheads are, however, only heterozygote. The MC1R is, therefore, a major determinant of sun sensitivity and a genetic risk factor for melanoma and non-melanoma skin cancer. Recent work suggests that the MC1R also shows a clear heterozygote effect on skin type, with up to 30% of the population harbouring loss-of-function mutations. Activating mutations of the MC1R in man have not been described. The MC1R is particularly informative and a tractable gene for studies of human evolution and migration. In particular, study of the MC1R may provide insights into the lightening of skin colour observed in most European populations. The world wide pattern of MC1R diversity is compatible with functional constraint operating in Africa, whereas the greater allelic diversity seen in non-African populations is consistent with neutral predictions rather than selection. Whether this conclusion is as a result of weakness in the statistical testing procedures applied, or whether it will be seen in other pigment genes will be of great interest for studies of human skin colour evolution. | Which gene is responsible for red hair? | 5ace19420340b9f05800000a_016 | {
"answer_start": [
220
],
"text": [
"MC1R"
]
} |
Rapamycin inhibits the growth of glioblastoma. The molecular target of rapamycin (mTOR) is up-regulated in glioblastoma (GBM) and this is associated with the rate of cell growth, stem cell proliferation and disease relapse. Rapamycin is a powerful mTOR inhibitor and strong autophagy inducer. Previous studies analyzed the effects of rapamycin in GBM cell lines. However, to our knowledge, no experiment was carried out to evaluate the effects of rapamycin neither in primary cells derived from GBM patients nor in vivo in brain GBM xenograft. These data are critical to get a deeper insight into the effects of such adjuvant therapy in GBM patients. In the present study, various doses of rapamycin were tested in primary cell cultures from GBM patients. These effects were compared with that obtained by the same doses of rapamycin in GBM cell lines (U87Mg). The effects of rapamycin were also evaluated in vivo, in brain tumors developed from mouse xenografts. Rapamycin, starting at the dose of 10nm inhibited cell growth both in U87Mg cell line and primary cell cultures derived from various GBM patients. When administered in vivo to brain xenografts in nude mice rapamycin almost doubled the survival time of mice and inhibited by more than 95% of tumor volume. | Which is the molecular target of the immunosuppressant drug Rapamycin? | 53124bdae3eabad02100000b_003 | {
"answer_start": [
82
],
"text": [
"mTOR"
]
} |
Calcium and vitamin D in sarcoidosis: is supplementation safe? Granulomas in sarcoidosis express high levels of 1α-hydroxylase, an enzyme that catalyzes the hydroxylation of 25-OH vitamin D to its active form, 1,25(OH)2 vitamin D. Overproduction of 1α-hydroxylase is held responsible for the development of hypercalcemia in sarcoidosis patients. Corticosteroids are used as first-line treatment in organ-threatening sarcoidosis. In this light, osteoporosis prevention with calcium and vitamin D (CAD) supplementation is often warranted. However, sarcoidosis patients are at risk for hypercalcemia, and CAD supplementation affects the calcium metabolism. We studied calcium and vitamin D disorders in a large cohort of sarcoidosis patients and investigated if CAD supplementation is safe. Retrospectively, data of 301 sarcoidosis patients from July 1986 to June 2009 were analyzed for serum calcium, 25-hydroxy vitamin D (25-(OH)D), 1,25-dihydroxy vitamin D (1,25(OH)2 D), and use of CAD supplementation. Disease activity of sarcoidosis was compared with serum levels of vitamin D. Hypercalcemia occurred in 8%. A significant negative correlation was found between 25-(OH)D and disease activity of sarcoidosis measured by somatostatin receptor scintigraphy. In our study, 5 of the 104 CAD-supplemented patients developed hypercalcemia, but CAD supplementation was not the cause of hypercalcemia. Patients without CAD supplementation were at higher risk for developing hypercalcemia. During CAD supplementation, no hypercalcemia developed as a result of supplementation. Hypovitaminosis D seems to be related with more disease activity of sarcoidosis and, therefore, could be a potential risk factor for disease activity of sarcoidosis. Thus, vitamin D-deficient sarcoidosis patients should be supplemented. | What is the first line treatment for sarcoidosis? | 5a7877c0faa1ab7d2e00000c_008 | {
"answer_start": [
346
],
"text": [
"Corticosteroids"
]
} |
Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4. Oculocutaneous albinism (OCA) type 4 is a newly identified human autosomal recessive hypopigmentary disorder that disrupts pigmentation in the skin, hair and eyes. Three other forms of OCA have been previously characterized, each resulting from the aberrant processing and/or sorting of tyrosinase, the enzyme critical to pigment production in mammals. The disruption of tyrosinase trafficking occurs at the level of the endoplasmic reticulum (ER) in OCA1 and OCA3, but at the post-Golgi level in OCA2. The gene responsible for OCA4 is the human homologue of the mouse underwhite (uw) gene, which encodes the membrane-associated transporter protein (MATP). To characterize OCA4, we investigated the processing and sorting of melanogenic proteins in primary melanocytes derived from uw/uw mice and from wild-type mice. OCA4 melanocytes were found to be constantly secreted into the medium dark vesicles that contain tyrosinase and two other melanogenic enzymes, Tyrp1 (tyrosinase-related protein 1) and Dct (DOPAchrome tautomerase); this secretory process is not seen in wild-type melanocytes. Although tyrosinase was synthesized at comparable rates in wild-type and in uw-mutant melanocytes, tyrosinase activity in uw-mutant melanocytes was only about 20% of that found in wild-type melanocytes, and was enriched only about threefold in melanosomes compared with the ninefold enrichment in wild-type melanocytes. OCA4 melanocytes showed a marked difference from wild-type melanocytes in that tyrosinase was abnormally secreted from the cells, a process similar to that seen in OCA2 melanocytes, which results from a mutation of the pink-eyed dilution (P) gene. The P protein and MATP have 12 transmembrane regions and are predicted to function as transporters. Ultrastructural analysis shows that the vesicles secreted from OCA4 melanocytes are mostly early stage melanosomes. Taken together, our results show that in OCA4 melanocytes, tyrosinase processing and intracellular trafficking to the melanosome is disrupted and the enzyme is abnormally secreted from the cells in immature melanosomes, which disrupts the normal maturation process of those organelles. This mechanism explains the hypopigmentary phenotype of these cells and provides new insights into the involvement of transporters in the normal physiology of melanocytes. | Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism? | 58cbb98c02b8c60953000034_011 | {
"answer_start": [
554
],
"text": [
"tyrosinase"
]
} |
Right cerebral hemiatrophy: neurocognitive and electroclinical features. The purpose of this study was to retrospectively evaluate the cognitive and electroclinical characteristics of right cerebral hemiatrophy (Dyke-Davidoff-Masson syndrome [DDMS]). Cognitive assessments with a particular emphasis on visuospatial functions, electroclinical features, and neuroimaging characteristics were analyzed for five patients with a clinically and neuroradiologically confirmed diagnosis of right-sided DDMS. Intelligence tests revealed mental retardation in all but one. Neuropsychological assessments demonstrated consistent impairments in tasks that have a spatial component (spatial processing and orientation discrimination), whereas attention, executive functions and verbal memory domains were variably impaired. Electroclinically, the main seizure types were simple partial motor, complex partial, and secondarily generalized seizures. Interictal EEG delineated lower amplitudes and slow background activity in the affected hemisphere. Overall, the cognitive performance of patients with DDMS encompasses a broad spectrum of impairments affecting multiple domains. Our findings support the concept that dorsal visual pathways responsible for spatial processing may be lateralized to the right hemisphere. | What is the characteristic feature of the Dyke-Davidoff-Masson syndrome. | 55032e65e9bde69634000034_020 | {
"answer_start": [
190
],
"text": [
"cerebral hemiatrophy"
]
} |
A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease. The interpretation of non-coding variants still constitutes a major challenge in the application of whole-genome sequencing in Mendelian disease, especially for single-nucleotide and other small non-coding variants. Here we present Genomiser, an analysis framework that is able not only to score the relevance of variation in the non-coding genome, but also to associate regulatory variants to specific Mendelian diseases. Genomiser scores variants through either existing methods such as CADD or a bespoke machine learning method and combines these with allele frequency, regulatory sequences, chromosomal topological domains, and phenotypic relevance to discover variants associated to specific Mendelian disorders. Overall, Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes, allowing effective detection and discovery of regulatory variants in Mendelian disease. | Which method is available for whole genome identification of pathogenic regulatory variants in mendelian disease? | 5a67c497b750ff4455000012_004 | {
"answer_start": [
351
],
"text": [
"Genomiser"
]
} |
SEF, a new protein required for flowering repression in Arabidopsis, interacts with PIE1 and ARP6. The SWR1/SRCAP complex is a chromatin-remodeling complex that has been shown to be involved in substitution of histone H2A by the histone variant H2A.Z in yeast (Saccharomyces cerevisiae) and animals. Here, we identify and characterize SERRATED LEAVES AND EARLY FLOWERING (SEF), an Arabidopsis (Arabidopsis thaliana) homolog of the yeast SWC6 protein, a conserved subunit of the SWR1/SRCAP complex. SEF loss-of-function mutants present a pleiotropic phenotype characterized by serrated leaves, frequent absence of inflorescence internodes, bushy aspect, and flowers with altered number and size of organs. sef plants flower earlier than wild-type plants both under inductive and noninductive photoperiods. This correlates with strong reduction of FLOWERING LOCUS C and MADS-AFFECTING FLOWERING4 transcript levels and up-regulation of FLOWERING LOCUS T and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 gene expression. The sef phenotype is similar to that of the photoperiod-independent early flowering1 (pie1) and the actin-related protein 6 (arp6) mutants. PIE1 and ARP6 proteins are also homologs of SWR1/SRCAP complex subunits. Analysis of sef pie1 double mutants demonstrates genetic interaction between these two genes. We also show physical interactions between SEF, ARP6, and PIE1 proteins. Taken together, our data indicate that SEF, ARP6, and PIE1 might form a molecular complex in Arabidopsis related to the SWR1/SRCAP complex identified in other eukaryotes. | Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae? | 58a6db8660087bc10a00002c_021 | {
"answer_start": [
103
],
"text": [
"SWR1"
]
} |
Phospholamban interactome in cardiac contractility and survival: A new vision of an old friend. Depressed sarcoplasmic reticulum (SR) calcium cycling, reflecting impaired SR Ca-transport and Ca-release, is a key and universal characteristic of human and experimental heart failure. These SR processes are regulated by multimeric protein complexes, including protein kinases and phosphatases as well as their anchoring and regulatory subunits that fine-tune Ca-handling in specific SR sub-compartments. SR Ca-transport is mediated by the SR Ca-ATPase (SERCA2a) and its regulatory phosphoprotein, phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA2a and phosphorylation by protein kinase A (PKA) or calcium-calmodulin-dependent protein kinases (CAMKII) relieves these inhibitory effects. Recent studies identified additional regulatory proteins, associated with PLN, that control SR Ca-transport. These include the inhibitor-1 (I-1) of protein phosphatase 1 (PP1), the small heat shock protein 20 (Hsp20) and the HS-1 associated protein X-1 (HAX1). In addition, the intra-luminal histidine-rich calcium binding protein (HRC) has been shown to interact with both SERCA2a and triadin. Notably, there is physical and direct interaction between these protein players, mediating a fine-cross talk between SR Ca-uptake, storage and release. Importantly, regulation of SR Ca-cycling by the PLN/SERCA interactome does not only impact cardiomyocyte contractility, but also survival and remodeling. Indeed, naturally occurring variants in these Ca-cycling genes modulate their activity and interactions with other protein partners, resulting in depressed contractility and accelerated remodeling. These genetic variants may serve as potential prognostic or diagnostic markers in cardiac pathophysiology. | Which is the main regulatory molecule of SERCA2A function in the cardiac muscle? | 54cb9c94f693c3b16b000005_003 | {
"answer_start": [
633
],
"text": [
"PLN"
]
} |
(18)F-FDG-PET/CT imaging in an IL-6- and MYC-driven mouse model of human multiple myeloma affords objective evaluation of plasma cell tumor progression and therapeutic response to the proteasome inhibitor ixazomib. (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are useful imaging modalities for evaluating tumor progression and treatment responses in genetically engineered mouse models of solid human cancers, but the potential of integrated FDG-PET/CT for assessing tumor development and new interventions in transgenic mouse models of human blood cancers such as multiple myeloma (MM) has not been demonstrated. Here we use BALB/c mice that contain the newly developed iMyc(ΔEμ) gene insertion and the widely expressed H2-L(d)-IL6 transgene to demonstrate that FDG-PET/CT affords an excellent research tool for assessing interleukin-6- and MYC-driven plasma cell tumor (PCT) development in a serial, reproducible and stage- and lesion-specific manner. We also show that FDG-PET/CT permits determination of objective drug responses in PCT-bearing mice treated with the investigational proteasome inhibitor ixazomib (MLN2238), the biologically active form of ixazomib citrate (MLN9708), that is currently in phase 3 clinical trials in MM. Overall survival of 5 of 6 ixazomib-treated mice doubled compared with mice left untreated. One outlier mouse presented with primary refractory disease. Our findings demonstrate the utility of FDG-PET/CT for preclinical MM research and suggest that this method will play an important role in the design and testing of new approaches to treat myeloma. | Which type of myeloma is ixazomib being evaluated for? | 56ed0ffe2ac5ed1459000008_006 | {
"answer_start": [
73
],
"text": [
"multiple myeloma"
]
} |
Randomized, controlled trial of telcagepant over four migraine attacks. METHODS: This study evaluated the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant (tablet formulation) for treatment of a migraine attack and across four attacks. Adults with migraine were randomized, double-blind, to telcagepant 140 mg, telcagepant 280 mg, or control treatment sequences to treat four moderate-to-severe migraine attacks. Control patients received placebo for three attacks and telcagepant 140 mg for one attack. Efficacy for the first attack (Attack 1) and consistency of efficacy over multiple attacks were assessed. For an individual patient, consistent efficacy was defined as > 3 successes, and lack of consistent efficacy was defined as > 2 failures, in treatment response. A total of 1677 patients treated > 1 attack and 1263 treated all four attacks. RESULTS: Based on Attack 1 data, telcagepant 140 mg and 280 mg were significantly (p < .001) more effective than placebo for 2-hour pain freedom, 2-hour pain relief, 2-hour absence of migraine-associated symptoms (phonophobia, photophobia, nausea), and 2-24 hours sustained pain freedom. The percentage of patients with 2-hour pain freedom consistency and 2-hour pain relief consistency was significantly (p < .001) higher for both telcagepant treatment sequences versus control. Adverse events within 48 hours for telcagepant with an incidence > 2% and twice that of placebo were somnolence (placebo = 2.3%, 140 mg = 5.9%, 280 mg = 5.7%) and vomiting (placebo = 1.4%, 140 mg = 1.0%, 280 mg = 2.9%). CONCLUSION: Telcagepant 140 mg and 280 mg were effective for treatment of a migraine attack and were more consistently effective than control for intermittent treatment of up to four migraine attacks. Telcagepant was generally well tolerated. (Clinicaltrials.gov; NCT00483704). | Which receptor is targeted by telcagepant? | 55032efde9bde69634000035_015 | {
"answer_start": [
106
],
"text": [
"calcitonin gene-related peptide"
]
} |
TNF-α: a treatment target or cause of sarcoidosis? Sarcoidosis is a systemic granulomatous disease that affects numerous organs, commonly manifesting at the lungs and skin. While corticosteroids remain the first line of treatment, tumour necrosis factor alpha (TNF-α) inhibitors have been investigated as one potential steroid sparing treatment for sarcoidosis. TNF-α is one of many components involved in the formation of granulomas in sarcoidosis. While there have been larger scale studies of biologic TNF-α inhibition in systemic sarcoidosis, studies in cutaneous disease are limited. Paradoxically, in some patients treated with biologic TNF-α inhibitors for other diseases, treatment can induce the development of sarcoidosis. In the light of this complexity, we discuss the role of TNF-α in granuloma formation, the therapeutic role of TNF-α inhibition and immunologic abnormalities following treatment with these TNF-α inhibitors including drug-specific alterations involving interferon-γ, lymphotoxin-α, TNF receptor 2 (TNFR2) and T-regulatory cells. | What is the first line treatment for sarcoidosis? | 5a7877c0faa1ab7d2e00000c_004 | {
"answer_start": [
179
],
"text": [
"corticosteroids"
]
} |
OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica. We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. OikoBase facilitates retrieval and mining of a variety of useful genomics information. First, it includes a genome browser which interrogates 1260 genomic sequence scaffolds and features gene, transcript and CDS annotation tracks. Second, we annotated gene models with gene ontology (GO) terms and InterPro domains which are directly accessible in the browser with links to their entries in the GO (http://www.geneontology.org/) and InterPro (http://www.ebi.ac.uk/interpro/) databases, and we provide transcript and peptide links for sequence downloads. Third, we introduce the transcriptomics of a comprehensive set of developmental stages of O. dioica at high resolution and provide downloadable gene expression data for all developmental stages. Fourth, we incorporate a BLAST tool to identify homologs of genes and proteins. Finally, we include a tutorial that describes how to use OikoBase as well as a link to detailed methods, explaining the data generation and analysis pipeline. OikoBase will provide a valuable resource for research in chordate development, genome evolution and plasticity and the molecular ecology of this important marine planktonic organism. | Mention the only available genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica | 56ae6e650a360a5e4500000e_007 | {
"answer_start": [
0
],
"text": [
"OikoBase"
]
} |
[SERM]. SERM is the abbreviation of the selective estrogen receptor modulator which is the synthetic ligands of estrogen receptor (ER) acting estrogenically or anti-estrogenically among various tissues through modifying the ER function. Clomifene, tamoxifen, toremifene and raloxifene are generally classified as SERM in the clinical use. The main cause of postmenopausal osteoporosis is estrogen deficiency and it was revealed that the continuous combined use of conjugated estrogen and medroxyprogesterone acetate reduced the relative risk of femoral neck fracture to 0.66, however increased the relative risk of cardiovascular event and breast cancer to 1.29 or 1.26, respectively. From the standpoint of safe and clinical compliance for the breast and uterine tissue, raloxifene is recommendable for middle aged postmenopausal osteoporosis. | What is a SERM? | 5a74e9ad0384be955100000a_008 | {
"answer_start": [
40
],
"text": [
"selective estrogen receptor modulator"
]
} |
Mechanisms of activation of NADPH oxidases. The members of the NOX family of enzymes are expressed in a variety of tissues and serve a number of functions. There is a high level of conservation of primary protein sequence, as well as functional features, although specialized responses are beginning to emerge. In this context, our data demonstrate that the NOX1 cytoplasmic domains interact efficiently with the cytoplasmic subunits of the phagocyte NADPH oxidase and identify the second cytoplasmic loop of NOX electron transporters as a crucial domain for enzyme function. Studies of cytosolic co-factors showed that the C-terminal cytoplasmic domain of NOX1 was absolutely required for activation with NOXO1 and NOXA1 and that this activity required interaction of the putative NADPH-binding region of this domain with NOXA1. Finally, we have provided the first example of how alternative splicing of a NOX co-factor may be involved in the regulation of NADPH oxidase function. | Which NADPH oxidase family member requires interaction with NOXO1 for function? | 58a5a51060087bc10a000021_011 | {
"answer_start": [
657
],
"text": [
"NOX1"
]
} |
Ribosomal protein mutations in Korean patients with Diamond-Blackfan anemia. Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by hypoproliferative anemia, associated physical malformations and a predisposition to cancer. DBA has been associated with mutations and deletions in the large and small ribosomal protein genes, and genetic aberrations have been detected in ∼50-60% of patients. In this study, nine Korean DBA patients were screened for mutations in eight known DBA genes (RPS19, RPS24, RPS17, RPS10, RPS26, RPL35A, RPL5 and RPL11) using the direct sequencing method. Mutations in RPS19, RPS26 and RPS17 were detected in four, two and one patient, respectively. Among the mutations detected in RPS19, two mutations were novel (c.26T>A, c.357-2A>G). For the mutation-negative cases, array-CGH analysis was performed to identify copy-number variations, and no deletions involving the known DBA gene regions were identified. The relative mRNA expression of RPS19 estimated using real-time quantitative PCR analysis revealed two- to fourfold reductions in RPS19 mRNA expression in three patients with RPS19 mutations, and p53 protein expression analysis by immunohistochemistry showed variable but significant nuclear staining in the DBA patients. In conclusion, heterozygous mutations in the known DBA genes RPS19, RPS26 and RPS17 were detected in seven out of nine Korean DBA patients. Among these patients, RPS19 was the most frequently mutated gene. In addition, decreased RPS19 mRNA expression and p53 overexpression were observed in the Korean DBA patients, which supports the hypothesis that haploinsufficiency and p53 hyperactivation represent a central pathway underlying the pathogenesis of DBA. | In which syndrome is the RPS19 gene most frequently mutated? | 5a896c26fcd1d6a10c000007_030 | {
"answer_start": [
102
],
"text": [
"DBA"
]
} |
FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. BACKGROUND: The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury. METHODS AND RESULTS: Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts. CONCLUSIONS: During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure. | The drug JTV519 is derivative of which group of chemical compounds? | 54f9b74306d9727f76000004_043 | {
"answer_start": [
370
],
"text": [
"benzothiazepine"
]
} |
Should the annular tendon of the eye be named 'annulus of Zinn' or 'of Valsalva'? The annular tendon is commonly named 'annulus of Zinn', from the German anatomist and botanist Johann Gottfried Zinn (1727-1759) who described this structure in his Descriptio anatomica oculi humani (Anatomical Description of the Human Eye, 1755). This structure, however, had been previously discovered not by Zinn, but by Antonio Maria Valsalva (1666-1723) some decades before the publication of Zinn, in his Dissertatio anatomica prima and Dissertatio anatomica altera (First and Second Anatomical Dissertations), inside Valsalva's Opera omnia published in 1740. We advance that this structure could be re-named such as 'annulus of Valsalva-Zinn' because Valsalva, even making a mistake in its functional interpretation, first described this anatomical structure. Likewise, Valsalva, with his discovery, advanced a revolutionary idea for that time on the usefulness of anatomy for clinic and pathology. | Where can you find the annulus of Zinn? | 58917c88621ea6ff7e00000a_013 | {
"answer_start": [
33
],
"text": [
"eye"
]
} |
Identification of recombinant alleles using quantitative real-time PCR implications for Gaucher disease. Pseudogenes, resulting from duplications of functional genes, contribute to the functional complexity of their parental genes. The glucocerebrosidase gene (GBA), located in a gene-rich region on chromosome 1q 21, is mutated in Gaucher disease. The presence of contiguous, highly homologous pseudogenes for both GBA and metaxin 1 at this locus increases the likelihood of DNA rearrangement. We describe a facile method to identify and analyze recombinant alleles in patients with Gaucher disease. Genomic DNA from 20 patients with recombinant GBA alleles and five controls was evaluated to identify DNA rearrangements or copy number variation using six probes specific for either the GBA gene or pseudogene. Quantitative real-time PCR was performed on genomic DNA, and Southern blot analyses using HincII together with sequencing confirmed the real-time results. Both GBA fusions and duplications could be detected. Different sites of crossover were identified, and alleles resulting from gene conversion could be distinguished from reciprocal recombinant alleles. Quantitative real-time PCR is a sensitive and rapid method to detect fusions and duplications in patients with recombinant GBA alleles. This technique is more sensitive, faster, and cheaper than Southern blot analysis, and can be used in diagnostic laboratories, and to detect other recombinant alleles within the genome. | What is the gene mutated in the Gaucher disease? | 532f55fed6d3ac6a34000036_001 | {
"answer_start": [
236
],
"text": [
"glucocerebrosidase"
]
} |
Histone methyltransferase MLL1 regulates MDR1 transcription and chemoresistance. The multidrug resistance 1 gene (MDR1) encodes P-glycoprotein (Pgp), a member of the ATP-binding cassette (ABC) transporter family that confers tumor drug resistance by actively effluxing a number of antitumor agents. We had previously shown that MDR1 transcription is regulated by epigenetic events such as histone acetylation, and had identified the histone acetylase P/CAF and the transcription factor NF-Y as the factors mediating the enzymatic and DNA-anchoring functions, respectively, at the MDR1 promoter. It has also been shown that MDR1 activation is accompanied by increased methylation on lysine 4 of histone H3 (H3K4). In this study, we further investigated histone methylation in MDR1 regulation and function. We show that the mixed lineage leukemia 1 (MLL1) protein, a histone methyltransferase specific for H3K4, is required for MDR1 promoter methylation, as knockdown of MLL1 resulted in a decrease in MDR1 expression. The regulation of MDR1 by MLL1 has functional consequences in that downregulation of MLL1 led to increased retention of the Pgp-specific substrate DIOC(2)(3), as well as increased cellular sensitivity to several Pgp substrates. Regulation of MDR1 by MLL1 was dependent on the CCAAT box within the proximal MDR1 promoter, similar to what we had shown for MDR1 promoter acetylation, and also requires NF-Y. Finally, overexpression of the most prevalent MLL fusion protein, MLL-AF4, led to increased MDR1 expression. This is the first identification of a histone methyltransferase and its leukemogenic rearrangement that regulates expression of an ABC drug transporter, suggesting a new target for circumvention of tumor multidrug resistance. | Which is the histone residue methylated by MLL1? | 533be71dfd9a95ea0d000009_007 | {
"answer_start": [
904
],
"text": [
"H3K4"
]
} |
A New Less Invasive Technique for Multiple-Level Spontaneous Spinal Epidural Hematomas: Wash-and-Go Technique. Aim Spinal epidural hematomas are rare entity in neurosurgery practice. Most of them are spontaneous due to anticoagulant therapy and called spontaneous spinal epidural hematomas (SSEHs). Laminectomy or hemilaminectomy for affected levels is still the first choice in the operative treatment of an SSEH. We describe a new less invasive surgical technique, performing single-level laminectomy and washing with 0.9% sodium chloride through a thin soft catheter for a 12-level thoracic-cervical SSEH in a patient under anticoagulant therapy. Patient and Operative Technique A 55-year-old woman was brought to the emergency department with a rapid onset of pain in her upper back and both legs with weakness of her lower extremities. An urgent magnetic resonance imaging (MRI) of the whole spine showed a SEH. During the operation, after T2 laminectomy, a thin soft catheter was epidurally placed under the T1 lamina and gently pushed forward rostrally. Then continuous saline irrigation was utilized and aspiration made via the catheter to wash out the hematoma. Drainage of blood was observed. The procedure was performed for 15 minutes. Then the catheter was epidurally placed under the T3 lamina, and the procedure for the hematoma in the lower segment was repeated. Decompression of spinal cord and nerve roots was observed. Result Postoperative early MRI of the thoracic-cervical spine showed gross total evacuation of the SEH. Accordingly, the patient's muscle strength improved. Conclusion Although multiple laminectomy or hemilaminectomy for affected levels to evacuate the hematoma and decompress the spinal cord is the main choice of surgical treatment, single-level laminectomy and irrigation plus aspiration via a thin soft catheter can be performed successfully with good results in SSEH. | What drug treatment can cause a spinal epidural hematoma? | 5ab90a79fcf456587200001b_001 | {
"answer_start": [
219
],
"text": [
"anticoagulant therapy"
]
} |
An important role for cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors. Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium's effectiveness on these mice remain unclear. Here, we find that cholecystokinin (Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockΔ19 mice. Selective knockdown of Cck expression via RNA interference in the VTA of wild-type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild-type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective antimanic agent. | Which is the histone residue methylated by MLL1? | 533be71dfd9a95ea0d000009_001 | {
"answer_start": [
982
],
"text": [
"H3K4"
]
} |
Multiple Myeloma Gets Three New Drugs. In the last few weeks, the FDA approved three new therapies for multiple myeloma: ixazomib, the first oral proteasome inhibitor; and daratumumab and elotuzumab, two monoclonal antibodies that target CD38 and SLAMF7, respectively. | What is the target of daratumumab? | 5880aef4c872c95565000001_002 | {
"answer_start": [
238
],
"text": [
"CD38"
]
} |
PU.1 positively regulates GATA-1 expression in mast cells. Coexpression of PU.1 and GATA-1 is required for proper specification of the mast cell lineage; however, in the myeloid and erythroid lineages, PU.1 and GATA-1 are functionally antagonistic. In this study, we report a transcriptional network in which PU.1 positively regulates GATA-1 expression in mast cell development. We isolated a variant mRNA isoform of GATA-1 in murine mast cells that is significantly upregulated during mast cell differentiation. This isoform contains an alternatively spliced first exon (IB) that is distinct from the first exon (IE) incorporated in the major erythroid mRNA transcript. In contrast to erythroid and megakaryocyte cells, in mast cells we show that PU.1 and GATA-2 predominantly occupy potential cis-regulatory elements in the IB exon region in vivo. Using reporter assays, we identify an enhancer flanking the IB exon that is activated by PU.1. Furthermore, we observe that in PU.1(-/-) fetal liver cells, low levels of the IE GATA-1 isoform is expressed, but the variant IB isoform is absent. Reintroduction of PU.1 restores variant IB isoform and upregulates total GATA-1 protein expression, which is concurrent with mast cell differentiation. Our results are consistent with a transcriptional hierarchy in which PU.1, possibly in concert with GATA-2, activates GATA-1 expression in mast cells in a pathway distinct from that seen in the erythroid and megakaryocytic lineages. | Which gene controls the expression of GATA-1 isoforms? | 58e75d483e8b6dc87c000005_002 | {
"answer_start": [
1112
],
"text": [
"PU.1"
]
} |
traseR: an R package for performing trait-associated SNP enrichment analysis in genomic intervals. UNLABELLED: Genome-wide association studies (GWASs) have successfully identified many sequence variants that are significantly associated with common diseases and traits. Tens of thousands of such trait-associated SNPs have already been cataloged, which we believe form a great resource for genomic research. Recent studies have demonstrated that the collection of trait-associated SNPs can be exploited to indicate whether a given genomic interval or intervals are likely to be functionally connected with certain phenotypes or diseases. Despite this importance, currently, there is no ready-to-use computational tool able to connect genomic intervals to phenotypes. Here, we present traseR, an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD. AVAILABILITY AND IMPLEMENTATION: The traseR R package preloaded with up-to-date collection of trait-associated SNPs are freely available in Bioconductor CONTACT: zhaohui.qin@emory.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. | Which R / bioconductor package is used for performing SNP enrichment analysis? | 587e3129c32c812009000002_002 | {
"answer_start": [
784
],
"text": [
"traseR"
]
} |
The glial sodium-calcium exchanger: a new target for nitric oxide-mediated cellular toxicity. The plasma membrane Na(+)/Ca(2+) exchanger (NCX) is a bidirectional ion transporter that couples the translocation of Na(+) in one direction with that of Ca(2+) in the opposite direction. This system contributes to the regulation of intracellular Ca(2+) concentration via the forward mode (Ca(2+) efflux) or the reverse mode (Ca(2+) influx). We have previously demonstrated that the Ca(2+) paradox, an in vitro reperfusion model, causes the sustained activation of the reverse mode of the NCX, the disruption of Ca(2+) homeostasis, and subsequent delayed apoptotic-like death in astrocytes. In addition, we found that the nitric oxide (NO)-cyclic GMP signaling pathway inhibits Ca(2+) paradox-mediated astrocyte apoptosis, while a high concentration of NO induces cytotoxicity. In this way, Ca(2+) and NO may work together in the pathogenesis of several cells in the central nervous system. Concerning the role of NCX in NO cytotoxicity, we have found, using the specific inhibitor of NCX 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), that NCX is involved in NO-induced cytotoxicity in cultured microglia, astrocytes, and neuronal cells. This review summarizes the pathological roles of the NCX as a new target for NO-mediated cellular toxicity, based on our studies on NO-NCX-mediated glial toxicity. | The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger? | 5506c3e38e1671127b00000a_004 | {
"answer_start": [
1079
],
"text": [
"NCX"
]
} |
Disruption of long-distance highly conserved noncoding elements in neurocristopathies. One of the key discoveries of vertebrate genome sequencing projects has been the identification of highly conserved noncoding elements (CNEs). Some characteristics of CNEs include their high frequency in mammalian genomes, their potential regulatory role in gene expression, and their enrichment in gene deserts nearby master developmental genes. The abnormal development of neural crest cells (NCCs) leads to a broad spectrum of congenital malformation(s), termed neurocristopathies, and/or tumor predisposition. Here we review recent findings that disruptions of CNEs, within or at long distance from the coding sequences of key genes involved in NCC development, result in neurocristopathies via the alteration of tissue- or stage-specific long-distance regulation of gene expression. While most studies on human genetic disorders have focused on protein-coding sequences, these examples suggest that investigation of genomic alterations of CNEs will provide a broader understanding of the molecular etiology of both rare and common human congenital malformations. | Which is the process that Conserved noncoding elements mostly regulate? | 51387022bee46bd34c000002_003 | {
"answer_start": [
413
],
"text": [
"development"
]
} |
diffloop: a computational framework for identifying and analyzing differential DNA loops from sequencing data. Summary: The 3D architecture of DNA within the nucleus is a key determinant of interactions between genes, regulatory elements, and transcriptional machinery. As a result, differences in DNA looping structure are associated with variation in gene expression and cell state. To systematically assess changes in DNA looping architecture between samples, we introduce diffloop, an R/Bioconductor package that provides a suite of functions for the quality control, statistical testing, annotation, and visualization of DNA loops. We demonstrate this functionality by detecting differences between ENCODE ChIA-PET samples and relate looping to variability in epigenetic state. Availability and implementation: Diffloop is implemented as an R/Bioconductor package available at https://bioconductor.org/packages/release/bioc/html/diffloop.html. Contact: aryee.martin@mgh.harvard.edu. Supplementary information: Supplementary data are available at Bioinformatics online. | Which package in Bioconductor has been developed with the aim to analyze differential DNA loops from sequencing data? | 5a6e2578b750ff445500003d_002 | {
"answer_start": [
476
],
"text": [
"diffloop"
]
} |
subSeq: determining appropriate sequencing depth through efficient read subsampling. MOTIVATION: Next-generation sequencing experiments, such as RNA-Seq, play an increasingly important role in biological research. One complication is that the power and accuracy of such experiments depend substantially on the number of reads sequenced, so it is important and challenging to determine the optimal read depth for an experiment or to verify whether one has adequate depth in an existing experiment. RESULTS: By randomly sampling lower depths from a sequencing experiment and determining where the saturation of power and accuracy occurs, one can determine what the most useful depth should be for future experiments, and furthermore, confirm whether an existing experiment had sufficient depth to justify its conclusions. We introduce the subSeq R package, which uses a novel efficient approach to perform this subsampling and to calculate informative metrics at each depth. AVAILABILITY AND IMPLEMENTATION: The subSeq R package is available at http://github.com/StoreyLab/subSeq/. | Which method for subsampling of NGS reads requires only gene counts? | 5a39453d966455904c000006_001 | {
"answer_start": [
837
],
"text": [
"subSeq"
]
} |
Dinutuximab: A Review in High-Risk Neuroblastoma. Dinutuximab (ch14.18; Unituxin™) is a chimeric human-mouse monoclonal antibody that binds to the glycolipid antigen disialoganglioside, which is highly expressed on the surface of neuroblastoma cells. This intravenous drug is approved in the EU and USA as combination therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-2 and isotretinoin for the postconsolidation treatment of patients with high-risk neuroblastoma. In a multinational, phase III study in this patient population, event-free survival (EFS) benefits with the dinutuximab-containing regimen versus isotretinoin alone were observed at the time of the primary (p = 0.0115) and confirmatory (p = 0.0330) efficacy analyses, although the observed p-value for the between-group difference in EFS for the primary efficacy analysis did not cross the prespecified boundary for statistical significance (p < 0.0108). Significant and sustained (5 years) overall survival benefits were seen with the dinutuximab-containing regimen versus isotretinoin alone. Despite pretreatment with analgesics, antihistamines and antipyretics, serious adverse reactions have been reported with the dinutuximab-containing regimen, with infusion reactions and neuropathy prompting the US FDA to issue boxed warnings. Dinutuximab administered in combination with GM-CSF, IL-2 and isotretinoin represents an important advance in the postconsolidation treatment of patients with high-risk neuroblastoma, with its benefits outweighing its risks in a patient population with a poor prognosis and limited therapeutic options. | Dinutuximab is used for treatment of which disease? | 589a247078275d0c4a000035_002 | {
"answer_start": [
35
],
"text": [
"Neuroblastoma"
]
} |
Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. OBJECTIVE: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). METHODS: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. RESULTS: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. CONCLUSIONS: Results from this study support continued development of nusinersen for treatment of SMA. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns. | Which disease is treated with Nusinersen? | 589185cc621ea6ff7e00000b_022 | {
"answer_start": [
1623
],
"text": [
"SMA"
]
} |
Gene expression during normal and FSHD myogenesis. BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contraction of an array of tandem 3.3-kb repeats (D4Z4) at 4q35. Within each repeat unit is a gene, DUX4, that can encode a protein containing two homeodomains. A DUX4 transcript derived from the last repeat unit in a contracted array is associated with pathogenesis but it is unclear how. METHODS: Using exon-based microarrays, the expression profiles of myogenic precursor cells were determined. Both undifferentiated myoblasts and myoblasts differentiated to myotubes derived from FSHD patients and controls were studied after immunocytochemical verification of the quality of the cultures. To further our understanding of FSHD and normal myogenesis, the expression profiles obtained were compared to those of 19 non-muscle cell types analyzed by identical methods. RESULTS: Many of the ~17,000 examined genes were differentially expressed (>2-fold, p<0.01) in control myoblasts or myotubes vs. non-muscle cells (2185 and 3006, respectively) or in FSHD vs. control myoblasts or myotubes (295 and 797, respectively). Surprisingly, despite the morphologically normal differentiation of FSHD myoblasts to myotubes, most of the disease-related dysregulation was seen as dampening of normal myogenesis-specific expression changes, including in genes for muscle structure, mitochondrial function, stress responses, and signal transduction. Other classes of genes, including those encoding extracellular matrix or pro-inflammatory proteins, were upregulated in FSHD myogenic cells independent of an inverse myogenesis association. Importantly, the disease-linked DUX4 RNA isoform was detected by RT-PCR in FSHD myoblast and myotube preparations only at extremely low levels. Unique insights into myogenesis-specific gene expression were also obtained. For example, all four Argonaute genes involved in RNA-silencing were significantly upregulated during normal (but not FSHD) myogenesis relative to non-muscle cell types. CONCLUSIONS: DUX4's pathogenic effect in FSHD may occur transiently at or before the stage of myoblast formation to establish a cascade of gene dysregulation. This contrasts with the current emphasis on toxic effects of experimentally upregulated DUX4 expression at the myoblast or myotube stages. Our model could explain why DUX4's inappropriate expression was barely detectable in myoblasts and myotubes but nonetheless linked to FSHD. | Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4? | 550f0e4c6a8cde6b72000003_015 | {
"answer_start": [
2100
],
"text": [
"FSHD"
]
} |
S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation. UNLABELLED: We previously showed that S-adenosylmethionine (SAMe) and its metabolite methylthioadenosine (MTA) blocked lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) expression in RAW (murine macrophage cell line) and Kupffer cells at the transcriptional level without affecting nuclear factor kappa B nuclear binding. However, the exact molecular mechanism or mechanisms of the inhibitory effect were unclear. While SAMe is a methyl donor, MTA is an inhibitor of methylation. SAMe can convert to MTA spontaneously, so the effect of exogenous SAMe may be mediated by MTA. The aim of our current work is to examine whether the mechanism of SAMe and MTA's inhibitory effect on proinflammatory mediators might involve modulation of histone methylation. In RAW cells, we found that LPS induced TNFalpha expression by both transcriptional and posttranscriptional mechanisms. SAMe and MTA treatment inhibited the LPS-induced increase in gene transcription. Using the chromatin immunoprecipitation assay, we found that LPS increased the binding of trimethylated histone 3 lysine 4 (H3K4) to the TNFalpha promoter, and this was completely blocked by either SAMe or MTA pretreatment. Similar effects were observed with LPS-mediated induction of inducible nitric oxide synthase (iNOS). LPS increased the binding of histone methyltransferases Set1 and myeloid/lymphoid leukemia to these promoters, which was unaffected by SAMe or MTA. The effects of MTA in RAW cells were confirmed in vivo in LPS-treated mice. Exogenous SAMe is unstable and converts spontaneously to MTA, which is stable and cell-permeant. Treatment with SAMe doubled intracellular MTA and S-adenosylhomocysteine (SAH) levels. SAH also inhibited H3K4 binding to TNFalpha and iNOS promoters. CONCLUSION: The mechanism of SAMe's pharmacologic inhibitory effect on proinflammatory mediators is mainly mediated by MTA and SAH at the level of histone methylation. | Which is the methyl donor of histone methyltransferases? | 516e7fda298dcd4e51000081_001 | {
"answer_start": [
554
],
"text": [
"SAM"
]
} |
DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent adult muscular dystrophies. The common clinical signs usually appear during the second decade of life but when the first molecular dysregulations occur is still unknown. Our aim was to determine whether molecular dysregulations can be identified during FSHD fetal muscle development. We compared muscle biopsies derived from FSHD1 fetuses and the cells derived from some of these biopsies with biopsies and cells derived from control fetuses. We mainly focus on DUX4 isoform expression because the expression of DUX4 has been confirmed in both FSHD cells and biopsies by several laboratories. We measured DUX4 isoform expression by using qRT-PCR in fetal FSHD1 myotubes treated or not with an shRNA directed against DUX4 mRNA. We also analyzed DUX4 downstream target gene expression in myotubes and fetal or adult FSHD1 and control quadriceps biopsies. We show that both DUX4-FL isoforms are already expressed in FSHD1 myotubes. Interestingly, DUX4-FL expression level is much lower in trapezius than in quadriceps myotubes, which is confirmed by the level of expression of DUX4 downstream genes. We observed that TRIM43 and MBD3L2 are already overexpressed in FSHD1 fetal quadriceps biopsies, at similar levels to those observed in adult FSHD1 quadriceps biopsies. These results indicate that molecular markers of the disease are already expressed during fetal life, thus opening a new field of investigation for mechanisms leading to FSHD. | Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4? | 550f0e4c6a8cde6b72000003_001 | {
"answer_start": [
694
],
"text": [
"FSHD"
]
} |
Antibodies to watch in 2014. Since 2010, mAbs has documented the biopharmaceutical industry's progress in transitioning antibody therapeutics to first Phase 3 clinical studies and regulatory review, and its success at gaining first marketing approvals for antibody-based products. This installment of the "Antibodies to watch" series outlines events anticipated to occur between December 2013 and the end of 2014, including first regulatory actions on marketing applications for vedolizumab, siltuximab, and ramucirumab, as well as the Fc fusion proteins Factor IX-Fc and Factor VIII-Fc; and the submission of first marketing applications for up to five therapeutics (secukinumab, ch14.18, onartuzumab, necitumumab, gevokizumab). Antibody therapeutics in Phase 3 studies are described, with an emphasis on those with study completion dates in 2014, including antibodies targeting interleukin-17a or the interleukin-17a receptor (secukinumab, ixekizumab, brodalumab), proprotein convertase subtilisin/kexin type 9 (alirocumab, evolocumab, bococizumab), and programmed death 1 receptor (lambrolizumab, nivolumab). Five antibodies with US Food and Drug Administration's Breakthrough Therapy designation (obinutuzumab, ofatumumab, lambrolizumab, bimagrumab, daratumumab) are also discussed. | Which enzyme is targeted by Evolocumab? | 54e0d1491388e8454a000014_004 | {
"answer_start": [
967
],
"text": [
"proprotein convertase subtilisin/kexin type 9"
]
} |
Effect of moderate liver impairment on the pharmacokinetics of opicapone. PURPOSE: Opicapone (OPC) is a novel catechol-O-methyltransferase (COMT) inhibitor to be used as adjunctive therapy in levodopa-treated patients with Parkinson's disease. The purpose of this study was to evaluate the effect of moderate liver impairment on the pharmacokinetics (PK) and pharmacodynamics (PD; effect on COMT activity) of OPC. METHODS: An open-label, parallel-group study in patients (n = 8) with moderate liver impairment (Child-Pugh category B, score of 7 to 9) and matched healthy subjects (n = 8, control) with normal liver function. All subjects received a single 50-mg oral dose of OPC, with plasma and urine concentrations of opicapone and its metabolites measured up to 72 h post-dose, including soluble COMT (S-COMT) activity. A one-way analysis of variance (ANOVA) was used to compare the main PK and PD parameters between groups. Point estimates (PE) of geometric mean ratios (GMR) and corresponding 90 % confidence intervals (90%CI) for the ratio hepatic/control subjects of each parameter were calculated and compared with the reference interval (80-125 %). RESULTS: Exposure to opicapone (AUC and Cmax) increased significantly in patients with moderate hepatic impairment (PE [90%CI]: AUC0-∞, 184 % [135-250 %]; Cmax, 189 % [144-249 %]). Although apparent total clearance (CL/F) of opicapone was decreased by ∼35 %, similar elimination half-life and unbound/bound fractions of opicapone were observed between the two groups. Both rate and extent of exposure to BIA 9-1103 were higher in the hepatically impaired group, but not statistically significant compared with the control group. Similar to the parent (opicapone), the observed increase in exposure to BIA 9-1106 was statistically significant in the hepatically impaired group over the control group. BIA 9-1106 was the only metabolite detected in urine and its urine PK parameters were in accordance with plasma data. Maximum S-COMT inhibition (Emax) occurred earlier for the hepatically impaired group with values of 100 % and 91.2 % for the hepatically impaired and control groups respectively. Both Emax and AUEC for the hepatically impaired group reached statistical significance over the control group. OPC was well tolerated in both hepatically impaired and control groups. CONCLUSION: The bioavailability of an orally administered single dose of 50 mg OPC was significantly higher in patients with moderate chronic hepatic impairment, perhaps by a reduced first-pass effect. As the tolerability profile of OPC was favourable under the conditions of this study and its exposure is completely purged from systemic circulation before the subsequent dose administration, no OPC dose adjustment is needed in patients with mild to moderate chronic hepatic impairment. However, as OPC is under clinical development for use as adjunctive therapy in levodopa-treated patients with Parkinson's disease, an adjustment of levodopa and/or OPC regimens in patients should be carefully considered based on a potentially enhanced levodopa dopaminergic response and the associated tolerability. | What enzyme is inhibied by Opicapone? | 56c1d857ef6e394741000033_001 | {
"answer_start": [
110
],
"text": [
"catechol-O-methyltransferase"
]
} |
hCINAP is an atypical mammalian nuclear adenylate kinase with an ATPase motif: structural and functional studies. Human coilin interacting nuclear ATPase protein (hCINAP) directly interacts with coilin, a marker protein of Cajal Bodies (CBs), nuclear organelles involved in the maturation of small nuclear ribonucleoproteins UsnRNPs and snoRNPs. hCINAP has previously been designated as an adenylate kinase (AK6), but is very atypical as it exhibits unusually broad substrate specificity, structural features characteristic of ATPase/GTPase proteins (Walker motifs A and B) and also intrinsic ATPase activity. Despite its intriguing structure, unique properties and cellular localization, the enzymatic mechanism and biological function of hCINAP have remained poorly characterized. Here, we offer the first high-resolution structure of hCINAP in complex with the substrate ADP (and dADP), the structure of hCINAP with a sulfate ion bound at the AMP binding site, and the structure of the ternary complex hCINAP-Mg(2+) ADP-Pi. Induced fit docking calculations are used to predict the structure of the hCINAP-Mg(2+) ATP-AMP ternary complex. Structural analysis suggested a functional role for His79 in the Walker B motif. Kinetic analysis of mutant hCINAP-H79G indicates that His79 affects both AK and ATPase catalytic efficiency and induces homodimer formation. Finally, we show that in vivo expression of hCINAP-H79G in human cells is toxic and drastically deregulates the number and appearance of CBs in the cell nucleus. Our findings suggest that hCINAP may not simply regulate nucleotide homeostasis, but may have broader functionality, including control of CB assembly and disassembly in the nucleus of human cells. | Which protein is the main marker of Cajal bodies? | 58eb9542eda5a57672000007_026 | {
"answer_start": [
195
],
"text": [
"coilin"
]
} |
[Alpha-synucleinopathies]. The term alpha-synucleinopathy is used to name a group of disorders having in common the abnormal deposition of alpha-synuclein in the cytoplasm of neurons or glial cells, as well as in extracellular deposits of amyloid. In Parkinson's disease and Lewy body dementia, alpha-synuclein is the main component of Lewy bodies and dystrophic neurites; alpha-synuclein also accumulates in the cytoplasm of glial cells. In multiple system atrophy, alpha-synuclein conforms the cytoplasmic oligodendroglial inclusions and the neuronal inclusions which are the hallmark of this disease. Finally, the amyloidogenic fragment 61-95 amino acids of alpha-synuclein is the non-Abeta component of senile plaque amyloid in Alzheimer disease. Accumulations of alpha-synuclein in all these disorders have in common a fibrilar configuration, but they differ in the binding of alpha-synuclein to distinct proteins with the exception of ubiquitin whose binding to alpha-synuclein is common to all alpha-synuclein inclusions. The mechanisms leading to alpha-synuclein fragmentation and aggegation into extracellular amyloid are not known, although alpha-synuclein fragment and betaA4 aggregates are the result of abnormal cleavage of large precursors. On the other hand, several studies have shown that alpha-synuclein may adopt a fibrilar conformation and give rise to insoluble forms and high molecular weight aggregates in vitro. Similar complexes have also been observed in alpha-synucleinopathies. Although studies in vitro and in vivo have shown toxic effects of alpha-synuclein, the consequence of alpha-synuclein deposition on cell survival in alpha-synucleinopathies is not known. | What is the main component of the Lewy bodies? | 550c3d45a103b78016000008_018 | {
"answer_start": [
373
],
"text": [
"alpha-synuclein"
]
} |
Aerial dispersal of meticillin-resistant Staphylococcus aureus in hospital rooms by infected or colonised patients. The aim of this study was to assess to what extent patients with meticillin-resistant Staphylococcus aureus (MRSA) at respiratory sites shed viable MRSA into the air of hospital rooms. We also evaluated whether the distance from the patient could influence the level of contamination. Air sampling was performed directly onto MRSA-selective agar in 24 hospital rooms containing patients with MRSA colonization or infection of the respiratory tract. Samplings were performed in duplicate at 0.5, 1 and 2-3 m from the patients' heads. Clinical and environmental isolates were compared using antimicrobial resistance patterns and pulsed-field gel electrophoresis. MRSA strains were isolated from 21 out of 24 rooms, in quantities varying from between 1 and 78 cfu/m3. In each of the 21 rooms, at least one of the environmental isolates was identical to a clinical isolate from the patient in that room. There was no significant difference in MRSA counts between the distance from the patient's head and the sampler. This study demonstrates that most patients with MRSA infection or colonisation of the respiratory tract shed viable MRSA into the air of their room. The results emphasise the need to study MRSA in air in more detail in order to improve infection control recommendations. | What is MRSA? | 58a32efe60087bc10a000013_007 | {
"answer_start": [
264
],
"text": [
"MRSA"
]
} |
Essential roles of Da transactivation domains in neurogenesis and in E(spl)-mediated repression. E proteins are a special class of basic helix-loop-helix (bHLH) proteins that heterodimerize with many bHLH activators to regulate developmental decisions, such as myogenesis and neurogenesis. Daughterless (Da) is the sole E protein in Drosophila and is ubiquitously expressed. We have characterized two transcription activation domains (TADs) in Da, called activation domain 1 (AD1) and loop-helix (LH), and have evaluated their roles in promoting peripheral neurogenesis. In this context, Da heterodimerizes with proneural proteins, such as Scute (Sc), which is dynamically expressed and also contributes a TAD. We found that either one of the Da TADs in the Da/Sc complex is sufficient to promote neurogenesis, whereas the Sc TAD is incapable of doing so. Besides its transcriptional activation role, the Da AD1 domain serves as an interaction platform for E(spl) proteins, bHLH-Orange family repressors which antagonize Da/Sc function. We show that the E(spl) Orange domain is needed for this interaction and strongly contributes to the antiproneural activity of E(spl) proteins. We present a mechanistic model on the interplay of these bHLH factors in the context of neural fate assignment. | What is the role of TAD protein domain? | 58dcb47c8acda34529000020_005 | {
"answer_start": [
401
],
"text": [
"transcription activation domain"
]
} |
Morpholino treatment improves muscle function and pathology of Pitx1 transgenic mice. Paired-like homeodomain transcription factor 1 (PITX1) was proposed to be part of the disease mechanisms of facioscapulohumeral muscular dystrophy (FSHD). We generated a tet-repressible muscle-specific Pitx1 transgenic mouse model which develops phenotypes of muscular dystrophy after the PITX1 expression is induced. In this study, we attempted to block the translation of PITX1 protein using morpholinos. Three groups of the transgenic mice received intravenous injections of phosphorodiamidate morpholino oligomers (PMO) (100 mg/kg), octaguanidinium dendrimer-conjugated morpholino (vivo-morpholino) (10 mg/kg), or phosphate-buffered saline (PBS) after the PITX1 expression was induced. Immunoblotting data showed that PITX1 expression in the triceps and quadriceps was significantly reduced 70% and 63% by the vivo-morpholino treatment, respectively. Muscle pathology of the mice treated with the vivo-morpholino was improved by showing 44% fewer angular-shaped atrophic myofibers. Muscle function determined by grip strength was significantly improved by the vivo-morpholino treatment. The study showed that systemic delivery of the vivo-morpholino reduced the PITX1 expression and improved the muscle phenotypes. Aberrant expression of DUX4 from the last unit of the D4Z4 array has been proposed to be the cause of FSHD. The findings of this study suggest that the same principle may be applied to suppress the aberrantly expressed DUX4 in FSHD. | Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4? | 550f0e4c6a8cde6b72000003_021 | {
"answer_start": [
234
],
"text": [
"FSHD"
]
} |
Evaluation of the Arabic version of STOP-Bang questionnaire as a screening tool for obstructive sleep apnea. PURPOSE: Obstructive sleep apnea (OSA) is a sleep-related breathing disorder that is underdiagnosed. OSA is usually diagnosed by polysomnography (PSG) and, if untreated, could lead to life-threatening complications. Many screening questionnaires have been developed to screen and identify patients at high risk for OSA. This study aimed to evaluate and validate the Arabic version of Stop-Bang questionnaire as a screening tool for patients with OSA symptoms referred to a sleep clinic. METHODS: All referred Arabic-speaking adult patients presenting to a Sleep Disorders Specialized Clinic in Al Ain for PSG were requested to complete an Arabic STOP-Bang questionnaire. A score of 3 or more out of a possible 8 was taken to indicate high risk for presence of OSA. These scores were then evaluated versus results from the overnight, monitored PSG. Apnea/hypopnea index (AHI) of > 5/h was considered for diagnosis of OSA. RESULTS: One hundred ninety-three sleep clinic patients were enrolled in this study. PSG was positive (AHI > 5) in 85 % of the studied population. STOP-Bang questionnaire was positive ( > 3) in 87 % of the population. Reproducibility of STOP-Bang questionnaire was tested, and the intraclass correlation coefficient of the total score of STOP-Bang questionnaire was 0.931 (95 % CI 0.834-0.972). The sensitivities of the STOP-Bang screening tool for an AHI of > 5, > 15, and > 30 were 90, 96.75, and 99.70 %, respectively, with negative predictive values (NPVs) of 36, 84, and 92 %, respectively. ROC curve was 0.77. CONCLUSION: The Arabic version of STOP-Bang questionnaire is an easy-to-use tool that can be implemented as a reliable, quick screening tool for OSA in patients referred to sleep clinic. It demonstrated high sensitivity and NPV especially for patients with moderate to severe OSA. We believe that this tool will help physicians to earlier identify cases at risk of OSA. | Which disease risk can be estimated with the Stop-Bang questionnaire? | 5a742d620384be9551000002_010 | {
"answer_start": [
84
],
"text": [
"obstructive sleep apnea"
]
} |
High frequency oscillations mirror disease activity in patients with focal cortical dysplasia. PURPOSE: The study analyzes the occurrence of high frequency oscillations in different types of focal cortical dysplasia in 22 patients with refractory epilepsy. High frequency oscillations are biomarkers for epileptic tissue, but it is unknown whether they can reflect increasingly dysplastic tissue changes as well as epileptic disease activity. METHODS: High frequency oscillations (80-450 Hz) were visually marked by two independent reviewers in all channels of intracranial implanted grid, strips, and depth electrodes in patients with focal cortical dysplasia and refractory epilepsy. Rates of high frequency oscillations in patients with pathologically confirmed focal cortical dysplasia of Palmini type 1a and b were compared with those in type 2a and b. KEY FINDINGS: Patients with focal cortical dysplasia type 2 had significantly more seizures than those with type 1 (p < 0.001). Rates of high frequency oscillations were significantly higher in patients with focal cortical dysplasia type 2 versus type 1 (p < 0.001). In addition, it could be confirmed that rates of high frequency oscillations were significantly higher in presumed epileptogenic areas than outside (p < 0.001). SIGNIFICANCE: Activity of high frequency oscillations mirrors the higher epileptogenicity of focal cortical dysplasia type 2 lesions compared to type 1 lesions. Therefore, rates of high frequency oscillations can reflect disease activity of a lesion. This has implications for the use of high frequency oscillations as biomarkers for epileptogenic areas, because a detailed analysis of their rates may be necessary to use high frequency oscillations as a predictive tool in epilepsy surgery. | Which disorder is rated by Palmini classification? | 56c1f020ef6e394741000047_024 | {
"answer_start": [
765
],
"text": [
"focal cortical dysplasia"
]
} |
In silico predicted robustness of viroids RNA secondary structures. I. The effect of single mutations. Viroids are plant subviral pathogens whose genomes are constituted by a single-stranded and covalently closed small RNA molecule that does not encode for any protein. Despite this genomic simplicity, they are able of inducing devastating symptoms in susceptible plants. Most of the 29 described viroid species fold into a rodlike or quasi-rodlike structure, whereas a few of them fold as branched structures. The shape of these RNA structures is perhaps one of the most characteristic properties of viroids and sometimes is considered their only phenotype. Here we use RNA thermodynamic secondary structure prediction algorithms to compare the mutational robustness of all viroid species. After characterizing the statistical properties of the distribution of mutational effects on structure stability and the wideness of neutral neighborhood for each viroid species, we show an evolutionary trend toward increased structural robustness during viroid radiation, giving support to the adaptive value of robustness. Differences in robustness among the 2 viroid families can be explained by the larger fragility of branched structures compared with the rodlike ones. We also show that genomic redundancy can contribute to the robustness of these simple RNA genomes. | Which are the smallest known subviral pathogens of plants? | 56e0447a51531f7e3300000b_003 | {
"answer_start": [
103
],
"text": [
"Viroids"
]
} |
New targets, new drugs for metastatic bone pain: a new philosophy. Bone pain is a common symptom in bone metastases. The therapies that are currently available include nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, steroids and gabapentin which have been demonstrated to improve neuropathic pain. In addition, preclinical studies indicate that agents such as transient receptor potential vanilloid 1 antagonists and cannabinoid 2 receptor agonist could be considered as adjuncts in ameliorating opioid side effects. New drugs are in the clinical phase of development, among which the most promising molecules seem to be anti-nerve growth factor (NGF) antibodies. Anti-NGF antibody therapy may be particularly effective in blocking bone cancer pain because NGF appears to be integrally involved in the upregulation, sensitization and disinhibition of multiple neurotransmitters, ion channels and receptors in the primary afferent nerve. The best way to treat bone metastases pain is to improve the control of skeletal disease burden. Recently, denosumab, a noncytotoxic IgG2 monoclonal antibody with high affinity for human RANKL, has been demonstrated to significantly prevent clinically relevant increase in pain compared with zoledronic acid across the tumor types. Based on these data, it has been suggested that denosumab has the potential to become a new standard of treatment in bone metastases management. | To the ligand of which receptors does Denosumab (Prolia) bind? | 52bf1d9e03868f1b06000010_010 | {
"answer_start": [
1132
],
"text": [
"RANKL"
]
} |
Hypermethylation of the CpG dinucleotide in epidermal growth factor receptor codon 790: implications for a mutational hotspot leading to the T790M mutation in non-small-cell lung cancer. Nearly one half of all cases of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small-cell lung cancer (NSCLC) are due to the T790M mutation in EGFR exon 20. The T790M mutation is a C→T transition mutation at a CpG dinucleotide. DNA methylation of cytosine (5-methylcytosine (5-mC)) in CpG dinucleotides is a common DNA modification; CpG dinucleotides are considered to be mutational hotspots that cause genetic diseases and cancers through spontaneous deamination of 5-mC, resulting in C→T transition mutations. This study aimed to examine the methylation level of cytosine of EGFR codon 790 and investigate whether DNA methylation was involved in acquiring the T790M mutation. We examined 18 NSCLC tumor tissues, 7 normal lymph node tissues, and 4 NSCLC cell lines (PC9, HCC827, 11-18, and A549). 5-mC was checked by bisulfite sequencing and quantified by pyrosequencing. We found that all tissue samples and cell lines had 5-mC in EGFR codon 790. The 5-mC range was 58.4-90.8%. Our results imply that hypermethylation of the CpG dinucleotide in EGFR codon 790 leads to the C→T transition mutation, causing resistance to EGFR-TKI treatment. | Which gene harbors the mutation T790M? | 56d1f790f22319765a000001_003 | {
"answer_start": [
242
],
"text": [
"epidermal growth factor receptor"
]
} |
Apixaban: first global approval. Apixaban (Eliquis™), an oral direct factor Xa inhibitor, is being developed by Bristol-Myers Squibb and Pfizer as a therapy for the prevention and/or treatment of thrombotic disorders. Apixaban has been approved in the EU for the prevention of venous thromboembolism (VTE) after hip or knee replacement. A rolling submission for approval of apixaban for the prevention of stroke in patients with atrial fibrillation has also been initiated in the US. Worldwide phase III development of apixaban is underway for the prevention and treatment of VTE, and prevention of stroke in patients with atrial fibrillation. Development for acute coronary syndromes has been stopped following the discontinuation of the phase III APPRAISE-II trial. This article summarizes the milestones in the development of apixaban leading to this first approval for the prevention of VTE after hip or knee replacement. | What is the drug target for Eliquis (Apixaban)? | 5abbe429fcf456587200001c_004 | {
"answer_start": [
69
],
"text": [
"factor Xa"
]
} |
[New therapeutical options for heavy gastrointestinal bleeding]. The number of patients taking new oral anticoagulants is rising, so is the number of serious bleeding events. In severe bleeding, the decision to start a procoagulant therapy is difficult to take. With Idarucizumab and Andexanet Alfa, specific antidotes have been developed against both, direct thrombin inhibitors as well as direct Factor Xa inhibitors. In the endoscopic treatment of severe gastrointestinal bleeding, alternative treatment options are available with Hemospray™, Endoclot™ and new hemostasis clips. Especially in the recurrent ulcer bleeding, the newly developed clips can achieve hemostasis and prevent an operational procedure. | Andexanet Alfa is an antidote of which clotting factor inhibitors? | 5880b073c872c95565000003_048 | {
"answer_start": [
398
],
"text": [
"Factor Xa"
]
} |
Effects of BCR-ABL inhibitors on anti-tumor immunity. In chronic myeloid leukemia (CML), BCR-ABL-mediated oncogenic signaling can be successfully targeted with the BCRABL- inhibitors imatinib, nilotinib, and dasatinib leading to complete cytogenetic (Philadelphia chromosome not detectable upon cytogenetic testing of bone marrow) and even complete molecular (BCR-ABL not detectable by PCR in peripheral blood) responses. However, CML apparently can not be cured by BCR-ABL inhibitors alone, likely due to treatment-resistance of CML stem/progenitor cells, which provokes a relapse of disease after cessation of therapy. Evidence from patients treated with allogenic stem cell transplantation or IFN-α points to an important role of anti-tumor immunity for durable control of CML disease. Data from multiple in vitro and ex vivo studies indicate that BCR-ABL inhibitors may also influence anti-tumor immunity. Varying effects on different immune effector cell subsets and of the different compounds have been reported, the latter being due to their particular and diverse potency and spectrum of target kinases. As multiple approaches presently aim to combine BCR-ABL inhibition with immunotherapeutic strategies to improve disease control in CML, immunomodulatory effects of the available BCR-ABL inhibitors may be of direct clinical relevance. Here we review the available data regarding the effects of imatinib, nilotinib, and dasatinib on dendritic cells, T cells and natural killer cells as important cellular components of anti-tumor immunity. | What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)? | 5324a8ac9b2d7acc7e000018_021 | {
"answer_start": [
89
],
"text": [
"BCR-ABL"
]
} |
Development of an early biomarker for the ovarian liability of selective estrogen receptor modulators in rats. Selective estrogen receptor modulators (SERMs) have the potential to treat estrogen sensitive diseases such as uterine leiomyoma and endometriosis, which are prevalent in reproductive age women. However, SERMs also increase the risk of developing ovarian cysts in this population, a phenomenon that is not seen in postmenopausal women. It is believed that current SERMs partially block estradiol's ability to downregulate gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus thereby interfering with estradiol's negative feedback, leading to increased ovarian stimulation by gonadotropins, and cyst formation. It has been postulated that a SERM with poor brain exposure would have less negative effect on the HPO axis, therefore reducing the risk of developing ovarian cysts. In order to test this hypothesis, we identified an early marker of SERM-dependent ovarian effects: upregulation of Cyp17a1 mRNA. SERMs known to cause ovarian cysts upregulate Cyp17a1 after only 4 days of dosing and suppression of the HPO axis prevented this regulation, indicating that ovarian expression of Cyp17a1 was secondary to SERM's effect on the brain. We then characterized three SERMs with similar binding affinity and antagonist effects on the uterus for their relative brain/plasma exposure and ovarian effects. We found that the degree of brain exposure correlated very well with Cyp17a1 expression. | What is a SERM? | 5a74e9ad0384be955100000a_010 | {
"answer_start": [
111
],
"text": [
"Selective estrogen receptor modulator"
]
} |
A new procedure for extraction of collagen from modern and archaeological bones for 14C dating. Bones are potentially the best age indicators in a stratigraphic study, because they are closely related to the layer in which they are found. Collagen is the most suitable fraction and is the material normally used in radiocarbon dating. Bone contaminants can strongly alter the carbon isotopic fraction values of the samples, so chemical pretreatment for (14)C dating by accelerator mass spectrometry (AMS) is essential. The most widespread method for collagen extraction is based on the Longin procedure, which consists in HCl demineralization to dissolve the inorganic phase of the samples, followed by dissolution of collagen in a weak acid solution. In this work the possible side effects of this procedure on a modern bone are presented; the extracted collagen was analyzed by ATR-IR spectroscopy. An alternative procedure, based on use of HF instead of HCl, to minimize unwanted degradation of the organic fraction, is also given. A study by ATR-IR spectroscopic analysis of collagen collected after different demineralization times and with different acid volumes, and a study of an archaeological sample, are also presented. | Which bone protein is used in archaelogy for dating and species identification? | 55054f8af73303d458000002_010 | {
"answer_start": [
239
],
"text": [
"Collagen"
]
} |
APOBEC3B and AID have similar nuclear import mechanisms. Members of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) protein family catalyze DNA cytosine deamination and underpin a variety of immune defenses. For instance, several family members, including APOBEC3B (A3B), elicit strong retrotransposon and retrovirus restriction activities. However, unlike the other proteins, A3B is the only family member with steady-state nuclear localization. Here, we show that A3B nuclear import is an active process requiring at least one amino acid (Val54) within an N-terminal motif analogous to the nuclear localization determinant of the antibody gene diversification enzyme AID (activation-induced cytosine deaminase). Mechanistic conservation with AID is further suggested by A3B's capacity to interact with the same subset of importin proteins. Despite these mechanistic similarities, enforced A3B expression cannot substitute for AID-dependent antibody gene diversification by class switch recombination. Regulatory differences between A3B and AID are also visible during cell cycle progression. Our studies suggest that the present-day A3B enzyme retained the nuclear import mechanism of an ancestral AID protein during the expansion of the APOBEC3 locus in primates. Our studies also highlight the likelihood that, after nuclear import, specialized mechanisms exist to guide these enzymes to their respective physiological substrates and prevent gratuitous chromosomal DNA damage. | Is APOBEC3B protein predominantly cytoplasmic or nuclear? | 54e0ace81388e8454a000010_002 | {
"answer_start": [
499
],
"text": [
" nuclear"
]
} |
[Familial isolated pituitary adenoma syndrome]. Familial pituitary adenomas occur in multiple endocrine neoplasia type 1, Carney complex, as well as in familial isolated pituitary adenoma syndrome. Familial isolated pituitary adenoma syndrome is an autosomal dominant disease with incomplete penetrance. Pituitary adenomas occur in familial setting but without any other specific tumors. In 20-40% of families with this syndrome, mutations have been identified in the aryl hydrocarbon receptor interacting protein gene while in the rest of the families the causative gene or genes have not been identified. Families carrying aryl hydrocarbon receptor interacting protein gene mutations have a distinct phenotype with younger age at diagnosis and a predominance of somatotroph and lactotroph adenomas. Germline mutations of the aryl hydrocarbon receptor interacting protein gene can be occasionally identified in usually young-onset seemingly sporadic cases. Genetic and clinical testing of relatives of patients with aryl hydrocarbon receptor interacting protein gene mutations can lead to earlier diagnosis and treatment at an earlier stage of the pituitary tumor. | Mutation of which gene is implicated in the familial isolated pituitary adenoma? | 551c23bc6b348bb82c00000b_005 | {
"answer_start": [
468
],
"text": [
"aryl hydrocarbon receptor interacting protein"
]
} |
RNA editing in P transposable element read-through transcripts in Drosophila melanogaster. RNA editing is proposed as a modulator of transcriptomes, but its biological impact has not been fully elucidated. In particular, its importance for transposable elements is controversial. We found RNA editing on antisense read-through transcripts of KP elements, one of the deletion derivatives of P transposable elements in Drosophila melanogaster. Three kinds of RNA editing were detected at 20 sites around the terminal inverted repeats (TIR); 15 A-to-G, four U-to-C, and one C-to-U conversions. A-to-G conversions are suggested to be attributed to A-to-I RNA editing on KP element RNAs, because inosine (I) in RNA is recognized as G by reverse transcriptase. TIRs were deduced to form dsRNAs as a putative target of ADAR. This is the first report of RNA editing on mobile elements of Drosophila. | Which is the major RNA editing enzyme in Drosophila melanogaster? | 58e9e7aa3e8b6dc87c00000d_002 | {
"answer_start": [
812
],
"text": [
"ADAR"
]
} |
The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team. | ROSIER scale is used for which disorder? | 551fd9c06b348bb82c000012_028 | {
"answer_start": [
2234
],
"text": [
"stroke"
]
} |
The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema. Hereditary angioedema (HAE) manifests as intermittent, painful attacks of submucosal oedema affecting the larynx, gastrointestinal tract or limbs. Currently, acute treatment is available in Europe but not USA, and requires intravenous administration of a pooled blood product. HAE is most likely caused by dysinhibition of the contact cascade, resulting in overproduction of bradykinin. DX-88 (ecallantide, Dyax Corp.) is a highly specific recombinant plasma kallikrein inhibitor that halts the production of bradykinin and can be dosed subcutaneously. In a placebo-controlled Phase II trial in patients with HAE, DX-88 resulted in significant improvement in symptoms compared with placebo. A Phase III trial is ongoing. This review explains the pathophysiology of HAE and the mechanism by which DX-88, a non-intravenous, nonplasma-derived therapy, might improve the disease, and discusses the clinical course of HAE and available treatments. Finally, it explores the potential value and efficacy of DX-88 in treating HAE. | DX-88 is investigational name of which drug? | 54f1e031c409818c32000001_009 | {
"answer_start": [
482
],
"text": [
"ecallantide"
]
} |
Breakpoint characterization of a novel NF1 multiexonic deletion: a case showing expression of the mutated allele. Neurofibromatosis type 1 (NF1) is a common genetic disease caused by haploinsufficiency of the NF1 tumor-suppressor gene. Different pathogenetic mechanisms have been identified, with the majority (95%) causing intragenic lesions. Single or multiexon NF1 copy number changes occur in about 2% of patients, but little is known about the molecular mechanisms behind these intragenic deletions. We report here on the molecular characterization of a novel NF1 multiexonic deletion. The application of a multidisciplinary approach including multiplex ligation-dependent probe amplification, allelic segregation analysis, and fluorescent in situ hybridization allowed us to map the breakpoints in IVS27b and IVS48. Furthermore, the breakpoint junction was characterized by sequencing. Using bioinformatic analysis, we identified some recombinogenic motifs in close proximity to the centromeric and telomeric breakpoints and predicted the presence of a mutated messenger ribonucleic acid, which was deleted between exons 28 and 48 and encodes a neurofibromin that lacks some domains essential for its function. Through reverse transcriptase-polymerase chain reaction, the expression of the mutated allele was verified, showing the junction between exons 27b and 49 and, as expected, was not subjected to nonsense-mediated decay. Multiexonic deletions represent 2% of NF1 mutations, and until now, the breakpoint has been identified in only a few cases. The fine characterization of multiexonic deletions broadens the mutational repertoire of the NF1 gene, allowing for the identification of different pathogenetic mechanisms causing NF1. | Which is the gene mutated in type 1 neurofibromatosis? | 5343fc1aaeec6fbd07000003_008 | {
"answer_start": [
209
],
"text": [
"NF1"
]
} |
LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations. In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource (larva.gersteinlab.org). | Which tool is used for the identification of recurrent variants in noncoding regions? | 589635dd78275d0c4a000009_005 | {
"answer_start": [
1293
],
"text": [
"LARVA"
]
} |
Stabilities of folding of clustered, two-repeat fragments of spectrin reveal a potential hinge in the human erythroid spectrin tetramer. The large size of spectrin, the flexible protein promoting reversible deformation of red cells, has been an obstacle to elucidating the molecular mechanism of its function. By studying cloned fragments of the repeating unit domain, we have found a correspondence between positions of selected spectrin repeats in a tetramer with their stabilities of folding. Six fragments consisting of two spectrin repeats were selected for study primarily on the basis of the predicted secondary structures of their linker regions. Fragments with a putatively helical linker were more stable to urea- and heat-induced unfolding than those with a putatively nonhelical linker. Two of the less stably folded fragments, human erythroid alpha-spectrin repeats 13 and 14 (HEalpha13,14) and human erythroid beta-spectrin repeats 8 and 9 (HEbeta8,9), are located opposite each other on antiparallel spectrin dimers. At least partial unfolding of these repeats under physiological conditions indicates that they may serve as a hinge. Also less stably folded, the fragment of human erythroid alpha-spectrin repeats 4 and 5 (HEalpha4,5) lies opposite the site of interaction between the partial repeats at the C- and N-terminal ends of beta- and alpha-spectrin, respectively, on the opposing dimer. More stably folded fragments, human erythroid alpha-spectrin repeats 1 and 2 (HEalpha1,2) and human erythroid alpha-spectrin repeats 2 and 3 (HEalpha2,3), lie nearly opposite each other on antiparallel spectrin dimers of a tetramer. These clusterings along the spectrin tetramer of repeats with similar stabilities of folding may have relevance for spectrin function, particularly for its well known flexibility. | Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers? | 5540b9800083d1bf0e000002_003 | {
"answer_start": [
1002
],
"text": [
"antiparallel"
]
} |
Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. BACKGROUND: The "long/short"polymorphism (5HTTLPR) in the promoter of the serotonin transporter gene (SLC6A4) has been proposed as a pharmacogenetic marker for antidepressant efficacy. Some but not all studies have found that the short form of 5HTTLPR (S allele) results in decreased efficacy of selective serotonin reuptake inhibitors. OBJECTIVE: To determine if the 5HTTLPR polymorphism influences the efficacy and tolerability of mirtazapine and paroxetine hydrochloride, 2 frequently prescribed antidepressants with differing pharmacologic profiles, in geriatric depression. DESIGN: Double-blind, randomized 8-week study. SETTING: Eighteen academic and private outpatient clinics. PATIENTS: We evaluated 246 cognitively intact patients 65 years or older with major depression. INTERVENTIONS: Antidepressant therapy with 15 to 45 mg/d of mirtazapine (n = 124) or 20 to 40 mg/d of paroxetine (n = 122). MAIN OUTCOME MEASURES: The Hamilton Depression Rating Scale-17 and Geriatric Depression Scale, severity of adverse events and dosing compliance indexes, and discontinuations due to adverse events. Outcome measures were stratified according to 5HTTLPR genotypes. RESULTS: Geriatric Depression Scale scores indicated that S allele carriers treated with paroxetine showed a small impairment in antidepressant response. Among mirtazapine-treated patients, there was little indication that the 5HTTLPR genotype affected antidepressant efficacy. However, the 5HTTLPR polymorphism had a dramatic effect on adverse events. Among paroxetine-treated subjects, S allele carriers experienced more severe adverse events during the course of the study, achieved significantly lower final daily doses, and had more discontinuations at days 14, 21, 28, 42, and 49. Surprisingly, among mirtazapine-treated subjects, S allele carriers had fewer discontinuations due to adverse events, experienced less severe adverse events, and achieved higher final daily doses. CONCLUSIONS: These results support the hypothesis that the S allele of 5HTTLPR at the SLC6A4 locus is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors. However, the major effect was on the tolerability of these drugs rather than efficacy. Results from mirtazapine-treated patients indicate that the effect of this polymorphism on outcome may depend on the mechanism of antidepressant action. | What disease is mirtazapine predominantly used for? | 5156be17d24251bc05000086_001 | {
"answer_start": [
916
],
"text": [
"major depression"
]
} |
Idarucizumab Improves Outcome in Murine Brain Hemorrhage Related to Dabigatran. Lack of specific antidotes is a major concern in intracerebral hemorrhage (ICH) related to direct anticoagulants including dabigatran (OAC-ICH). We examined the efficacy of idarucizumab, an antibody fragment binding to dabigatran, in a mouse model of OAC-ICH. Dabigatran etexilate (DE) dose-dependently prolonged diluted thrombin time and tail-vein bleeding time, which were reversed by idarucizumab. Pretreatment with DE increased intracerebral hematoma volume and cerebral hemoglobin content. Idarucizumab in equimolar dose prevented excess hematoma expansion for both DE doses. In more extensive ICH, idarucizumab significantly reduced mortality. Thus, idarucizumab prevents excess intracerebral hematoma formation in mice anticoagulated with dabigatran and reduces mortality. | Idarucizumab is an antidote of which drug? | 56c079b1ef6e394741000022_003 | {
"answer_start": [
340
],
"text": [
"Dabigatran"
]
} |
Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24-40. Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, an autosomal dominant disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular system. There is a remarkable degree of clinical variability both within and between families with Marfan syndrome as well as in individuals with related disorders of connective tissue caused by FBN1 mutations and collectively termed type-1 fibrillinopathies. The so-called neonatal region in FBN1 exons 24-32 comprises one of the few generally accepted genotype-phenotype correlations described to date. In this work, we report 12 FBN1 mutations identified by temperature-gradient gel electrophoresis screening of exons 24-40 in 127 individuals with Marfan syndrome or related disorders. The data reported here, together with other published reports, document a significant clustering of mutations in exons 24-32. Although all reported mutations associated with neonatal Marfan syndrome and the majority of point mutations associated with atypically severe presentations have been found in exons 24-32, mutations associated with classic Marfan syndrome occur in this region as well. It is not possible to predict whether a given mutation in exons 24-32 will be associated with classic, atypically severe, or neonatal Marfan syndrome. | Which gene mutations cause the Marfan syndrome? | 58d8e6818acda3452900000a_035 | {
"answer_start": [
170
],
"text": [
"FBN1"
]
} |
Clinical and genetic studies in a Chinese family with giant axonal neuropathy. The objective of the study was to investigate a girl with giant axonal neuropathy and detect the mutation of GAN gene in her family. The encoding exons of GAN gene were amplified from genomic DNA of the proband and her parents by polymerase chain reaction and directly sequenced after purification. The proband manifested typical neurological symptoms and pathological abnormalities. The case had 2 heterozygous missense mutations in GAN gene: 1. c. 224 T>A in exon 2, her mother was a heterozygote of this mutation and had normal phenotype; 2. c.1634G>A in exon 10, and her father was a heterozygote of this mutation and had normal phenotype. Both of the mutations caused amino acid changes in the gigaxonin protein. In this family, missense mutation of c.224 T>A and missense mutation of c.1634G>A in GAN gene caused the phenotype of giant axonal neuropathy in the proband. Her parents are heterozygotes of the disease without symptoms. | Which gene is involved in Giant Axonal Neuropathy? | 572096c90fd6f91b6800000e_007 | {
"answer_start": [
882
],
"text": [
"GAN gene"
]
} |
Perisigmoid Abscess Leading to a Diagnosis of Ehlers-Danlos Syndrome Type IV. The Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders characterized by triad of joint hypermobility, skin extensibility, and tissue fragility. Ehlers-Danlos syndrome type IV places patients at risk for life-threatening, spontaneous, vascular or visceral rupture due to reduced or abnormal secretion of type III collagen. We present an adolescent male who was found to have a perisigmoid abscess with a fistula connecting to adjacent sigmoid colon secondary to undiagnosed EDS type IV. Conservative management with antibiotics and bowel rest was pursued to allow for elective resection for his acute complicated diverticulitis at a safer time. | What tissue is most affected in Ehlers-Danlos syndromes? | 58cdb41302b8c60953000042_001 | {
"answer_start": [
127
],
"text": [
"connective tissue"
]
} |
Spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome. BACKGROUND: Sotos syndrome is an overgrowth syndrome with characteristic facial gestalt and mental retardation of variable severity. Haploinsufficiency of the NSD1 gene has been implicated as the major cause of Sotos syndrome, with a predominance of microdeletions reported in Japanese patients. This study was conducted to investigate into the spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome. METHODS: Thirty-six Chinese patients with Sotos syndrome and two patients with Weaver syndrome were subject to molecular testing. RESULTS: NSD1 gene mutations were detected in 26 (72%) Sotos patients. Microdeletion was found in only 3 patients, while the other 23 had point mutations (6 frameshift, 8 nonsense, 2 spice site, and 7 missense). Of these, 19 mutations were never reported. NSD1 gene mutations were not found in the two patients with Weaver syndrome. CONCLUSIONS: Most cases of Sotos syndrome are caused by NSD1 gene defects, but the spectrum of mutations is different from that of Japanese patients. Genotype-phenotype correlation showed that patients with microdeletions might be more prone to congenital heart disease but less likely to have somatic overgrowth. The two patients with Weaver syndrome were not found to have NSD1 gene mutations, but the number was too small for any conclusion to be drawn. | Which gene is responsible for the development of Sotos syndrome? | 571f33bd0fd6f91b68000003_010 | {
"answer_start": [
241
],
"text": [
"NSD1 gene"
]
} |
Chromosomal mobilization and reintegration of Sleeping Beauty and PiggyBac transposons. The Sleeping Beauty and PiggyBac DNA transposon systems have recently been developed as tools for insertional mutagenesis. We have compared the chromosomal mobilization efficiency and insertion site preference of the two transposons mobilized from the same donor site in mouse embryonic stem (ES) cells under conditions in which there were no selective constraints on the transposons' insertion sites. Compared with Sleeping Beauty, PiggyBac exhibits higher transposition efficiencies, no evidence for local hopping and a significant bias toward reintegration in intragenic regions, which demonstrate its utility for insertional mutagenesis. Although Sleeping Beauty had no detectable genomic bias with respect to insertions in genes or intergenic regions, both Sleeping Beauty and PiggyBac transposons displayed preferential integration into actively transcribed loci. | Do the Sleeping Beauty or the piggyBac transposons have higher transposition efficiency? | 56c4d14ab04e159d0e000003_005 | {
"answer_start": [
521
],
"text": [
"PiggyBac"
]
} |
Dextromethorphan poisoning: an evidence-based consensus guideline for out-of-hospital management. The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial out-of-hospital management of patients with a suspected ingestion of dextromethorphan by 1) describing the process by which an ingestion of dextromethorphan might be managed, 2) identifying the key decision elements in managing cases of dextromethorphan ingestion, 3) providing clear and practical recommendations that reflect the current state of knowledge, and 4) identifying needs for research. This guideline applies to the ingestion of dextromethorphan alone. Co-ingestion of additional substances could require different referral and management recommendations depending on the combined toxicities of the substances. This guideline is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions might be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. This guideline does not substitute for clinical judgment. The grade of recommendation is in parentheses. 1) All patients with suicidal intent, intentional abuse, or in cases in which a malicious intent is suspected (e.g., child abuse or neglect) should be referred to an emergency department (Grade D). 2) Patients who exhibit more than mild effects (e.g., infrequent vomiting or somnolence [lightly sedated and arousable with speaking voice or light touch]) after an acute dextromethorphan ingestion should be referred to an emergency department (Grade C). 3) Patients who have ingested 5-7.5 mg/kg should receive poison center-initiated follow-up approximately every 2 hours for up to 4 hours after ingestion. Refer to an emergency department if more than mild symptoms develop (Grade D). 4) Patients who have ingested more than 7.5 mg/kg should be referred to an emergency department for evaluation (Grade C). 5) If the patient is taking other medications likely to interact with dextromethorphan and cause serotonin syndrome, such as monoamine oxidase inhibitors or selective serotonin reuptake inhibitors, poison center-initiated follow-up every 2 hours for 8 hours is recommended (Grade D). 6) Patients who are asymptomatic and more than 4 hours have elapsed since the time of ingestion can be observed at home (Grade C). 7) Do not induce emesis (Grade D). 8) Do not use activated charcoal at home. Activated charcoal can be administered to asymptomatic patients who have ingested overdoses of dextromethorphan within the preceding hour. Its administration, if available, should only be carried out by health professionals and only if no contraindications are present. Do not delay transportation in order to administer activated charcoal (Grade D). 9) For patients who have ingested dextromethorphan and are sedated or comatose, naloxone, in the usual doses for treatment of opioid overdose, can be considered for prehospital administration, particularly if the patient has respiratory depression (Grade C). 10) Use intravenous benzodiazepines for seizures and benzodiazepines and external cooling measures for hyperthermia (>104 degrees F, >40 degrees C) for serotonin syndrome. This should be done in consultation with and authorized by EMS medical direction, by a written treatment protocol or policy, or with direct medical oversight (Grade C). 11) Carefully ascertain by history whether other drugs, such as acetaminophen, were involved in the incident and assess the risk for toxicity or for a drug interaction. | Which medication should be administered when managing patients with suspected acute opioid overdose? | 5149f494d24251bc0500004c_003 | {
"answer_start": [
3016
],
"text": [
"naloxone"
]
} |
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