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Do R-loops tend to form at sites of DNA replication?
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['Escherichia coli rnhA mutants devoid of RNase HI exhibit constitutive stable DNA replication, cSDR, which is thought to be initiated from R-loops stabilized in the absence of RNase HI.', 'We propose that the organized structure of the R-loop is critical for primer RNA function in vivo with important implications for the RNA processing and DNA replication machinery.', 'The precursor primer RNA exists as a persistent RNA-DNA hybrid, known as an R-loop, formed during transcription through the replication origin (Xu, B., and Clayton, D. A. (1996) EMBO J. 15, 3135-3143).', 'We found that overproduction of RecG protein drastically decreased copy numbers of ColE1-type plasmids, which require R-loop formation between the template DNA and a primer RNA transcript (RNA II) for the initiation of replication.', 'These results suggest that overproduced RecG inhibits the initiation of replication by prematurely resolving the R-loops formed at the replication origin region of these plasmids with its unique helicase activity. The possibility that RecG regulates the initiation of a unique mode of DNA replication, oriC-independent constitutive stable DNA replication, by its activity in resolving R-loops is discussed.', 'We propose that downstream of a replication block, RNA at R-loops is extended by DNA polymerase I, opening up the DNA duplex and leading to the recruitment of the replisome. This would allow replication to proceed while the original block is repaired or bypassed', 'Furthermore, increased RNaseH expression significantly alleviated genomic instability in deficient fibroblasts suggesting that cotranscriptional R-loops formation contributes to the genesis of replication-dependent DSBs in these cells.', 'Transcription is an important source of replicative stress and consequently, maintenance of genome integrity requires the protection of chromosomes from the deleterious effects arising from the interaction between nascent RNAs and template DNA, leading to stable DNA-RNA hybrids (R-loop) formation.', 'Strikingly, we found that attenuation of replication strongly suppresses R-loop-mediated DNA rearrangements in both E. coli and HeLa cells.', 'More importantly, we then show that R-loop formation causes DNA replication fork stalling, and that this in fact underlies the effects of R loops on genomic stabilit', 'R-loop-mediated genomic instability is caused by impairment of replication fork progression', 'When any of these processes are not properly coordinated, aberrant outcomes such as fork reversal and R-loop formation arise and trigger unscheduled recombinogenic events and genome rearrangements. ', 'Many studies show that cells can manage R loop formation with efficiency, and can also process the R-loops already formed in the cell, and by which, the bad effects of R-loops on DNA replication, gene mutation and homologous recombination can be regulated.', 'Here we propose that physiological R-loop formation at CpG island promoters can contribute to DNA replication origin specification at these regions, the most efficient replication initiation sites in mammalian cells. ', 'In agreement with this, we found that R-loops co-localize with the ORC within the same CpG island region in a significant fraction of these efficient replication origins, precisely at the position displaying the highest density of G4 motifs. ', 'connection between transcription and replication in human cells and suggests that R-loop dysregulation at CpG island promoter-origins might contribute to the phenotype of DNA replication abnormalities and loss of genome integrity detected in cancer cells.', 'We show that RNA:DNA hybrids (R-loops) form at sites of transcription/replication collisions and that RNase H1 functions to suppress CFS instability.', 'R-loops and initiation of DNA replication in human cells: a missing link?', 'Stable RNA-DNA hybrids (R-loops) prime the initiation of replication in Escherichia coli cells.', 'We propose that downstream of a replication block, RNA at R-loops is extended by DNA polymerase I, opening up the DNA duplex and leading to the recruitment of the replisome.', 'Immediately after infection, RNA-DNA hybrids (R-loops) occur on (at least some) replication origins, with the annealed RNA serving as a primer for leading-strand synthesis in one direction.', 'Here we propose that physiological R-loop formation at CpG island promoters can contribute to DNA replication origin specification at these regions, the most efficient replication initiation sites in mammalian cells.', 'ColE1 plasmid origins of replication and oriK sites initiate primosome assembly by an RNA-DNA hybrid structure known as R-loop.', 'This scenario builds on the connection between transcription and replication in human cells and suggests that R-loop dysregulation at CpG island promoter-origins might contribute to the phenotype of DNA replication abnormalities and loss of genome integrity detected in cancer cells.', 'The multiple cleavage sites on the R-loop substrate match the priming sites observed in vivo, suggesting that RNase MRP alone is capable of generating virtually all of the leading-strand replication primers.', 'Mechanisms of primer RNA synthesis and D-loop/R-loop-dependent DNA replication in Escherichia coli.', 'Alternative oriC-independent modes of replication initiation are possible, one of which is constitutive stable DNA replication (cSDR) from transcription-associated RNA-DNA hybrids or R-loops.', 'Our results suggest that Top1 execute this function by suppressing the formation of DNA-RNA hybrids during transcription, these so-called R-loops interfering with the progression of replication forks.', 'Critical role of R-loops in processing replication blocks.', 'The possibility that RecG regulates the initiation of a unique mode of DNA replication, oriC-independent constitutive stable DNA replication, by its activity in resolving R-loops is discussed.', 'Competition between the RNA transcript and the nontemplate DNA strand during R-loop formation in vitro: a nick can serve as a strong R-loop initiation site.', 'More importantly, we then show that R-loop formation causes DNA replication fork stalling, and that this in fact underlies the effects of R loops on genomic stability. ', "Consistent with this hypothesis, the 3' ends of the mitochondrial R-loop formed by in vitro transcription are located close to the initiation sites of the mitochondrial DNA replication. ", 'A hybrid G-quadruplex structure formed between RNA and DNA explains the extraordinary stability of the mitochondrial R-loop.', 'Previous studies have shown that the newly synthesized primers form a stable and persistent RNA-DNA hybrid, a R-loop, near the leading-strand origin of DNA replication. ', 'Escherichia coli rnhA mutants devoid of RNase HI exhibit constitutive stable DNA replication, cSDR, which is thought to be initiated from R-loops stabilized in the absence of RNase HI. ']
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['R-loops co-localize with the ORC within the same CpG island region in a significant fraction of these efficient replication origins. Physiological R-loop formation at CpG island promoters can contribute to DNA replication origin specification at these regions, the most efficient replication initiation sites in mammalian cells. One mechanism may be that downstream of a replication block, RNA at R-loops is extended by DNA polymerase I, opening up the DNA duplex and leading to the recruitment of the replisome. This would allow replication to proceed while the original block is repaired or bypassed. Thus, the organized structure of the R-loop is critical for primer RNA function in vivo with important implications for the RNA processing and DNA replication machinery.', 'We found that overproduction of RecG protein drastically decreased copy numbers of ColE1-type plasmids, which require R-loop formation between the template DNA and a primer RNA transcript (RNA II) for the initiation of replication. ColE1 plasmid origins of replication and oriK sites initiate primosome assembly by an RNA-DNA hybrid structure known as R-loop. We propose that downstream of a replication block, RNA at R-loops is extended by DNA polymerase I, opening up the DNA duplex and leading to the recruitment of the replisome. We review evidence suggesting that R-loops are frequent during normal cell growth and that R-loops are critical for the maintenance of genome integrity.']
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['yes']
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List functional roles of the FtsZ protein.
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['bacterial homologue FtsZ establishes the cytokinetic ring that constricts during cell division. ', 'In Escherichia coli, initial assembly of the Z ring for cell division requires FtsZ plus the essential Z ring-associated proteins FtsA and ZipA.', 'FtsZ is an essential cell division protein in Escherichia coli, and its localization, filamentation, and bundling at the mid-cell are required for Z-ring stability.', 'the bacterial division FtsZ protein', 'The GTPase-dependent polymerization/depolymerization dynamics of FtsZ regulate bacterial cell division in vivo. ', 'Bacterial cytokinesis depends upon the tubulin-like GTPase FtsZ, which polymerizes into an annular structure at midcell (the Z-ring) that defines the division site.', 'FtsZ is the first of the divisome proteins to accumulate at the division site and is widely thought to function as a force generator that constricts the cell envelope. ', 'the cell division protein FtsZ', 'FtsZ, the key protein of bacterial cell division was selected as a potent anti bacterial target. ', 'the cell-division protein FtsZ', ' FtsZ and PG together function in orchestrating cell division and maintaining cell shape in almost all other bacteria.', ' the tubulin-like protein of the division septum FtsZ', 'FtsZ is a widely distributed major cytoskeletal protein involved in the archaea and bacteria cell division. ', 'Four major roles of FtsZ have been characterized: cell elongation, GTPase, cell division, and bacterial cytoskeleton. ', 'Bacterial cell division involves a complex and dynamic sequence of events whereby polymers of the protein FtsZ assemble at the division plane and rearrange to achieve the goal of contracting the cell membrane at the site of cell division, thus dividing the parent cell into two daughter cells. ', 'the cell division protein FtsZ', 'FtsZ, the homolog of eukaryotic tubulin, is a GTPase that assembles into cytokinetic Z rings essential for cell division in prokaryotic cells']
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['Four major roles of FtsZ have been characterized: cell elongation, GTPase, cell division, and bacterial cytoskeleton.']
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['cell elongation', 'GTPase', 'cell division', 'bacterial cytoskeleton']
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What role do gluten proteins play in the development of celiac disease?
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['["Celiac disease (CD) is a frequent inflammatory intestinal disease, with a genetic background, caused by gliadin-containing food. ", "Celiac disease (CD) is an autoimmune enteropathy initiated and sustained by the ingestion of gluten in genetically susceptible individuals. It is caused by a dysregulated immune response toward both dietary antigens, the gluten proteins of wheat, rye, and barley, and autoantigens, the enzyme tissue transglutaminase (TG2)", "Celiac disease (CD) is an autoimmune gastrointestinal disorder characterized by the presence of anti-transglutaminase 2 (TG2) and anti-gliadin antibodies", "Transglutaminase 2 (TG2) catalyzes cross-linking or deamidation of glutamine residues in peptides and proteins. The in vivo deamidation of gliadin peptides plays an important role in the immunopathogenesis of celiac disease (CD).", "Tissue transglutaminase (TG2) modifies proteins and peptides by transamidation or deamidation of specific glutamine residues. TG2 also has a central role in the pathogenesis of celiac disease. The enzyme is both the target of disease-specific autoantibodies and generates deamidated gliadin peptides recognized by intestinal T cells from patients."]']
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Gluten proteins from wheat, rye, and barley are dietary antigens that trigger a dysregulated immune response in genetically susceptible individuals, leading to the development of celiac disease. The immune response targets both gluten proteins and autoantigens like tissue transglutaminase 2 (TG2), contributing to the autoimmune enteropathy characteristic of the disease.
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[]
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Is skin color affected by variations of the SLC24A5 gene?
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['the alleles of single-nucleotide polymorphisms rs1426654 and rs1834640 (SLC24A5) associated with light skin pigmentation in Eurasian populati', 'Associations between five single nucleotide polymorphisms (SNPs) known to play a role in pigmentation (rs1426654-SLC24A5, rs1042602-TYR, rs16891982-SLC45A2, rs6058017-ASIP, and rs642742-KITLG) and MI measures were tested using standard one-way analysis of variance (ANOVA) within each population.']
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['Yes. The alleles of single-nucleotide polymorphisms rs1426654 and rs1834640 (SLC24A5) are associated with light skin pigmentation in Eurasian population.']
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['yes']
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Which receptors are targeted by suvorexant?
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['Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, 1 (SB-649868), or suvorexant have shown promise for the treatment of insomnias and sleep disorders in several recent clinical trials in volunteers and primary insomnia patients. ', 'Several such compounds have entered into clinical development, including the dual orexin receptor antagonists, suvorexant and almorexant.', ' Suvorexant (MK-4305) is an orexin receptor antagonist being developed for the treatment of insomnia. ', 'Indeed, phase III clinical trials were completed last year of suvorexant, a non-selective (dual) antagonist for orexin receptors, for the treatment of primary insomnia, and demonstrate promising results.', 'METHODS: We evaluated suvorexant, an orexin receptor antagonist, for treating patients with primary insomnia in a randomized, double-blind, placebo-controlled, 2-period (4 weeks per period) crossover polysomnography study.', 'Suvorexant is a dual orexin antagonist currently in Phase III clinical trials for the modulation of sleep and is being developed by Merck.', "Merck's suvorexant (MK-4305) is the first compound of the so-called dual orexin receptor antagonist (DORA) class expected to be submitted for FDA approval, with a new drug application anticipated in 2012. ", 'A concise, enantioselective synthesis of the potent dual orexin inhibitor suvorexant (1) is reported. ', 'Reaction development and mechanistic study of a ruthenium catalyzed intramolecular asymmetric reductive amination en route to the dual Orexin inhibitor Suvorexant (MK-4305).', 'The first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an aliphatic amine has been developed for the synthesis of Suvorexant (MK-4305), a potent dual Orexin antagonist under development for the treatment of sleep disorders. ', 'Suvorexant (MK-4305) is a potent, selective, and orally bioavailable antagonist of OX(1)R and OX(2)R currently under clinical investigation as a novel therapy for insomnia.', 'Suvorexant is a pharmacologically novel dual antagonist of orexin receptors OX1R and OX2R, which has an effect that promotes sleep by reducing arousal and wakefulness.', ' Indeed, phase III clinical trials were completed last year of suvorexant, a non-selective (dual) antagonist for orexin receptors, for the treatment of primary insomnia, and demonstrate promising results.', ' In order to understand the differential contribution of both receptors in regulating sleep/wakefulness states we compared the pharmacological effects of a newly developed OX2R antagonist (2-SORA), Compound 1 m (C1 m), with those of a dual orexin receptor antagonist (DORA), suvorexant, in C57BL/6J mice.', 'Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist.']
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['Suvorexant is a potent, selective, and orally bioavailable antagonist of orexin 1 receptor and orexin 2 receptor currently under clinical investigation as a novel therapy for insomnia.']
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['orexin 1', 'orexin 2']
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Does thyroid hormone regulate calcium transient in the myocardium?
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['3-iodothyronamine (T(1)AM) is a novel endogenous relative of thyroid hormone, able to interact with trace amine-associated receptors, a class of plasma membrane G protein-coupled receptors, and to produce a negative inotropic and chronotropic effect', 'In adult rat cardiomyocytes acute exposure to 20 microM T(1)AM decreased the amplitude and duration of the calcium transient.', 'In normal porcine myocardium T3 had no effect on the extent of isometric force generation but accelerated the time course of force development (p < 0.05) and increased the calcium transient (p < 0.001). After induction of myocardial depression by epinephrine exposure T3 accelerated the intracellular calcium transients and reduced diastolic calcium', 'The experimental data showing increased force amplitudes at unaltered amplitudes of the intracellular calcium transient and an even-reduced calcium time integral provide strong evidence for a sensitization of the contractile apparatus for calcium by triiodothyronine', 'hese results indicate that the thyroid state influences the time course of the calcium transient and are consistent with the abbreviation in the duration of contraction that is observed in the hyperthyroid state.']
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['YES']
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['yes']
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Are thyroid hormone receptor alpha1 mutations implicated in thyroid hormone resistance syndrome?
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['This study reports the consequences of LT4 treatment over a prolonged period of time in 2 of the first patients with a heterozygous mutation in TRα1.', 'Here we show that the dysregulation of the pituitary-thyroid axis was worsened by the lack of TR alpha1 in TR betaPV mice, and severe impairment of postnatal growth was manifested in TR betaPV mice deficient in TR alpha1.', 'Heterozygous 2- to 3-week- old mice exhibit a severe retardation of post-natal development and growth, but only a minor reduction in serum thyroxine levels. ', 'The data demonstrate a novel array of effects mediated by a dominant negative TRalpha1, and may provide important clues for identification of a potentially unrecognized human disorder and its treatment.', 'No mutations in DNA- and hormone-binding-domains of TRbeta1 and TRalpha1 genes were found in proband, suggesting that the defect could be due to an unknown mutation in either the TR gene or a post receptor abnormality', 'These results demonstrate that the lack of TR alpha1 exacerbates the manifestation of RTH in TR betaPV mice. Therefore, TR alpha1 could play a compensatory role in mediating the functions of T3 in heterozygous patients with RTH. ']
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['The lack of TR alpha1 exacerbates the manifestation of RTH in TR betaPV mice. Therefore, TR alpha1 could play a compensatory role in mediating the functions of T3 in heterozygous patients with RTH']
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['yes']
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With which complexes is the protein SUS1 associated?
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['The yeast DUBm comprises a catalytic subunit, Ubp8, and three additional subunits, Sgf11, Sus1 and Sgf73, all of which are required for DUBm activity.', 'the deubiquitination module (DUBm) of SAGA, which is composed of Ubp8, Sus1, Sgf11, and Sgf73.', 'The conserved Sac3:Thp1:Sem1:Sus1:Cdc31 (TREX2) complex binds to nuclear pore complexes (NPCs)', 'Sus1 (hENY2) participates in this coordination as part of two protein complexes: SAGA, a transcriptional co-activator; TREX-2, which functions in mRNA biogenesis and export.', 'The deubiquitinating module (DUBm) of the SAGA coactivator contains the Ubp8 isopeptidase, Sgf11, Sus1, and Sgf73, which form a highly interconnected complex. ', 'Sus1/ENY2, a component of the SAGA and TREX-2 complexes, is involved in both transcription and mRNA export', 'Sus1 is a component of both the SAGA transcriptional co-activator complex and the TREX-2 complex that binds to nuclear pore complexes.', ' distinct subcomplex called the deubiquitinating module (DUBm), which contains the ubiquitin-specific protease Ubp8, bound to Sgf11, Sus1, and Sgf73.', 'The yeast deubiquitinase Ubp8 protein is recruited and activated by the SAGA complex and, together with Sgf11, Sus1, and Sgf73, forms a DUB module responsible for deubiquitinating histone H2B during gene expression. ', 'In the nucleus, Sus1 is associated to the transcriptional co-activator SAGA and to the NPC associated complex termed TREX2/THSC']
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['Sus1/ENY2 is a component of the SAGA and TREX-2 complexes']
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['SAGA complex', 'TREX-2 complex']
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Is pregnancy an additional risk during during H1N1 infection?
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['H1N1 influenza in pregnancy can be associated with severe complications', 'This case series confirms a high number of complications in pregnant women due to pandemic H1N1/09.', 'Pregnant women might be at increased risk for complications from pandemic H1N1 virus infection.', 'Pregnant women are at increased risk for complications from pandemic influenza H1N1 virus infection. ', 'Vaccination of pregnant women against influenza A (H1N1) by Russian subunit formulation (MonoGrippol plus) showed reactogenicity comparable to control group by the level of influence on general metabolic and immunologic homeostasis and on the course of pregnancy, which is an evidence of its safety', 'Pregnancy was identified as a major risk factor for increased mortality and morbidity due to H1N1 influenza in the pandemic of 2009 to 2010', 'While it is not possible to ascertain retrospectively if myocarditis was caused by either infection with H1N1 virus or as a result of pregnancy (in the absence of endomyocardial biopsies), the significant association with myocardial involvement in both women demonstrates the increased risk of exposure to H1N1 influenza virus in pregnant women.', 'Although limited in size, the fully prospective nature of the safety follow-up of these women vaccinated during pregnancy is unique and offers an important degree of reassurance for the use of the AS03 adjuvanted H1N1 (2009) vaccine in this high risk group for H1N1 infection.', 'During the H1N1 2009 pandemic, pregnant women constituted one of the priority groups for vaccination in many countries, creating a need for close monitoring of the safety of the vaccine in pregnant women', 'Emerging data suggest that pregnancy conveys high risk for severe complications from the 2009 pandemic influenza A virus (2009 H1N1) infection', 'Pregnant women have been identified as a group at risk, both for respiratory complications than for the admissions to the Intensive Care Unit (ICU) during the 2009 H1N1 influenza pandemic', 'This report mitigates substantially the presumed severity of pandemic H1N1/09 influenza infection during pregnancy', 'The results of our study do not indicate a risk for the pregnant woman and the developing embryo/fetus after H1N1 vaccination', 'This large cohort study found no evidence of an increased risk of fetal death associated with exposure to an adjuvanted pandemic A/H1N1 2009 influenza vaccine during pregnancy', 'Our results suggest that second- or third-trimester H1N1 vaccination was associated with improved fetal and neonatal outcomes during the recent pandemic', 'Pregnant women might thus be at increased risk of complications from pandemic H1N1 virus infection, and illness may progress rapidly', 'Pregnant women with H1N1 infection seem to benefit from antiviral therapy.', 'arly identification and treatment were the most important factors in different countries and areas examined.', 'The vaccine and antiviral drugs that have been the most efficient means to control the novel virus appear to be safe but require more extensive study', 'However, there were significant differences between the two groups in relation to mean age, treatment with oseltamivir, schooling, and presence of other risk factors', 'To investigate whether exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was associated with increased risk of adverse fetal outcomes.', 'In this Danish cohort, exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was not associated with a significantly increased risk of major birth defects, preterm birth, or fetal growth restriction', 'Most people affected by the virus, including pregnant women, suffer a mild viral illness, and make a full recovery', 'Pregnant women, because of their altered immunity and physiological adaptations, are at higher risk of developing pulmonary complications, especially in the second and third trimesters', 'The pregnancy outcomes were also poor for women who were affected by the virus with a fivefold increase in the perinatal mortality rate and threefold increase in the preterm delivery rate', 'regnant women were at increased risk for serious outcomes of 2009 pandemic influenza A virus subtype H1N1 (influenza A[H1N1]pdm09) infection, but little is known about the overall impact of the pandemic on neonatal and maternal outcomes', 'In this large, geographically diverse population, A(H1N1)pdm09 infection increased the risk for hospitalization during pregnancy', 'Vaccination during pregnancy with Pandemrix(®) appeared to have no ill effects on the pregnancy. On the contrary, the rate of preterm birth and low birthweight was lower than expected, which agrees with some previous results', 'During the influenza A(H1N1)pmd09 pandemic, although many cases occurred in younger adults, the risk factors identified for severe infections and complications were similar to those for seasonal influenza, including chronic respiratory, renal, liver, and heart diseases.', 'In terms of pregnancy, the studies have shown contradictory results due to variations in methodology and medical care.', 'However, it seems that pregnancy, particularly during the third trimester, increases the risk of complications, and that early antiviral treatment is associated with improved outcomes.', 'Pregnant women with mild clinical illness secondary to 2009 H1N1 were not at a greater risk of adverse pregnancy outcomes', 'However, severely infected women were more likely to deliver SGA infants', 'Gestational age is associated with the risk of developing critical infection. The risk increases with increasing weeks of gestation.', ' Following the start of winter in Liaoning province in China, the number of pregnant women infected with influenza increased significantly', 'regnancy, with or without additional complications, constitutes a high-risk condition for complications of influenza infection and warrants early intervention with neuraminidase inhibitors such as oseltamivir, if influenza is suspected']
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['Pregnant women are at increased risk for complications from pandemic influenza H1N1 virus infection. Pregnant women, because of their altered immunity and physiological adaptations, are at higher risk of developing pulmonary complications, especially in the second and third trimesters. Pregnancy, particularly during the third trimester, increases the risk of complications and early antiviral treatment is associated with improved outcomes.']
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['yes']
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Where is X-ray free electron laser used?
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['In conjunction with the XFEL temporal profile and high-flux, it is a powerful tool for studying the dynamics of time-dependent systems. Photo-induced processes and fast catalytic reaction kinetics, ranging from femtoseconds to milliseconds, will be resolvable in a wide array of systems circumventing radiation damage.', 'We discuss the pertinent physics of the intense X-ray-matter interactions, and illustrate the importance of electron-ion collisions. Detailed simulations of the interaction process conducted with a radiative-collisional code show good qualitative agreement with the experimental results. We obtain insights into the evolution of the charge state distribution of the system, the electron density and temperature, and the timescales of collisional processes. Our results should inform future high-intensity X-ray experiments involving dense samples, such as X-ray diffractive imaging of biological systems, material science investigations, and the study of matter in extreme conditions.', 'employment of "exotic" systems, such as the Free Electron LASER (FEL), that are expected to focus on the fundamental processes of life, following chemical reactions and biological processes as they happen, on unprecedented time and size scales.', 'New data analysis approaches are outlined for the correlated fluctuations in fast WAXS, for protein nanocrystals just a few molecules on a side, and for the continuous x-ray scattering from a single virus', 'Research opportunities and techniques are reviewed for the application of hard x-ray pulsed free-electron lasers (XFEL) to structural biology. These include the imaging of protein nanocrystals, single particles such as viruses, pump--probe experiments for time-resolved nanocrystallography, and snapshot wide-angle x-ray scattering (WAXS) from molecules in solution. The use of femtosecond exposure times, rather than freezing of samples, as a means of minimizing radiation damage is shown to open up new opportunities for the molecular imaging of biochemical reactions at room temperature in solution', 'New opportunities for solving the phase problem for XFEL data are outlined. A summary of the latest results is given, which now extend to atomic resolution for nanocrystals. Possibilities for time-resolved chemistry using fast WAXS (solution scattering) from mixtures is reviewed, toward the general goal of making molecular movies of biochemical processes.', 'Molecular imaging using X-ray free-electron lasers.', 'The recent development of X-ray free-electron laser sources has created new opportunities for the structural analysis of protein nanocrystals.', 'X-ray free electron lasers hold the promise of enabling atomic-resolution diffractive imaging of single biological molecules.', 'The emergence of femtosecond diffractive imaging with X-ray lasers has enabled pioneering structural studies of isolated particles, such as viruses, at nanometer length scales.', 'In this paper we report room temperature X-ray diffraction data of PS\xa0II microcrystals obtained using ultrashort (<\xa050\xa0fs) 9\xa0keV X-ray pulses from a hard X-ray free electron laser, namely the Linac Coherent Light Source.', 'High-resolution protein structure determination by serial femtosecond crystallography', 'We applied serial femtosecond crystallography (SFX) using an x-ray free-electron laser (XFEL) to obtain high-resolution structural information from microcrystals (less than 1 micrometer by 1 micrometer by 3 micrometers) of the well-characterized model protein lysozyme.', 'X-ray free electron laser (X-FEL)-based serial femtosecond crystallography is an emerging method with potential to rapidly advance the challenging field of membrane protein structural biology. Here we recorded interpretable diffraction data from micrometer-sized lipidic sponge phase crystals of the Blastochloris viridis photosynthetic reaction center delivered into an X-FEL beam', 'Here we show that high-quality diffraction data can be obtained with a single X-ray pulse from a non-crystalline biological sample, a single mimivirus particle, which was injected into the pulsed beam of a hard-X-ray free-electron laser, the Linac Coherent Light Source.', 'Single mimivirus particles intercepted and imaged with an X-ray laser', 'Femtosecond X-ray protein nanocrystallography', "Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes.", 'These methods can be used to image biological and materials science samples at high resolution with x-ray undulator radiation and establishes the techniques to be used in atomic-resolution ultrafast imaging at x-ray free-electron laser sources.', 'With the prospects of the x-ray free electron lasers, this approach could provide a major new opportunity for the high-resolution three-dimensional structure determination of single biomolecules.', 'X-ray free-electron lasers (XFELs) generate sequences of ultra-short spatially coherent pulses of X-ray radiation.', 'Diffractive imaging using the intense and coherent beam of X-ray free-electron lasers opens new perspectives for structural studies of single nanoparticles and biomolecules.', 'The opening of hard X-ray free-electron laser facilities, such as the Linac Coherent Light Source (LCLS) at SLAC National Accelerator Laboratory in the United States, has ushered in a new era in structural determination.', 'Where possible we also highlight areas that we think could push this field forward with emerging technologies, such as X-ray free electron lasers (X-feL), which could have a big impact on the membrane protein structural biology community.', 'X-ray free electron lasers (XFELs) deliver short (<100 fs) and intense (∼10(12) photons) pulses of hard X-rays, making them excellent sources for time-resolved studies.', 'Modern imaging techniques at the molecular scale rely on utilizing novel coherent light sources like X-ray free electron lasers for the ultimate goal of visualizing such objects as individual biomolecules rather than crystals.', 'In single-particle coherent x-ray diffraction imaging experiments, performed at x-ray free-electron lasers (XFELs), samples are exposed to intense x-ray pulses to obtain single-shot diffraction patterns.', 'The structure reveals the mechanism of native TbCatB inhibition and demonstrates that new biomolecular information can be obtained by the "diffraction-before-destruction" approach of x-ray free-electron lasers from hundreds of thousands of individual microcrystals.', 'Coherent diffraction imaging (CDI) of single molecules at atomic resolution is a major goal for the x-ray free-electron lasers (XFELs).', 'Ultrashort X-ray pulses from free-electron laser X-ray sources make it feasible to conduct small- and wide-angle scattering experiments on biomolecular samples in solution at sub-picosecond timescales.', 'The short and intense pulses of the new X-ray free electron lasers, now operational or under construction, may make possible diffraction experiments on single molecule-sized objects with high resolution, before radiation damage destroys the sample.', 'The recent development of x-ray free electron lasers providing coherent, femtosecond-long pulses of high brilliance and variable energy opens new areas of scientific research in a variety of disciplines such as physics, chemistry, and biology.', 'X-ray free electron laser (X-FEL)-based serial femtosecond crystallography is an emerging method with potential to rapidly advance the challenging field of membrane protein structural biology.', 'X-ray free-electron lasers (FELs) show promise for revealing the structure of single molecules or nanocrystals, but the phase problem remains largely unsolved.', 'Coherent diffractive imaging using x-ray free-electron lasers (XFELs) may provide a unique opportunity for high-resolution structural analysis of single particles sprayed from an aqueous solution into the laser beam.', "Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source.", 'This work is directly relevant to the time-resolved imaging of magnetic dynamics using coherent and ultrafast radiation from x-ray free-electron lasers and also to broader classes of diffractive imaging experiments which suffer noisy data, missing data, or both.', 'By combining serial nanocrystallography with x-ray free-electron laser sources in the future, it may be possible to produce molecular-resolution electron-density maps using membrane protein crystals that contain only a few hundred or thousand unit cells.', 'Very strong soft X-ray free electron laser (FEL) pulses must be short to allow for investigations of ultra-fast wet chemistry, according to the principle of collect and destroy.']
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['X-ray free electron laser (XFEL) technologies provide coherent and extremely intense photon pulses of short duration. XFELs are particularly useful in structural biology and imaging, in structural studies of single biological macromolecules (e.g. high resolution protein structure determination) and assemblies (e.g. viruses) or nanocrystals, which are not amenable to investigation with traditional crystallographic methods. Moreover, XFELs have the potential to be used for studying enzyme kinetics.']
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['high resolution protein structure determination', 'molecular imaging', 'single-particle imaging', 'study of enzyme kinetics', 'time resolved protein crystallography']
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Which enzyme is deficient in Gaucher's disease?
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["Gaucher's disease is caused by deficient lysosomal glucocerebrosidase activity", 'Gaucher\'s disease is due to glucocerebrosidase deficiency which is responsible for the accumulation of non degraded glucosylceramide within the lysosomes of macrophages: these "Gaucher cells", overloaded and alternatively activated, release in patient\'s plasma numerous compounds (cytokines, chemokines, hydrolases...) some of which contribute to the various tissue damages', "Gaucher's disease is an uncommon inborn recessive autosomal disease, due to a deficient activity of the lysosomal enzyme beta glucocerebrosidase", 'Gaucher disease is an inborn recessive autosomal disease due to a partial deficiency of the lysosomal enzyme beta glucocerebrosidase. The deficient activity leads to accumulation of the lipid glucocerebroside in the liver, the spleen and bone marrow with concomitant anemia and thrombocytopenia', "Alglucerase is a modified form of human placental glucocerebrosidase used as enzyme replacement therapy for patients with Gaucher's disease, in whom functional glucocerebrosidase is deficient", 'The common mutations found in the lysosomal enzyme deficient in Gaucher disease, beta-glucocerebrosidase, earmark these proteins for destruction by the endoplasmic reticulum-localised protein folding machinery, resulting in enzyme insufficiency, lysosomal glycolipid storage and subsequent pathology.', 'Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls.', 'It is an essential activator for glucocerebrosidase, the enzyme deficient in Gaucher disease.', 'GBA encodes for glucocerebrosidase (GCase), the enzyme deficient in the lysosomal storage disorder, Gaucher disease (GD).', 'The gene for glucocerebrosidase ( GBA), the enzyme deficient in Gaucher disease, is located in a gene-rich region on 1q21.', 'β-glucocerebrosidase, the enzyme deficient in Gaucher disease, also has an essential role in maintaining epidermal permeability function, by regulating the ratio of ceramides to glucosylceramides in the stratum corneum of the skin.', 'Recently, it was recognized that mutations in the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are associated with an increased incidence of parkinsonism.', 'Mutations in glucocerebrosidase (GBA), the enzyme deficient in Gaucher disease, are also identified at an increased frequency among Parkinson probands, including those of Ashkenazi Jewish ancestry.', 'Structure/function relationships of acid beta-glucosidase, the enzyme deficient in Gaucher disease, were evaluated by characterizing the proteins expressed from cDNAs encoding normal and mutant enzymes.', 'Gaucher disease is an autosomal recessive disorder resulting from deficient activity of the lysosomal enzyme glucocerebrosidase (GBA, E.C.3.2.1.45)', 'GBA encodes for glucocerebrosidase (GCase), the enzyme deficient in the lysosomal storage disorder, Gaucher disease (GD)', 'LIMP-2 is required for the normal biogenesis and maintenance of lysosomes and endosomes and has been identified as the specific receptor for glucocerebrosidase, the enzyme deficient in Gaucher disease', 'Mutations in glucocerebrosidase (GCase), the enzyme deficient in Gaucher disease, are a common genetic risk factor for the development of Parkinson disease and related disorders, implicating the role of this lysosomal hydrolase in the disease etiology', 'This gene is involved in lysosomal mannose-6-phosphate-independent trafficking of β-glucocerebrosidase (GC), an enzyme deficient in Gaucher disease', 'Gaucher disease (GD) is a lysosomal storage disorder, caused by deficient activity of the enzyme glucocerebrosidase', 'Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls', 'The common mutations found in the lysosomal enzyme deficient in Gaucher disease, beta-glucocerebrosidase, earmark these proteins for destruction by the endoplasmic reticulum-localised protein folding machinery, resulting in enzyme insufficiency, lysosomal glycolipid storage and subsequent pathology', "Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease.", 'Gaucher disease (GD) is an autosomal recessive lysosomal disorder caused by a deficiency of glucocerebrosidase.', "Gaucher's disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase).", "Pathogenic variants in the glucocerebrosidase gene (GBA) encoding the enzyme deficient in Gaucher's disease (GD) are associated with Parkinson's disease (PD).", "Gaucher's disease is an uncommon inborn recessive autosomal disease, due to a deficient activity of the lysosomal enzyme beta glucocerebrosidase.", 'Recently, it was recognized that mutations in the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are associated with an increased incidence of parkinsonism.', "Gaucher's disease is caused by deficient lysosomal glucocerebrosidase activity.", "Functional glucocerebrosidase is deficient in Gaucher's disease, an autosomal recessive lipid storage disorder that affects people of all ethnic backgrounds, but has a higher incidence among East European Jews (Ashkenazim).", "We studied two patients with type IV glycogen storage disease 37 and 91 months after liver transplantation and a third patient with lysosomal glucocerebrosidase deficiency (type 1 Gaucher's disease), in whom tissue glucocerebroside deposition had decreased 26 months after liver replacement, to determine whether the migration of cells from the allograft (microchimerism) could explain the improved metabolism of enzyme-deficient tissues in the recipient."]
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["Gaucher's disease is caused by deficient lysosomal glucocerebrosidase activity", 'Gaucher disease is an inborn recessive autosomal disease due to a partial deficiency of the lysosomal enzyme beta glucocerebrosidase. The deficient activity leads to accumulation of the lipid glucocerebroside in the liver, the spleen and bone marrow with concomitant anemia and thrombocytopenia.']
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['Beta glucocerebrosidase']
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Is cystatin C or cystatin 3 used as a biomarker of kidney function?
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['to explore the effect of ageing on renal function with cystatin C as the marker of glomerular filtration rate (GFR) in the general population without vascular disease or diabetes.', 'Cystatin C, a more specific kidney function biomarker, was also elevated at 24 h after CLP.', 'This study evaluated FGF-23 as well as traditional markers of kidney disease, namely urine albumin-to-creatinine ratio (UACR) and creatinine-cystatin C estimated GFR (eGFRCrCyC), as risk factors for AKI in elderly individuals. ', 'he primary predictor was estimated GFR (eGFR) calculated using serum cystatin C (eGFR(cys)).', 'A number of recent reports have suggested that the cystatin C/creatinine (CysC/Cr) ratio might be a useful biomarker of renal function in pediatric patients.', 'The CKD-EPI equation using cystatin C was the most precise method of renal function evaluation in patients with neurogenic bladder.', 'Serum cystatin C (CysC) is an endogenous marker of kidney function.', 'The urinary content of CysC reflects tubular epithelial dysfunction whereas that of NGAL also characterizes tubular atrophy.', 'Estimated kidney function based on serum cystatin C ', ': Several formulas for glomerular filtration rate (GFR) estimation, based on serum creatinine or cystatin C, have been proposed. ', 'he highest and lowest eGFR levels corresponded to the cystatin C-based and MDRD-4 equations, respectively. ', 'The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recently proposed an equation to estimate GFR in subjects without cirrhosis using both serum creatinine and cystatin C levels.', 'Emerging evidence has shown that cystatin C may improve classification of glomerular filtration rate for defining chronic kidney disease in certain clinical populations and assist in understanding the complications of chronic kidney disease', 'Beta-trace protein (BTP) and cystatin C (CysC) are novel biomarkers of renal function. ', 'Cystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine.', ' Iohexol clearance and cystatin C formulae identify a greater proportion of patients with a GFR <60 mL/min/1.73 m(2), which also predicts the development of AKI.', ' Cystatin C was recently reported to be an endogenous surrogate of kidney function, and a high level of cystatin C is reported to be a strong predictor of CVD;', 'Studies that have simultaneously compared measured GFR and estimated GFR (using endogenous filtration markers such as creatinine, or newer ones such as cystatin C or β-trace protein)']
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['Yes, cystatin C (CysC) is a novel biomarker of renal function.']
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['yes']
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Does Rad9 interact with Aft1 in S.cerevisiae?
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['Rad9 interacts with Aft1 to facilitate genome surveillance in fragile genomic sites under non-DNA damage-inducing conditions in S. cerevisiae.', 'Here we show that Rad9 checkpoint protein, known to mediate the damage signal from upstream to downstream essential kinases, interacts with Aft1 transcription factor in the budding yeast. Aft1 regulates iron homeostasis and is also involved in genome integrity having additional iron-independent functions. Using genome-wide expression and chromatin immunoprecipitation approaches, we found Rad9 to be recruited to 16% of the yeast genes, often related to cellular growth and metabolism, while affecting the transcription of ∼2% of the coding genome in the absence of exogenously induced DNA damage. Importantly, Rad9 is recruited to fragile genomic regions (transcriptionally active, GC rich, centromeres, meiotic recombination hotspots and retrotransposons) non-randomly and in an Aft1-dependent manner. Further analyses revealed substantial genome-wide parallels between Rad9 binding patterns to the genome and major activating histone marks, such as H3K36me, H3K79me and H3K4me. Thus, our findings suggest that Rad9 functions together with Aft1 on DNA damage-prone chromatin to facilitate genome surveillance, thereby ensuring rapid and effective response to possible DNA damage events.', 'Here we show that Rad9 checkpoint protein, known to mediate the damage signal from upstream to downstream essential kinases, interacts with Aft1 transcription factor in the budding yeast', 'Rad9 interacts with Aft1 to facilitate genome surveillance in fragile genomic sites under non-DNA damage-inducing conditions in S. cerevisiae', 'Here we show that Rad9 checkpoint protein, known to mediate the damage signal from upstream to downstream essential kinases, interacts with Aft1 transcription factor in the budding yeast. Aft1 regulates iron homeostasis and is also involved in genome integrity having additional iron-independent functions. Using genome-wide expression and chromatin immunoprecipitation approaches, we found Rad9 to be recruited to 16% of the yeast genes, often related to cellular growth and metabolism, while affecting the transcription of ?2% of the coding genome in the absence of exogenously induced DNA damage. ', 'Importantly, Rad9 is recruited to fragile genomic regions (transcriptionally active, GC rich, centromeres, meiotic recombination hotspots and retrotransposons) non-randomly and in an Aft1-dependent manner. Further analyses revealed substantial genome-wide parallels between Rad9 binding patterns to the genome and major activating histone marks, such as H3K36me, H3K79me and H3K4me. Thus, our findings suggest that Rad9 functions together with Aft1 on DNA damage-prone chromatin to facilitate genome surveillance, thereby ensuring rapid and effective response to possible DNA damage events.']
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['Yes. Rad9 functions together with Aft1 on DNA damage-prone chromatin to facilitate genome surveillance, thereby ensuring rapid and effective response to possible DNA damage events.']
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['yes']
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Which disease is treated with ZMapp?
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['This includes agents belonging to various therapeutic classes, namely direct antiviral agents (favipiravir and BCX4430), a combination of antibodies (ZMapp), type I interferons, RNA interference-based drugs (TKM-Ebola and AVI-7537), and anticoagulant drugs (rNAPc2). ', 'During the latest outbreak of Ebola virus disease in West Africa, monoclonal antibody therapy (e.g., ZMapp) was utilized to treat patients. ', 'Recent successes with monoclonal antibody cocktails ZMapp(TM) and MIL77 against Ebola virus (EBOV) infections have reignited interest in antibody-based therapeutics. ', 'The human-mouse chimeric monoclonal antibody (mAb) cocktail ZMapp, previously shown to be efficacious in EBOV (variant Kikwit) lethally infected nonhuman primates (NHPs) when administration was initiated up to 5 days, was used in some patients during the outbreak. We show that a two-antibody cocktail, MIL77E, is fully protective in NHPs when administered at 50 mg/kg 3 days after challenge with a lethal dose of EBOV variant Makona, the virus responsible for the ongoing 2014-2015 outbreak, whereas a similar formulation of ZMapp protected two of three NHPs. ', 'The growing promise of plant-made biologics is highlighted by the success story of ZMapp™ as a potentially life-saving drug during the Ebola outbreak of 2014-2016. ', 'Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp.', 'Background Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD).', 'Several patients with Ebola virus disease (EVD) managed in the United States have received ZMapp monoclonal antibodies, TKM-Ebola small interfering RNA, brincidofovir, and/or convalescent plasma as investigational therapeutics.', 'Also there is no specific vaccine and treatment for Ebola virus; however, many candidate vaccines and antiviral-drugs such as ZMapp and TKM-Ebola are being developed for Ebola virus disease.', 'A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection.', 'ELISA and neutralizing antibody assays indicate that ZMapp is cross-reactive with the Guinean variant of Ebola. ', 'Going forward, this work now provides a basis for strategic selection of next-generation antibody cocktails against Ebola and related viruses and a model for predicting the impact of ZMapp on potential escape mutations in ongoing or future Ebola outbreaks.', 'Some potential therapeutic materials including ZMapp were supplied and the treated people got over the EVD.', 'Cocktails of inhibitory monoclonal antibodies (MAbs), such as ZMAb, MB-003, and in particular ZMapp, have demonstrated in animal models some of the most significant therapeutic potential for treating EVD, and in 2014, 15 patients were treated with ZMapp or ZMAb under compassionate-use protocols.', 'This review explores some of the more prominent recent advances in the biofarming of viral vaccines and therapies, including the recent use of ZMapp for Ebolavirus infection, and explores some possible future applications of the technology.', 'During the latest outbreak of Ebola virus disease in West Africa, monoclonal antibody therapy (e.g., ZMapp) was utilized to treat patients.', 'ELISA and neutralizing antibody assays indicate that ZMapp is cross-reactive with the Guinean variant of Ebola.', 'Cocktails of inhibitory monoclonal antibodies (MAbs), such as ZMAb, MB-003, and in particular ZMapp, have demonstrated in animal models some of the most significant therapeutic potential for treating EVD, and in 2014, 15 patients were treated with ZMapp or ZMAb under compassionate-use protocols.', 'For example, several patients of the present Ebola virus outbreak in West Africa were treated with ZMapp, a cocktail of three monoclonal antibodies which are expressed in Nicotiana benthamiana.', 'Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp.']
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['ZMapp is a combination of antibodies for treatment of Ebola virus disease.']
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['Ebola virus disease']
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Are there clinical trials using stem cells for the treatment of cardiac disease?
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['Therapy with mesenchymal stem cells is one of the promising tools to improve outcomes after myocardial infarction. Adipose-derived stem cells (ASCs) are an ideal source of mesenchymal stem cells due to their abundance and ease of preparation.', 'Furthermore, several ongoing clinical trials using ASCs are producing promising results for heart diseases.', 'Among the cell types under investigation, adult mesenchymal stem cells are widely studied, and in early stage, clinical studies show promise for repair and regeneration of cardiac tissues.', ' Accumulating data from preclinical and early phase clinical trials document their safety when delivered as either autologous or allogeneic forms in a range of cardiovascular diseases, but also importantly define parameters of clinical efficacy that justify further investigation in larger clinical trials. ', 'several ongoing clinical trials using ASCs are producing promising results for heart diseases. ', 'Clinical application of adult stem cells for therapy for cardiac disease.', 'Stem cell-based therapies have the potential to fundamentally transform the treatment of ischemic cardiac injury and heart failure by achieving what would have been unthinkable only a few years ago-the Holy Grail of myocardial regeneration. Recent therapeutic approaches involve bone marrow (BM)-derived mononuclear cells and their subsets such as mesenchymal stem/stromal cells (MSCs), endothelial progenitor cells as well as adipose tissue-derived MSCs, cardiac tissue-derived stem cells, and cell combinations. Clinical trials employing these cells have demonstrated that cellular therapy is feasible and safe.', 'Accumulating data from preclinical and early phase clinical trials document their safety when delivered as either autologous or allogeneic forms in a range of cardiovascular diseases, but also importantly define parameters of clinical efficacy that justify further investigation in larger clinical trials.', 'se of stem and precursor cells as a therapeutic agent for chronically injured organs. Among the cell types under investigation, adult mesenchymal stem cells are widely studied, and in early stage, clinical studies show promise for repair and regeneration of cardiac tissues. ', 'Over the past 2 decades, there have been numerous stem cell studies focused on cardiac diseases, ranging from proof-of-concept to phase 2 trials. ', 'Small uncontrolled clinical trials have demonstrated cardiac stem cells as a treatment option for cardiomyopathy.', 'Stem cell populations are rapidly increasing, and we are still in the search of optimal cell types to use in clinical trials as bone marrow stem cells did not show significant improvement in cardiac function following transplantation.', 'Several clinical trials using adult stem cell have shown improvements in cardiac function, however, the mechanism of their action is unclear and widespread tissue regeneration is not evident.', 'As we await results from larger and more prolonged clinical trials, the science of stem cell therapy in cardiac disease keeps progressing.', 'Stem cell therapy for treatment of cardiac disease has shown therapeutic potential.', 'It should be noted that stem cell therapy is not limited to the treatment of ischemic cardiac disease.', 'Over the past 2 decades, there have been numerous stem cell studies focused on cardiac diseases, ranging from proof-of-concept to phase 2 trials.', 'This series of papers focuses on the legacy of these studies and the outlook for future treatment of cardiac diseases with stem cell therapies.', 'Cell transplantation to repair or regenerate injured myocardium is a new frontier in the treatment of cardiovascular disease. ', 'Current therapies only delay progression of the cardiac disease or replace the diseased heart with cardiac transplantation. Stem cells represent a recently discovered novel approach to the treatment of cardiac failure that may facilitate the replacement of diseased cardiac tissue and subsequently lead to improved cardiac function and cardiac regeneration.', ' Over the past 2 decades, there have been numerous stem cell studies focused on cardiac diseases, ranging from proof-of-concept to phase 2 trials. This series of papers focuses on the legacy of these studies and the outlook for future treatment of cardiac diseases with stem cell therapies.', 'Stem cell therapy for treatment of cardiac disease has shown therapeutic potential.', 'Over the past 2 decades, there have been numerous stem cell studies focused on cardiac diseases, ranging from proof-of-concept to phase 2 trials. This series of papers focuses on the legacy of these studies and the outlook for future treatment of cardiac diseases with stem cell therapies.', 'It should be noted that stem cell therapy is not limited to the treatment of ischemic cardiac disease. Non-ischemic cardiomyopathy, peripheral vascular disease, and aging may be treated by stem cells.', ' Recent clinical trials have achieved favorable initial endpoints with improvements in cardiac function and clinical symptoms following cellular therapy.', 'we consider how cardiac stem cell biology has led us into clinical trials, and we suggest that achieving true cardiac regeneration in patients may ultimately require resolution of critical controversies in experimental cardiac regeneration.', 'Cell-based therapies and tissue engineering provide new promising platforms to develop upcoming therapeutic options. Initial clinical trials were able to generate promising results. A variety of different stem cell types have been used for the clinical application. ', ' Insights gained from clinical trials of adult stem cells, together with fundamental scientific advances in cardiac stem cell and regenerative biology, are beginning to yield potential new targets and strategies for regenerative therapies. ', 'Early animal trials have demonstrated the ability to improve cardiac function by transfer of HSCs into the myocardium, and early human studies have demonstrated the feasibility and safety of this approach.']
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['Yes, there exists clinical trials for cardiac stem cell based treatment.', 'Yes, there are several clinical trials on the use of stem cells for the treatment of cardiac (heart) disease.']
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['yes']
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List three major features of the CCFDN syndrome.
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['Because of our experience in neuromuscular disorders, we choose six, frequent, autosomal recessive disorders for these clinical and genetic studies: hereditary motor and sensory neuropathy type Lom (HMSNL), hereditary motor and sensory neuropathy type Russe (HMSNR), congenital cataracts facial dysmorphism syndrome (CCFDN), limb-girdle muscular dystrophy 2C (LGMD2C), congenital myasthenic syndrome (CMS) and spinal muscular atrophy (SMA).', 'The congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome (OMIM 604168) is a recently described autosomal recessive developmental disorder. ', 'Congenital cataracts-facial dysmorphism-neuropathy syndrome (CCFDN, MIM: 604168), is a recently delineated neurogenetic disease causing recurrent episodes of rhabdomyolysis; prevention and early diagnosis of rhabdomyolysis should be part of the clinical management of the disease.', 'Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN) syndrome is a complex developmental disorder of autosomal recessive inheritance. ', 'OBJECTIVE: To determine the nature and course of ophthalmologic abnormalities in congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome in a genetically verified group of 9 patients.', 'Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome (OMIM 604168) is an autosomal recessive developmental disorder that occurs in an endogamous group of Vlax Roma (Gypsies; refs. 1-3). ', 'The major differential diagnosis of MSS is the syndrome defined by congenital cataracts, facial dysmorphism and peripheral neuropathy (CCFDN), which is localised to 18qter.', 'The CCFDN syndrome is a complex phenotype involving multiple systems, characterized by facial dysmorphism, congenital cataracts, microcorneae, delayed early motor and intellectual development, hypogonadotrop hypogonadism, hypomyelination of the peripheral nervous system, and serious complications related to general anaesthesia. ', 'Developmental abnormalities include congenital cataracts and microcorneae, primary hypomyelination of the peripheral nervous system, impaired physical growth, delayed early motor and intellectual development, mild facial dysmorphism and hypogonadism. Para-infectious rhabdomyolysis is a serious complication reported in an increasing number of patients. ', 'CONCLUSIONS: Early-onset congenital cataracts associated with microcornea, microphthalmos, and micropupil are essential ocular features of the CCFDN syndrome and are the first recognizable signs during early infancy. ', 'All patients showed a peripheral, demyelinating neuropathy and varying degrees of ataxia. In the older patients, muscular atrophy in distal muscles and facial dysmorphism was evident. Early-onset bilateral congenital cataracts associated with microcornea, microphthalmos, and micropupil could be found in all patients. All children had floppy eyelid syndrome and pseudoptosis.', 'All patients had syndrome-associated nystagmus and congenital esotropia. Distant visual acuity could be classified as severe to moderate impairment, whereas near visual acuity was much better (mild to moderate impairment).', 'Because these families originated from the same genetically isolated founder population as did patients with congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome, and because the two syndromes have clinical manifestations in common, we hypothesized that the two related, albeit distinct, syndromes may represent clinical variants of a single genetic disorder. ', 'Peripheral nerve abnormalities in the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome.', 'Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome: a novel developmental disorder in Gypsies maps to 18qter.', 'We propose to refer to the syndrome as congenital cataracts facial dysmorphism neuropathy (CCFDN). ', 'The disorder has been termed the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome to emphasize its salient features. ', 'Associated neurological features are a moderate nonprogressive cognitive deficit in most affected individuals together with pyramidal signs and mild chorea in some. Accompanying nonneurological features include short stature, characteristic facial dysmorphism, and hypogonadotrophic hypogonadism. Nerve conduction studies suggest a hypomyelinating/demyelinating neuropathy, confirmed by nerve biopsy. ', 'Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome: a rare cause of parainfectious rhabdomyolysis.', 'CONCLUSIONS: Early-onset congenital cataracts associated with microcornea, microphthalmos, and micropupil are essential ocular features of the CCFDN syndrome and are the first recognizable signs during early infancy.', 'The disorder has been termed the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome to emphasize its salient features.', 'Because these families originated from the same genetically isolated founder population as did patients with congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome, and because the two syndromes have clinical manifestations in common, we hypothesized that the two related, albeit distinct, syndromes may represent clinical variants of a single genetic disorder.', 'Congenital cataracts-facial dysmorphism-neuropathy syndrome (CCFDN, MIM: 604168), is a recently delineated neurogenetic disease causing recurrent episodes of rhabdomyolysis; prevention and early diagnosis of rhabdomyolysis should be part of the clinical management of the disease', 'The major differential diagnosis of MSS is the syndrome defined by congenital cataracts, facial dysmorphism and peripheral neuropathy (CCFDN), which is localised to 18qter']
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['Congenital cataracts, facial dysmorphism and peripheral neuropathy are three major features of the CCFDN syndrome. Other described signs and symptoms of the CCFDN syndrome include microcornea, microphthalmos, micropupil, floppy eyelid syndrome, pseudoptosis, nystagmus, congenital esotropia, impairment of distant visual acuity, ataxia, pyramidal signs, mild chorea, short stature, muscular atrophy, delayed early motor and intellectual development, hypogonadotrop hypogonadism, hypomyelination of the peripheral nervous system, serious complications related to general anaesthesia and parainfectious rhabdomyolysis.']
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['congenital cataracts', 'facial dysmorphism', 'peripheral neuropathy']
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Which is the cellular target of gefitinib?
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['Gefitinib, the specific inhibitor of the epidermal growth factor receptor (EGFR), may cause growth delay in cancer cell lines.', 'Gefitinib (Iressa) is a specific and effective epidermal growth factor receptor inhibitor.', 'Gefitinib is a specific inhibitor of the epidermal growth factor receptor (EGFR) that causes growth delay in cancer cell lines and human tumor xenografts expressing high levels of EGFR.']
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['The specific cellular target of Gefitinib (Iressa) is the epidermal growth factor receptor (EGFR).']
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['Epidermal growth factor receptor (EGFR)']
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What is MIRA-seq?
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['MIRA-seq for DNA methylation analysis of CpG islands.', 'MIRA-seq is a reliable, genome-scale DNA methylation analysis platform for scoring DNA methylation differences at CpG-rich genomic regions. The method is not limited by primer or probe design and is cost effective.', 'Using MIRA-seq, we have characterized the DNA methylome of metastatic melanoma and normal melanocytes.', 'Global gene expression was measured by RNA-Seq, while an epigenetic basis for expression differences was examined by methylated CpG island recovery assay sequencing (MIRA-Seq) analysis.', 'Global gene expression was measured by RNA-Seq, while an epigenetic basis for expression differences was examined by methylated CpG island recovery assay sequencing (MIRA-Seq) analysis.', 'MIRA-seq for DNA methylation analysis of CpG islands.', 'MIRA-seq is a reliable, genome-scale DNA methylation analysis platform for scoring DNA methylation differences at CpG-rich genomic regions.', 'Despite extensive breed differences in the transcriptome, MIRA-Seq unveiled relatively similar patterns of genome-wide DNA methylation between breeds, with an overall hypomethylation of gene promoters.', 'Methylated CpG island recovery assay sequencing (MIRA-Seq) revealed numerous methylation peaks spread across the genome, combined with an overall hypomethylation of gene promoter regions, and a remarkable similarity, except for 20 regions along the genome, between the fibroblasts collected at the two ages from the same animals.']
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['MIRA-seq is a reliable, genome-scale DNA methylation analysis platform for scoring DNA methylation differences at CpG-rich genomic regions. The method is not limited by primer or probe design and is cost effective.']
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[]
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What is the physiological role of LKB1 involved in Peutz-Jeghers syndrome?
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['Recent functional genetic studies have pointed out that LKB1 plays a physiological role in controlling the Wnt-signaling pathway and activation of the pathway as a consequence of LKB1 haploinsufficiency might be responsible for the development of harmatomatous polyps.', 'PJS polyps from all patients showed generalized membrane and cytoplasmic localizations of beta-catenin along the mucosal endothelium.']
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['LKB1 plays a physiological role in controlling the Wnt-signaling.']
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['LKB1 plays a physiological role in controlling the Wnt-signaling.']
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Is diphosphatidylglycerol (cardiolipin) a phospholipid of the mitochondrial membranes?
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['A unique organelle for studying membrane biochemistry is the mitochondrion whose functionality depends on a coordinated supply of proteins and lipids. Mitochondria are capable of synthesizing several lipids autonomously such as phosphatidylglycerol, cardiolipin and in part phosphatidylethanolamine, phosphatidic acid and CDP-diacylglycerol.', 'A small decrease of diphosphatidylglycerol also occurred in the hepatoma mitochondria inner membrane. ', 'Diphosphatidylglycerol was confined to the mitochondrial fraction, where it represented about 7% of the total phosphoacylglycerols. ', 'Mitochondrial membranes were isolated from the myocardium of young (4-month-old) and aged (33-month-old) male Long-Evans rats and compared in terms of cholesterol content and phospholipid and fatty acid composition. In aged rats, as compared to young, the major observations include: markedly higher cholesterol content; increased percentage of sphingomyelin and diphosphatidylglycerol (cardiolipin); ', 'The polyglycerophosphatides (typified by diphosphatidylglycerol) were apparently synthesized in situ by intramitochondrial membrane-bound enzymes using CDP-diglycerides as intermediates. ', 'Both the mitochondrial and microsomal fractions contained significant proportions of solvent front phospholipid (SFP) and whereas the mitochondrial SFP displayed the relatively unsaturated fatty acid composition characteristic of diphosphatidylglycerol (cardiolipin), the fatty acids of the microsomal SFP were distinctly more saturated.', 'Ten to 15% of microsomal radioactive CDP-diglycerides was transferred to mitochondrial membranes and incorporated into mitochondrial radioactive lipids identified as phosphatidylglycerol, phosphatidylglycerophosphate, and, when [14C]linoleoyl CDP-diglycerides were used, diphosphatidylglycerol (cardiolipin).', 'The enzyme responsible for the conversion of phosphatidylglycerol to diphosphatidylglycerol (cardiolipin) in the presence of cytidine diphosphate diacylglycerol is firmly associated with mitochondrial membranes and is not extracted with hypotonic or hypertonic media or with nonionic detergents.', 'The mechanism of cardiolipin (diphosphatidylglycerol) biosynthesis was examined in mitochondria and outer and inner mitochondrial membranes prepared from guinea pig and rat livers to determine whether this formation from phosphatidylglycerol was absolutely dependent on cytidinediphosphodiglyceride, as previously reported for intact mitochondria.', 'In isolated mitochondrial outer membranes, cardiolipin (diphosphatidylglycerol) increased CPT1 activity 4-fold and the Km for carnitine 6-fold.', 'Ten to 15% of microsomal radioactive CDP-diglycerides was transferred to mitochondrial membranes and incorporated into mitochondrial radioactive lipids identified as phosphatidylglycerol, phosphatidylglycerophosphate, and, when [14C]linoleoyl CDP-diglycerides were used, diphosphatidylglycerol (cardiolipin).', '90% or more of the phospholipid, cardiolipin was found in the mitochondrial membranes of wild type and petite yeast.', 'Furthermore, the same mechanism for the biosynthesis of cardiolipin was operational in the outer and inner mitochondrial membranes.', 'The mechanism of cardiolipin (diphosphatidylglycerol) biosynthesis was examined in mitochondria and outer and inner mitochondrial membranes prepared from guinea pig and rat livers to determine whether this formation from phosphatidylglycerol was absolutely dependent on cytidinediphosphodiglyceride, as previously reported for intact mitochondria', 'Cardiolipin (CL) is a key phospholipid in mitochondrial membranes, playing important roles in maintaining the functional integrity and dynamics of mitochondria in animals and yeasts', 'Cardiolipin, the specific phospholipid of mitochondria, is involved in the biogenesis, the dynamics, and the supramolecular organization of mitochondrial membranes', 'Cardiolipin (CL), the signature phospholipid of mitochondrial membranes, is crucial for both mitochondrial function and cellular processes outside of the mitochondria', 'Since it has been recognized that mitochondria are crucial not only for energy metabolism but also for other cellular functions, there has been a growing interest in cardiolipin, the specific phospholipid of mitochondrial membranes', 'Cardiolipin, the main anionic phospholipid in mitochondrial membranes, is expected to be a determinant in this adaptive mechanism since it modulates the activity of most membrane proteins', 'Ten to 15% of microsomal radioactive CDP-diglycerides was transferred to mitochondrial membranes and incorporated into mitochondrial radioactive lipids identified as phosphatidylglycerol, phosphatidylglycerophosphate, and, when [14C]linoleoyl CDP-diglycerides were used, diphosphatidylglycerol (cardiolipin)', 'Cardiolipin is normally localized to the inner mitochondrial membrane; however, when cardiolipin becomes externalized to the surface of dysregulated mitochondria, it promotes inflammasome activation and stimulates the elimination of damaged or nonfunctional mitochondria by mitophagy', 'In isolated mitochondrial outer membranes, cardiolipin (diphosphatidylglycerol) increased CPT1 activity 4-fold and the Km for carnitine 6-fold. ', 'Increasing levels of cardiolipin differentially influence packing of phospholipids found in the mitochondrial inner membrane.', 'Here, we used Saccharomyces cerevisiae subjected to conditions that affect mitochondrial metabolism as a model to determine the possible role of cardiolipin in stress adaptation. ', 'This decline of respiration was attributed to a progressive diminution of the number of mitochondria in copper-treated cells, based on the demonstration of the concomitant decline of (1) cardiolipin (diphosphatidylglycerol) and cytochrome aa3 (cytochrome oxidase), two specific markers of mitochondrial inner membrane, and (2) fumarase activity, a specific marker of mitochondrial matrix space.', 'Diphosphatidylglycerol (DPG) or cardiolipin, a specific component of the inner mitochondrial membrane, represents about 4% of the total lipid content.', 'Experimental results confirmed that the biosynthesis of cardiolipin, from the membrane-bound radioactive phosphatidylglycerol in intact mitochondria isolated from guinea pig and rat liver, was absolutely dependent on CDP-diglycerides and required the addition of divalent cations.', 'We have shown that decrease of cardiolipin in mitochondrial membrane occurs early during ischemia, and only during the irreversible phase of ischemia are phosphatidylethanolamine and phosphatidylcholine broken down.', 'Partial purification of diphosphatidylglycerol synthetase from liver mitochondrial membranes.', 'A small decrease of diphosphatidylglycerol also occurred in the hepatoma mitochondria inner membrane.']
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['Yes, diphosphatidylglycerol (cardiolipin) is a phospholipid of the mitochondrial membranes.']
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['yes']
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List the releases of JASPAR database
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['JASPAR is an open-access database of annotated, high-quality, matrix-based transcription factor binding site profiles for multicellular eukaryotes. The profiles were derived exclusively from sets of nucleotide sequences experimentally demonstrated to bind transcription factors. The database is complemented by a web interface for browsing, searching and subset selection, an online sequence analysis utility and a suite of programming tools for genome-wide and comparative genomic analysis of regulatory regions.', 'JASPAR is the most complete open-access collection of transcription factor binding site (TFBS) matrices. In this new release, JASPAR grows into a meta-database of collections of TFBS models derived by diverse approaches. We present JASPAR CORE--an expanded version of the original, non-redundant collection of annotated, high-quality matrix-based transcription factor binding profiles, JASPAR FAM--a collection of familial TFBS models and JASPAR phyloFACTS--a set of matrices computationally derived from statistically overrepresented, evolutionarily conserved regulatory region motifs from mammalian genomes. JASPAR phyloFACTS serves as a non-redundant extension to JASPAR CORE, enhancing the overall breadth of JASPAR for promoter sequence analysis', 'JASPAR 2010: the greatly expanded open-access database of transcription factor binding profiles.', 'JASPAR 2014: an extensively expanded and updated open-access database of transcription factor binding profiles.', 'The fifth major release greatly expands the heart of JASPAR-the JASPAR CORE subcollection, which contains curated, non-redundant profiles-with 135 new curated profiles (74 in vertebrates, 8 in Drosophila melanogaster, 10 in Caenorhabditis elegans and 43 in Arabidopsis thaliana; a 30% increase in total) and 43 older updated profiles (36 in vertebrates, 3 in D. melanogaster and 4 in A. thaliana; a 9% update in total). The new and updated profiles are mainly derived from published chromatin immunoprecipitation-seq experimental datasets. In addition, the web interface has been enhanced with advanced capabilities in browsing, searching and subsetting. Finally, the new JASPAR release is accompanied by a new BioPython package, a new R tool package and a new R/Bioconductor data package to facilitate access for both manual and automated methods.', 'JASPAR, the open access database of transcription factor-binding profiles: new content and tools in the 2008 update.', 'In this new release, JASPAR grows into a meta-database of collections of TFBS models derived by diverse approaches. We present JASPAR CORE--an expanded version of the original, non-redundant collection of annotated, high-quality matrix-based transcription factor binding profiles, JASPAR FAM--a collection of familial TFBS models and JASPAR phyloFACTS--a set of matrices computationally derived from statistically overrepresented, evolutionarily conserved regulatory region motifs from mammalian genomes.', 'JASPAR phyloFACTS serves as a non-redundant extension to JASPAR CORE, enhancing the overall breadth of JASPAR for promoter sequence analysis. The new release of JASPAR is available at http://jaspar.genereg.net. .', 'JASPAR phyloFACTS serves as a non-redundant extension to JASPAR CORE, enhancing the overall breadth of JASPAR for promoter sequence analysis. The new release of JASPAR is available at http://jaspar.', 'JASPAR phyloFACTS serves as a non-redundant extension to JASPAR CORE, enhancing the overall breadth of JASPAR for promoter sequence analysis. The new release of JASPAR is available at http://jaspar.genereg.net.']
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['JASPAR, JASPAR CORE, JASPAR FAM, JASPAR phyloFACTS, JASPAR 2008 update, JASPAR 2010, JASPAR 2014.']
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['JASPAR', 'JASPAR CORE', 'JASPAR FAM', 'JASPAR phyloFACTS', 'JASPAR 2008 update', 'JASPAR 2010', 'JASPAR 2014']
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Is intense physical activity associated with longevity?
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['Our major finding is that repeated very intense exercise prolongs life span in well trained practitioners.', 'Death rates declined with increased levels of total activity (estimated in kilocalories), and declined also with increased intensity of effort measured as from none, to light, to moderately vigorous or vigorous sports play. Death rates at any given quantity of physical exercise were lower for men playing moderately intense sports than for less vigorous men.', 'he purpose of this study was to investigate if jogging, which can be very vigorous, is associated with increased all-cause mortality in men and women.', 'This long-term study of joggers showed that jogging was associated with significantly lower all-cause mortality and a substantial increase in survival for both men and women.', 'Light activities (<4 multiples of resting metabolic rate (METs)) were not associated with reduced mortality rates, moderate activities (4-<6 METs) appeared somewhat beneficial, and vigorous activities (> or =6 METs) clearly predicted lower mortality rates (p, trend = 0.72, 0.07, and <0.001, respectively).', 'These data demonstrate a graded inverse relationship between total physical activity and mortality. Furthermore, vigorous activities but not nonvigorous activities were associated with longevity.', 'The capacity for prolonged and vigorous physical exercise, particularly if the exercise is recreational, is a strong indicator of longevity.']
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['YES:']
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['yes']
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Can exosomes be detected in urine?
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['Exosomes are nanovesicles secreted into the extracellular environment upon internal vesicle fusion with the plasma membrane. The molecular content of exosomes is a fingerprint of the releasing cell type and of its status. For this reason, and because they are released in easily accessible body fluids such as blood and urine, they represent a precious biomedical tool. ', 'Exosomes are vesicles that are released from the kidney into urine.', 'Quantification of human urinary exosomes by nanoparticle tracking analysis.', 'Urinary extracellular vesicles (uEVs) are released by cells throughout the nephron and contain biomolecules from their cells of origin.', 'Urinary exosomes have been proposed as potential diagnostic tools.', 'Urinary exosomes as a source of kidney dysfunction biomarker in renal transplantation', '. Here we sought to optimize the methodologies for the isolation and quantification of urinary exosomal microRNA as a prelude to biomarker discovery studies. ', 'Exosomes are small (30-150\u2009nm) vesicles containing unique RNA and protein cargo, secreted by all cell types in culture. They are also found in abundance in body fluids including blood, saliva, and urine. ', 'Urinary exosome-like vesicles (ELVs) are a heterogenous mixture (diameter 40-200\u2009nm) containing vesicles shed from all segments of the nephron including glomerular podocytes', 'Exosomes are cytoplasm containing vesicles released by many cells that can be found in several biological fluids including urine.', 'Proteomic analysis of urinary exosomes in cardiovascular and associated kidney diseases by two-dimensional electrophoresis and LC-MS/MS']
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['Yes, urinary exosomes can be detected in urine.']
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['yes']
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What histone trimethylation has been associated to RNA splicing?
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['histone H3 lysine 36 tri-methylation (H3K36Me3), exhibits different patterns around the cleavage sites of genes using multiple polyadenylation sites from those of genes using a single polyadenylation site.', 'ChIP-sequencing data mapped onto skipped exon events reveal a correlation between histone H3K36 trimethylation peaks and skipped exons, suggesting epigenetic marks being part of alternative splicing regulation.', 'Vezf1 interacts with Mrg15/Mrgbp, a protein that recognizes H3K36 trimethylation, consistent with the role of histone modifications at alternatively spliced sites', 'H2BK123ub1 is also a feature of introns in the yeast genome, and the disruption of this modification alters the intragenic distribution of H3 trimethylation on lysine 36 (H3K36me3), which functionally correlates with alternative RNA splicing in humans', 'We investigated whether a causal relationship exists between splicing and chromatin modification by asking whether splice-site mutations affect the methylation of histone H3K36', ' splicing can also contribute to histone modification,', 'Genome-wide analysis of histone methylation in human cell lines and mouse primary T cells reveals that intron-containing genes are preferentially marked with histone H3 Lys36 trimethylation (H3K36me3) ', ' transcription and splicing are functionally intertwined, and that modified nucleosomes with trimethylation of lysine 36 in histone subunit 3 (H3K36me3) are enriched at internal exons and the downstream flanking intronic regions of highly expressed genes', 'methylated H3K4 serves to facilitate the competency of pre-mRNA maturation ']
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['Mostly H3K36me3 but there is some evidence that H3K4me3 may also play a role in splicing']
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['H3K36me3']
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What is Cerebral Cavernous Malformation?
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['Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences', 'Cerebral cavernous malformations (CMs) are vascular malformations of the central nervous system, which can be detected in the absence of any clinical symptoms. Nodules and cysts with mixed signal intensity and a peripheral hemosiderin rim are considered brain magnetic resonance imaging (MRI) findings typical of CMs', 'Cerebral cavernous malformations (CCM) are enlarged vascular lesions affecting 0.1-0.5% of the population worldwide and causing hemorrhagic strokes, seizures, and neurological deficits', 'Although most cerebral cavernous malformations showed evolution of hemorrhage or no change in size or shape on follow-up MR images, cerebral cavernous malformations represented as mixture of subacute and chronic hemorrhage with hemosiderin rim (type II) have a higher frequency to rebleed than other types of cerebral cavernous malformations.', 'Mutations in Krev1 interaction trapped gene 1 (KRIT1) cause cerebral cavernous malformation, an autosomal dominant disease featuring malformation of cerebral capillaries resulting in cerebral hemorrhage, strokes, and seizures.', 'Cerebral cavernous malformation is a vascular disease of the brain causing headaches, seizures, and cerebral hemorrhage.', 'Cerebral cavernous malformation (CCM) is a common vascular disease in central nervous system that frequently predisposes to stroke, seizure, and cerebral hemorrhage', 'Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences.', 'Although most cerebral cavernous malformations showed evolution of hemorrhage or no change in size or shape on follow-up MR images, cerebral cavernous malformations represented as mixture of subacute and chronic hemorrhage with hemosiderin rim (type II) have a higher frequency to rebleed than other types of cerebral cavernous malformations. Cerebral cavernous malformations represented as hemosiderin deposition without central core (type IV) have a lower tendency to rebleed than other types and do not need any treatment.', 'Adverse reaction of irradiation was observed in five of 22 patients treated with gamma knife surgery. Although most cerebral cavernous malformations showed evolution of hemorrhage or no change in size or shape on follow-up MR images, cerebral cavernous malformations represented as mixture of subacute and chronic hemorrhage with hemosiderin rim (type II) have a higher frequency to rebleed than other types of cerebral cavernous malformations.', 'Cerebral cavernous malformations often remain clinically silent until a mutation carrier suffers a stroke or seizure. Presymptomatic genetic testing has been valuable to follow and manage cerebral cavernous malformation mutation carriers.', 'Although most cerebral cavernous malformations showed evolution of hemorrhage or no change in size or shape on follow-up MR images, cerebral cavernous malformations represented as mixture of subacute and chronic hemorrhage with hemosiderin rim (type II) have a higher frequency to rebleed than other types of cerebral cavernous malformations.', 'Cerebral cavernous malformation is a vascular disease of the brain causing headaches, seizures, and cerebral hemorrhage.']
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['Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences', 'Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences ', 'Cerebral cavernous malformations (CMs) are vascular malformations of the central nervous system, causing hemorrhagic strokes, seizures, and neurological deficits.']
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[]
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How was quantitative proteomic analysis used in isolating and studying the pseudopodium from migratory cells?
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['["we developed an approach to biochemically isolate the pseudopodium from the cell body using 3.0-micrometer porous filters for large-scale quantitative proteomic and phosphoproteomic analysis.", "Recent work using unique subcellular fractionation methodologies combined with spatial genomic, proteomic, and phosphoproteomic profiling has provided insight into the invadopodiome and pseudopodiome signaling networks ", "ere, we purified the pseudopodial proteomes", "tumor cells were placed on a fibronectin-coated porous membrane to form pseudopodia. According to the motile potentials of the cells, the cells formed pseudopodial microprocesses in the pores. An excimer laser, which was used for ophthalmic refractive surgeries, horizontally ablated cells at the membrane surface to remove the cell body. ", "we describe methods for the immunoaffinity purification of phosphotyrosine proteins (pY) from pseudopodia that have been isolated from migratory cells. These methods are compatible with current mass spectrometry-based protein identification technologies and can be utilized for the large-scale identification of the pseudopodium pY proteome in various migratory cell lines, including primary and cancer cells."]']
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An approach was developed to biochemically isolate the pseudopodium from the cell body using 3.0-micrometer porous filters for large-scale quantitative proteomic and phosphoproteomic analysis.
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[]
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Which type of GTPases is required for amino acid-dependent activation of mTORC1?
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['Heterodimeric Rag GTPases are required for amino-acid-mediated mTORC1 activation at the lysosome', 'Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb', 'mTORC1 promotes growth in response to the availability of nutrients, such as amino acids, which drive mTORC1 to the lysosomal surface, its site of activation. How amino acid levels are communicated to mTORC1 is only recently coming to light by the discovery of a lysosome-based signaling system composed of Rags (Ras-related GTPases) and Ragulator v-ATPase, GATOR (GAP activity towards Rags), and folliculin (FLCN) complexes', 'The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a major regulator of cell growth that responds to numerous environmental cues. A key input is amino acids, which act through the heterodimeric Rag GTPases (RagA or RagB bound to RagC or RagD) in order to promote the translocation of mTORC1 to the lysosomal surface, its site of activation', 'The heterodimeric Rag GTPases localize mTORC1 to lysosomes by their amino-acid-dependent interaction with the lysosomal Ragulator complex.', 'These new findings define the lysosome as a site of action for FLCN and indicate a critical role for FLCN in the amino acid-dependent activation of mTOR via its direct interaction with the RagA/B GTPases.', 'We show that LRS directly binds to Rag GTPase, the mediator of amino acid signaling to mTORC1, in an amino acid-dependent manner and functions as a GTPase-activating protein (GAP) for Rag GTPase to activate mTORC1.', 'Activation of mammalian target of rapamycin complex 1 (mTORC1) by amino acids is mediated in part by the Rag GTPases, which bind the raptor subunit of mTORC1 in an amino acid-stimulated manner and promote mTORC1 interaction with Rheb-GTP, the immediate activator', 'The Rag GTPases interact with mTORC1 and signal amino acid sufficiency by promoting the translocation of mTORC1 to the lysosomal surface, its site of activation', 'Amino acids stimulate mTORC1 activation at the lysosome in a manner thought to be dependent on the Rag small guanosine triphosphatases (GTPases), the Ragulator complex, and the vacuolar H(+)-adenosine triphosphatase (v-ATPase)', 'Heterodimeric Rag GTPases are required for amino-acid-mediated mTORC1 activation at the lysosome. ', 'Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. ', 'These new findings define the lysosome as a site of action for FLCN and indicate a critical role for FLCN in the amino acid-dependent activation of mTOR via its direct interaction with the RagA/B GTPases.', 'Interestingly, p62 colocalizes with Rags at the lysosomal compartment and is required for the interaction of mTOR with Rag GTPases in vivo and for translocation of the mTORC1 complex to the lysosome, a crucial step for mTOR activation.', 'Our results indicate that FLCN is specifically required for the amino acid-stimulated recruitment of mTORC1 to lysosomes by Rag GTPases. ', 'Mutation of LRS amino acid residues important for leucine binding renders the mTORC1 pathway insensitive to intracellular levels of amino acids. We show that LRS directly binds to Rag GTPase, the mediator of amino acid signaling to mTORC1, in an amino acid-dependent manner and functions as a GTPase-activating protein (GAP) for Rag GTPase to activate mTORC1.']
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['Heterodimeric Rag GTPases are required for amino-acid-mediated mTORC1 activation at the lysosome', 'Amino acids act through the heterodimeric Rag GTPases (RagA or RagB bound to RagC or RagD) in order to promote the translocation of mTORC1 to the lysosomal surface, its site of activation.']
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['Heterodimeric Rag GTPases']
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Is SLC22A3 expressed in the brain?
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['The organic cation transporter (OCT) 3 is widely expressed in various organs in humans, and involved in the disposition of many exogenous and endogenous compounds. Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission. ', 'The organic cation transporter 3 (OCT3; synonymous: extraneuronal monoamine transporter, EMT, Slc22a3) encodes an isoform of the organic cation transporters and is expressed widely across the whole brain.', 'In agreement with this distribution, OCT3/Slc22a3-deficient mice show evidence of altered monoamine neurotransmission in the brain, with decreased intracellular content and increased turnover of aminergic transmitters.', 'CRT, taurine transporter (TauT/SLC6A6) and organic cation transporter (OCT3/SLC22A3) expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF.', 'The organic cation transporter 3 (OCT3; synonymous: extraneuronal monoamine transporter, EMT, Slc22a3) encodes an isoform of the organic cation transporters and is expressed widely across the whole brain', 'The organic cation transporter 3 (OCT3; synonymous: extraneuronal monoamine transporter, EMT, Slc22a3) encodes an isoform of the organic cation transporters and is expressed widely across the whole brain. ', 'CRT may be a key factor facilitating blood-to-brain guanidinoacetate transport in patients deficient in S-adenosylmethionine:guanidinoacetate N-methyltransferase, the creatine biosynthetic enzyme, resulting in cerebral accumulation of guanidinoacetate. CRT, taurine transporter (TauT/SLC6A6) and organic cation transporter (OCT3/SLC22A3) expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF.', 'Slc22a3) encodes an isoform of the organic cation transporters and is expressed widely across the whole brain.', 'CRT, taurine transporter (TauT/SLC6A6) and organic cation transporter (OCT3/SLC22A3) expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF. Interestingly, BBB efflux transport of GCs, including guanidinoacetate and creatinine, is negligible, though the BBB has a variety of efflux transport systems for synthetic precursors of GCs, such as amino acids and neurotransmitters.', ' The organic cation transporter (OCT) 3 is widely expressed in various organs in humans, and involved in the disposition of many exogenous and endogenous compounds. Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission.', 'CRT, taurine transporter (TauT/SLC6A6) and organic cation transporter (OCT3/SLC22A3) expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF.', 'Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission.', 'The organic cation transporter 3 (OCT3; synonymous: extraneuronal monoamine transporter, EMT, Slc22a3) encodes an isoform of the organic cation transporters and is expressed widely across the whole brain.', 'OCT2-OCT-3 display differential tissue distribution: OCT1 is predominantly found in liver of humans, and liver and kidney in rodents; OCT2 is most strongly expressed in both human and rodent kidney, whereas is OCT3 primarily expressed in placenta, but also more widely detected in various tissues, including brain and lung.']
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['Yes, SLC22A3 (organic cation transporter (OCT3)) is widely expressed in various organs in humans, and involved in the disposition of many exogenous and endogenous compounds. Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission.']
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['yes']
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How is Lambert-Eaton myasthenic syndrome (LEMS) associated with small cell lung cancer?
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[' directed initially against voltage-gated Ca2+ channels found on the lung tumor cells.", "Radiological, bronchoscopic and histological investigations revealed small-cell lung cancer, and neurophysiological investigations confirmed a diagnosis of LEMS.", "Physicians need to be aware that patients may develop PCD and LEMS associated with anti-VGCC antibody caused by small cell lung cancer, and a mass survey should be conducted and careful examinations performed.", "Biopsy revealed small cell lung cancer (SCLC) indicating the importance of repeated chest CT in LEMS even when an existing autoimmune-like disease and negative CT may suggest an autoimmune origin.", "BACKGROUND: Neuromuscular symptoms in patients with Lambert-Eaton myasthenic syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in LEMS patients without a SCLC.", "The detection of SOX1 antibodies in patients with Lambert-Eaton myasthenic syndrome (LEMS) predicts the presence of small cell lung cancer and may be used to follow more closely those LEMS patients with no evidence of cancer at the initial workup.", "The presence of a particular symptom associated with LEMS did not predict the presence of SCLC, but in patients with rapidly progressive LEMS the possibility of underlying lung cancer should be of particular concern.", "We report a case of small-cell lung cancer (SCLC) presenting with LEMS and ventilatory failure in a 67-year-old man who initially presented with progressive limb weakness for 6 months and tachypnea with shallow breathing for 1 week.", "Using this protein, we demonstrated that anti-beta-subunit antibodies are present in the sera of 23% of LEMS patients and only, in low titer, in 2% of small cell lung cancer patients without LEMS.", "The gene encoding the beta 2 protein, first described as a Lambert-Eaton myasthenic syndrome (LEMS) antigen in humans, is found close to a region that undergoes chromosome rearrangements in small cell lung cancer, which occurs in association with LEMS.", "We then tested sera from 72 LEMS patients\' 25 with proven small cell lung cancer (SCLC) and 66 healthy or other neurological, SCLC or autoimmune disease controls in an immunoprecipitation assay using 125I-omega-CmTx-labelled (P/Q-type) VGCCs in human cerebellar extract.", "In the majority of patients LEMS is associated with small cell lung cancer (SCLC).", "Patients with small cell lung cancer (SCLC) in particular may develop LEMS, and SCLC is very often detected in patients affected by LEMS.", "We present a 69-year-old woman who had preventive whole brain radiation after a diagnosis of paraneoplastic Lambert-Eaton syndrome related to small cell lung cancer Five months after radiation therapy, she developed radiation-induced leukoencephalopathy manifested by ataxia.", "Among the symptoms of lung cancer LEMS can be seen, but it is very rare.", "A patient with the Lambert-Eaton syndrome (LES) and small cell lung cancer developed respiratory failure several hours after verapamil was given."]']
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Lambert-Eaton myasthenic syndrome (LEMS) is associated with small cell lung cancer (SCLC) in the majority of patients. Patients with SCLC may develop LEMS, and SCLC is often detected in patients affected by LEMS.
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[]
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Does thyroid hormone affect cardiac remodeling?
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['The aim of this brief paper is to highlight new developments in understanding the cardioprotective role of thyroid hormone in reverting regulatory networks involved in adverse cardiac remodeling.', 'Thyroid hormone receptor α1 (TRα1) is shown to be critical for the maturation of cardiomyocytes and for the cellular response to stress. TRα1 is altered during post ischemic cardiac remodeling but the physiological significance of this response is not fully understood. ', 'AMI induces downregulation of thyroid hormone signaling and pharmacological inhibition of TRα1 further depresses post-ischemic cardiac function.', 'These findings reveal crucial roles for Dio3 in heart function and remodeling, which may have pathophysiologic implications for human restrictive cardiomyopathy.', 'TH administration after AMI prevented tissue hypothyroidism and resulted in decreased beta-MHC expression, increased wall thickening and normalized wallstress, while stretch-induced p38 MAPK activation was increased. We conclude that diabetes exacerbates post-ischemic cardiac remodeling and that tissue hypothyroidism may be involved in this response.', 'Thyroid hormone can favorably remodel the diabetic myocardium after acute myocardial infarction.', 'It has been previously shown that regulators of physiological growth such as thyroid hormone (TH) can favorably remodel the post ischaemic myocardium.', 'Acute myocardial infarction in diabetic rats results in TH receptor down-regulation with important physiological consequences. TH treatment prevents this response and improves cardiac hemodynamics.', 'TH affects cardiac remodeling by limiting reperfusion injury, and, at later states, by inducing distinct changes in cardiac chamber geometry in a time-dependent manner.', 'Furthermore, administration of TH can convert pathologic to physiologic hypertrophy. These effects are the result of favorable cellular remodeling.', 'Thyroid hormone (TH) is critical in cardiac cell differentiation (regulating contractile proteins and cell geometry) and this effect could be potentially exploited therapeutically in reversing the process of de-differentiation which underlies postischemic cardiac remodeling. ', 'TH treatment partially reverses cardiac dysfunction in rats with old myocardial infarction by favorably changing cardiac chamber geometry and expression of myosin isoforms. Thyroid hormone, unlike current treatments, appears to be a paradigm of therapeutic intervention which aims at restoring cardiac geometry and may prove new effective treatment for heart failure.', 'Changes in thyroid hormone (TH)-TH receptors (TRs) axis occur in the course of post-infarction cardiac remodeling and seem to contribute to cardiac fetal phenotype. TH can "rebuild" the post-infarcted heart by preventing the fetal-like pattern of contractile proteins expression, normalizing wall tension, and optimizing cardiac chamber geometry. ', 'TH, apart from its "classical" actions on cardiac contractility and heart rhythm, appears to regulate various intracellular signaling pathways related to stress responses and cardiac remodelling.', 'More importantly, experimental and clinical studies demonstrate that TH can limit ischaemic injury, attenuate cardiac remodeling and improve cardiac hemodynamics. ', 'Thyroid hormone attenuates cardiac remodeling and improves hemodynamics early after acute myocardial infarction in rats.', 'Thyroid hormone administration early after infarction attenuates cardiac remodeling and significantly improves myocardial performance.', 'It has previously been shown that thyroid hormone can reverse cardiac remodeling in failing hearts by reducing myocardial wall stress due to the unique changes induced in cardiac myocyte shape. ']
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['TH affects cardiac remodeling']
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['yes']
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Which is the gene mutated in type 1 neurofibromatosis?
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['Individuals with NF1 harbor 1 mutated NF1 allele', 'type 1 (NF1) is a hereditary disorder caused by mutations in the NF1 gene', 'The NF1 gene, mutated in NF1, is also commonly mutated in sporadic glioblastoma multiforme (GBM)', ' type 1 (NF1) is a common genetic disease caused by haploinsufficiency of the NF1 tumor-suppressor gene', 'Neurofibromatosis type 1 (NF1) is a common disorder of dysregulated tissue growth secondary to mutations in the tumor suppressor gene NF1', 'tumor suppressor protein neurofibromin, which is mutated in NF1', ' Neurofibromatosis type 1 is one of the most common autosomal dominant disorders, affecting about 1:3,500 individuals. NF1 exon 7 displays weakly defined exon-intron boundaries', 'Loss of heterozygosity (LOH) of NF1', 'Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder resulting in the growth of a variety of tumours, ', 'ten occur in both children and adults as sporadic events with no family history of the disease, but they are also among the clinical manifestations of a significant number of familial cancer syndromes, including familial retinoblastoma, neurofibromatosis 1 and 2, tuberous sclerosis, and Cowden, Turcot, Li-Fraumeni and nevoid basal cell carcinoma (Gorlin) syndromes. ', 'These genes include RB1, NF1, NF2, TSC1, TSC2, TP53, PTEN, APC, hMLH1, hPSM2, and PTCH', 'von Recklinghausen syndrome (NF-1) (OMIM 162200) carrying NF1 germline mutations', 'mutations of the NF1 gene have been reported in patients with neurofibromatosis type 1 (NF1)', 'NF1 gene mutation in a Japanese patient with neurofibromatosis type 1 ', 'Neurofibromatosis 1 gene (NF1 ) fulfills the criteria of a tumor suppressor gene and is deleted or mutated heterozygously in patients with NF1', 'type 1 (NF1) is one of the most common human genetic disorders and is associated with significant morbidity and mortality. The gene responsible for this disorder, NF1, encodes neurofibromin,', ' genes mutated in these two disorders encode tumor suppressor proteins, termed neurofibromin (NF1)', ' tumour-suppressor genes, Nf1 and Trp53. Humans with mutations in NF1 develop neurofibromatosis type I (NF1', 'type 1 (NF1) is an autosomal dominant genetic disorder affecting one in 3,500 individuals. The mutation rate in the NF1 gene is one of the highest known for human genes.', 'patients with neurofibromatosis type 1 (NF1) were screened for mutations in the NF1 gene.', 'It is caused by a wide spectrum of mutations affecting the NF1 gene. ', 'NF1) is a common familial tumour syndrome with multiple clinical features such as neurofibromas', 'This neoplastic lesion is a common feature of neurofibromatosis type 1 (NF1), one of the most common autosomal dominant disorders. The NF1 gene codes for a protein called "neurofibromin.', 'type 1 (NF1) and type 2 (NF2) are connected with genes localized on chromosomes 17 and 22, respectively. The genes that are inactivated in neurofibromatosis code for the proteins neurofibromine and merline', 'neurofibromatosis type 1 (NF1) gene, well recognized for its high frequency of spontaneous mutations.', 'An NF1 gene was identified as a gene whose loss of function causes an onset of human disorder, neurofibromatosis type I.', 'type 1 (NF1) is caused by deletions, insertions, translocations, and point mutations in the NF1 gene', 'type 1 (NF1) gene is a tumor suppressor gene, and the NF1 gene product, neurofibromin', 'ysine 1423 of neurofibromin (neurofibromatosis type I gene product [NF1]) plays a crucial role in the function of NF1.']
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['NF1 gene, encoding neurofibromin 1']
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['NF1']
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Is oxalate renal excretion increased after bariatric surgery?
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['Despite the fact that bariatric surgery-induced weight loss is associated with a significant decrease in morbidity and mortality and improvement in renal function, bariatric surgery has recently been shown to be associated with a significant risk of nephrolithiasis. The main risk factor for nephrolithiasis is increased excretion of urinary oxalate.', 'Enteric hyperoxaluria, nephrolithiasis, and oxalate nephropathy must be considered with the other risks of RYGBP.', 'The urinary excretion of oxalate was high: 1.112 mumol/24 h (normal range: 55-400 mumol/24 h), and citrate excretion was low: 1.48 mmol/24 h (normal range: 2-5 mmol/24 h). ', 'Hyperoxaluria in patients with JIB was found to be a result of hyperabsorption of oxalate, and these patients displayed altered oxalate kinetics with continued urinary excretion of orally administered 14C-oxalate for more than 48 hours. ', 'Malabsorption of calcium and low fasting urinary calcium excretion in the JIB patients were associated with high tubular reabsorption of calcium, the latter presumably attributable to a compensatory increase in circulating parathyroid hormone (PTH). In most recurrent renal stone formers the urinary calcium concentration was increased, with an inverse relationship to serum PTH, indicating intestinal hyperabsorption of calcium. A']
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['Bariatric surgery is associated with a significant risk of nephrolithiasis.\nEnteric hyperoxaluria, nephrolithiasis, and oxalate nephropathy must be considered with the other risks of bariatric surgery\nHyperoxaluria in patients treated with bariatric surgery was found to be a result of hyperabsorption of oxalate', 'Urinary oxalate increases after bariatric surgery']
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['yes']
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Is the transcriptional regulator BACH1 an activator or a repressor?
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['the impact of BACH1 repression on transcription', 'Bach1 is a repressor of the oxidative stress response', 'transcriptional repressor Bach-1, ', 'Bach1, a transcriptional repressor of the HMOX1 gene', 'The mechanism underlying Bach1-mediated HO-1 repression is less well understood', "Transcription factor BACH1 [BTB (broad-complex, tramtrack and bric-a-brac) and CNC (cap'n'collar protein) homology 1] binds to ARE-like sequences, functioning as a transcriptional repressor ", 'Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1)', ' its regulatory mechanism by the transcriptional repressor, BTB and CNC homology 1 (Bach1),', 'Bach1, a basic leucine zipper mammalian transcriptional repressor, negatively regulates heme oxygenase 1 (HMOX1),', 'Bach1, the negative regulator of Nrf2', 'ach1 is a transcriptional repressor of the heme oxygenase (HO)-1 gene. ', 'The inhibitory role for Bach1 may stem from its activity to repress gene expression including HO-1', 'Bach1 is a transcriptional repressor of the HO-1 gene (Hmox-1)', 'Here we show that the transcription factor Bach1 (BTB and CNC homology 1, basic leucine zipper transcription factor 1), which inhibits oxidative stress-inducible genes, is a crucial negative regulator of oxidative stress-induced cellular senescence', 'Bach1 is a transcriptional repressor of the HO-1 gene', 'Bach1 repressively controls myocardial HO-1 expression ', ' the transcriptional repressor BACH1 binds ARE-like enhancers', ' transcription factor Bach1 functions as a repressor of the enhancers of heme oxygenase-1 (HO-1) gene (Hmox-1)', 'Bach1, a transcription factor that suppresses the HO-1 gene', 'Bach1, a transcriptional repressor that is negatively regulated by heme in mammalian cells', 'Bach1 normally represses HO-1 expression. ', 'Bach1, a heme binding protein that represses gene expression', 'complexes with Bach1 repress MARE-dependent gene expression', 'transcriptional repressor Bach1', 'bach1-ablation resulted in increased expression of HO-1 ', 'Bach1 contributes to the down-regulation of ARE-regulated genes', 'evidence that BACH1 acts as a transcriptional repressor in the regulation of MARE-dependent genes', 'Bach1 forms a heterodimer with small Maf family, and functions as a repressor of the Maf recognition element (MARE) in vivo', 'ach1 is a transcriptional repressor of heme oxygenase-1 and beta-globin genes,', 'BACH1 suppresses expression of HO1', 'transcription factor Bach1 heterodimerizes with small Maf proteins to repress Maf recognition element (MARE)-dependent gene expression', ' Bach1 as a heme-regulated and hypoxia-inducible repressor for transcription of the HO-1 gene', 'Bach1, a transcriptional repressor of heme oxygenase-1 gene', 'Bach1, a heme-regulated transcriptional repressor', 'a heme-binding factor, Bach1, is a critical physiological repressor of ho-1', 'transcription repressor Bach1']
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['BACH1, a basic leucine zipper mammalian transcriptional repressor, negatively regulates heme oxygenase 1 (HMOX1), a key cytoprotective enzyme that has antioxidant and anti-inflammatory activities. In the absence of elevated intracellular heme or oxidative stress, BACH1 functions as a repressor of the enhancers of heme oxygenase-1 (HO-1) gene (Hmox-1) by forming heterodimers with the small Maf proteins such as MafK. Bach1 is recruited to a subset of p53 target genes and contributes to impeding p53 action by promoting histone deacetylation.', 'BACH1 is, in most contexts, a transcriptional repressor']
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['Repressor']
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Which is the prevalence of cystic fibrosis in the human population?
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['The allelic frequency of this variant was calculated to be 0.7% for this population', 'The results of literature reviews, surveys, and registry analyses revealed a mean prevalence of 0.737/10,000 in the 27 EU countries, which is similar to the value of 0.797 in the United States, and only one outlier, namely the Republic of Ireland at 2.98', 'The age related prevalence of CF among the South Asian and general populations was: 0-14 years, 1:9200 versus 1:6600; 15-24 years, 1:13,200 versus 1:7600; older than 25 years, 1:56,600 versus 1:12,400.', 'A theoretical estimate of the prevalence of cystic fibrosis based on anthropological data suggested a frequency of 25 affected individuals/100,000 inhabitants. However, our data indicated that the true prevalence in the population was considerably lower (6.9 cases/100,000 inhabitants)', 'CF mutations were identified in 374 (4.0%) individuals.', 'The aim of this study was to evaluate the screening policies of cystic fibrosis (CF) in the Jewish population.']
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['Prevalence of Cystic Fibrosis varies according to the population. A theoretical estimate of the prevalence of cystic fibrosis based on anthropological data suggested a frequency of 25 affected individuals/100,000 inhabitants. However, real data indicated that the true prevalence in the population was considerably lower (6.9 cases/100,000 inhabitants). Results of literature reviews, surveys, and registry analyses revealed a mean prevalence of 0.737/10,000 in the 27 EU countries, which is similar to the value of 0.797 in the United States, and only one outlier, namely the Republic of Ireland at 2.98.', 'The results of literature reviews, surveys, and registry analyses revealed a mean prevalence of 0.737/10,000 in the 27 EU countries, which is similar to the value of 0.797 in the United States, and only one outlier, namely the Republic of Ireland at 2.98 (PMID: 18442953) The allelic frequency of this variant was calculated to be 0.7% for this population (PMID: 22627569) CF mutations were identified in 374 (4.0%) individuals. (PMID: 11336401)']
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['0.7–7/100000 inhabitants']
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Which is the histone residue methylated by MLL1?
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['lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription', 'histone H3K4me3 methylase MLL1 complex', 'MEN1 encodes menin, a subunit of MLL1/MLL2-containing histone methyltransferase complexes that trimethylate histone H3 at lysine 4 (H3K4me3', 'MLL1, MLL5, Set1 and ASH1 to be highly up-regulated during transdifferentiation of HSCs. All of these histone methyltransferases regulate methylation of lysine 4 of histone H3, which is a signature of actively transcribed genes', 'MLL1 (Mixed Lineage Leukemia 1), a histone methyltransferase that methylates H3K4 residues', 'H3K4) in Saccharomyces cerevisiae is implemented by Set1/COMPASS, which was originally purified based on the similarity of yeast Set1 to human MLL1 and Drosophila melanogaster Trithorax (Trx)', 'istone H3 lysine 4 (K4) methylation is a prevalent mark associated with transcription activation and is mainly catalyzed by the MLL/SET1 family histone methyltransferase', 'Mutations in the MLL1 SET domain that fail to support overall H3 K4 methylation', 'MLL1, a mammalian homolog of Drosophila trithorax, is an H3K4-specific methyltransferase implicated in transcriptional control', 'We show that the mixed lineage leukemia 1 (MLL1) protein, a histone methyltransferase specific for H3K4', 'MLL1 histone H3 Lys4 methyltransferase complexes', 'MLL1 histone methyltransferase (H3K4me3) complex', 'In the human MLL1 (mixed-lineage leukemia-1) HMT complex, DPY-30L binds to the BRE2 homolog ASH2L in order to regulate histone 3-lysine 4 trimethylation.', 'MLL1 and MLL2 H3K4 methyltransferase complexes are tethered by p52 on the MMP9 but not on the IkappaBalpha promoter, and the H3K4 trimethyltransferase activity r', 'The biological function of MLL1 is mediated by the histone H3K4 methyltransferase activity of the carboxyl-terminal SET domain.', 'Set1/COMPASS is capable of methylating H3K4, a posttranslational modification associated with actively transcribed genes. There is only one Set1 in yeast; yet in mammalian cells there are multiple H3K4 methylases, including Set1A/B, forming human COMPASS complexes, and MLL1-4', ' trimethylated H3K4 histones and histone methyltransferase MLL1', ' lacZ knock-in allele of mixed-lineage leukemia 1 (Mll1), a histone methyltransferase expressed in GABAergic and other cortical neurons, resulted in decreased H3K4 methylation', 'effectors of H3K4 methylation is mixed-lineage leukemia 1 (MLL1)', 'MLL1/MLL2 histone methyltransferase complexes specific for Lys4 of histone H3 (H3K4)', 'H3 K4 methyltransferase MLL1', 'purified complex has a robust MLL1-mediated histone methyltransferase activity that can effect mono-, di-, and trimethylation of H3 K4', "MLL1 localizes with RNA polymerase II (Pol II) to the 5' end of actively transcribed genes, where histone H3 lysine 4 trimethylation occurs"]
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['Histone H3 at lysine 4 (H3K4)']
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['H3K4']
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What is known about thalidomide therapy and survival of glioblastoma patients?
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['In conclusion, thalidomide given simultaneously with radiation therapy was safe, but did not improve survival in patients with newly diagnosed glioblastoma.', 'The authors previously reported improved outcome in patients with recurrent glioblastoma treated with thalidomide and irinotecan compared with historical controls. ', 'CONCLUSIONS: The combination of thalidomide and irinotecan did not achieve sufficient efficacy to warrant further investigation against AG, although a subset of patients experienced prolonged PFS/OS. ', 'The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT.', 'The addition of celecoxib and thalidomide to adjuvant temozolomide was well tolerated but did not meet the primary end point of improvement of 4-month PFS from study enrollment.', 'CONCLUSION: The combination of irinotecan and thalidomide has limited activity against GBM.', 'The combination of irinotecan, a cytotoxic agent, and thalidomide, an antiangiogenic agent, shows promising activity against recurrent GBM in patients not receiving EIACs and warrants further study. ', 'CONCLUSION: The administration of temozolomide in association with thalidomide after radiotherapy (RT) does not offer an advantage over temozolomide alone in adults with newly diagnosed GBM. The two therapeutic strategies produce similar results for survival, but the latter regimen shows a moderate increase in toxicity.', 'CONCLUSION: This drug combination was reasonably safe, but with little indication of improvement compared to temozolomide alone.', 'In this small patient sample adding thalidomide to radiation did not improve TTP or TTD from historical controls, however, toxicity appeared to be increased.', 'Experimental studies have demonstrated that thalidomide has anti-tumor activity mediated by blockage of angiogenesis, with clinical efficacy in multiple myeloma, glioblastoma multiforme, and renal cell cancer. ', 'CONCLUSIONS: The combined therapy was relatively well tolerated, but there was no survival advantage compared with historical studies using XRT either with adjuvant nitrosourea chemotherapy, with TMZ alone, or with the combination of TMZ and thalidomide.', 'PURPOSE: The chemotherapeutic agent temozolomide (TMZ) and the antiangiogenic agent thalidomide have both demonstrated antitumor activity in patients with recurrent malignant glioma.', 'CONCLUSIONS: This strategy of combination TMZ, thalid and RT was relatively well tolerated with favorable survival outcome for patients with GM when compared to patients not treated with adjuvant chemotherapy and similar to those who have received nitrosourea adjuvant chemotherapy. It is unclear the added advantage thalid has in combination with TMZ for this patient population.', 'CONCLUSIONS: The combination of thalidomide and temozolomide in the treatment of GBM appears to be more effective than that of thalidomide alone with respect to survival, TTP, and neuroradiological documentation of progression, stable disease or response. ', 'In conclusion, thalidomide induces modest side effects and it may be considered a valid therapeutic option for patients with recurrent glioblastoma.', 'Thalidomide is a well-tolerated drug that may have some activity in the treatment of recurrent glioblastoma. ', 'Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. ', ' In conclusion, thalidomide given simultaneously with radiation therapy was safe, but did not improve survival in patients with newly diagnosed glioblastoma.', 'Thalidomide prolongs disease stabilization after conventional therapy in patients with recurrent glioblastoma.', 'In conclusion, thalidomide given simultaneously with radiation therapy was safe, but did not improve survival in patients with newly diagnosed glioblastoma.', 'No patients completed the planned 12 months of thalidomide therapy and all have since died of disease progression']
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['Findings regarding clinical value of thalidomide in terms of survival in patients with glioblastoma remain mixed. It has been shown that thalidomide can improve survival of recurrent glioblastoma patients. However, other authors have not confirmed these findings. Furthermore, thalidomide did not improve survival of newly diagnosed glioblastoma and pediatric glioblastoma patients.']
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[]
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List clinical trials for prevention of sarcopenia
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['several clinical trials with androgen replacement therapy have failed to show clinical benefit.', 'Clinical trials are needed to find better interventions for this syndrome.', 'emergence of many promising interventions towards this age-related condition (e.g., physical exercise [in particular, resistance training], testosterone, antioxidant supplementations), the need for Phase II trial designs is high. ', 'The objective of this study was to evaluate the effect of omega-3 fatty acid supplementation on the rate of muscle protein synthesis in older adults.', 'This trial was registered at clinical trials.gov as NCT00794079.', 'The extreme paucity of clinical trials on sarcopenia in literature is mainly due to difficulties in designing studies able to isolate the aging process from its multiple and interconnected consequences.']
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['Several clinical trials with androgen replacement therapy. \nStudy was to evaluate the effect of omega-3 fatty acid supplementation on the rate of muscle protein synthesis. This trial was registered at clinical trials.gov as NCT00794079']
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['androgen replacement trials', 'omega-3 fatty acid supplementation', 'NCT00794079']
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What is the function of the AIRE gene at the embryonic stage?
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['Autoimmune regulator (Aire) is one of the most well-characterized molecules in autoimmunity, but its function outside the immune system is largely unknown. The recent discovery of Aire expression in stem cells and early embryonic cells and its function in the self-renewal of embryonic stem (ES) cells highlight the importance of Aire in these cells.', 'we present evidence that Aire promotes the expression of the pluripotent factor Lin28 and the self-renewal of ES cells.', 'Instead, Aire reduced T cell mitochondrial reductase by negatively regulating a proinflammatory cytokine, early T cell activation factor (Eta)-1.', 'Aire regulates the expression of differentiation-associated genes and self-renewal of embryonic stem cells', 'Aire and Deaf1 help regulate the ectopic expression of diverse tissue-specific antigens to establish self-immune tolerance', 'Mutations in the autoimmune regulator (AIRE) protein cause a breakdown of central tolerance that is associated with decreased expression of self antigens in the thymus', 'Aire regulates the expression of differentiation-associated genes and self-renewal of embryonic stem cells.', 'The recent discovery of Aire expression in stem cells and early embryonic cells and its function in the self-renewal of embryonic stem (ES) cells highlight the importance of Aire in these cells', 'Aire promotes the self-renewal of embryonic stem cells through Lin28.', ' Abstract Autoimmune regulator (Aire) is one of the most well-characterized molecules in autoimmunity, but its function outside the immune system is largely unknown. The recent discovery of Aire expression in stem cells and early embryonic cells and its function in the self-renewal of embryonic stem (ES) cells highlight the importance of Aire in these cells.', 'The recent discovery of Aire expression in stem cells and early embryonic cells and its function in the self-renewal of embryonic stem (ES) cells highlight the importance of Aire in these cells. In this study, we present evidence that Aire promotes the expression of the pluripotent factor Lin28 and the self-renewal of ES cells.', 'Abstract Autoimmune regulator (Aire) is one of the most well-characterized molecules in autoimmunity, but its function outside the immune system is largely unknown. The recent discovery of Aire expression in stem cells and early embryonic cells and its function in the self-renewal of embryonic stem (ES) cells highlight the importance of Aire in these cells.']
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['Aire regulates the expression of differentiation-associated genes and self-renewal of embryonic stem cells. Aire and Deaf1 help regulate the ectopic expression of diverse tissue-specific antigens to establish self-immune tolerance. Knockdown of Aire in mouse ESCs resulted in significantly decreased clone-forming efficiency as well as attenuated cell cycle, suggesting Aire plays a role in ESC self-renewal. Aire promotes the expression of the pluripotent factor Lin28 and the self-renewal of ES cells.', 'Autoimmune regulator (Aire) is one of the most well-characterized molecules in autoimmunity, but its function outside the immune system is largely unknown. The recent discovery of Aire expression in stem cells and early embryonic cells and its function in the self-renewal of embryonic stem (ES) cells highlight the importance of Aire in these cells.', 'The recent discovery of Aire expression in stem cells and early embryonic cells and its function in the self-renewal of embryonic stem (ES) cells highlight the importance of Aire in these cells. The correlation between Aire and Lin28 expression in germ cells and early embryos indicated an in vivo function for Aire in toti- and pluripotent stem cells. Moreover, it presents the first evidence that microRNAs contribute to the regulatory function of Aire and highlights a novel function of Aire in stem cell biology and reproduction. Monitoring Aire expression in MSCs may thus be a critical parameter for clinical use.']
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['stem cell renewal and self-immune tolerance']
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Which are the musculoskeletal manifestations of Marfan syndrome?
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['Musculoskeletal manifestations include scoliosis, dural ectasia, protrusio acetabuli, and ligamentous laxity.', 'Scoliosis, pectus excavatum and carinatum, arachnodactyly, and acetabular protrusion are common musculoskeletal manifestations.', "Two cases are described in which protrusio acetabuli was a major problem. Otto pelvis should be considered as one of the musculoskeletal manifestations of Marfan's syndrome.", 'The following musculoskeletal abnormalities were found: pectus in 3 patients (11%), pectus and scoliosis in 19 (73%), dolichostenomelia in 11 (42%) and arachnodactyly in 21 (80%).', 'Musculoskeletal clinicians should be aware of the diagnostic features of Marfan syndrome. Patients with three to four physically evident features, or two highly specific features (e.g., thumb and wrist signs, craniofacial features, dural ectasia, or protrusio), should be carefully reexamined and possibly referred for an echocardiogram or a genetics consultation.']
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['Musculoskeletal manifestations of Marfan syndrome include scoliosis, dural ectasia, pectus excavatum and carinatum, arachnodactyly, otto pelvis (protrusio acetabuli), dolichostenomelia and ligamentous laxity.']
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['scoliosis', 'dural ectasia', 'pectus excavatum and carinatum', 'arachnodactyly', 'otto pelvis', 'protrusio acetabuli', 'dolichostenomelia', 'ligamentous laxity']
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Which are the major types of the motor speech disorder dysarthria?
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['Dysarthria is a motor speech disorder which can be classified according to the underlying neuropathology and is associated with disturbances of respiration, laryngeal function, airflow direction, and articulation resulting in difficulties of speech quality and intelligibility. There are six major types of dysarthria: flaccid dysarthria associated with lower motor neuron impairment, spastic dysarthria associated with damaged upper motor neurons linked to the motor areas of the cerebral cortex, ataxic dysarthria primarily caused by cerebellar dysfunction, and hyperkinetic dysarthria and hypokinetic dysarthria, which are related to a disorder of the extrapyramidal system. The sixth is generally termed a mixed dysarthria and is associated with damage in more than one area, resulting in speech characteristics of at least two groups.', 'address voice problems of stroke patients with mixed dysarthria', 'Characterizing intonation deficit in motor speech disorders: an autosegmental-metrical analysis of spontaneous speech in hypokinetic dysarthria, ataxic dysarthria', 'ataxic dysarthria (AT)', 'Acoustic analysis provides objective quantitative measures of speech that enable a comprehensive and accurate understanding of motor disorders and complement the traditional measures. This paper aims to distinguish between normal and pathological speech, more specifically between apraxia of speech and spastic dysarthria', 'Long-term phonatory instability in ataxic dysarthria.', 'The objective of this study is to evaluate phonation in ataxic dysarthria and a control group of normal speakers', 'Dysprosody is a common feature in speakers with hypokinetic dysarthria.', 'The prosodic profile of Cantonese speakers with hypokinetic dysarthria is similar to those of other languages (for example, English).', 'Classification of dysarthria types comprises flaccid, spastic, ataxic, hypo- and hyperkinetic and mixed dysarthria.', 'Dysarthria affects linguistic domains such as respiration, phonation, articulation, resonance and prosody due to upper motor neuron, lower motor neuron, cerebellar or extrapyramidal tract lesions.', 'The dysarthria types were spastic (15 subjects), flaccid (10), mixed (12), hypokinetic (12), hyperkinetic (9) and ataxic (8).', 'Dysarthria is a motor speech disorder which can be classified according to the underlying neuropathology and is associated with disturbances of respiration, laryngeal function, airflow direction, and articulation resulting in difficulties of speech quality and intelligibility.', 'There are six major types of dysarthria: flaccid dysarthria associated with lower motor neuron impairment, spastic dysarthria associated with damaged upper motor neurons linked to the motor areas of the cerebral cortex, ataxic dysarthria primarily caused by cerebellar dysfunction, and hyperkinetic dysarthria and hypokinetic dysarthria, which are related to a disorder of the extrapyramidal system.', 'There are six major types of dysarthria: flaccid dysarthria associated with lower motor neuron impairment, spastic dysarthria associated with damaged upper motor neurons linked to the motor areas of the cerebral cortex, ataxic dysarthria primarily caused by cerebellar dysfunction, and hyperkinetic dysarthria and hypokinetic dysarthria, which are related to a disorder of the extrapyramidal system.', 'Motor neuron disease encompasses a group of terminal, demyelinating diseases affecting upper- and lower-motor neurons and producing muscular weakness resulting in a flaccid, spastic, or spastic-flaccid dysarthria of speech.', 'Dysarthria is a frequently occurring motor speech disorder which can be caused by neurological trauma, cerebral palsy, or degenerative neurological diseases.', 'Dysarthria is a motor disorder of speech characterized by abnormalities of the articulation and intelligibility of speech.', 'There are six major types of dysarthria: flaccid dysarthria associated with lower motor neuron impairment, spastic dysarthria associated with damaged upper motor neurons linked to the motor areas of the cerebral cortex, ataxic dysarthria primarily caused by cerebellar dysfunction, and hyperkinetic dysarthria and hypokinetic dysarthria, which are related to a disorder of the extrapyramidal system']
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['Dysarthria is a motor speech disorder which can be classified according to the underlying neuropathology and is associated with disturbances of respiration, laryngeal function, airflow direction, and articulation resulting in difficulties of speech quality and intelligibility. There are six major types of dysarthria: "flaccid dysarthria" associated with lower motor neuron impairment, "spastic dysarthria" associated with damaged upper motor neurons linked to the motor areas of the cerebral cortex, "ataxic dysarthria" primarily caused by cerebellar dysfunction, and "hyperkinetic dysarthria" and "hypokinetic dysarthria", which are related to a disorder of the extrapyramidal system. The sixth is generally termed a "mixed dysarthria" and is associated with damage in more than one area, resulting in speech characteristics of at least two groups.']
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['flaccid dysarthria', 'spastic dysarthria', 'ataxic dysarthria', 'hyperkinetic dysarthria', 'hypokinetic dysarthria', 'mixed dysarthria']
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How do antihormonal agents help treat breast cancer in patients who have failed prior therapies?
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['["For women with hormone receptor-positive advanced breast cancer, endocrine therapies, including the selective estrogen receptor modulator tamoxifen, the aromatase inhibitors anastrozole, letrozole, and exemestane, and the selective estrogen receptor degrader fulvestrant, are recommended in clinical guidelines.", "Here we describe and characterize a novel, orally bioavailable small-molecule selective estrogen receptor degrader, RAD1901, and evaluate its therapeutic potential for the treatment of breast cancer.", "Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts.", "Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-\\u03b1 and is active in patients who have progressed on antihormonal agents. ", "Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader.", "However, being the only SERD currently known to access the brain, RAD1901 merits evaluation as a targeted therapy for the treatment of breast cancer brain metastases.", "Tamoxifen, toremifene, and the selective estrogen receptor degrader fulvestrant are used to treat breast cancer, and tamoxifen and raloxifene protect against breast cancer in high-risk women.", "The turnover of estrogen receptor \\u03b1 by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy.", "Currently, ICI 182,780 (ICI, fulvestrant) is the only SERD approved for the treatment of breast cancer. ", "Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-\\u00e1 and is active in patients who have progressed on antihormonal agents.", "Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-\\u03b1 and is active in patients who have progressed on antihormonal agents", "RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models.", "RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. ", "The selective estrogen receptor degrader, fulvestrant, significantly reduced the anchorage-independent growth of ESR1 mutant-expressing cells, while combination treatments with the mTOR inhibitor everolimus, or an inhibitor blocking IGF1R, and the insulin receptor significantly enhanced anti-proliferative responses.", "SUM-44\\u00a0cells do not require exogenous estrogen for growth in\\u00a0vitro; however, they are dependent on ER\\u03b1 expression, as ESR1 knock-down or exposure to the selective estrogen receptor degrader fulvestrant resulted in growth inhibition.", "Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader.", "Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-\\u03b1 and is active in patients who have progressed on antihormonal agents."]']
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Antihormonal agents, such as the selective estrogen receptor degrader fulvestrant, are used to treat breast cancer in patients who have failed prior therapies by antagonizing and degrading ER-α, which is active in patients who have progressed on antihormonal agents.
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[]
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How do value judgments, rather than cost, play a central role in coverage decisions for health insurance plans regarding treatments like Viagra and Zyban?
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['["Treatment with sildenafil was less costly and resulted in a greater gain in quality-adjusted life-years (QALYs) compared with other treatments. ", "Based on this model, sildenafil is a cost-effective treatment for PAH with a low price and a net increase in QALYs.", "Four treatment strategies, Viagra, Rivastigmine, statins, and lung transplants, are analysed with respect to whether either cost-effectiveness or need, or both, seem to have played a role in the decisions", "it seems that decisions are almost exclusively made with reference to the principle of need.", "In Sweden ", "decisions on priority setting are almost solely based on the principle of need. This implies that the principle of cost-effectiveness is given very little space, which is a problem as this means an obvious risk of inefficient resource use.", "The case of Viagra, it concludes, holds out two general lessons: first, allow exceptions to total bans on reimbursement; second, involve the medical profession in the decision-making process.", "This paper analyzes the rationing strategies adopted in four countries (United States, Britain, Germany, and Sweden),", "the question whether statutory social health insurances are obliged to reimburse the costs for the treatment of erectile dysfunction. ", "Coverage of sildenafil by health insurance plans is a contentious issue. ", "coverage of Viagra and Zyban was limited predominantly through generalized exclusion or through restrictions on quantity or duration of use. Value judgments, rather than cost, seem to play a central, though largely unspoken, role in these coverage decisions.", "availability of orphan drugs and in patient access to them in 11 pharmaceutical markets: Australia, Canada, England, France, Germany, Hungary, the Netherlands, Poland, Slovakia, Switzerland and the US. ", "lthough the present study showed some variations between countries in selected indicators of availability and access to orphan drugs, virtually all of the drugs in question were available and accessible in our sample. However, substantial co-payments in the US and Canada represent important barriers to patient access, especially in the case of expensive treatments such as those analysed in this study.", "Adults with evidence of PAH from 1 January 2004 (commercial and Medicaid) or 1 July 2006 (Medicare Advantage) through 30 June 2008 were identified.", "Most patients (94%) initiated treatment with monotherapy (most commonly sildenafil or bosentan)", "Mean PAH-related healthcare costs were $6617 per patient per month, comprising 71% of all-cause costs.", "Retrospective claims database analysis of 706 patients with PAH enrolled in a large, geographically diverse US managed-care organization.", "Of the oral agents approved for treating PAH at the time of this study, sildenafil was most commonly prescribed as index therapy and was also associated with the lowest costs, largely due to significantly lower pharmacy costs. This study is characterized by limitations inherent to claims database analyses, ", "Erectile dysfunction (ED) affects approximately 30 million men in the United States. The objectives of this study were to (1) assess the cost and utilization of sildenafil citrate (Viagra), an oral therapeutic agent for ED, in a large managed care organization (MCO) with a quantity limit of 6 units per 30-day supply and", "The total allowed charges for sildenafil pharmacy claims in 2001 were 3.56 million US dollars, of which patients paid 26.6% in average cost-share, and the net MCO cost per member per month (PMPM) was 0.18 US dollars. A total of 1,681 patients (8.3%) exceeded their quantity restrictions for sildenafil tablets in 2001, of which 1,362 (81.0%) paid cash and 319 (19.0%, or 1.6% of all sildenafil users) appealed and received approval from the MCO for additional sildenafil tablets beyond the restriction of 6 tablets per month", "A quantity limit of 6 tablets of sildenafil per 30-day period was associated with a drug cost to users and the MCO of 0.25 US dollars PMPM. Sildenafil users paid an average cost-share of 26.6%, resulting in a net drug cost of 0.18 US dollars PMPM to the MCO.", "Managed care companies are expected to counter runaway pharmacy costs for sildenafil by excluding it from coverage, imposing significant limitations, or requiring higher copayments."]']
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Value judgments, rather than cost, seem to play a central, though largely unspoken, role in coverage decisions for health insurance plans regarding treatments like Viagra and Zyban. The decisions are almost exclusively made with reference to the principle of need, giving very little space to cost-effectiveness considerations.
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Are alterations in ultraconserved elements associated with colorectal adenocarcinoma?
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['Genetic variants within ultraconserved elements and susceptibility to right- and left-sided colorectal adenocarcinoma', 'Our results strongly suggest that several genetic variants in the UCEs may contribute to CRC susceptibility, individually and jointly, and that different genetic etiology may be involved in RCRC and LCRC', 'Identification of polymorphisms in ultraconserved elements associated with clinical outcomes in locally advanced colorectal adenocarcinoma', "To the authors' knowledge, this is the first study to evaluate the association between SNPs within UCEs and clinical outcome in patients with CRC. The results suggested that SNPs within UCEs may be valuable prognostic biomarkers for patients with locally advanced CRC who receive 5-fluorouracil-based chemotherapy", 'Identification of polymorphisms in ultraconserved elements associated with clinical outcomes in locally advanced colorectal adenocarcinoma.', 'Genetic variants within ultraconserved elements and susceptibility to right- and left-sided colorectal adenocarcinoma.', 'We investigated whether single nucleotide polymorphisms within ultraconserved elements (UCEs) are associated with susceptibility to overall colorectal cancer (CRC) and susceptibility to tumor site-specific CRC.', 'We investigated whether single nucleotide polymorphisms within ultraconserved elements (UCEs) are associated with susceptibility to overall colorectal cancer (CRC) and susceptibility to tumor site-specific CRC', 'Identification of polymorphisms in ultraconserved elements associated with clinical outcomes in locally advanced colorectal adenocarcinoma.', 'Genetic variants within ultraconserved elements and susceptibility to right- and left-sided colorectal adenocarcinoma.', 'Expression levels of transcribed ultraconserved regions uc.73 and uc.388 are altered in colorectal cancer.']
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['yes', 'Yes. SNPs within ultraconserved elements (UCEs) may be valuable prognostic biomarkers for patients with locally advanced CRC who receive 5-fluorouracil-based chemotherapy.']
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['yes']
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Which micro-RNAs have been associated in the pathogenesis of Rheumatoid Arthritis?
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['This study provides the first description of increased expression of miRNA miR-155 and miR-146a in RA', 'In this study we investigated the expression, regulation, and function of miR-155 and miR-146a in rheumatoid arthritis (RA) synovial fibroblasts (RASFs) and RA synovial tissue', 'The objective of this study was to identify the expression pattern of microRNA-146 (miR-146) in synovial tissue from patients with rheumatoid arthritis (RA)', 'This study shows that miR-146 is expressed in RA synovial tissue and that its expression is induced by stimulation with TNFalpha and IL-1beta', 'pregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients', 'Total RNA was isolated from peripheral blood mononuclear cells obtained from patients with rheumatoid arthritis, and healthy and disease control individuals, and the expression of miR-146a, miR-155, miR-132, miR-16, and microRNA let-7a was analyzed using quantitative real-time PCR', 'Rheumatoid arthritis peripheral blood mononuclear cells exhibited between 1.8-fold and 2.6-fold increases in miR-146a, miR-155, miR-132, and miR-16 expression, whereas let-7a expression was not significantly different compared with healthy control individuals', 'Our data also suggest a possible mechanism contributing to rheumatoid arthritis pathogenesis, whereby miR-146a expression is increased but unable to properly function, leading to prolonged tumor necrosis factor-alpha production in patients with rheumatoid arthritis', 'Repression of TRAF6 and/or IRAK-1 in THP-1 cells resulted in up to an 86% reduction in tumor necrosis factor-alpha production, implicating that normal miR-146a function is critical for the regulation of tumor necrosis factor-alpha production', 'icroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis', 'We found that miR-124a levels significantly decreased in RA synoviocytes as compared with OA synoviocytes', 'Induction of miR-124a in RA synoviocytes significantly suppressed the production of the CDK-2 and MCP-1 proteins', 'he results of this study suggest that miR-124a is a key miRNA in the posttranscriptional regulatory mechanisms of RA synoviocytes', 'iR-223 is overexpressed in T-lymphocytes of patients affected by rheumatoid arthritis.', 'Although a multifactorial pathogenesis has been hypothesized, the precise mechanisms leading to the disease are still poorly understood at the molecular level. miRNA expression profile analysis highlighted that miR-223 is the only miRNA that is strikingly deregulated in peripheral T-lymphocytes from RA patients compared with healthy donors', 'In summary, our data provide a first characterization of the miRNA expression profiles of peripheral T-lymphocytes of RA patients, identifying miR-223 as overexpressed in CD4(+) naive T-lymphocytes from these individuals', 'Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis', 'The role of miR-146a overexpression in regulating T cell apoptosis was evaluated by flow cytometry', 'We have detected increased miR-146a in CD4+ T cells of RA patients and its close correlation with TNF-alpha levels. Our findings that miR-146a overexpression suppresses T cell apoptosis indicate a role of miR-146a in RA pathogenesis and provide potential novel therapeutic targets', 'icroRNA-146a expresses in interleukin-17 producing T cells in rheumatoid arthritis patients', 'Six miRNAs, let-7a, miR-26, miR-146a/b, miR-150, and miR-155 were significantly up regulated in the IL-17 producing T cells', 'These results indicated that miR-146a was associated with IL-17 expression in the PBMC and synovium in RA patients', "polymorphism in the 3'-UTR of interleukin-1 receptor-associated kinase (IRAK1), a target gene of miR-146a, is associated with rheumatoid arthritis susceptibility", 'MicroRNA-146a was found to be increased in synovial fibroblasts, synovial tissue and PBMC from patients with RA', 'This is the first study that addresses association of a variant in a target of miR-146a, IRAK1 gene, with RA susceptibility', 'ltered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation', 'Previously, we described increased expression of miR-155 and miR-146a in rheumatoid arthritis (RA) and showed a repressive effect of miR-155 on matrix metalloproteinase (MMP) expression in RA synovial fibroblasts (RASFs)', 'The current results demonstrate methylation-dependent regulation of miR-203 expression in RASFs', ' Importantly, they also show that elevated levels of miR-203 lead to increased secretion of MMP-1 and IL-6 via the NF-κB pathway and thereby contribute to the activated phenotype of synovial fibroblasts in RA', 'iR-124a as a key regulator of proliferation and MCP-1 secretion in synoviocytes from patients with rheumatoid arthritis', 'Transfection of miR-124a into RA synoviocytes significantly suppressed their proliferation and arrested the cell cycle at the G1 phase', 'It is proposed that miR-124a is a key miRNA in the post-transcriptional regulatory mechanisms of RA synoviocytes, and has a therapeutic potential', 'Expression of miR-146a and miR-16 in peripheral blood mononuclear cells of patients with rheumatoid arthritis and their correlation to the disease activity', 'The elevated expression levels of miR-146a and miR-16 are correlated to RA disease activity, suggesting their value in assessment of the clinical disease activity of RA', 'iR-346 controls release of TNF-α protein and stability of its mRNA in rheumatoid arthritis via tristetraprolin stabilization', "Using a microarray, we found two miRNAs, miR-125b and miR-939 predicted to target the 3'-UTR of TNF-α mRNA, to be up-regulated in RA FLS in response to LPS, but their repression did not restore mature TNF-α expression in FLS", 'We showed previously that miR-346, which is upregulated in LPS-activated FLS, inhibited Btk expression that stabilized TNF-α mRNA', 'Different expression patterns of mir-146a, miRNA-155, miRNA-124a, mir-203, mir-223, mir-346, mir-132, mir-363, mir-498, mir-15a, and mir-16 were documented in several tissue sample types of RA patients', 'own-regulation of microRNA-34a* in rheumatoid arthritis synovial fibroblasts promotes apoptosis resistance', 'Basal expression levels of miR-34a* were found to be reduced in synovial fibroblasts from RA patients compared to osteoarthritis patients, whereas levels of miR-34a, miR-34b/b*, and miR-34c/c* did not differ', 'Our data provide evidence of a methylation-specific down-regulation of proapoptotic miR-34a* in RASFs', 'dentification of microRNA-221/222 and microRNA-323-3p association with rheumatoid arthritis via predictions using the human tumour necrosis factor transgenic mouse model', 'miR-seq demonstrated that TghuTNF-SF exhibit a distinct pathogenic profile with 22 significantly upregulated and 30 significantly downregulated miR', 'Validation assays confirmed the dysregulation of miR-223, miR-146a and miR-155 previously associated with human rheumatoid arthritis (RA) pathology, as well as that of miR-221/222 and miR-323-3p', 'the authors identified miR-221/222 and miR-323-3p as novel dysregulated miR in RA SF', 'Further association studies may contribute to determining the role of miR-146a single-nucleotide polymorphisms in immune-mediated diseases', 'iR-146a polymorphism is associated with asthma but not with systemic lupus erythematosus and juvenile rheumatoid arthritis in Mexican patients.', 'verexpression of microRNA-223 in rheumatoid arthritis synovium controls osteoclast differentiation', 'MicroRNA-223 (miR-223) is reported to play critical roles in osteoclastogenesis', 'MiR-223 is intensely expressed in RA synovium, and overexpression of miR-223 suppresses osteoclastogenesis in vitro', 'This study demonstrates the possibility of gene therapy with miR-223 to treat bone destruction in RA patients', 'MiR-223 was more highly expressed in RA synovium than in osteoarthritis (OA) synovium due to the increased number of miR-223-positive cells in RA synovium', 'ssociation of pre-miRNA-146a rs2910164 and pre‑miRNA-499 rs3746444 polymorphisms and susceptibility to rheumatoid arthritis', 'Our findings demonstrated that the hsa-mir-499 rs3746444, but not mir-146a rs2910164, polymorphism is associated with an increased RA risk in a sample of the Iranian population', 'umor necrosis factor α-induced microRNA-18a activates rheumatoid arthritis synovial fibroblasts through a feedback loop in NF-κB signaling', 'To elucidate whether the microRNA (miRNA) cluster miR-17-92 contributes to the activated phenotype of rheumatoid arthritis synovial fibroblasts (RASFs', 'We found that TNFα induces the expression of miR-17-92 in RASFs in an NF-κB-dependent manner', 'Using reporter gene assays, we identified the NF-κB pathway inhibitor TNFα-induced protein 3 as a new target of miR-18a', 'Our data suggest that the miR-17-92-derived miR-18a contributes to cartilage destruction and chronic inflammation in the joint through a positive feedback loop in NF-κB signaling, with concomitant up-regulation of matrix-degrading enzymes and mediators of inflammation in RASFs', 'As inflammation and joint damage are the main hallmarks of RA, we focused on the three miRNAs, miR-146a, miR-155 and miR-223, whose functions have been studied in both the processes and the pathogenic role investigated in the experimental models', 'Focusing on the role of miR-146a, miR-155 and miR-223 in RA pathogenesis emphasizes the intertwined relationships between bone homeostasis and immunity, and the prominent role of monocytes in RA', 'In a final perspective section we discuss the potential impact of therapeutic miR-155 modulation in RA', 'correlation between whole blood and PBMC expression levels of miR-155 and miR-146a in healthy controls and rheumatoid arthritis patients', 'We demonstrated a highly significant linear correlation between miR-146a and miR-155 expression in PBMC and whole blood, from both healthy individuals and RA patients.', 'expression of specific microRNAs (miRNA) in peripheral blood-derived mononuclear cells (PBMC), particularly miR-146a and miR-155, is associated with rheumatoid arthritis (RA)', "icroRNA-323-3p with clinical potential in rheumatoid arthritis, Alzheimer's disease and ectopic pregnancy", "It has been shown that miR-323-3p associates with the pathogenesis of several diseases, such as rheumatoid arthritis, Alzheimer's disease and ectopic pregnancy"]
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['Different expression patterns of mir-146a, miRNA-155, miRNA-124a, mir-203, mir-223, mir-346, mir-132, mir-363, mir-498, mir-15a, and mir-16 were documented in several tissue sample types of RA patients.']
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['miR-155', 'miR-146a', 'miR-124a', 'miR-222', 'miR-223', 'miR-203', 'miR-346', 'miR-132', 'miR-363', 'miR-498', 'miR-15a', 'miR-16', 'miR-18a']
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What is Mondor's disease?
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["INTRODUCTION: Mondor's disease is a rare superficial thrombophlebitis, historically involving the thoracic venous system of women. ", "Mondor's disease is a rare benign and self-limiting condition characterized by thrombophlebitis of the superficial veins of the anterolateral thoracoabdominal wall.", "Mondor's disease is a rare condition characterized by a superficial thrombophlebitis that can occur in the thoracoabdominal and genital areas. ", "CONCLUSION: Penile Mondor disease is a rare complication that can be successfully treated with medical therapy and conservative approach. Our series showed that penile Mondor's disease does not lead to permanent deformation of the penis or erectile dysfunction.", 'Thrombophlebitis of the thoracoepigastric system of veins is a benign disease and, despite its localized involvement and presentation, the condition is known as Mondor disease (MD).', "Though penile Mondor's disease involving the dorsal vein of the penis has been reported by many authors, we report a peculiar case of penile Mondor's disease in a 26-year-old sexually active man with thrombophlebitis of the circumflex vein of the penis with sparing of the dorsal vein.", "Mondor's disease of the penis is an uncommon condition, which usually involves the superficial dorsal veins, it was first described by Braun-Falco in 1955.", "Penile Mondor's disease is rare disease that's characterized by thrombosis in the dorsal vein of the penis."]
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["Mondor's disease is a rare benign and self-limiting condition characterized by thrombophlebitis of the superficial veins of the anterolateral thoracoabdominal wall and genital area."]
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Which deficiency is the cause of restless leg syndrome?
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['We describe a unique case of a 23-yr-old female patient affected by a homozygous loss of function mutation in the L-ferritin gene, idiopathic generalized seizures, and atypical restless leg syndrome (RLS). We show that L chain ferritin is undetectable in primary fibroblasts from the patient, and thus ferritin consists only of H chains.', 'Our results demonstrate for the first time the pathophysiological consequences of L-ferritin deficiency in a human and help to define the concept for a new disease entity hallmarked by idiopathic generalized seizure and atypical RLS.', 'These results when viewed along with prior RLS SPECT and autopsy studies of DAT, and cell culture studies with iron deficiency and DAT, suggest that membrane-bound striatal DAT, but not total cellular DAT, may be decreased in RLS.', ' Compared with the PD or healthy group, the level of serum ferritin and the H-reflex latency of tibial nerve were significantly decreased in PD with RLS group (P < 0.05).', 'Deficiency of iron and decreased inhibition function of spinal cord may lead to the occurrence of RLS in PD patients. ', 'Association of iron deficiency with febrile seizures, pica, breath holding spells, restless leg syndrome and thrombosis is increasingly being recognized.', ' Iron status was generally poor among regular blood donors, especially in women, with a high incidence of iron depletion (>20%) and RLS (18%). ', 'Iron status is poor in regular blood donors, restless legs syndrome is common, and the routine iron supplementation is insufficient. ', 'Furthermore, there appears to be an association between iron deficiency and those suffering from Restless Leg Syndrome (RLS). ', 'The authors propose that PPIs, such as omeprazole, may interfere with iron absorption in certain patients and that a subpopulation of patients who develop significant iron deficiency characterized by low serum ferritin levels while on PPIs may also develop RLS-like symptoms (including RLSAP).', 'Clinical studies have implicated the dopaminergic system in RLS, while others have suggested that it is associated with insufficient levels of brain iron. ', 'The results are consistent with the hypothesis that a primary iron insufficiency produces a dopaminergic abnormality characterized as an overly activated dopaminergic system as part of the RLS pathology.', 'RLS may also be secondary to a number of conditions including iron deficiency, pregnancy and end-stage renal failure and, perhaps, neuropathy.', 'The pathogenesis of RLS probably involves the interplay of systemic or brain iron deficiency and impaired dopaminergic neurotransmission in the subcortex of the brain. ', 'All patients showed low levels of ferritin and iron supplementation was effective in five cases. ', 'Clinical and animal studies that support the benefits of iron supplementation, independent of increasing hemoglobin, such as those on immune function, physical performance, thermoregulation, cognition, and restless leg syndrome and aluminum absorption is the subject of this narrative review.', 'Restless leg syndrome (RLS) and periodic limb movement disorder (PLMD) are considered to be a continuum of a neurological sleep disorder associated with abnormal iron metabolism or deficiency. I describe a case of RLS and PLMD in a cystic fibrosis patient with iron deficiency from chronic hemoptysis. This is the first case that reports RLS and PLMD manifesting from iron deficiency caused by chronic hemoptysis in advanced cystic fibrosis lung disease.', 'Restless leg syndrome manifested by iron deficiency from chronic hemoptysis in cystic fibrosis.', 'Diurnal effects on motor control are evident in the human disease of Restless Leg Syndrome (RLS), which is purported to be linked to brain iron deficiency as well as alterations in dopaminergic systems. ', 'Iron deficiency in the central nervous system is known to cause motor impairment and cognitive deficits; more recently, it has been suggested that it may play a role in the pathophysiology of the restless leg syndrome. ', 'Restless leg syndrome (RLS), aging, pregnancy, uraemia, iron deficiency, polyneuropathy are some of the common causes of secondary PLMD.', 'The syndrome is increasingly often diagnosed, particularly in association with iron deficiency, during pregnancy, in chronic renal failure and in patients with peripheral neuropathy. ', 'Clinical, EEG, electromyographic and polysomnographic studies in restless legs syndrome caused by magnesium deficiency.', 'A frequent polymorphism in BTBD9 was significantly associated with serum ferritin. This polymorphism has previously been associated with RLS, but not low iron stores in blood donors.']
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['It has been well-documented that iron deficiency is the cause of restless leg syndrome. Magnesium and ferritin were also associated with restless leg syndrome.']
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['iron']
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What type of DNA repair pathways is initiated by AlkA glycosylase?
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['The Escherichia coli 3-methyladenine DNA glycosylase II protein (AlkA) recognizes a broad range of oxidized and alkylated base lesions and catalyzes the hydrolysis of the N-glycosidic bond to initiate the base excision repair pathway.', 'Schizosaccharomyces pombe has two paralogues of 3-methyladenine DNA glycosylase, Mag1p and Mag2p, which share homology with Escherichia coli AlkA. To clarify the function of these redundant enzymes in base excision repair (BER) of alkylation damage', 'Escherichia coli alkA tagA double mutants, which are deficient in the repair of alkylated bases.', 'AlkA, a monofunctional DNA glycosylase that acts on alkylated bases, is structurally homologous to endo III. We have now identified a shared active site motif amongst these three proteins. Using this motif as a protein database searching tool, we find that it is present in a number of other base-excision DNA repair proteins that process diverse lesions.', 'Alkylation damage is removed by the action of DNA glycosylases, which initiate the base excision repair pathway', 'Enzymatic repair of 5-formyluracil. I. Excision of 5-formyluracil site-specifically incorporated into oligonucleotide substrates by alka protein (Escherichia coli 3-methyladenine DNA glycosylase II).', 'These results suggest that fU present in DNA can be restored by two independent repair pathways, i.e. the base excision repair pathway initiated by AlkA and the methyl-directed mismatch repair pathway initiated by MutS.', '3-Methyladenine DNA glycosylase II (AlkA) is a DNA-repair enzyme that removes alkylated bases in DNA via the base-excision repair (BER) pathway.', 'Mismatch formation between 5-formyluracil and guanine during dna replication and its recognition by two proteins involved in base excision repair (AlkA) and mismatch repair (MutS).', 'These results suggest that fU present in DNA can be restored by two independent repair pathways, i.e. the base excision repair pathway initiated by AlkA and the methyl-directed mismatch repair pathway initiated by MutS.', 'Base excision repair is initiated by DNA glycosylases removing inappropriate bases from DNA.', 'The Escherichia coli AlkA protein is a base excision repair glycosylase that removes a variety of alkylated bases from DNA.', 'Human alkyladenine glycosylase (AAG) and Escherichia coli 3-methyladenine glycosylase (AlkA) are base excision repair glycosylases that recognize and excise a variety of alkylated bases from DNA.', 'the base excision repair pathway initiated by AlkA and the methyl-directed mismatch repair pathway initiated by MutS', 'The Escherichia coli 3-methyladenine DNA glycosylase II protein (AlkA) recognizes a broad range of oxidized and alkylated base lesions and catalyzes the hydrolysis of the N-glycosidic bond to initiate the base excision repair pathway', 'Alkylation damage is removed by the action of DNA glycosylases, which initiate the base excision repair pathway and protect the sequence information of the genome [3-5]', "The alkylbase DNA glycosylase, AlkA, initiates repair by removal of the damaged base, whereas endonuclease V, Endo V, hydrolyses the second phosphodiester bond 3' to the lesion", 'Base excision repair is initiated by DNA glycosylases removing inappropriate bases from DNA']
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['The AlkA protein (3-methyladenine DNA glycosylase II protein) is a monofunctional DNA glycosylase that recognizes a broad range of oxidized and alkylated base lesions and catalyzes the hydrolysis of the N-glycosidic bond to initiate the base excision repair (BER) pathway.']
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['base excision repair (BER) pathway']
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What DNA methylation patterns are common in high-grade thalamic gliomas in young adults with the H3F3A K27M mutation?
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[' transgenes are sufficient to reduce the amounts of H3K27me3 in vitro and in vivo.", "In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas.CONCLUSION: We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M.", "Gliomas with H3F3A K27M from pediatric or young adult patients had similar, characteristic DNA methylation profiles.", "Although the K27M mutation was frequently observed in adult brainstem and thalamic gliomas, this mutation tended to be associated with a poorer prognosis in brainstem gliomas but not in thalamic gliomas.", "Diffuse Midline Gliomas with Histone H3-K27M Mutation: A Series of 47 Cases Assessing the Spectrum of Morphologic Variation and Associated Genetic Alterations.", "In this series, histone H3-K27M mutation was mutually exclusive with IDH1 mutation and EGFR amplification, rarely co-occurred with BRAF-V600E mutation, and was commonly associated with p53 overexpression, ATRX loss (except in pontine gliomas), and monosomy 10.", "The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults.", "K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.", "Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78\\u00a0% of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36\\u00a0% of non-brainstem gliomas carrying either K27M or G34R/V mutations.", "Interestingly, the G34 mutations, the K36M mutations, and the majority of K27M mutations occur in genes encoding the replacement histone H3.3."]']
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High-grade thalamic gliomas in young adults with the H3F3A K27M mutation commonly have DNA methylation profiles similar to those of hemispheric glioblastomas.
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What are the effects of BMAL1 deficiency?
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['BMAL1 deficiency is associated with premature aging and reduced lifespan', 'BMAL1 deficiency leads to development of stress induced senescence in vivo.', ' Down-regulation of Bmal1 accelerates the development of tumours ', 'BMAL1 deficiency results in premature aging in mice', 'BMAL1 deficiency disrupts circadian oscillation in gene expression and reactive oxygen species homeostasis in the brain,', 'We demonstrate that attenuation of Bmal1 function resulted in down-regulation of genes in the canonical Wnt pathway, known to suppress adipogenesis. ']
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['BMAL1 deficiency is associated with premature aging and reduced lifespan and BMAL1 deficiency leads to development of stress induced senescence in vivo. Down-regulation of Bmal1 also accelerates the development of tumours, adipogenesis.']
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Which syndrome is associated with OATP1B1 and OATP1B3 deficiency?
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['Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3.', 'Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. ', 'Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver.', 'Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3.', 'Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3.', 'Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.', 'Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.', 'Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver', 'Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3', 'The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3.', 'The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3.', 'Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane.', 'Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane.', 'Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.', 'Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.', 'Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver.', 'Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3.', 'Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3.', 'Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.']
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['Complete and simultaneous deficiency of the organic anion transporting polypeptides OATP1B1 and OATP1B3 due to mutations in their corresponding genes, has been linked to Rotor syndrome.']
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['Rotor syndrome']
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List two chemotherapeutic agents that are used for treatment of Subependymal Giant Cell Astrocytoma
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['Everolimus has been approved by the FDA and the EMA for the treatment of advanced renal cell carcinoma (RCC), subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TSC), pancreatic neuroendocrine tumors (PNET), in combination with exemestane in advanced hormone-receptor (HR)-positive, HER2-negative breast cancer.', 'The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1.', 'Our objective was to evaluate everolimus, an mTOR inhibitor, in the treatment of angiomyolipoma in patients with subependymal giant cell astrocytoma (SEGA) associated with TSC. METHODS: EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 (NCT00789828), a prospective, double-blind, randomized, placebo-controlled, Phase 3 study, examined everolimus in treating SEGA associated with TSC. Patients with serial SEGA growth from pre-baseline to baseline scans were randomly assigned (2:1) to receive 4.5 mg/m(2)/day everolimus (target blood trough: 5-15 ng/mL; n = 78) or placebo (n = 39). ', 'CONCLUSIONS: Everolimus showed efficacy in reducing angiomyolipoma lesion volume in patients with SEGA associated with TSC.', 'Everolimus has demonstrated substantial clinical benefit in randomized, controlled, phase III studies leading to approval for the treatment of advanced renal cell carcinoma, advanced neuroendocrine tumors of pancreatic origin, renal angiomyolipoma and subependymal giant-cell astrocytoma associated with tuberous sclerosis complex, as well as advanced hormone-receptor-positive (HR(+)) and human epidermal growth factor receptor-2-negative advanced breast cancer. ', 'Everolimus for the treatment of subependymal giant cell astrocytoma probably causing seizure aggravation in a child with tuberous sclerosis complex: a case report.', 'We are reporting on a 13.5-year-old girl with tuberous sclerosis complex (TSC) who was treated with everolimus because of giant cell astrocytoma and bilateral angiomyolipoma.', 'Response of subependymal giant cell astrocytoma with spinal cord metastasis to everolimus.', 'BACKGROUND: Brain subependymal giant cell astrocytomas (SEGAs) in patients with tuberous sclerosis have been reported to respond to everolimus. ', 'CONCLUSIONS: We describe a rare case of metastatic SEGA, which was successfully treated with everolimus.', 'Additional oncology indications for everolimus include renal angiomyolipoma with tuberous sclerosis complex and subependymal giant-cell astrocytoma.', 'Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of advanced renal cell carcinoma, pancreatic neuroendocrine tumors, subependymal giant cell astrocytoma associated with tuberous sclerosis complex, renal angiomyolipoma and tuberous sclerosis complex, and, in combination with exemestane, for hormone receptor-positive HER2-negative advanced breast cancer after failure of treatment with letrozole or anastrozole. ', 'Long-term effect of everolimus on epilepsy and growth in children under 3 years of age treated for subependymal giant cell astrocytoma associated with tuberous sclerosis complex.', 'AIMS: To show the long-term safety data and the effect of everolimus treatment on epilepsy in children under the age of 3 who received everolimus for SEGAs associated with TSC. ', 'CONCLUSIONS: This study suggests that everolimus is effective and safe in infants and young children with epilepsy and SEGA associated with TSC and offers a valuable treatment option.', 'Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma.', 'OBJECTIVE: To report long-term efficacy and safety data for everolimus for the treatment of subependymal giant cell astrocytoma (SEGA) in patients with tuberous sclerosis complex (TSC).', 'CONCLUSION: Everolimus therapy is safe and effective for longer term (median exposure 34.2 months) treatment of patients with TSC with SEGA. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that everolimus, titrated to trough serum levels of 5-15 ng/mL, was effective in reducing tumor size in patients with SEGA secondary to TSC for a median of 34 months.', 'Everolimus (RAD001): first systemic treatment for subependymal giant cell astrocytoma associated with tuberous sclerosis complex.', 'In patients with subependymal giant cell astrocytomas (SEGAs) associated with tuberous sclerosis complex who are not candidates for surgery, single-agent everolimus has demonstrated the ability to significantly reduce SEGA volume with good tolerability. In the Phase III, randomized, placebo-controlled trial, everolimus was associated with a SEGA response rate of 35% compared with 0% in the placebo group. ', 'Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial.', 'In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex. ', 'INTERPRETATION: These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis.', 'Everolimus for tumor recurrence after surgical resection for subependymal giant cell astrocytoma associated with tuberous sclerosis complex.', 'A recent phase 1/2 study demonstrated that treatment with the mammalian target of rapamycin inhibitor everolimus reduced subependymal giant cell astrocytoma volume by 30% in 75% of the patients, all of whom were poor candidates for surgical resection. ', 'All 4 experienced over 50% initial reduction in the volume of their subependymal giant cell astrocytoma after 2 to 3 years of therapy with everolimus.', 'METHODS: Recently, a phase I/II trial of everolimus demonstrated significant reductions in subependymal giant cell astrocytoma (SEGA) volume and decreased seizure frequency.', 'TSC patients with SEGA received everolimus, titrated to tolerability to achieve target trough concentrations of 5-15 ng/mL.', 'Everolimus: in patients with subependymal giant cell astrocytoma associated with tuberous sclerosis complex.', 'Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR). Everolimus (starting dosage 3.0\u2009mg/m(2)) was associated with a significant reduction in the volume of the largest subependymal giant cell astrocytoma (SEGA) in 28 patients aged ≥3 years with tuberous sclerosis complex (TSC) in a phase II trial (C2485). ', 'During the extension phase of this trial (median duration 34 months), the reduction in SEGA volume was maintained, with no everolimus recipient requiring surgery or other therapy for SEGA or hydrocephalus. ', 'Effective everolimus treatment of inoperable, life-threatening subependymal giant cell astrocytoma and intractable epilepsy in a patient with tuberous sclerosis complex.', 'We present successful everolimus treatment of a huge subependymal giant cell astrocytoma in a 10-year old boy with tuberous sclerosis complex. ', 'Everolimus tablets for patients with subependymal giant cell astrocytoma.', 'Recently, mTOR inhibitors such as everolimus have shown encouraging benefit for patients with SEGAs. ', 'The authors also examine the rationale for targeted agents against this pathway therapeutically and describe the clinical evidence underlying the FDA approval of everolimus for patients with inoperable SEGAs. EXPERT OPINION: Everolimus (Afinitor) selectively targets a molecular defect of SEGAs in TSC patients.', 'Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis.', 'An alternative may be the use of everolimus, which inhibits the mammalian target of rapamycin, a protein regulated by gene products involved in the tuberous sclerosis complex.', 'Everolimus therapy was associated with a clinically meaningful reduction in volume of the primary subependymal giant-cell astrocytoma, as assessed on independent central review (P<0.001 for baseline vs. 6 months), with a reduction of at least 30% in 21 patients (75%) and at least 50% in 9 patients (32%). ', 'CONCLUSIONS: Everolimus therapy was associated with marked reduction in the volume of subependymal giant-cell astrocytomas and seizure frequency and may be a potential alternative to neurosurgical resection in some cases, though long-term studies are needed.', 'The authors present a 21-year-old woman who has been receiving rapamycin for 5 months for bilateral subependymal giant cell astrocytomas.', 'We present successful everolimus treatment of a huge subependymal giant cell astrocytoma in a 10-year old boy with tuberous sclerosis complex.', 'A recent phase 1/2 study demonstrated that treatment with the mammalian target of rapamycin inhibitor everolimus reduced subependymal giant cell astrocytoma volume by 30% in 75% of the patients, all of whom were poor candidates for surgical resection.', 'This review provides an overview of TSC, everolimus, and the clinical trials that led to its approval for the treatment of TSC-associated subependymal giant cell astrocytoma and renal angiomyolipoma.', 'Everolimus in the treatment of subependymal giant cell astrocytomas, angiomyolipomas, and pulmonary and skin lesions associated with tuberous sclerosis complex.', 'In patients with subependymal giant cell astrocytomas (SEGAs) associated with tuberous sclerosis complex who are not candidates for surgery, single-agent everolimus has demonstrated the ability to significantly reduce SEGA volume with good tolerability', 'The authors also examine the rationale for targeted agents against this pathway therapeutically and describe the clinical evidence underlying the FDA approval of everolimus for patients with inoperable SEGAs.']
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['Everolimus and rapamycin are chemotherapeutic agents that are used for treatment of Subependymal Giant Cell Astrocytoma.']
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['everolimus', 'rapamycin']
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Which type of myeloma is ixazomib being evaluated for?
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['Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials. ', 'The disease focus for all the proteasome inhibitors is multiple myeloma.', 'In addition, novel drug classes have shown promising activity in RR MM, including the orally-administered proteasome inhibitors ixazomib and oprozomib; monoclonal antibodies such as the anti-CS1 monoclonal antibody elotuzumab and anti-CD38 monoclonal antibody daratumumab; and histone deacetylase inhibitors such as panobinostat and rocilinostat.', 'These findings have informed the subsequent clinical development of ixazomib in multiple myeloma.', 'Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients.', 'An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma.', 'Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma.', '(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.', 'Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks.', 'Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks', 'Among second-generation proteasome inhibitors, ixazomib (MLN9708) is the first oral compound to be evaluated for the treatment of MM', 'Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. ', 'Ixazomib is the first investigational oral proteasome inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day cycles). ', 'Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study.', 'In a phase 1/2 trial we aimed to assess the safety, tolerability, and activity of ixazomib in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma.METHODS: We enrolled patients newly diagnosed with multiple myeloma aged 18 years or older with measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and no grade 2 or higher peripheral neuropathy, and treated them with oral ixazomib (days 1, 8, 15) plus lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to 12 28-day cycles, followed by maintenance therapy with ixazomib alone. ', 'Among second-generation proteasome inhibitors, ixazomib (MLN9708) is the first oral compound to be evaluated for the treatment of MM. Ixazomib has shown improved pharmacokinetic and pharmacodynamic parameters compared with bortezomib, in addition to similar efficacy in the control of myeloma growth and prevention of bone loss.', 'Among 55 response-evaluable patients, 15% achieved partial response or better (76% stable disease or better). These findings have informed the subsequent clinical development of ixazomib in multiple myeloma.', 'Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks.']
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['The disease focus for the irreversible epoxyketone proteasome inhibitor ixazomib is multiple myeloma.']
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['Multiple myeloma']
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Is it possible to visualize subtahalamic nucleus by using transcranial ultrasound?
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['After measuring thermal effects of TCS and imaging artefact sizes of DBS lead using a skull phantom, we prospectively enrolled 34 patients with DBS of globus pallidus internus, ventro-intermediate thalamic or subthalamic nucleus. TCS had no influence on lead temperature, electrical parameters of DBS device or clinical state of patients. TCS measures of lead coordinates agreed with MRI measures in anterior-posterior and medial-lateral axis. Lead dislocation requiring reinsertion was reliably detected.', 'TCS may therefore become a first-choice modality to monitor lead location.', 'Two pilot studies have demonstrated that the intraoperative visualization with TCS and the TCS-assisted insertion of deep-brain stimulation (DBS) electrodes into the subthalamic nucleus and the globus pallidus interna are feasible and safe provided there is exact knowledge on the extent of electrode TCS imaging artifacts. ', 'Peroperative transcranial sonography for electrode placement into the targeted subthalamic nucleus of patients with Parkinson disease: technical note', 'The correct anatomic position of the electrode tip could be indirectly assessed thanks to the topographic relationship of the STN with the hyperechogenic substantia nigra and the nucleus ruber.', "CONCLUSIONS: Transcranial sonography is easily feasible during stereotactic surgery. In combination with the clinical effects of electrostimulation on the symptoms of Parkinson's disease and with stereotactic x-ray images, it enables the assessment and the documentation of the correct position of implanted STN electrodes in real time.", 'After measuring thermal effects of TCS and imaging artefact sizes of DBS lead using a skull phantom, we prospectively enrolled 34 patients with DBS of globus pallidus internus, ventro-intermediate thalamic or subthalamic nucleus', 'Two pilot studies have demonstrated that the intraoperative visualization with TCS and the TCS-assisted insertion of deep-brain stimulation (DBS) electrodes into the subthalamic nucleus and the globus pallidus interna are feasible and safe provided there is exact knowledge on the extent of electrode TCS imaging artifacts']
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['Yes, it has been shown that it is possible to visualize subtahalamic nucleus by using transcranial ultrasound. Transcranial ultrasound is safe and reliable method that can be employed to monitor lead location and intraoperative visualization of deep-brain stimulation (DBS) electrodes.']
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['yes']
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Which trancription factor activates the betalain pathway?
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['The beet Y locus encodes an anthocyanin MYB-like protein that activates the betalain red pigment pathway.', 'Some putative MYB, bHLH, and environmental stress-responsive transcription factor binding sites were detected in the PaDOD1 and PaDOD2 promoter regions.']
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['The beet Y locus encodes an anthocyanin MYB-like protein that activates the betalain red pigment pathway.']
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['The beet Y locus encodes an anthocyanin MYB-like protein that activates the betalain red pigment pathway.']
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List kinases that phosphorylates the protein Bora.
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['During cell division Bora becomes multiply phosphorylated by a variety of cell cycle kinases, including Aurora A and Plk1, albeit at distinctive sites.', 'Likewise, we find that phosphorylation of Bora by Cdk1 promotes phosphorylation of human Plk1 by Aurora A suggesting that this mechanism is conserved in humans. ', 'we show that the master mitotic kinase Cdk1 contributes to Plk1 activation through SPAT-1/Bora phosphorylation', 'the potential role of Bora phosphorylation by Cdk1 in this process', 'phosphorylation of Bora on the Cdk consensus site T52 blocks Bora degradation.', 'Here, we used the LC-MS/MS phosphopeptide mapping assay to identify 13 in vivo hBora phosphorylation sites and characterized that GSK3β can interact with hBora and phosphorylate hBora at Ser274 and Ser278.']
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['During cell division Bora becomes multiply phosphorylated by a variety of cell cycle kinases, including Aurora A and Plk1, and GSK3β and Cdk1 albeit at distinctive sites.']
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['Cdk1', 'Plk1', 'Aurora A', 'GSK3β']
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What is Tarlov Cyst?
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['She underwent ultrasound, CT, and eventually MRI evaluations that led to the diagnosis of a giant (6.7 × 6.4 × 6.6 cm) Tarlov cyst originating from the right S-2 nerve root sleeve/sacral foramen with intrapelvic extension.', 'We report here a case of multiloculated disseminated perineural or Tarlov cysts (TCs). ', 'TCs are typically benign, asymptomatic lesions that can simply be monitored.', 'Tarlov cyst syndrome is a rare, often asymptomatic disorder, characterised by isolated or multiple nerve-root cysts, usually occurring in the sacral spine, near the dorsal root ganglion, between the perineurium and endoneurium. ', 'Perineural (Tarlov) cysts are most often found in the sacral region and are rare in the cervical spine. ', 'A case of symptomatic cervical perineural (Tarlov) cyst: clinical manifestation and management.', 'Tarlov cysts or spinal perineurial cysts are uncommon lesions.', 'Tarlov cyst syndrome is a rare, often asymptomatic disorder, characterised by isolated or multiple nerve-root cysts, usually occurring in the sacral spine, near the dorsal root ganglion, between the perineurium and endoneurium.', 'Symptomatic sacral perineurial (Tarlov) cysts.', 'Subsequent MRI and CT myelography demonstrated the nature of the photopenic area as secondary to vertebral erosion by sacral perineurial cyst (Tarlov cyst).', 'Tarlov cysts are sacral perineural cysts. This case report describes the clinical course after biopsy of a very large Tarlov cyst via laparoscopy, which was thought preoperatively to be an adnexal mass.', 'Subsequent MRI and CT myelography demonstrated the nature of the photopenic area as secondary to vertebral erosion by sacral perineurial cyst (Tarlov cyst).', 'A spinal MRI scan was then performed and revealed a sacral fracture which drained into an unknown perineurial cyst (Tarlov cyst).', 'Tarlov or perineurial cysts are lesions of the nerve root most often found in the sacral region. Although there is agreement that asymptomatic Tarlov cysts should be followed, it is still debated whether patients with symptomatic Tarlov cysts should be treated surgically.', 'Tarlov cysts (sacral perineural cysts) are nerve root cysts found most commonly in the sacral roots,', 'Tarlov cysts or spinal perineurial cysts are uncommon lesions.', 'Sacral perineurial (Tarlov) cysts are rare lesions.']
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['Tarlov or perineural cysts are nerve root cysts found most commonly at the sacral spine level arising between covering layers of the perineurium and the endoneurium near the dorsal root ganglion and are usually asymptomatic.']
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[]
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What type of genome, (RNA or DNA, double stranded single stranded) is found in the the virus that causes blue tongue disease?
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['Bluetongue virus (BTV) genome contains ten double-stranded RNA segments']
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['The Bluetongue virus (BTV) genome contains ten double-stranded RNA segments.', 'Bluetongue virus (BTV) genome contains ten double-stranded RNA segments. ', 'Bluetongue virus (BTV) genome contains ten double-stranded RNA segments.', 'Bluetongue virus (BTV) genome contains ten double-stranded RNA segments', 'bluetongue virus (btv) genome contains ten double-stranded rna segments.']
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['double stranded, segmented RNA']
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What is the implication of histone lysine methylation in medulloblastoma?
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['Through targeted re-sequencing, we identified mutations of MLL2 in 8 % (14/175) of MBs, the majority of which were loss of function. Notably, we also report mutations affecting the MLL2-binding partner KDM6A, in 4 % (7/175) of tumors. While MLL2 mutations were independent of age, gender, histological subtype, M-stage or molecular subgroup, KDM6A mutations were most commonly identified in Group 4 MBs, and were mutually exclusive with MLL2 mutations. Immunohistochemical staining for H3K4me3 and H3K27me3, the chromatin effectors of MLL2 and KDM6A activity, respectively, demonstrated alterations of the histone code in 24 % (53/220) of MBs across all subgroups. Correlating these MLL2- and KDM6A-driven histone marks with prognosis, we identified populations of MB with improved (K4+/K27-) and dismal (K4-/K27-) outcomes, observed primarily within Group 3 and 4 MBs', 'we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro', 'Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.', 'Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma.', 'Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.', 'Recent studies showed frequent mutations in histone H3 lysine 27 (H3K27) demethylases in medulloblastomas of Group 3 and Group 4, suggesting a role for H3K27 methylation in these tumors.']
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['Aberrant patterns of H3K4, H3K9, and H3K27 histone lysine methylation were shown to result in histone code alterations, which induce changes in gene expression, and affect the proliferation rate of cells in medulloblastoma.']
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[]
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Which biomarker is widely used in the diagnosis of Ewing sarcoma?
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["half of B-LBL patients are negative for CD45 (leucocyte common antigen, LCA), a widely used marker for the diagnosis of lymphoma, and a significant portion express CD99, a marker for Ewing's sarcoma (ES) or primitive neuroectodermal tumor (PNET)", "Moreover, half of B-LBL patients are negative for CD45 (leucocyte common antigen, LCA), a widely used marker for the diagnosis of lymphoma, and a significant portion express CD99, a marker for Ewing's sarcoma (ES) or primitive neuroectodermal tumor (PNET)"]
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['CD99 is a hallmark marker for Ewing sarcoma and primitive neuroectodermal tumors.']
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['CD99']
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Which disease is linked to mutations within BRAG1?
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['Mutations in BRAG1 have been identified in families with X-linked intellectual disability (XLID)']
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['Mutations in BRAG1 have been identified in families with X-linked intellectual disability (XLID).']
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['X-linked intellectual disability']
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Which transcription factors (TFs) participate in the formation of the interferon-beta (IFN-b) enhanceosome?
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['The dimer formed by the ATF-2 and c-Jun transcription factors is one of the main components of the human interferon-beta enhanceosome.', 'The induction of IFN transcription resulted from the activation of the components of the IFN-beta enhanceosome, i.e. IFN regulatory factor (IRF) 3, nuclear factor (NF)-kappaB, activating transcription factor (ATF)-2 and c-Jun.', 'Transcriptional activation of the interferon-beta (IFN-beta) gene requires assembly of an enhanceosome containing the transcription factors ATF-2/c-Jun, IRF-3/IRF-7, NF-kappaB and HMGI(Y). These factors cooperatively bind a composite DNA site and activate expression of the IFN-beta gene.', 'Here we report that within the IFN-beta enhanceosome the ATF-2-c-jun heterodimer binds in a specific orientation, which is required for assembly of a complex between ATF-2-c-jun and interferon regulatory factor 3 (IRF-3).', ' Here, we identified a small molecule that induces the assembly of the interferon-beta (IFN-beta) enhanceosome by stimulating all the enhancer-binding activator proteins: ATF2/c-JUN, IRF3, and p50/p65 of NF-kappaB.', 'Transcriptional activation of the virus inducible enhancer of the human interferon-beta (IFN-beta) gene in response to virus infection requires the assembly of an enhanceosome, consisting of the transcriptional activators NF-kappaB, ATF-2/c-Jun, IRFs and the architectural protein of the mammalian high mobility group I(Y) [HMG I(Y)].', 'Here, we demonstrate that the first step in enhanceosome assembly, i.e. HMG I(Y)-dependent recruitment of NF-kappaB and ATF-2/c-Jun to the enhancer, is facilitated by discrete regions of HMG I and is mediated by allosteric changes induced in the DNA by HMG I(Y) and not by protein-protein interactions between HMG I(Y) and these proteins. However, we show that completion of the enhanceosome assembly process requires protein-protein interactions between HMG I(Y) and the activators.', 'Transcriptional activation of the human interferon-beta (IFN-beta) gene by virus infection requires the assembly of a higher order nucleoprotein complex, the enhanceosome, which consists of the transcriptional activators NF-kappa B (p50/p65), ATF-2/c-jun, IRF-3 and IRF-7, architectural protein HMGI(Y), and the coactivators p300 and CBP. ', 'The transcriptional coactivators CBP and P/CAF are required for activation of transcription from the IFN beta enhanceosome. We show that CBP and P/CAF acetylate HMG I(Y), the essential architectural component required for enhanceosome assembly, at distinct lysine residues, causing distinct effects on transcription.', 'The transcriptional activity of an in vitro assembled human interferon-beta gene enhanceosome is highly synergistic. This synergy requires five distinct transcriptional activator proteins (ATF2/c-JUN, interferon regulatory factor 1, and p50/p65 of NF-kappaB), the high mobility group protein HMG I(Y), and the correct alignment of protein-binding sites on the face of the DNA double helix.', 'In addition, we provide evidence that recruitment of the holoenzyme by the enhanceosome is due, at least in part, to interactions between the enhanceosome and the transcriptional coactivator CREB, cAMP responsive element binding protein (CBP). ', 'Transcriptional activation of the IFN beta gene in response to virus infection requires the assembly of an enhanceosome, consisting of the transcriptional activators NF-kappa B, IRF1, ATF2/c-Jun, and the architectural protein HMG I(Y).', 'Transcriptional synergy requires recruitment of the CBP/p300 coactivator to the enhanceosome, via a new activating surface assembled from the novel p65 domain and the activation domains of all of the activators.', 'A functional interferon-beta gene enhanceosome was assembled in vitro using the purified recombinant transcriptional activator proteins ATF2/c-JUN, IRF1, and p50/p65 of NF-kappa B. Maximal levels of transcriptional synergy between these activators required the specific interactions with the architectural protein HMG I(Y) and the correct helical phasing of the binding sites of these proteins on the DNA helix.', 'We present evidence that transcriptional activation of the human interferon-beta (IFN beta) gene requires the assembly of a higher order transcription enhancer complex (enhanceosome). This multicomponent complex includes at least three distinct transcription factors and the high mobility group protein HMG I(Y).', 'Thus, HMG I(Y) plays an essential role in the assembly and function of the IFN beta gene enhanceosome.', 'Transcriptional activation of the interferon-beta (IFN-beta) gene requires assembly of an enhanceosome containing the transcription factors ATF-2/c-Jun, IRF-3/IRF-7, NF-kappaB and HMGI(Y).', 'A functional interferon-beta gene enhanceosome was assembled in vitro using the purified recombinant transcriptional activator proteins ATF2/c-JUN, IRF1, and p50/p65 of NF-kappa B', 'Transcriptional activation of the human interferon-beta (IFN-beta) gene by virus infection requires the assembly of a higher order nucleoprotein complex, the enhanceosome, which consists of the transcriptional activators NF-kappa B (p50/p65), ATF-2/c-jun, IRF-3 and IRF-7, architectural protein HMGI(Y), and the coactivators p300 and CBP', 'Transcriptional activation of the IFN beta gene in response to virus infection requires the assembly of an enhanceosome, consisting of the transcriptional activators NF-kappa B, IRF1, ATF2/c-Jun, and the architectural protein HMG I(Y)']
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['Transcriptional activation of the IFN beta gene in response to virus infection requires the assembly of an enhanceosome, consisting of the transcriptional activators NF-kappa B, IRF1, ATF2/c-Jun, and the architectural protein HMG I(Y). Transcriptional activation of the human interferon-beta (IFN-beta) gene by virus infection requires the assembly of a higher order nucleoprotein complex, the enhanceosome, which consists of the transcriptional activators NF-kappa B (p50/p65), ATF-2/c-jun, IRF-3 and IRF-7, architectural protein HMGI(Y), and the coactivators p300 and CBP. ', 'Transcriptional activation of the human interferon-beta (IFN-beta) gene by virus infection requires the assembly of a higher order nucleoprotein complex, the enhanceosome, which consists of the transcriptional activators NF-kappa B (p50/p65), ATF-2/c-jun, IRF-3 and IRF-7, architectural protein HMGI(Y), and the coactivators p300 and CBP. A functional interferon-beta gene enhanceosome was assembled in vitro using the purified recombinant transcriptional activator proteins ATF2/c-JUN, IRF1, and p50/p65 of NF-kappa B. However, HMG I(Y) plays an essential role in the assembly and function of the IFN beta gene enhanceosome.']
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['NF-kappa B (p50/p65)', 'ATF-2', 'c-jun', 'IRF-3', 'IRF-7', 'IRF-1']
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What is the treatment of neuropathic pain in children?
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['Oxcarbazepine, a metabolite of carbamazepine, is used as an antiepileptic, analgesic for neuropathic pain and in the treatment of affective disorders. It has been approved by the Food and Drug Administration for partial seizures in adults as both adjunctive and monotherapy, and as adjunctive therapy in children aged from 2 to 16 years', 'For difficult to treat neuropathic pain from cancer, adjuvant analgesics are often used with opioids', 'Ketamine and lidocaine can be safely infused together with concomitant opioids for the treatment of refractory neuropathic pain caused by cancer.', 'Patient-controlled analgesia with morphine as continuous subcutaneous or intravenous infusions and the possibility of a bolus injection is suited for children aged 6 years.', 'In neuropathic pain or phantom pain coanalgetics should be used to effectively treat pain in young patients.', 'Pregabalin is one of the first drugs registered for the treatment of neuropathic pain. It is also indicated as adjuvant therapy in the treatment of epilepsy and for generalized anxiety disorder. Pregabalin is a GABA analogue', 'Treatment was typically initiated with a tricyclic antidepressant, and 5 of the 6 girls noted improvement in their symptoms, including 2 who had marked improvement, and another 3 with substantial improvement who were able to discontinue therapy without a recurrence. CONCLUSIONS: Vulvodynia does occur among young girls and, when treated as a neuropathic pain disorder, was found to dramatically improve or remit in the majority of those treated in this small case series.', 'We describe a case series of five adolescents who were managed with lidocaine 5% patches for chronic localized neuropathic pain from a variety of causes with minimal adverse effects. Treatment was effective in four of five patients with only one patient complaining of minimal pain relief', 'Twenty-two children or 14% of children on opioid therapy underwent 30 opioid rotations. Mucositis was the cause of pain in 19 (70%) children, bone pain in 3 (11%) children, and postoperative, visceral, or neuropathic pain in the remainder. The opioid was rotated either for excessive side effects with adequate analgesia (70%), excessive side effects with inadequate analgesia (16.7%), or tolerance (6.7%). Five (23%) children required two rotations, 3 during the same admission. The favored rotations were morphine to fentanyl in 20 (67%) children and fentanyl to hydromorphone in 6 (20%). Adverse opioid effects were resolved in 90% of cases, all failures occurred when morphine was rotated to fentanyl.', 'To test the hypothesis that children with terminal cancer and neuropathic pain require rapid increases of opioids and benzodiazepines immediately before death, we compared drug usage in the last 72 hours of life in children with and without neuropathic pain', 'Dying children with cancer and neuropathic pain have higher baseline requirements of morphine and benzodiazepines and require rapid increases of both drugs in the last 72 hours of life than dying children without neuropathic pain.', 'ketamine treatment may be effective in children with severe neuropathic pain not responsive to other analgesics. This patient also demonstrates the feasibility of long-term ketamine treatment in pediatric oncology and that such treatment can be administered in a home care setting.', "Oral amitriptyline has been used as an analgesic in a wide range of pain settings. Despite long-term availability of a parenteral form, the few reports about this formulation have been limited to pharmacokinetic studies in normal volunteers, trials in depressed patients, and analyses of electroencephalogram (EEG) activation. We retrospectively reviewed our experience using intravenous (IV) amitriptyline at Children's Hospital, Boston and at Children's Hospital at Stanford. Eight children (aged 5-16.6 years), who were unable to tolerate medications by the oral route, received IV amitriptyline for a variety of indications, including neuropathic pain, depression, sleep disturbance, and as an adjuvant agent for opioid analgesia."]
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['It is unclear if any treatment is registered for pediatric use. The reported treatments are:\nOxcarbazepine \nOpioids alone, in rotations or with Analgesics (e.g. Ketamine and Lidocaine infusion)\nOpioids and Benzodiazepines\nPregabalin - is one of the first drugs registered for the treatment of neuropathic pain. It is unclear if Pregabalin is registered for the treatment of neuropathic pain in children specifically but it is being used in practice.\nTricyclic Antidepressants\nLidocaine 5% patches for chronic localized neuropathic pain']
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['Oxcarbazepine', 'Opioids alone, in rotations or with Analgesics (e.g. Ketamine and Lidocaine infusion)', 'Opioids and Benzodiazepines - for terminal care', 'Pregabalin', 'Tricyclic Antidepressants', 'Lidocaine 5% patches for chronic localized neuropathic pain', 'Ketamine']
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Is there any link between CTF4 and CTF18 during sister chromatid cohesion?
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['Our results suggest that Elg1, Ctf4, and Ctf18 may coordinate the relative movement of the replication fork with respect to the cohesin ring', 'These data defined two cohesion pathways, one containing CSM3, TOF1, CTF4, and CHL1, and the second containing MRC1, CTF18, CTF8, and DCC1', 'Here we show that three proteins required for sister chromatid cohesion, Eco1, Ctf4, and Ctf18, are found at, and Ctf4 travels along chromosomes with, replication forks. The ring-shaped cohesin complex is loaded onto chromosomes before S phase in an ATP hydrolysis-dependent reaction. Cohesion establishment during DNA replication follows without further cohesin recruitment and without need for cohesin to re-engage an ATP hydrolysis motif that is critical for its initial DNA binding. This provides evidence for cohesion establishment in the context of replication forks and imposes constraints on the mechanism involved', 'Sister-chromatid cohesion mediated by the alternative RF-CCtf18/Dcc1/Ctf8, the helicase Chl1 and the polymerase-alpha-associated protein Ctf4 is essential for chromatid disjunction during meiosis II', 'In budding yeast, a specialized replication factor C called RF-C(Ctf18/Dcc1/Ctf8) and the DNA-polymerase-alpha-associated protein Ctf4 are required to maintain sister-chromatid cohesion in cells arrested for long periods in mitosis', 'We also show that, in contrast to mitosis, RF-C(Ctf18/Dcc1/Cft8), Ctf4 and Chl1 are essential for chromosome segregation during meiosis and for the viability of meiotic products.', 'Ctf8p is a component of Ctf18-RFC, an alternative replication factor C-like complex required for efficient sister chromatid cohesion in Saccharomyces cerevisiae. We performed synthetic genetic array (SGA) analysis with a ctf8 deletion strain as a primary screen to identify other nonessential genes required for efficient sister chromatid cohesion. We then assessed proficiency of cohesion at three chromosomal loci in strains containing deletions of the genes identified in the ctf8 SGA screen. Deletion of seven genes (CHL1, CSM3, BIM1, KAR3, TOF1, CTF4, and VIK1) resulted in defective sister chromatid cohesion', 'Saccharomyces cerevisiae CTF18 and CTF4 are required for sister chromatid cohesion', 'CTF4 and CTF18 are required for high-fidelity chromosome segregation. Both exhibit genetic and physical ties to replication fork constituents. We find that absence of either CTF4 or CTF18 causes sister chromatid cohesion failure and leads to a preanaphase accumulation of cells that depends on the spindle assembly checkpoint. The physical and genetic interactions between CTF4, CTF18, and core components of replication fork complexes observed in this study and others suggest that both gene products act in association with the replication fork to facilitate sister chromatid cohesion.', 'The requirement for CTF4 and CTF18 in robust cohesion identifies novel roles for replication accessory proteins in this process', 'Here we show that three proteins required for sister chromatid cohesion, Eco1, Ctf4, and Ctf18, are found at, and Ctf4 travels along chromosomes with, replication forks.', 'Saccharomyces cerevisiae CTF18 and CTF4 are required for sister chromatid cohesion.', 'We find that absence of either CTF4 or CTF18 causes sister chromatid cohesion failure and leads to a preanaphase accumulation of cells that depends on the spindle assembly checkpoint.', 'In budding yeast, a specialized replication factor C called RF-C(Ctf18/Dcc1/Ctf8) and the DNA-polymerase-alpha-associated protein Ctf4 are required to maintain sister-chromatid cohesion in cells arrested for long periods in mitosis.', 'The physical and genetic interactions between CTF4, CTF18, and core components of replication fork complexes observed in this study and others suggest that both gene products act in association with the replication fork to facilitate sister chromatid cohesion.', 'Sister-chromatid cohesion mediated by the alternative RF-CCtf18/Dcc1/Ctf8, the helicase Chl1 and the polymerase-alpha-associated protein Ctf4 is essential for chromatid disjunction during meiosis II.', 'Genetic analyses revealed that Rmi1 promoted sister chromatid cohesion in a process that was distinct from both the cohesion establishment pathway involving Ctf4, Csm3, and Chl1 and the pathway involving the acetylation of Smc3.', 'The physical and genetic interactions between CTF4, CTF18, and core components of replication fork complexes observed in this study and others suggest that both gene products act in association with the replication fork to facilitate sister chromatid cohesion.', 'Here we show that three proteins required for sister chromatid cohesion, Eco1, Ctf4, and Ctf18, are found at, and Ctf4 travels along chromosomes with, replication forks.', 'We find that absence of either CTF4 or CTF18 causes sister chromatid cohesion failure and leads to a preanaphase accumulation of cells that depends on the spindle assembly checkpoint.', 'In budding yeast, a specialized replication factor C called RF-C(Ctf18/Dcc1/Ctf8) and the DNA-polymerase-alpha-associated protein Ctf4 are required to maintain sister-chromatid cohesion in cells arrested for long periods in mitosis.', 'Here we show that three proteins required for sister chromatid cohesion, Eco1, Ctf4, and Ctf18, are found at, and Ctf4 travels along chromosomes with, replication forks', 'The physical and genetic interactions between CTF4, CTF18, and core components of replication fork complexes observed in this study and others suggest that both gene products act in association with the replication fork to facilitate sister chromatid cohesion', 'We find that absence of either CTF4 or CTF18 causes sister chromatid cohesion failure and leads to a preanaphase accumulation of cells that depends on the spindle assembly checkpoint', 'In addition to Eco1, several other factors contribute to cohesion establishment, including Ctf4, Ctf18, Tof1, Csm3, Chl1 and Mrc1, but little is known about their roles']
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['Yes. CTF4 and CTF18 are required for high-fidelity chromosome segregation. Both exhibit genetic and physical ties to replication fork constituents. Absence of either CTF4 or CTF18 causes sister chromatid cohesion failure and leads to a preanaphase accumulation of cells that depends on the spindle assembly checkpoint. The physical and genetic interactions between CTF4, CTF18, and core components of replication fork complexes suggest that both gene products act in association with the replication fork to facilitate sister chromatid cohesion.']
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['yes']
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How homoplasy affects phylogenetic reconstruction?
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['Phylogenetic reconstruction using molecular data is often subject to homoplasy, leading to inaccurate conclusions about phylogenetic relationships among operational taxonomic units.', 'Our use of nonhomoplastic whole-genome SNP characters allows branch points and clade membership to be estimated with great precision', 'The control region proved to be a less useful molecular marker for the population genetics and the phylogenetic reconstruction of closely related taxa in A. urticae than it has for other species. The extreme bias in adenine and thymine content (A+T=90.91%) probably renders this region highly susceptible to homoplasy, resulting in a less informative molecular marker.', 'Minimal homoplasy (consistency index = 0.9591) was detected among parsimony-informative SNPs, allowing for the generation of a highly accurate phylogenetic reconstruction of the CC398 clonal lineage.', 'These findings provide evidence for the occurrence of a high degree of homoplasy in the DR locus leading to convergent evolution to identical spoligotypes. The incongruence between Large Sequence Polymorphism and spoligotype polymorphism argues against the use of spoligotyping for establishing phylogenetic relationships within the Euro-American lineage.', 'The species diversity of the phylum Rotifera has been largely studied on the basis of morphological characters. However, cladistic relationships within this group are poorly resolved due to extensive homoplasy in morphological traits', 'Molecular evolutionary processes modify DNA over time, creating both newly derived substitutions shared by related descendant lineages (phylogenetic signal) and "false" similarities which confound phylogenetic reconstruction (homoplasy).', 'This added level of homoplasic "noise" can make DNA regions with repeats less reliable in phylogenetic reconstruction than those without repeats.', 'Computational and phylogenetic analyses suggest that only some BH3 motifs arose by divergent evolution from a common ancestor (homology), whereas others arose by convergent evolution or random coincidence (homoplasy)', 'The high frequency of morphological homoplasy in pennatulaceans has led to many misinterpretations in the systematics of the group.', 'Conflict among data sources can be frequent in evolutionary biology, especially in cases where one character set poses limitations to resolution. Earthworm taxonomy, for example, remains a challenge because of the limited number of morphological characters taxonomically valuable. An explanation to this may be morphological convergence due to adaptation to a homogeneous habitat, resulting in high degrees of homoplasy. This sometimes impedes clear morphological diagnosis of species.', 'We also report one of the first findings of homoplasy in mitochondrial gene order, namely a shared relative position of trnV in unrelated isopod lineages.', 'This taxon therefore provides the opportunity to evaluate those neural characters common to these two clades likely to be results of shared ancestry (homology) versus convergence (homoplasy). ', 'Taxa that experienced molecular homoplasy, recent selection, a spur of evolution, and so forth may disrupt the inference and cause incongruences in the estimated phylogeny.', 'myrmecophagy in these mammalian lineages was more likely because of homoplasy (convergent evolution) than being an ancestral character.', 'The four regions were equally affected by homoplasy and were, therefore, equally unreliable for phylogenetic reconstruction.', 'Early hominid masticatory characters are widely considered to be more prone to homoplasy than characters from other regions of the early hominid skull and therefore less reliable for phylogenetic reconstruction.', 'These findings are in clear contrast with the views that rapidly evolving regions and the 3rd codon position have inevitable negative impact on phylogenetic reconstruction at deep historic level due to accumulation of multiple hits and subsequent elevation in homoplasy and saturation.', 'Phylogenetic reconstructions are often plagued by difficulties in distinguishing phylogenetic signal (due to shared ancestry) from phylogenetic noise or homoplasy (due to character-state convergences or reversals).', 'Homoplasy, in particular, is a difficulty faced by all methods of phylogenetic inference.', 'Homoplasy, in particular, is a difficulty faced by all methods of phylogenetic inference.', 'Sequence-based methods for phylogenetic reconstruction from (nucleic acid) sequence data are notoriously plagued by two effects: homoplasies and alignment errors', 'Early hominid masticatory characters are widely considered to be more prone to homoplasy than characters from other regions of the early hominid skull and therefore less reliable for phylogenetic reconstruction', 'Molecular evolutionary processes modify DNA over time, creating both newly derived substitutions shared by related descendant lineages (phylogenetic signal) and "false" similarities which confound phylogenetic reconstruction (homoplasy)', 'The four regions were equally affected by homoplasy and were, therefore, equally unreliable for phylogenetic reconstruction', 'mellifera that the detection of size homoplasy may alter phylogenetic reconstructions.']
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['Evolutionary processes create both newly derived characteristics shared by related descendant lineages (homology) and "false" similarities which confound phylogenetic reconstruction (homoplasy). Homology arises by divergent evolution from a common ancestor and provides us with a phylogenetic signal, while homoplasy arises by convergent evolution or random coincidence. Homoplastic characters do not allows branch points and clade membership to be accurately estimated, as they may group unrelated taxa together. Such characters add "noise" in phylogenetic analysis and are not informative for the population genetics and the phylogenetic reconstruction of closely related taxa. In phylogenetic reconstruction, homoplasy leads to inaccurate conclusions about phylogenetic relationships among operational taxonomic units, and characters with high degree of homoplasy result in incongruences of cladistic relationships.']
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[]
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Which gene strand is targeted by transcription-coupled repair (TCR)?
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['Transcription-coupled repair (TCR) is the major pathway involved in the removal of UV-induced photolesions from the transcribed strand of active genes.', 'transcription-coupled repair (TCR) provides faster repair of the transcribed strand of active genes.', 'there are two sub-pathways of nucleotide excision repair (NER), the global genome (gg) NER and the transcription-coupled repair (TCR). TCR can preferentially remove the bulky DNA lesions located at the transcribed strand of a transcriptional active gene more rapidly than those at the untranscribed strand or overall genomic DNA.', 'transcription-coupled repair (TCR) since targets for DNA damage are situated on the transcribed or coding strand of DNA', 'Nucleotide Excision Repair (NER), which removes a variety of helix-distorting lesions from DNA, is initiated by two distinct DNA damage-sensing mechanisms. Transcription Coupled Repair (TCR) removes damage from the active strand of transcribed genes', 'Transcription-coupled repair (TCR) is a sub-pathway of nucleotide excision repair that allows for the enhanced repair of the transcribed strand of active genes.', 'Transcription coupled repair (TCR) is a nucleotide excision repair (NER) pathway that is dedicated to repair in the transcribed strand of an active gene.', 'Transcription-coupled repair (TCR) is a pathway dedicated to the removal of damage from the template strands of actively transcribed genes.', 'Although the detailed mechanism of TCR is not yet understood, it is believed to be triggered when a translocating RNA polymerase is arrested at a lesion or unusual structure in the DNA.', 'Among these is a process called transcription-coupled repair (TCR) that catalyzes the removal of DNA lesions from the transcribed strand of expressed genes, often resulting in a preferential bias of damage clearance from this strand relative to its non-transcribed counterpart.', 'These results suggest that UV treatment results in an induced repair of UV-damaged DNA in the transcribed strand of an active gene in XP-C and normal cells through an enhancement of TCR or a mechanism which involves the TCR pathway.', 'TCR can preferentially remove the bulky DNA lesions located at the transcribed strand of a transcriptional active gene more rapidly than those at the untranscribed strand or overall genomic DNA.', 'The proficient repair of the nontranscribed strand cannot be explained by the dedicated subpathway of transcription-coupled repair (TCR), which is targeted to the transcribed strand in expressed genes.', 'Transcription-coupled repair (TCR) is a universal sub-pathway of the nucleotide excision repair (NER) system that is limited to the transcribed strand of active structural genes.', 'NER can operate via two subpathways: global genome repair (GGR) and a specialized pathway coupled to active transcription (transcription-coupled repair, TCR) and directed to DNA lesions in the transcribed strand of active genes.', 'Transcription coupled repair (TCR), a special sub-pathway of nucleotide excision repair (NER), removes transcription blocking lesions rapidly from the transcribing strand of active genes.', 'Transcription-coupled repair (TCR) acts solely on the transcribed strand of expressed genes, while global genomic repair (GGR) is responsible for the ubiquitous repair of the genome.', 'In addition to the recognition and excision of DNA damage throughout the genome (GGR), there exists a mechanism, transcription-coupled nucleotide excision repair (TCR), for recognizing some types of DNA damage in the transcribed strand of genes in Escherichia coli, yeast and mammalian cells.', 'The proficient repair of the nontranscribed strand cannot be explained by the dedicated subpathway of transcription-coupled repair (TCR), which is targeted to the transcribed strand in expressed genes.', 'TCR can preferentially remove the bulky DNA lesions located at the transcribed strand of a transcriptional active gene more rapidly than those at the untranscribed strand or overall genomic DNA.', 'Transcription-coupled repair (TCR) is a subpathway of nucleotide excision repair (NER) that acts specifically on lesions in the transcribed strand of expressed genes.', 'The blockage of transcription elongation by RNA polymerase II (pol II) at a DNA damage site on the transcribed strand triggers a transcription-coupled DNA repair (TCR), which rapidly removes DNA damage on the transcribed strand of the expressed gene and allows the resumption of transcription.', 'It has been previously shown that disruption of RAD26 in yeast strain W303-1B results in a strain that is deficient in transcription-coupled repair (TCR), the preferential repair of the transcribed strand of an expressed gene over the non-transcribed strand and the rest of the genome.', 'The proficient repair of the nontranscribed strand cannot be explained by the dedicated subpathway of transcription-coupled repair (TCR), which is targeted to the transcribed strand in expressed genes', 'A dedicated excision repair pathway, termed transcription-coupled repair (TCR), targets the removal of DNA lesions from transcribed strands of expressed genes', 'NER can operate via two subpathways: global genome repair (GGR) and a specialized pathway coupled to active transcription (transcription-coupled repair, TCR) and directed to DNA lesions in the transcribed strand of active genes', 'Transcription coupled repair (TCR) is a nucleotide excision repair (NER) pathway that is dedicated to repair in the transcribed strand of an active gene', 'Transcription-coupled repair (TCR) is generally observed as more rapid or more efficient removal of certain types of DNA damage from the transcribed strands of expressed genes compared with the nontranscribed strands', 'In addition to the recognition and excision of DNA damage throughout the genome (GGR), there exists a mechanism, transcription-coupled nucleotide excision repair (TCR), for recognizing some types of DNA damage in the transcribed strand of genes in Escherichia coli, yeast and mammalian cells']
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['Nucleotide Excision Repair (NER) removes a variety of helix-distorting lesions from DNA. It has two sub-pathways, the global genome (gg) NER and the transcription-coupled repair (TCR). TCR is triggered when a RNA polymerase, translocating along the transcribed strand, is arrested at a lesion or unusual structure in the DNA. TCR is dedicated to target and repair the transcribed strand of an active gene.']
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['the transcribed strand']
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Which methyl-CpG-binding protein when mutant becomes the hallmark for Rett syndrome?
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['Rett syndrome (RTT) results from loss-of-function mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2) and is characterized by abnormal motor, respiratory and autonomic control, cognitive impairment, autistic-like behaviors and increased risk of seizures. ', 'Rett syndrome (RTT) is an autism spectrum disorder caused by mutation in the gene encoding methyl CpG binding protein 2 (MECP2).', 'Severely arrhythmic breathing is a hallmark of Rett syndrome (RTT) and profoundly affects quality of life for patients and their families. The last decade has seen the identification of the disease-causing gene, methyl-CpG-binding protein 2 (Mecp2) and the development of mouse models that phenocopy many aspects of the human syndrome, including breathing dysfunction.', 'Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that manifests in females, typically after the first year of life.', 'It was recently discovered that RTT is caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. MECP2 assists in the transcriptional silencing process via DNA methylation; we hypothesize that disruption of this gene alters the normal developmental expression of various other genes, some of which must account for the peculiar neurologic phenotype of RTT.', 'Molecular studies have identified MECP2 mutations in up to 80% of classic RTT patients; mutation type has some effect on the phenotypic manifestation of RTT, but the pattern of X inactivation seems to determine phenotypic severity.']
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['Rett syndrome (RTT) was shown to be caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, with molecular studies identifying MECP2 mutations in up to 80% of classic RTT patients. MECP2 protein was found to assist in the transcriptional silencing process via DNA methylation. We therefore hypothesize that disruption of this gene alters the normal developmental expression of various other genes, some of which must account for the peculiar neurologic phenotype of RTT.']
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['Methyl-CpG-binding protein 2 (MECP2)']
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Are cutaneous porphyrias inherited with a recessive pattern?
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['Five of the porphyrias are low-penetrance autosomal dominant conditions in which clinical expression results from additional factors that act by increasing demand for haem or by causing an additional decrease in enzyme activity or by a combination of these effects', 'Molecular mechanisms of dominant expression in porphyria.', 'Variegate porphyria (VP) is an autosomal-dominant disorder that is caused by inheritance of a partial deficiency of the enzyme protoporphyrinogen oxidase (EC 1.3.3.4). It is characterized by cutaneous photosensitivity and/or various neurological manifestations. ', 'The acute porphyrias constitute a group of metabolic disorders engaging enzymes in the haem synthetic chain and generally following dominant inheritance patterns.']
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['No, cutaneous porphyrias are inherited in a dominant (not recessive) pattern.']
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['no']
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Proteomic analyses have revealed proteins associated with the triple-negative breast cancers. List some proposed proteins.
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['Some of these proteins are of outstanding interest in the biology and clinical management of this disease, such as CD44 and PARP1.', 'We present here our results, including a large cumulative database of proteins based on the analysis of 78 TNBCs, and the identification and validation of one specific protein, Mage-A4, which was expressed in a significant fraction of TNBC and Her2-positive/ER negative lesions.', 'Proteomic profiling of triple-negative breast carcinomas in combination with a three-tier orthogonal technology approach identifies Mage-A4 as potential therapeutic target in estrogen receptor negative breast cancer.', 'Further, we performed comparative quantitative proteomic and gene array analyses of these cells and identified potential novel markers of breast cancer cells with tumor-initiating features, such as lipolysis-stimulated lipoprotein receptor (LSR), RAB25, S100A14 and mucin 1 (MUC1), as well as a novel 31-gene signature capable of predicting distant metastasis in cohorts of estrogen receptor-negative human breast cancers.', 'he results identify Hsp90 as a critical and multimodal target in this most difficult to treat breast cancer subtype and support the use of the Hsp90 inhibitor PU-H71 for clinical trials involving patients with TNBC.', 'We obtained differential expression patterns for several glycolytic enzymes (as for example MDH2, PGK1, TKT, Aldolase1), cytokeratins (CK7, 8, 9, 14, 17, 19), further structure proteins (vimentin, fibronectin, L-plastin), for NME1-NME2, lactoferrin, and members of the Annexin family.', 'he expression of calreticulin, cellular retinoic acid-binding protein II, chloride intracellular channel protein 1, EF-1-beta, galectin 1, peroxiredoxin-2, platelet-derived endothelial cell growth factor, protein disulfide isomerase and ubiquitin carboxyl-terminal hydrolase 5 were further validated using a tissue microarray containing 70 malignant breast carcinomas of various grades of atypia.', 'The first is characterized by high expression of Stat1, Mx1, and CD74.', 'This effect was accompanied with a marked increase in the membrane expression of beta-catenin, MUC18, plexins, integrins, and other proteins involved in cell adhesion and cancer metastasis. Taken together, our results show that Stat1/CD74 positive triple-negative tumors are more aggressive and suggest an approach for development of better diagnostics and more targeted therapies for triple negative breast cancer.', 'Proteomic analysis also identified high levels of IDH2 and CRABP2 and low levels of SEC14L2 to be prognostic markers for overall breast cancer survival.', 'Proteomic and validation immunohistochemical analyses revealed that alpha-defensins (DEFA) were overexpressed in tumors from patients with a pCR.', 'The expression of a selected group of high abundance and/or breast cancer-specific potential biomarkers including thromobospondin 1, galectin-3 binding protein, cathepsin D, vimentin, zinc-α2-glycoprotein, CD44, and EGFR from the breast cancer cell lines and in their culture media were further validated by Western blot analysis.', 'his provided novel evidence for PMA regulation of the enzymes glyceraldehyde-3-phosphate dehydrogenase, nucleolar RNA helicase 2 and Heterogeneous nuclear ribonucleoprotein M.', 'Among them, we identify downregulation of components of the Ras/Raf/MAPK pathway and G(2)-M phase to contribute to its anti-proliferative effect, degradation of activated Akt and Bcl-xL to induce apoptosis, and inhibition of activated NF-kappaB, Akt, ERK2, Tyk2, and PKC to reduce TNBC invasive potential.']
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['Selected proteins of interest proposed from triple-negative cancer proteomic studies are CD44, PARP1, Mage-A4, LSR, RAB25, S100A14, MUC1, Hsp90, Actin, 14-3-3, vimentin, HSP70, CK18, moesin, IDH2, CRABP2, SEC14L2, beta-catenin, MUC18, Stat1 and CD74.']
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['CD44', 'PARP1', 'Mage-A4', 'LSR', 'RAB25', 'S100A14', 'MUC1', 'Hsp90', 'Actin', '14-3-3', 'vimentin', 'HSP70', 'CK18', 'moesin', 'IDH2', 'CRABP2', 'SEC14L2', 'beta-catenin', 'MUC18', 'Stat1', 'CD74']
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What is HbVar?
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['HbVar: A relational database of human hemoglobin variants and thalassemia mutations at the globin gene server.', 'We have constructed a relational database of hemoglobin variants and thalassemia mutations, called HbVar, which can be accessed on the web at http://globin.cse.psu.edu. Extensive information is recorded for each variant and mutation, including a description of the variant and associated pathology, hematology, electrophoretic mobility, methods of isolation, stability information, ethnic occurrence, structure studies, functional studies, and references. The initial information was derived from books by Dr. Titus Huisman and colleagues [Huisman et al., 1996, 1997, 1998]. The current database is updated regularly with the addition of new data and corrections to previous data. Queries can be formulated based on fields in the database. Tables of common categories of variants, such as all those involving the alpha1-globin gene (HBA1) or all those that result in high oxygen affinity, are maintained by automated queries on the database. Users can formulate more precise queries, such as identifying "all beta-globin variants associated with instability and found in Scottish populations." This new database should be useful for clinical diagnosis as well as in fundamental studies of hemoglobin biochemistry, globin gene regulation, and human sequence variation at these loci.', 'A registry of these Hb variants and other information, a legacy from Professor Huisman, is now available online, at HbVar database (hhtp://globin.bx.psu.edu/hbvar).', 'HbVar (http://globin.bx.psu.edu/hbvar) is a locus-specific database (LSDB) developed in 2001 by a multi-center academic effort to provide timely information on the genomic sequence changes leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies.', 'HbVar (http://globin.cse.psu.edu/globin/hbvar/) is a relational database developed by a multi-center academic effort to provide up-to-date and high quality information on the genomic sequence changes leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies.', 'HbVar (http://globin.bx.psu.edu/hbvar) is one of the oldest and most appreciated locus-specific databases launched in 2001 by a multi-center academic effort to provide timely information on the genomic alterations leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies.', 'HbVar database of human hemoglobin variants and thalassemia mutations: 2007 update.', 'Updates of the HbVar database of human hemoglobin variants and thalassemia mutations.', 'Improvements in the HbVar database of human hemoglobin variants and thalassemia mutations for population and sequence variation studies.', 'HbVar (http://globin.bx.psu.edu/hbvar) is one of the oldest and most appreciated locus-specific databases launched in 2001 by a multi-center academic effort to provide timely information on the genomic alterations leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies. ', 'We have constructed a relational database of hemoglobin variants and thalassemia mutations, called HbVar, which can be accessed on the web at http://globin.cse.psu.edu. ', 'We have constructed a relational database of hemoglobin variants and thalassemia mutations, called HbVar, which can be accessed on the web at http://globin.cse.psu.edu.', 'HbVar (http://globin.bx.psu.edu/hbvar) is a locus-specific database (LSDB) developed in 2001 by a multi-center academic effort to provide timely information on the genomic sequence changes leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies.', 'HbVar (http://globin.cse.psu.edu/globin/hbvar/) is a relational database developed by a multi-center academic effort to provide up-to-date and high quality information on the genomic sequence changes leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies.', 'HbVar (http://globin.bx.psu.edu/hbvar) is one of the oldest and most appreciated locus-specific databases launched in 2001 by a multi-center academic effort to provide timely information on the genomic alterations leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies.', 'A registry of these Hb variants and other information, a legacy from Professor Huisman, is now available online, at HbVar database (hhtp://globin.bx.psu.edu/hbvar).']
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['HbVar (http://globin.cse.psu.edu) is a relational database of hemoglobin variants and thalassemia mutations. Extensive information is recorded for each variant and mutation, including a description of the variant and associated pathology, hematology, electrophoretic mobility, methods of isolation, stability information, ethnic occurrence, structure studies, functional studies, and references. The initial information was derived from books by Dr. Titus Huisman and colleagues [Huisman et al., 1996, 1997, 1998]. The current database is updated regularly with the addition of new data and corrections to previous data. Queries can be formulated based on fields in the database. Tables of common categories of variants, such as all those involving the alpha1-globin gene (HBA1) or all those that result in high oxygen affinity, are maintained by automated queries on the database. Users can formulate more precise queries, such as identifying "all beta-globin variants associated with instability and found in Scottish populations." This new database should be useful for clinical diagnosis as well as in fundamental studies of hemoglobin biochemistry, globin gene regulation, and human sequence variation at these loci.']
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Are there randomised controlled trials on sevoflurane?
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['After Ethics Review Board approval, 44 ASA I-III patients undergoing elective gynaecological surgery were randomised after surgery to either hypercapnic hyperpnoea or control groups.', 'Hypercapnic hyperpnoea in spontaneously breathing patients halves the time of recovery from sevoflurane-induced anaesthesia in the operating room.', 'A total of 200 women undergoing first trimester abortion (American Society of Anesthesiologists physical status I) participated in the study. Patients were randomly assigned to receive either sevoflurane or propofol for short-term sedation.', 'The results showed the incidence of dreaming was significantly different between anaesthesia groups with 60% (60/100) of the sevoflurane group and 33% (33/100) of the propofol group (P=0.000)', 'Anaesthesia administered had no effect on patient satisfaction. The results suggest that the incidence of dreaming was not affected by recovery time. Patient satisfaction was not influenced by choice of sedative and/or by the occurrence of dreaming during sevoflurane or propofol short-term sedation.', 'Prior reports suggest that dreaming during anaesthesia is dependent on recovery time. Dreaming during sedation may impact patient satisfaction', 'Sevoflurane vs. propofol in patients with coronary disease undergoing mitral surgery: a randomised study.', 'We therefore performed a randomised controlled trial (sevoflurane vs. propofol) to compare cardiac troponin release in patients with coronary disease undergoing mitral surgery.', 'Myocardial injury in remifentanil-based anaesthesia for off-pump coronary artery bypass surgery: an equipotent dose of sevoflurane versus propofol', 'This randomised controlled trial compared the effect of equipotent anaesthetic doses of sevoflurane (S group) versus propofol (P group), during remifentanil-based anaesthesia for off-pump coronary artery bypass surgery, on myocardial injury. Either sevoflurane or propofol was titrated to maintain bispectral index values between 40 and 50.', 'This randomised, multicentre, parallel-group trial included 98 adult patients. Patients received intravenous propofol for induction followed by sevoflurane maintenance anaesthesia.', 'Patients were randomly allocated to receive sugammadex 2.0 mg kg(-1) or neostigmine 50 microg', 'We compared the haemodynamics, emergence and recovery characteristics of total intravenous anaesthesia using propofol/remifentanil with sevoflurane/remifentanil anaesthesia, under bispectral index guidance, in 103 patients undergoing surgical procedures lasting > 3.5 h', 'A randomised controlled trial of paediatric conscious sedation for dental treatment using intravenous midazolam combined with inhaled nitrous oxide or nitrous oxide/sevoflurane', 'Intravenous midazolam, especially in combination with inhaled nitrous oxide or sevoflurane and nitrous oxide, are effective techniques, with the combination of midazolam and sevoflurane the one most likely to result in successful treatment.', 'We randomly assigned 1063 adult and 322 paediatric elective patients to one of four (adult) or two (paediatric) anaesthesia groups', 'In both studies, there was no difference in postdischarge outcomes at Day 7. Sevoflurane/sevoflurane was more costly with higher PONV rates in both studies. In adults, the cost per extra episode of PONV avoided was pound 296 (propofol/propofol vs. propofol/ sevoflurane) and pound 333 (propofol/sevoflurane vs. propofol/isoflurane).', 'Comparison of sevoflurane and nitrous oxide mixture with nitrous oxide alone for inhalation conscious sedation in children having dental treatment: a randomised controlled trial.', 'We studied 411 children aged 3-10 years who were referred for dental treatment. They were randomly allocated to have inhalation conscious sedation with either sevoflurane/nitrous oxide mixture or nitrous oxide alone']
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['Yes. There are < 10 studies reported, answering questions like : how to improve speed of recovery, relationship to dreaming and anesthetic experience, effect on cardiac troponin release, effect on myocardial injury, postoperative delirium, haemodynamics & emergence and recovery characteristics of total intravenous anaesthesia, costs of postoperative nausea and vomiting, pediatric conscious sedation for dental procedures']
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['yes']
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Is there any data to suggest that TRH (thyrotropin releasing hormone) administration can improve symptom severity of amyotrophic lateral sclerosis patients?
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["These central nervous system (CNS)-mediated effects provide the rationale for use of TRH and its analogs in the treatment of brain and spinal injury, and CNS disorders like schizophrenia, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, Parkinson's disease, depression, shock and ischemia.", 'The Effect of TRH to correct the abnormal F responses in SSP might be consistent with effects of TRH to reduce spasticity in amyotrophic lateral sclerosis described previously', 'Agents undergoing therapeutic trials at present include CNTF, IGF1 glutamate antagonists, branched-chain amino acids and TRH analogue.', 'Evidence that thyrotropin-releasing hormone (TRH) has prominent trophic effects on the motor system led to several negative therapeutic trials in amyotrophic lateral sclerosis, a disease of the motor system.', 'The results of the clinical evaluation at the beginning and end of the treatment as well as after patient follow up demonstrated that beneficial effects do not occur equally in all patients but rather are transitory and do not improve the natural evolution of the disease.', 'The neurological evaluation after acute TRH-T treatment showed an objective improvement in 3 of the 8.', 'The outcome of the study, in agreement with some and at variance with other studies, was that TRH induced a statistically significant neurological improvement in 17 of the 23 ALS patients but little or none in the other ALS patients and in patients with other neurological diseases.', '[A case of amyotrophic lateral sclerosis with disturbance of vertical ocular movement responding to thyrotropin releasing hormone (TRH)].', 'TRH injections resulted in improvement of disturbance of vertical ocular movement, but no effect was seen on the weakness of the limb.', '13 patients with amyotrophic lateral sclerosis (ALS) were treated with intravenous infusion of thyrotropin-releasing hormone (TRH). ', 'Similar improvements in speech, swallowing and in tongue and jaw movements were seen after iv and oral administration in nine, five and eight patients respectively. ', 'No clinical improvement was detected. ', 'A trial of Thyrotropin Releasing Hormone (TRH) 5.0 mg/kg body weight subcutaneously every other day for two weeks produced transient increased tone in muscles, along with other (side-) effects in patients with Amyotrophic Lateral Sclerosis (ALS).', 'Although the mechanism is not known, several reports of the effectiveness of thyrotropin releasing hormone (TRH) in ALS were recently published.', 'Protirelin (thyrotropin-releasing hormone) appears to be a neuromodulator in the extrahypothalamic nervous system and has been suggested as an adjunct in the treatment of amyotrophic lateral sclerosis (ALS). ', 'Clinical studies have shown that response to TRH is state dependent, that is, it depends on whether the patient has bulbar or nonbulbar signs and is male or female. Future studies must take into consideration this state dependence as a specific feature of the pharmacological action of TRH and its analogues.', 'Three of the studies showed a transient, statistically significant effect in at least some muscles. The two studies that demonstrated no such effect both used TRH in very small doses. It therefore seems reasonable to conclude that the effect of TRH in ALS is a definite, acute, and transient response. ', 'It was found that in only 3 out of 14 patients with moderately progressed disease no improvement was achieved, while in 11 cases the improvement was from 10 to 20%. However, the improvement was transient, and TRH treatment failed to stop the progression of the disease.', 'Only 3 patients noted subjective improvement of strength.', 'In 6 of the 9, TRH induced a significant increase in vibratory inhibition. This suggests that the TRH-induced reduction of spasticity might be due to an increase in presynaptic inhibition acting on Ia fibres.', 'However, 2 mg DN-1417, IM twice a day for 1 month in an open-label trial, produced no objective improvement of strength in nine patients with ALS. ', 'Our experience suggests that this approach is safe, has high patient acceptance, and is worthy of more careful evaluation.', 'Focal, small-to-moderate and transient improvement occurred in the muscle strength and function of patients with ALS who received TRH in dose-response and screening studies. In a small pilot study of 12 patients, 3 months administration of TRH at 10 mg per kg on alternate days resulted in localized increased strength of jaw muscles as well as significant improvement in lower extremity function. Aerobic exercise capacity was particularly improved in patients with ALS following administration of TRH. ', 'Mild to moderate improvement was found in 9 (56%) of 16 patients. ', 'We thought such action of TRH to be useful to the therapy of ALS.', 'With daily TRH, 10 patients noted subjective improvement without objective evidence, and 10 patients complained of worsening of the disease with objective decline after TRH was stopped. Statistical analysis, however, showed no beneficial effects from either acute or chronic TRH trials.', 'A temporary increase in the strength of some muscles was detected following the administration of TRH, but no change in functional performance was noted. Neither the patients nor the investigators believed the effects were of any marked clinical significance.', 'Nevertheless, statistically significant improvement was seen only in dynametric strength 1 hour after subcutaneous injection (p less than 0.05). Significant improvement occurred, in one patient only, on subjective speech testing during IV infusion of TRH. In none of six other ratings was there a significant difference between TRH and placebo. Subjective improvement was noted by 11 of 12 patients.', 'Significant improvement, as shown by statistical analysis, was noted in muscle strength in the 9 patients by 5 infusions over a 4-week period and a sub-group of 5 patients treated by 8 infusions over 10 weeks.', 'The progressive course of this disease, manifested by increasing atrophy, paralysis and disability score, was not altered. ', 'Very high intravenous doses (2-19 mg/min) of thyrotropin-releasing hormone (TRH, L-pyroglutamyl-L-histidyl-L-prolinamide) given to 12 patients with amyotrophic lateral sclerosis (ALS) produced a moderate to marked improvement of functions caused by deficiency of lower motor neurons (weakness) and upper motor neurons (spasticity). The improvement was sustained throughout the infusion and for about 1 h thereafter; sometimes a slight improvement was evident 20 h after infusion.', 'Aerobic exercise capacity was particularly improved in patients with ALS following administration of TRH']
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['Yes, there are studies demonstrating that TRH (thyrotropin releasing hormone) administration can improve symptom severity of amyotrophic lateral sclerosis patients. However, some studies have failed to demonstrate symptom improvement following TRH administration.', 'Very high intravenous doses (2-19 mg/min) of thyrotropin-releasing hormone (TRH, L-pyroglutamyl-L-histidyl-L-prolinamide) given to 12 patients with amyotrophic lateral sclerosis (ALS) produced a moderate to marked improvement of functions caused by deficiency of lower motor neurons (weakness) and upper motor neurons (spasticity). The improvement was sustained throughout the infusion and for about 1 h thereafter; sometimes a slight improvement was evident 20 h after infusion. ']
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['yes']
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Which gene is responsible for the development of the Mowat-Wilson syndrome?
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['The cause of MWS is a de novo mutation in the ZEB2 gene.', 'zfhz1b is the causative gene for Mowat-Wilson syndrome, in which patients demonstrate developmental delay and Hirschsprung disease, as well as other anomalies.', 'Intrahepatic biliary anomalies in a patient with Mowat-Wilson syndrome uncover a role for the zinc finger homeobox gene zfhx1b in vertebrate biliary development', 'We used the zebrafish model system to determine whether zfhx1b has a role in vertebrate biliary development', 'Comprehensive ZEB2 gene analysis for Mowat-Wilson syndrome in a North American cohort: a suggested approach to molecular diagnostics.', 'A case of Mowat-Wilson syndrome caused by a truncating mutation within exon 8 of the ZEB2 gene', 'All typical cases result from haploinsufficiency of the ZEB2 (also known as ZFHX1B or SIP-1) gene, with over 100 distinct mutations now described.', 'Approximately 80% of patients have a nonsense or frameshift mutation detectable by sequencing, with the rest having gross deletions necessitating a dosage sensitive assay.', 'Six patients had deletions in the ZEB2 gene, including two novel partial gene deletions.', 'This report, the first such analysis in North American patients, adds to the growing list of both novel pathogenic mutations associated with MWS, as well as other variants in the ZEB2 gene. In addition, we suggest an economical testing strategy.', 'Nonsense mutations of the ZFHX1B gene in two Japanese girls with Mowat-Wilson syndrome', 'Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly-mental retardation complex caused by mutations in the Zinc Finger Homeobox 1 B gene (ZFHX1B)', 'According to the gene analysis using white blood cells, they had nonsense mutations in ZFHX1B, R695X and Q433X, respectively.', 'In conclusion, molecular genetic analysis of ZFHX1B is important for a definite diagnosis of MWS which has a wide phenotypic spectrum of congenital anomalies.', 'A missense mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype', 'Mutations leading to haploinsufficiency of the ZFHX1B gene have been described as the underlying cause of this condition. We report on the clinical findings in a 2(1/2)-year-old boy with some aspects out of the MWS-spectrum in addition to unusual anomalies and a novel missense mutation in the ZFHX1B gene.', 'Genitourinary anomalies in Mowat-Wilson syndrome with deletion/mutation in the zinc finger homeo box 1B gene (ZFHX1B).', 'It is caused by mutations in the zinc finger homeo box 1B gene, ZFHX1B (SIP1).', 'Pleiotropic and diverse expression of ZFHX1B gene transcripts during mouse and human development supports the various clinical manifestations of the "Mowat-Wilson" syndrome', 'ZFHX1B encodes Smad-interacting protein 1, a transcriptional corepressor involved in the transforming growth factors beta (TGFbeta) signaling pathway', 'ZFHX1B mutations cause a complex developmental phenotype characterized by severe mental retardation (MR) and multiple congenital defects', 'Frameshift mutation of the zinc finger homeo box 1 B gene in syndromic corpus callosum agenesis (Mowat-Wilson syndrome)', 'Mutation analysis of the zinc finger homeo box 1 B (ZFHX1 B) gene revealed a de novo 7 bp deletion (TGGCCCC) at nucleotide 1773 (1773 delTGGCCCC) resulting in a frameshift and leading to a termination codon at amino acid residue 604 (604 X) in exon 8 C', '"Mowat-Wilson" syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene', 'Recently mutations in the gene ZFHX1B (SIP1) were shown in patients with "syndromic Hirschsprung disease" with mental retardation (MR) and multiple congenital anomalies (MCA), but it was unclear if Hirschsprung disease is an obligate symptom of these mutations and if the distinct facial phenotype delineated by Mowat et al. [1998: J Med Genet 35: 617-623] is specific for ZFHX1B mutations.', 'Intrahepatic biliary anomalies in a patient with Mowat-Wilson syndrome uncover a role for the zinc finger homeobox gene zfhx1b in vertebrate biliary development.', 'Haploinsufficiency of a gene termed ZFHX1B (also known as SIP1) on chromosome 2 is responsible for this condition, and clinical genetic testing for MWS recently became available', 'Mowat-Wilson syndrome is a recently delineated autosomal dominant developmental anomaly, whereby heterozygous mutations in the ZFHX1B gene cause mental retardation, delayed motor development, epilepsy and a wide spectrum of clinically heterogeneous features, suggestive of neurocristopathies at the cephalic, cardiac and vagal levels', 'zfhz1b is the causative gene for Mowat-Wilson syndrome, in which patients demonstrate developmental delay and Hirschsprung disease, as well as other anomalies.', 'ZFHX1B mutations in patients with Mowat-Wilson syndrome.', 'A similar issue of differential diagnosis was raised by a large 4.3 Mb 2q22.3q23.1 deletion encompassing ZEB2, the gene responsible for the Mowat-Wilson syndrome, whose signs may overlap with RSTS', 'Mowat-Wilson syndrome is a genetic disease caused by heterozygous mutations or deletions of the zinc finger E-box-binding homeobox 2 (ZEB2) gene', 'At molecular level, MWS is characterized by many different described mutations in the zinc finger E-box protein 2 (ZEB2) gene, ultimately leading to loss of gene function', 'Individuals with Mowat-Wilson syndrome (MWS; OMIM#235730) have characteristic facial features, a variety of congenital anomalies such as Hirschsprung disease, and intellectual disabilities caused by mutation or deletion of ZEB2 gene', 'Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene rarely diagnosed prenatally and with little fetal description reported', 'MWS is caused by de novo heterozygous mutations in the ZEB2 gene']
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['Mowat-Wilson syndrome is a genetic disease caused by heterozygous mutations or deletions of the zinc finger E-box-binding homeobox 2 (ZEB2) gene.', 'Nonsense mutations of the ZFHX1B gene in two Japanese girls with Mowat-Wilson syndromezfhz1b is the causative gene for Mowat-Wilson syndrome, in which patients demonstrate developmental delay and Hirschsprung disease, as well as other anomalies.', 'Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly-mental retardation complex caused by mutations in the Zinc Finger Homeobox 1 B gene (ZFHX1B, also known as ZEB2 or SIP-1).', 'zfhz1b is the causative gene for Mowat-Wilson syndrome, in which patients demonstrate developmental delay and Hirschsprung disease, as well as other anomalies. Intrahepatic biliary anomalies in a patient with Mowat-Wilson syndrome uncover a role for the zinc finger homeobox gene zfhx1b in vertebrate biliary development']
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['ZFHX1B', 'ZEB2', 'SIP-1']
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Is cancer related to global DNA hypo or hypermethylation?
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['Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer', 'Regions of focal hypermethylation in the tumor were located primarily at CpG islands and were concentrated within regions of long-range (>100 kb) hypomethylation. These hypomethylated domains covered nearly half of the genome and coincided with late replication and attachment to the nuclear lamina in human cell lines', 'the confluence of hypermethylation and hypomethylation', 'Comparison of CpG island hypermethylation and repetitive DNA hypomethylation in premalignant stages of gastric cancer', 'CpG island hypermethylation and genomic DNA hypomethylation are found not only in gastric cancers but also in associated premalignant lesions', 'Methylation of repetitive DNA elements in gastric lesions generally decreased with progression of the gastric lesion along the multistep carcinogenesi', 'our findings suggest that CpG island hypermethylation and repetitive DNA hypomethylation are enhanced with progression of the gastric lesion', 'DNA hypomethylation arises later in prostate cancer progression than CpG island hypermethylation', 'Hypomethylation of CpG dinucleotides in genomic DNA was one of the first somatic epigenetic alterations discovered in human cancers. DNA hypomethylation is postulated to occur very early in almost all human cancers, perhaps facilitating genetic instability and cancer initiation and progression.', 'Contrary to the prevailing view that global DNA hypomethylation changes occur extremely early in all human cancers, we show that reductions in (5me)C content in the genome occur very late in prostate cancer progression, appearing at a significant extent only at the stage of metastatic disease', 'These findings provide evidence that DNA hypomethylation changes occur later in prostate carcinogenesis than the CpG island hypermethylation changes and occur heterogeneously during prostate cancer progression and metastatic dissemination.', 'revealed a high incidence of hypermethylation only in poorly differentiated (early and late) tumors.', 'In contrast to gene hypermethylation, genomic DNA hypomethylation, including hypomethylation of repetitive elements and loss of genomic 5-methyldeoxycytidine, occurred in both early and late stages of prostate cancer.', 'Tumors have reduced levels of genomic DNA methylation and contain hypermethylated CpG islands', 'The results are consistent with a specific defect in methylation of repetitive DNA sequences in human cancer.', 'Both hypomethylation and hypermethylation in a 0.2-kb region of a DNA repeat in cancer', 'Differential DNA hypermethylation and hypomethylation signatures in colorectal cancer', 'Cancer cells are characterized by a generalized disruption of the DNA methylation pattern involving an overall decrease in the level of 5-methylcytosine together with regional hypermethylation of particular CpG islands', 'We conclude that DNA hypermethylation and hypomethylation are independent processes and appear to play different roles in colorectal tumor progression']
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['DNA hypermethylation and hypomethylation are independent processes and appear to play different roles in tumor progression. Cancer cells are characterized by a generalized disruption of the DNA methylation pattern involving an overall decrease in the level of 5-methylcytosine together with regional hypermethylation of particular CpG islands. Tumors have reduced levels of genomic DNA methylation and contain hypermethylated CpG islands.']
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['Global hypomethylation is coupled with focal hypermethylation at CpG islands']
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Which is the treatment strategy followed in spinocerebellar ataxia type 3 for CAG removal?
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['Ataxin-3 protein modification as a treatment strategy for spinocerebellar ataxia type 3: removal of the CAG containing exon', 'Spinocerebellar ataxia type 3 is caused by a polyglutamine expansion in the ataxin-3 protein, resulting in gain of toxic function of the mutant protein. The expanded glutamine stretch in the protein is the result of a CAG triplet repeat expansion in the penultimate exon of the ATXN3 gene', 'we propose a novel protein modification approach to reduce mutant ataxin-3 toxicity by removing the toxic polyglutamine repeat from the ataxin-3 protein through antisense oligonucleotide-mediated exon skipping while maintaining important wild type functions of the protein', 'exon skipping may be a novel therapeutic approach to reduce polyglutamine-induced toxicity in spinocerebellar ataxia type 3', 'Ataxin-3 protein modification as a treatment strategy for spinocerebellar ataxia type 3: removal of the CAG containing exon.', 'Ataxin-3 protein modification as a treatment strategy for spinocerebellar ataxia type 3: removal of the CAG containing exon.']
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['The novel treatment strategy proposed for treatment of Spinocerebellar ataxia type 3 is the removal of the toxic polyglutamine repeat from the ataxin-3 protein through antisense oligonucleotide-mediated exon skipping while maintaining important wild type functions of the protein.']
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Which are the main causes of fetal echogenic bowel?
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['In group 2 and 3, two anomalies, anorectal malformation and cystic fibrosis, were detected postnatally', 'Six had chromosomal/genetic abnormalities, two had congenital cytomegalovirus, none had cystic fibrosis', 'Primary bowel pathology is rare following the finding of FEB', 'Maternal serology for cytomegalovirus (CMV) was performed in 49 (78%) cases', 'Thirty-three pregnancies (53%) were tested for cystic fibrosis (CF) and 1 baby was confirmed to have CF postnatally', 'This study reiterates the increased prevalence of aneuploidy, CMV, CF and fetal growth restriction in pregnancies complicated by the midtrimester sonographic finding of FEB', 'Primary outcomes were IUGR, defined as birth weight less than the 10th percentile for gestational age and intrauterine fetal demise at 20 weeks or more of gestatio', 'Analyses were repeated after excluding cases of aneuploidy, cytomegalovirus (CMV) infection,', 'The presence of echogenic bowel on ultrasonography is independently associated with an increased risk for both IUGR and intrauterine fetal demise', 'This study highlights the importance of pregnancy ultrasound examinations and their efficiency in detecting cystic fibrosis', 'A disorder was diagnosed in 32.2% of the fetuses, cystic fibrosis being the most commonly identified (7.6%). We also found digestive malformations (7.0%), chromosomal abnormalities (3.7%), and maternofetal infections (3.7%).', 'A potential association with placental abnormalities and a low prevalence of viral infections was observed', 'Our data suggests an inverse relationship between the maternal BMI and the detection of fetal EIF and/or EB', "Fetal echogenic bowel at 17 weeks' gestational age as the early and only sign of a very long segment of Hirschsprung disease.", 'fetal ultrasound findings associated with intrauterine cytomegalovirus (CMV) infection', 'the combination of hydrops fetalis, cerebral hemorrhage, and hyperechoic bowel should raise the possibility of a CMV infection', 'strongly associated with adverse pregnancy outcome due to utero-placental insufficiency, particularly in women with elevated maternal serum alpha-fetoprotein concentration due to severe feto-maternal bleeding', 'Congenital cytomegalovirus infection presenting with echogenic bowel and oligohydramnios.', 'Five cases of trisomy 21 and one case of trisomy 18 were detected', 'Brightly echogenic bowel in the second trimester was found to be associated with a significant risk of fetal aneuploidy.', 'echogenic bowel does not uniformly herald an abnormal outcome. Echogenic bowel coexistent with other abnormalities (such as growth deficiency or structural malformations) may be a comarker for aneuploidy.', "Congenital cytomegalovirus infection with oligohydramnios and echogenic bowel at 14 weeks' gestation", 'Parental CF carrier testing and amniocentesis to identify aneuploidy or fetal CF status has a high positive ascertainment rate in fetuses with echogenic bowel grades 2 and 3.', 'Swallowing of amniotic fluid after intraamniotic bleeding seems implicated in the etiology of second-trimester echogenic bowel in both euploid and aneuploid fetuses', 'Fetal echogenic bowel and a dilated loop of bowel associated with cystic fibrosis (CF) mutations delta F508 and 2183AA-->G', 'Fifteen cases (19%) were associated with maternal vaginal bleeding', 'Five fetuses (6.3%) had evidence of bowel obstruction or perforation not associated with cystic fibrosis (CF)', 'Chromosomal aberrations were found in 5 fetuses (6.3%). Intrauterine infection with cytomegalovirus, herpes simplex virus, varicella-zoster virus, or parvovirus B-19 was documented in 5 patients (6.3%).', 'Fetal echogenic bowel has been reported as a normal variant in the second trimester, and has also been associated with an adverse fetal outcome, including cystic fibrosis (CF)', 'Intra-amniotic bleeding can lead to echogenic bowel', '112 cases (57%) had a known etiology, which included chromosomal abnormality (7%), infection (4%), cystic fibrosis (1.5%), bowel abnormality (3%), bleeding or stained amniotic fluid (11%), Doppler abnormality (14%), malformation (16%) and miscellaneous (0.5%)']
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['Fetal echogenic bowel is mainly associated to feto-maternal, intramniotic bleeding but in several cases it is linked to cystic fibrosis, cytomegalovirus (CMV), herpes simplex virus and other viral infections and fetal aneuploidy.', 'Fetal echogenic bowel (FEB) is a soft marker found on second trimester sonography. (PMID: 22990134) A disorder was diagnosed in 32.2% of the fetuses, cystic fibrosis being the most commonly identified (7.6%). We also found digestive malformations (7.0%), chromosomal abnormalities (3.7%), and maternofetal infections (3.7%). (PMID: 20932506) Brightly echogenic bowel in the second trimester was found to be associated with a significant risk of fetal aneuploidy. (PMID: 1415421) echogenic bowel does not uniformly herald an abnormal outcome. Echogenic bowel coexistent with other abnormalities (such as growth deficiency or structural malformations) may be a comarker for aneuploidy. (PMID: 8142051) 112 cases (57%) had a known etiology, which included chromosomal abnormality (7%), infection (4%), cystic fibrosis (1.5%), bowel abnormality (3%), bleeding or stained amniotic fluid (11%), Doppler abnormality (14%), malformation (16%) and miscellaneous (0.5%) (PMID: 12835583)']
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['Itramniotic bleeding', 'CMV infection', 'Cystic Fibrosis (CF)', 'Fetal aneuploidy']
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What can Nothobranchius furzeri be used as a model system for?
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['The short-lived annual fish Nothobranchius furzeri shows extremely short captive life span and accelerated expression of age markers, making it an interesting model system to investigate the effects of experimental manipulations on longevity and age-related pathologies.', 'Owing to large differences in aging phenotypes in different lines, N. furzeri could represent a model system for studying the genetic control of life-history traits in natural populations.', 'It is very close to the Japanese Medaka, and close to the pufferfishes and stickleback and might represent a very useful model for comparative genomics of aging.', 'In the last three years, N. furzeri has moved from biological curiosity to a promising model system for drug validation.', ' This result identifies resveratrol as the first molecule which consistently retards aging in organisms as diverse as yeast, worm, fly and fish, but it also reveals the potential of this short-lived fish as an animal model for pharmacological research. Moreover, being related to stickleback (Gasterosteus aculeatus) the "pufferfishes" Takifugu and Tetraodon, and even more closely related to medaka (Oryzias latipes), it can greatly beneficiate from the recent development of genomic resources for these fish models and in the future become a complete model system for the aging research community.', 'These fishes can become excellent models for aging studies. They can be employed to test the effects of experimental manipulation on aging at a pace comparable with that of Drosophila and to probe the effects of natural selection on the evolution of aging-related genes.']
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['N. furzeri an interesting model system to investigate the effects of experimental manipulations on longevity and age-related pathologies.\nN. furzeri could represent a model system for studying the genetic control of life-history traits in natural populations.\nN. furzeri could be a very useful model for comparative genomics of aging.\nIt can be employed to test the effects of experimental manipulation on aging and apharmacological research.']
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['aging research']
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What is known as Calcium Induced Calcium Release (CICR) and its role in cardiomyocyte contractility?
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['Cardiomyocyte contraction depends on rapid changes in intracellular Ca(2+). In mammals, Ca(2+) influx as L-type Ca(2+) current (ICa) triggers the release of Ca(2+) from sarcoplasmic reticulum (SR) and Ca(2+)-induced Ca(2+) release (CICR) is critical for excitation-contraction coupling.', 'Release of calcium (Ca(2+)) from the sarcoplasmic reticulum (SR) induced by Ca(2+) influx through voltage-dependent sarcolemmal L-type Ca(2+) channels (CICR) in cardiac muscle cells has been implicated as a potential target contributing to anesthetic-induced myocardial depression. ', 'It is well known that calcium-induced calcium-release in cardiac myocytes takes place in spatially restricted regions known as dyads, where discrete patches of junctional sarcoplasmic reticulum tightly associate with the t-tubule membrane. ', 'Calcium (Ca(2+))-induced Ca(2+) release (CICR) is widely accepted as the principal mechanism linking electrical excitation and mechanical contraction in cardiac cells. The CICR mechanism has been understood mainly based on binding of cytosolic Ca(2+) with ryanodine receptors (RyRs) and inducing Ca(2+) release from the sarcoplasmic reticulum (SR).', 'Waves of calcium-induced calcium release occur in a variety of cell types and have been implicated in the origin of cardiac arrhythmias. ', 'Calcium-induced calcium release (CICR) has been observed in cardiac myocytes as elementary calcium release events (calcium sparks) associated with the opening of L-type Ca(2+) channels. In heart cells, a tight coupling between the gating of single L-type Ca(2+) channels and ryanodine receptors (RYRs) underlies calcium release. ', 'L-type Ca(2+) channels activate RYRs to produce CICR in smooth muscle cells in the form of Ca(2+) sparks and propagated Ca(2+) waves.', ' the importance of Ca-induced Ca release in excitation-contraction coupling in the heart.', 'Calcium-induced calcium release (CICR) is an inherently regenerative process due to the Ca(2+)-dependent gating of ryanodine receptors (RyRs) in the sarco/endoplasmic reticulum (SR) and is critical for cardiac excitation-contraction coupling.', 'PURPOSE: Release of calcium (Ca(2+)) from the sarcoplasmic reticulum (SR) induced by Ca(2+) influx through voltage-dependent sarcolemmal L-type Ca(2+) channels (CICR) in cardiac muscle cells has been implicated as a potential target contributing to anesthetic-induced myocardial depression.', 'The Ca(2+)-induced Ca(2+) release (CICR) process that governs cardiac contractility is defective in hypertrophy/heart failure, but the molecular mechanisms remain elusive.', 'The Ca(2+)-induced Ca(2+) release (CICR) process that governs cardiac contractility is defective in hypertrophy/heart failure, but the molecular mechanisms remain elusive', 'The majority of contractile calcium in cardiac muscle is released from stores in the sarcoplasmic reticulum (SR), by a process of calcium-induced calcium release (CICR) through ryanodine receptors']
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['the cicr mechanism has been understood mainly based on binding of cytosolic ca(2+) with ryanodine receptors (ryrs) and inducing ca(2+) release from the sarcoplasmic reticulum (sr). l-type ca(2+) channels activate ryrs to produce cicr in smooth muscle cells in the form of ca(2+) sparks and propagated ca(2+) waves. in heart cells, a tight coupling between the gating of single l-type ca(2+) channels and ryanodine receptors (ryrs) underlies calcium release. the importance of ca-induced ca release in excitation-contraction coupling in the heart. waves of calcium-induced calcium release occur in a variety of cell types and have been implicated in the origin of cardiac arrhythmias. in mammals, ca(2+) influx as l-type ca(2+) current (ica) triggers the release of ca(2+) from sarcoplasmic reticulum (sr) and ca(2+)-induced ca(2+) release (cicr) is critical for excitation-contraction coupling. ', 'Cardiomyocyte contraction depends on rapid changes in intracellular Ca(2+). Ca(2+) influx as L-type Ca(2+) current (ICa) triggers the release of Ca(2+) from sarcoplasmic reticulum (SR) and Ca(2+)-induced Ca(2+) release (CICR) is critical for excitation-contraction coupling. Calcium-induced calcium-release in cardiac myocytes takes place in spatially restricted regions known as dyads, where discrete patches of junctional sarcoplasmic reticulum tightly associate with the t-tubule membrane. Calcium-induced calcium release (CICR) has been observed in cardiac myocytes as elementary calcium release events (calcium sparks) associated with the opening of L-type Ca(2+) channels. Waves of calcium-induced calcium release occur in a variety of cell types and have been implicated in the origin of cardiac arrhythmias.']
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Which domain allowing self-association do exist in TDP-43 and FUS proteins?
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['Using transient expression of a panel of deletion and chimeric FUS variants in various cultured cells, we demonstrated that FUS accumulating in the cytoplasm nucleates a novel type of RNA granules, FUS granules (FGs), that are structurally similar but not identical to physiological RNA transport granules. Formation of FGs requires FUS N-terminal prion-like domain and the ability to bind specific RNAs. Clustering of FGs coupled with further recruitment of RNA and proteins produce larger structures, FUS aggregates (FAs), that resemble but are clearly distinct from stress granules.', 'Approximately 1% of human proteins harbor a prion-like domain (PrLD) of similar low complexity sequence and amino acid composition to domains that drive prionogenesis of yeast proteins like Sup35. PrLDs are over-represented in human RNA-binding proteins and mediate phase transitions underpinning RNP granule assembly. This modality renders PrLDs prone to misfold into conformers that accrue in pathological inclusions that characterize various fatal neurodegenerative diseases. For example, TDP-43 and FUS form cytoplasmic inclusions in amyotrophic lateral sclerosis (ALS) and mutations in TDP-43 and FUS can cause ALS.', 'FUS and TDP-43, which rank 1st and 10th among RRM-bearing prion candidates, form cytoplasmic inclusions in the degenerating motor neurons of ALS patients and mutations in TDP-43 and FUS cause familial ALS. ', 'Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS.', "two RNA-binding proteins, FUS and TDP-43, which form cytoplasmic aggregates in amyotrophic lateral sclerosis, harbor a 'prion domain' similar to those found in several yeast prion proteins.", 'Mutations in related RNA-binding proteins TDP-43, FUS/TLS and TAF15 have been connected to ALS. These three proteins share several features, including the presence of a bioinformatics-predicted prion domain, aggregation-prone nature in vitro and in vivo and toxic effects when expressed in multiple model systems.', "Moreover, two RNA-binding proteins, FUS and TDP-43, which form cytoplasmic aggregates in amyotrophic lateral sclerosis, harbor a 'prion domain' similar to those found in several yeast prion proteins", 'TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate.', 'Molecular cloning of subunit 4 of the complex revealed that it is a proteasome-COP9 complex-eIF3 domain protein encoded by a gene that maps to chromosome 5, near the chromosomal location of the cop8 and fus4 mutations. ', 'Deletions in the C-terminal domain of TDP-43 that preclude interactions with hnRNP A2/B1 abolish TDP-43-dependent rescue of CGG repeat toxicity.', 'The rescue appears specific to TDP-43, as co-expression of another ALS-associated RNA-binding protein, FUS, exacerbates the toxic effects of CGG repeats', 'Recently, through Next-Generation Exome sequencing approaches a mutation resulting in a substitution (p.Q290X) in the nuclear export domain of the FUS protein was nominated as a cause of autosomal dominant essential tremor (ET) in a large kindred', 'TDP-43 is another RNA-binding protein implicated in ALS', 'We also provide multiple independent lines of in vitro and in vivo evidence that EWSR1 has similar properties as TDP-43, FUS and TAF15, including aggregation-prone behavior in vitro and ability to confer neurodegeneration in Drosophila.', 'For TDP-43, both the RRM1 and the C-terminal glycine-rich domain are required for SG localization.', 'Furthermore, TDP-43 and FUS display distinct domain requirements in aggregate formation and cytotoxicity.', 'Binding was mediated by an unstructured TDP-43 C-terminal domain and occurred within the context of a 300-400-kDa complex that also contained C-terminal cleavage products of TDP-43 linked to neuropathology.', 'It was recently found that dominant mutations in two related RNA-binding proteins, TDP-43 (43-kDa TAR DNA-binding domain protein) and FUS/TLS (fused in sarcoma/translated in liposarcoma) cause a subset of ALS.']
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['PRION PROTEINS', "Mutations in related RNA-binding proteins TDP-43, FUS/TLS and TAF15 have been connected to ALS. These three proteins share several features, including the presence of a bioinformatics-predicted prion domain, aggregation-prone nature in vitro and in vivo and toxic effects when expressed in multiple model systems. TDP-43, FUS and TAF15 share similar properties, including aggregation-prone behavior in vitro and ability to confer neurodegeneration in Drosophila. For TDP-43, both the RRM1 and the C-terminal glycine-rich domain are required for SG localization. Moreover, two RNA-binding proteins, FUS and TDP-43, which form cytoplasmic aggregates in amyotrophic lateral sclerosis, harbor a 'prion domain' similar to those found in several yeast prion protein", "Scouring the human genome with this algorithm enriches a select group of RNA-binding proteins harboring a canonical RNA recognition motif (RRM) and a putative prion domain. Moreover, two RNA-binding proteins, FUS and TDP-43, which form cytoplasmic aggregates in amyotrophic lateral sclerosis, harbor a 'prion domain' similar to those found in several yeast prion proteins. PrLDs are over-represented in human RNA-binding proteins and mediate phase transitions underpinning RNP granule assembly. For example, TDP-43 and FUS form cytoplasmic inclusions in amyotrophic lateral sclerosis (ALS) and mutations in TDP-43 and FUS can cause ALS.", "Two RNA-binding proteins, FUS and TDP-43, which form cytoplasmic aggregates in amyotrophic lateral sclerosis, harbor a 'prion domain' similar to those found in several yeast prion proteins."]
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['Prion-like domain']
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The CXCR2 receptor is targeted in cancer. Name five antagonists.
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['CXCR2 small-molecule antagonist (SB225002)', 'G31P, an antagonist against CXC chemokine receptors 1 and 2, inhibits growth of human prostate cancer cells in nude mice.', 'The CXCR2 antagonist, SCH-527123, shows antitumor activity', 'retreatment with the CXCR2 antagonist AZ10397767', 'The aim of this study was to investigate whether the CXCR2 antagonist, SCH-527123, inhibits colorectal cancer proliferation and if it can sensitize colorectal cancer cells to oxaliplatin both in vitro and in vivo.', 'we report that targeting CXCR2 and CXCR1 activity using orally active small molecule antagonist (SCH-527123, SCH-479833) inhibits human colon cancer liver metastasis mediated by decreased neovascularization and enhanced malignant cell apoptosis.', 'CXCR2-specific small molecule inhibitor (AZ10397767) to investigate the recruitment and function of human neutrophils in tumors']
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['There are numerous CXCR2 receptor antagonists, such as SB225002, G31P, SCH-527123, AZ10397767, SCH-479833.']
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['SB225002', 'G31P', 'SCH-527123', 'AZ10397767', 'SCH-479833']
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Can the iPS cell technology be used in Fanconi anemia therapy?
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['We explain a protocol for the reproducible generation of genetically corrected iPSCs starting from the skin biopsies of Fanconi anemia patients using retroviral transduction with OCT4, SOX2 and KLF4', 'Before reprogramming, the fibroblasts and/or keratinocytes of the patients are genetically corrected with lentiviruses expressing FANCA.', 'Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells', 'Here we show that, on correction of the genetic defect, somatic cells from Fanconi anaemia patients can be reprogrammed to pluripotency to generate patient-specific iPS cells. These cell lines appear indistinguishable from human embryonic stem cells and iPS cells from healthy individuals', 'Most importantly, we show that corrected Fanconi-anaemia-specific iPS cells can give rise to haematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, that is, disease-free']
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['iPS cell technology can be used for the generation of disease-corrected, patient-specific cells with potential value for cell therapy applications in Fanconi anemia.']
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['yes']
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What is TOPAZ1?
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['TOPAZ1, a germ cell specific factor, is essential for male meiotic progression', 'Topaz1 (Testis and Ovary-specific PAZ domain gene 1) is a germ cell specific gene highly conserved in vertebrates', 'Topaz1 is supposed to have a role during gametogenesis and may be involved in the piRNA pathway and contribute to silencing of transposable elements and maintenance of genome integrity', 'TOPAZ1, a novel germ cell-specific expressed gene conserved during evolution across vertebrates']
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['TOPAZ1 is a novel germ cell-specific expressed gene conserved during evolution across vertebrates. Its PAZ-domain protein is abundantly expressed in the gonads during germ cell meiosis. The expression pattern of TOPAZ1, and its high degree of conservation, suggests that it may play an important role in germ cell development. Further characterization of TOPAZ1 may elucidate the mechanisms involved in gametogenesis, and particularly in the RNA silencing process in the germ line.', 'TOPAZ1 (Testis and Ovary-specific PAZ domain gene 1) is a germ cell specific factor that is essential for male meiotic progression. Topaz1 is supposed to have a role during gametogenesis and may be involved in the piRNA pathway and contribute to silencing of transposable elements and maintenance of genome integrity. It is highly conserved in vertebrates.']
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What is the lay name of the treatment for CCSVI (chronic cerebro-spinal venous insufficiency) in multiple sclerosis.
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['patients with relapsing-remitting (RR) multiple sclerosis (MS) receiving standard medical treatment who had been diagnosed with chronic cerebrospinal venous insufficiency (CCSVI) and underwent percutaneous transluminal angioplasty (PTA)', 'Although it is debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients undergo endovascular treatment (ET) of CCSVI', 'Endovascular treatment of CCSVI in patients with multiple sclerosis', 'Although it is still debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients underwent endovascular treatment (ET) of CCSVI.', 'Chronic Cerebro-Spinal Venous Insufficiency (CCSVI) has been proposed to be associated with Multiple Sclerosis (MS). Zamboni et\xa0al reported significant improvement in neurological outcomes in MS patients who underwent Percutaneous Transluminal Angioplasty (PTA)', 'Our open-label study included 94 MS patients who fulfilled ultrasound sonographic criteria required for CCSVI. The internal jugular and/or azygous veins by a catheter venography were dilated.', 'Disability caused by multiple sclerosis is associated with the number of extra cranial venous stenoses: possible improvement by venous angioplasty. Results of a prospective study.', 'Clinical improvement after extracranial venoplasty in multiple sclerosis', 'This study proposed to prospectively evaluate safety and clinical changes in outpatient endovascular treatment in patients with multiple sclerosis (MS) and chronic cerebrospinal venous insufficiency (CCSVI).', 'Twenty-nine patients with clinically definite relapsing-remitting MS underwent percutaneous transluminal angioplasty for CCSVI, outside a clinical relapse.', 'The European Society of Neurosonology and Cerebral Hemodynamics (ESNCH) has considerable concerns regarding the accuracy of the proposed criteria for CCSVI in MS. Therefore, any potentially harmful interventional treatment such as transluminal angioplasty and/or stenting should be strongly discouraged.', 'Catheter venography and endovascular treatment of chronic cerebrospinal venous insufficiency.', 'The work of Dr. Zamboni, et al, who reported that treating the venous stenoses causing CCSVI with angioplasty resulting in significant improvement in the symptoms and quality of life of patients with MS (2', 'Endovascular treatment of patients with chronic cerebrospinal venous insufficiency and multiple sclerosis', 'Endovascular treatment (percutaneous transluminal angioplasty (PTA) with or without stenting) of CCSVI was reported to be feasible with a minor complication rate', 'Safety of endovascular treatment of chronic cerebrospinal venous insufficiency:', 'For patients treated primarily, 87% (208 of 239) had angioplasty, and 11% (26 of 239) had stent placement; 5 patients were not treated. Of patients with restenosis, 50% (9 of 18) had angioplasty, and 50% (9 of 18) had stent placement.', 'An endovascular treatment of Chronic Cerebro-Spinal Venous Insufficiency in multiple sclerosis patients', 'In this study, the mid-term results (6 month follow-up) of the endovascular treatment in patients with Chronic Cerebro-Spinal Venous Insufficiency (CCSVI) and multiple sclerosis (MS) were prospectively evaluated.', 'Thirty-six patients with confirmed MS and CCSVI underwent endovascular treatment by the means of the uni- or bilateral jugular vein angioplasty with optional stent placement.', 'stent implantation into the jugular vein,', 'As the debate about CCSVI and its relationship to MS continues, the complications and risks associated with venous stenting and angioplasty in jugular and azygous veins are becoming clearer.', 'Chronic cerebrospinal venous insufficiency (CCSVI) is associated with multiple sclerosis (MS). The objective of the study was to see if percutaneous transluminal angioplasty (PTA) of duplex-detected lesions, of the internal jugular and/or azygous veins, was safe,', 'CCSVI theory has generated a scientific and mass media debate with a great hope for the miracle of a new possible endovascular treatment of MS ("liberation procedure").', 'Internal jugular thrombosis post venoplasty for chronic cerebrospinal venous insufficiency.', 'The treatment based on the CCSVI theory has appealingly been called "liberation treatment"', 'MS patients (261 women; mean age 45.4 years, range 21-79) with CCSVI underwent endovascular treatment of 1012 venous lesions during 495 procedures', 'While balloon angioplasty was preferred, 98 stents were implanted in 76 patients for lesion recoil, restenosis, or suboptimal dilation.', 'The aim of this report is to assess the safety of endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI)', 'A total of 564 endovascular procedures (balloon angioplasty or, if this procedure failed, stenting)', 'A potential shift in the treatment paradigm of MS involving endovascular balloon angioplasty or venous stent placement has been proposed as well as conducted in small patient series', 'She underwent percutaneous balloon angioplasty of the associated chronic cerebrospinal venous insufficiency (CCSVI)', 'A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency', 'Sixty-five consecutive patients with CCSVI, subdivided by MS clinical course into 35 with relapsing remitting (RR), 20 with secondary progressive (SP), and 10 with primary progressive (PP) MS, underwent percutaneous transluminal angioplasty (PTA)']
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['The so-called "LIberation therapy" is in fact Endovascular Treatment and consists of PTA (Percutaneous Transluminal Angioplasty), which is dilatation of the internal jugular and/or azygous veins by a catheter venography. Stent placement is optional but has been strongly advised against as being dangerous.']
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['LIberation therapy']
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What is smFISH?
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['Single-molecule fluorescence in situ hybridization: quantitative imaging of single RNA molecules.', 'In situ hybridization-based analysis methods complement these studies by providing information about how expression levels change between cells within normal and diseased tissues, and they provide information about the localization of transcripts within cells, which is important in understanding mechanisms of gene regulation. Multi-color, single-molecule fluorescence in situ hybridization (smFISH) is particularly useful since it enables analysis of several different transcripts simultaneously. Combining smFISH with immunofluorescent protein detection provides additional information about the association between transcription level, cellular localization, and protein expression in individual cells.', 'We combine immunofluorescence and single-molecule fluorescence in situ hybridization (smFISH), followed by automated image analysis, to quantify the concentration of nuclear transcription factors, number of transcription factors bound, and number of nascent mRNAs synthesized at individual gene loci. ', 'Multi-color, single-molecule fluorescence in situ hybridization (smFISH) is particularly useful since it enables analysis of several different transcripts simultaneously. Combining smFISH with immunofluorescent protein detection provides additional information about the association between transcription level, cellular localization, and protein expression in individual cells. .', 'Multi-color, single-molecule fluorescence in situ hybridization (smFISH) is particularly useful since it enables analysis of several different transcripts simultaneously. Combining smFISH with immunofluorescent protein detection provides additional information about the association between transcription level, cellular localization, and protein expression in individual cells.']
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['smFISH (Single-molecule fluorescence in situ hybridization) allows for quantitative imaging of single RNA molecules. Multi-color, single-molecule fluorescence in situ hybridization (smFISH) is particularly useful since it enables analysis of several different transcripts simultaneously. Combining smFISH with immunofluorescent protein detection provides additional information about the association between transcription level, cellular localization, and protein expression in individual cells.']
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What is known about diseases associated with mutations in the CHCHD10 gene?
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['Late onset spinal motor neuronopathy is caused by mutation in CHCHD10.', 'Mutation c.197G>T p.G66V in CHCHD10 is the cause of the lower motor neuron syndrome LOSMoN/SMAJ. During the preparation of this article other mutations were reported to cause frontotemporal dementia-amyotrophic lateral sclerosis syndrome, indicating that the CHCHD10 gene is largely important for the motor and cognitive neuronal systems.', 'Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.', 'Our findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes. ', 'Mutations in the CHCHD10 gene have been recently identified in a large family with a complex phenotype variably associating frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS), cerebellar ataxia, myopathy, and hearing impairment.', 'The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. ', 'This study demonstrates the implication of CHCHD10 in FTD and ALS spectrum.', 'However, the exact contribution of CHCHD10 in FTD and ALS diseases spectrum remains unknown.', 'In this study, we evaluated the frequency of CHCHD10 mutations in 115 patients with FTD and FTD-ALS phenotypes.', 'The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis.', 'Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients.', 'A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.', 'Mutations in the CHCHD10 gene have been recently identified in a large family with a complex phenotype variably associating frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS), cerebellar ataxia, myopathy, and hearing impairment', 'The mutation was shown to segregate with the disease in 55 patients from 17 families.INTERPRETATION: Mutation c.197G>T p.G66V in CHCHD10 is the cause of the lower motor neuron syndrome LOSMoN/SMAJ. ', 'Mutations in the CHCHD10 gene have been recently identified in a large family with a complex phenotype variably associating frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS), cerebellar ataxia, myopathy, and hearing impairment. ', 'However, the exact contribution of CHCHD10 in FTD and ALS diseases spectrum remains unknown. ', 'The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. ', 'This study demonstrates the implication of CHCHD10 in FTD and ALS spectrum. ', 'Mutations in the CHCHD10 gene have been recently identified in a large family with a complex phenotype variably associating frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS),']
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['Mutation c.197G>T p.G66V in CHCHD10 is the cause of the lower motor neuron syndrome LOSMoN/SMAJ. \nMutations in the CHCHD10 gene have been identified in a large family with a complex phenotype variably associating frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS), cerebellar ataxia, myopathy, and hearing impairment.\nOther findings links CHCHD10 mutations to mitochondrial myopathy.', 'Mutations in the CHCHD10 gene have been recently identified in a large family with a complex phenotype variably associating frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS), cerebellar ataxia, myopathy, and hearing impairment.']
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[]
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List bacteria that may be useful in uranium bioremediation.
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['Members of the Betaproteobacteria (i.e. Dechloromonas, Ralstonia, Rhodoferax, Polaromonas, Delftia, Chromobacterium) and the Firmicutes dominated the biostimulated aquifer community.', 'Shewanella oneidensis is an important model organism for bioremediation studies because of its diverse respiratory capabilities, conferred in part by multicomponent, branched electron transport systems.', 'metal-reducing Geobacter species', ' Identifications based on bacterial 16S rRNA sequence analysis showed that the dominant cultivable bacteria belonged to the genus Bacillus. Members of the genera Paenibacillus, Lysinibacillus, Klebsiella, Microbacterium and Chryseobacterium were also isolated from the LAAs soil samples.', ' Geobacter', 'Geobacteraceae', 'Geobacteraceae will be responsible for much of the Fe(III) and U(VI) reduction during uranium bioremediation in these sediments.', ' Our previous studies have demonstrated that the microbial communities involved in uranium bioremediation and energy harvesting are both dominated by microorganisms in the family Geobacteraceae and that the organisms in this family are responsible for uranium bioremediation and electron transfer to electrodes. ', 'the organisms in the family Geobacteraceae that have been found to be associated with metal reduction in previous studies ', 'to stimulate the activity of Geobacter species during in situ uranium bioremediation.', 'Geobacteraceae', ' Geobacter species are known to be important members of the microbial community: (1) a uranium-contaminated aquifer located in Rifle, CO, USA undergoing in situ bioremediation;', 'Geobacteraceae feoB transcripts in groundwater samples from a site undergoing in situ uranium bioremediation ', ' Geobacteraceae activity during metal reduction in carbon-amended microcosms, with the highest expression observed in the glucose treatment.', 'Geobacter uraniireducens sp. nov., isolated from subsurface sediment undergoing uranium bioremediation.', 'A Gram-negative, rod-shaped, motile bacterium, strain Rf4T, which conserves energy from dissimilatory Fe(III) reduction concomitant with acetate oxidation, was isolated from subsurface sediment undergoing uranium bioremediation. ', '. Constant levels of Geobacter ompB transcripts were detected in groundwater during a field experiment in which acetate was added to the subsurface to promote in situ uranium bioremediation. ', 'Geobacter species are the predominant organisms, ', 'Firmicutes were the predominant organisms whereas no Firmicutes sequences were detected in background sediments which did not have the capacity to sorb U(VI),', 'Geobacter species that predominates during in situ uranium bioremediation at this site.', 'As part of an effort to diagnose the physiological status of Geobacter species during in situ bioremediation of uranium-contaminated groundwater, ', 'Geobacter uraniireducens', ' Geobacter species are often the dominant members of the groundwater community during active bioremediation and the primary organisms catalysing U(VI) reduction.', 'Anaeromyxobacter dehalogenans strains implicated in hexavalent uranium reduction and immobilization are present in the fractured saprolite subsurface environment at the U.S. Department of Energy Integrated Field-Scale Subsurface Research Challenge (IFC) site near Oak Ridge, TN. ', 'Both enrichments were capable of reducing U(VI) rapidly. 16S rRNA gene clone libraries of the two enrichments revealed that Desulfovibrio spp. are dominant in the sulfate-reducing enrichment, and Clostridium spp. are dominant in the iron-reducing enrichment.', '. The results demonstrate that Geobacter species can effectively reduce U(VI)', 'Uranium biomineralization by a metal-resistant Pseudomonas aeruginosa strain isolated from uranium mine waste was characterized for its potential in bioremediation. ', 'Uranium biomineralization by a metal resistant Pseudomonas aeruginosa strain isolated from contaminated mine waste.', 'Geobacter-mediated bioremediation of uranium', 'The cytochrome genes detected were primarily from Geobacter sp.', 'Acetate amendment at uranium contaminated sites in Rifle, CO. leads to an initial bloom of Geobacter accompanied by the removal of U(VI) from the groundwater, followed by an increase of sulfate-reducing bacteria (SRBs) which are poor reducers of U(VI).', 'Whole-genome microarray analyses of a subsurface isolate of Geobacter uraniireducens,', " At the US Department of Energy's Integrated Field Research Challenge (IFRC) site in Rifle, CO, the stimulation of Geobacter growth and activity via subsurface acetate addition leads to precipitation of U(VI) from groundwater as U(IV)", 'Here, we report a proteomics-based approach for simultaneously documenting the strain membership and microbial physiology of the dominant Geobacter community members during in situ acetate amendment of the U-contaminated Rifle,']
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['The main bacteria studied in uranium bioremediation are Geobacteraceae. Other bacteria are: \nFirmicutes, \nShewanella oneidensis\nPseudomonas aeruginosa\nAnaeromyxobacter dehalogenans \nstrain Rf4T']
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['Betaproteobacteria', 'Firmicutes', 'Geobacter', 'Geobacteraceae', 'Geobacter uraniireducens', 'Shewanella oneidensis', 'Pseudomonas aeruginosa', 'Anaeromyxobacter dehalogenans', 'strain Rf4T']
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Where can you find the annulus of Zinn?
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["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).", 'It arose at the annulus of Zinn, passing forwards between the inferior rectus muscle and lateral rectus muscle, and insert directly on the sclera. ', 'Drilling was continued toward the annulus of Zinn (AZ) and optic nerve superiorly and over the intracavernous ICA posteriorly.', 'Measurements before and after resection of the ACP included the length of C6 segment of the ICA on its lateral aspect; C6 segment length on its medial aspect; and medial length of the optic nerve from the optic chiasm to falciform ligament (before ACP resection) then to the annulus of Zinn (after ACP resection).', 'The muscles, situated between the optic nerve and the lateral rectus muscle, originated from the annulus of Zinn and branched off two heads; one inserted into the medial inferior side of the superior rectus muscle and the other inserted into the central superior side of the inferior rectus muscle. ', ' In 30 cadavers, the superior division of the oculomotor nerve was severed en bloc 1.5 cm anterior to the annulus of Zinn with the levator palpebrae superioris (LPS) and the superior rectus muscles. ', 'The optic canal was subsequently removed en bloc, beginning at the annulus of Zinn and extending to the optic chiasm.', '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.', '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.', '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.A retrospective, noncomparative, interventional case series.All patients who underwent optic nerve glioma resections using this technique with the authors between 1994 and 2010.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', '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.Postoperative outcome measures include: health of the ipsilateral globe, paralytic ptosis, postoperative complications, and tumor recurrence.Eleven patients underwent resection of optic nerve gliomas using this technique', 'No patients had tumor recurrence or developed postoperative paralytic ptosis.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', 'The orbital surface of the medial rectus and inferior rectus are exposed from the annulus of Zinn to a position close to where the muscles penetrate Tenons capsule', "The orbital surface of the medial rectus and inferior rectus are exposed from the annulus of Zinn to a position close to where the muscles penetrate Tenon's capsule. ", 'The muscles, situated between the optic nerve and the lateral rectus muscle, originated from the annulus of Zinn and branched off two heads; one inserted into the medial inferior side of the superior rectus muscle and the other inserted into the central superior side of the inferior rectus muscle.', 'The optic canal was subsequently removed en bloc, beginning at the annulus of Zinn and extending to the optic chiasm.', 'The distance from the annulus of Zinn to the trochlea was the same in both eyes.The findings for our patients, particularly in those who underwent additional high resolution MRI, did not provide evidence of a lack of CN IV as a cause of Brown syndrome.', "Should the annular tendon of the eye be named 'annulus of Zinn' or 'of Valsalva'?", 'The distance from the annulus of Zinn to the trochlea was the same in both eyes.', 'The optic canal was subsequently removed en bloc, beginning at the annulus of Zinn and extending to the optic chiasm.', 'Through a superior orbitotomy exposure, the entire retrobulbar segment of the tumor is transected from the globe to the annulus of Zinn.']
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['Annulus of Zinn is in the orbit.']
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['orbit', 'EYE']
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Does metformin interfere thyroxine absorption?
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[]
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['There are not reported data indicating that metformin interferes with thyroxine absorption']
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['no']
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What clinical use aptamers may have?
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['In murine tumor models, the aptamer-targeted siRNA-mediated NMD inhibition in tumor cells led to significant inhibition of tumor growth, which was superior to best-in-class "conventional" cancer vaccination protocols. Tumor-targeted NMD inhibition forms the basis of a simple, broadly useful, and clinically feasible approach to enhance the antigenicity of disseminated tumors leading to their immune recognition and rejection.', 'This study is focused on one aptamer (termed A2). Transfection of this molecule into HPV16-transformed cells resulted in inhibition of cell proliferation (shown using real-time cell electronic sensing and MTT assays) due to the induction of apoptosis (as demonstrated by Annexin V/propidium iodide staining).', 'Transfection of cells with A2 was correlated with the loss of E7 and the induction of apoptosis.', 'Aptamers specific for a number of cellular and viral proteins have been documented previously; one aptamer (Macugen) is approved for clinical use and several others are in clinical trials.', 'The high binding affinity and specificity of aptamers allows for isolation of an artificial ligand for theoretically any therapeutic target of interest.', 'Aptamers are a special class of nucleic acid molecules that are beginning to be investigated for clinical use. These small RNA/DNA molecules can form secondary and tertiary structures capable of specifically binding proteins or other cellular targets; they are essentially a chemical equivalent of antibodies. Aptamers have the advantage of being highly specific, relatively small in size, and non-immunogenic.', 'In the last two decades, many aptamers have been clinically developed as inhibitors for targets such as vascular endothelial growth factor (VEGF) and thrombin.', 'The first aptamer based therapeutic was FDA approved in 2004 for the treatment of age-related macular degeneration and several other aptamers are currently being evaluated in clinical trials.', 'Preclinical studies using aptamer-siRNA chimeras and aptamer targeted nanoparticle therapeutics have been very successful in mouse models of cancer and HIV.', 'In summary aptamers are in several stages of development, from pre-clinical studies to clinical trials and even as FDA approved therapeutics.', 'In subcutaneous and metastatic tumour models, tumour-targeted delivery of NMD factor-specific siRNAs conjugated to oligonucleotide aptamer ligands led to significant inhibition of tumour growth that was superior to that of vaccination with granulocyte-macrophage colony-stimulating factor (GM-CSF)-expressing irradiated tumour cells, and could be further enhanced by co-stimulation.', 'An assortment of non-viral carriers including liposomes, peptides, polymers, and aptamers are being evaluated for their ability to shepherd siRNA to the target tissue and cross the plasma membrane barrier into the cell.', 'In addition, a new thromboxane receptor antagonist, NCX-4016, a newly discovered protease-activated receptor antagonist that targets thrombin-induced platelet aggregation, and anti-von Willebrand factor aptamers show tremendous promise in refining antiplatelet therapy by targeting different receptors and molecules.', 'First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers', 'ARC1779 is a therapeutic aptamer antagonist of the A1 domain of von Willebrand Factor (vWF), the ligand for receptor glycoprotein 1b on platelets. ARC1779 is being developed as a novel antithrombotic agent for use in patients with acute coronary syndromes.', 'This is the first-in-human evaluation of a novel aptamer antagonist of vWF. ARC1779 produced dose- and concentration-dependent inhibition of vWF activity and platelet function with duration of effect suitable for the intended clinical use in acute coronary syndromes.', 'Wet age-related macular degeneration and diabetic retinopathy are pathological consequences of vascular endothelial growth factor (VEGF) release as a reaction to deficiency of oxygen and nutrients in the macular cells.', 'FDA recently approved two drugs specifically aimed at VEGF, bevacizumab, a humanized monoclonal antibody, and pegaptinib, a pegylated aptamer with application in ophthalmic pathologies.', 'Delivery of double-stranded DNA thioaptamers into HIV-1 infected cells for antiviral activity', 'Our lead thioaptamer, R12-2, targets the RNase H domain of the HIV-1 reverse transcriptase (RT) and inhibits viral infection in U373-MAGI-CCR5 cells.', 'In this report, we demonstrate that monothioate-modified DNA duplex oligonucleotides can be efficiently delivered into cells by liposome-based transfection agents to inhibit HIV replication.', 'Nucleic acid aptamers in therapeutic anticoagulation', 'Pegaptanib sodium for the treatment of neovascular age-related macular degeneration', 'Pegaptanib sodium is one of the first therapeutics belonging to the class of compounds known as aptamers.', 'The article highlights and summarises the results of the multi-centre, randomised, sham-controlled clinical trials with pegaptanib sodium to treat subfoveal choroidal neovascularisation in AMD. In addition, the safety profile is reviewed.', 'Regulatable aptamers in medicine: focus on antithrombotic strategies', 'After a decade of intensive research, technology development and initial clinical evaluation, aptamers have now demonstrated broad potential as direct protein ligands and inhibitors, and thus represent an exciting class of compounds for the development of new therapeutic and diagnostic agents. ', 'Two R-aptamers (R10-60 and D-R15-8) with the predominant shared characteristics were selected for further study on primary human chronic lymphocytic leukemia (CLL) B cells, which are well known to be difficult to transfect and activate.', 'Together, these findings suggest that the sequence compositions in R-aptamers that promote multimerization and contain optimal ISS CpG motifs facilitate the delivery of ISS-ODN to CLL cells and enhance the activation of these cells.', 'In particular, the use of aptamers for the alleviation of blood clotting and the treatment of AIDS are considered.', 'We synthesized an RNA aptamer probe specific for human CD4 using a reported sequence and investigated the potential use of this probe in cell phenotyping. Studies in cultured cells demonstrated that the synthetic CD4 aptamer had a nearly identical cell-binding specificity as the standard CD4 antibody. Fluorescent microscopy confirmed that the aptamer and antibody generated the same CD4 staining pattern in cells without competing with one another.', 'transfection of HPV16-transformed cells with A2 appeared to result in the loss of E7 and rise in pRb levels']
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['In the clinic, aptamers may be used to enhance the antigenicity of disseminated tumors, leading to their immune recognition and rejection; to target HPV16 E7 oncoprotein, inhibiting cell proliferation and activating apoptosis of infected cells; to act as inhibitors for targets such as VEGF, in age-related macular degeneration, and thrombin, or von Willebrand factor, in patients with acute coronary syndromes; to target the RNase H domain of the HIV-1 reverse transcriptase and inhibit viral replication; to transfect and activate B cells in human chronic lymphocytic leukemia (CLL); or finally, to be used as probes in CD4-cell phenotyping.']
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Which are the lipid lowering drugs administered in patients with Coronary Artery Disease (CAD)?
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['Impact of adding ezetimibe to statin to achieve low-density lipoprotein cholesterol goal (from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE] trial).', 'After maximizing statin dose, ezetimibe was added to reach the LDL cholesterol goal in 34% of patients (n\xa0= 734). ', 'Using Cox regression analysis, the most significant factors associated with achieving LDL cholesterol goals were lower baseline LDL cholesterol, average statin dose, and ezetimibe use. In conclusion, after maximizing statin dose, the addition of ezetimibe results in a substantial increase in the percentage of patients who reach LDL cholesterol goal, a key component of optimal medical therapy.', 'Comparative study of bezafibrate and pravastatin in patients with coronary artery disease and high levels of remnant lipoprotein.', 'Remnant lipoproteinemia is a strong risk factor for cardiovascular (CV) diseases. This study examined which of 2 common lipid-lowering drugs (fibrates and statins) is more effective in patients with remnant lipoproteinemia and if lowering remnant lipoprotein levels can reduce CV risk.', 'RLP-C levels at 1 year of treatment were reduced more by bezafibrate than pravastatin (37% and 25% from baseline, respectively). ', 'Bezafibrate therapy decreased RLP-C levels to a greater extent than pravastatin and a decrease in RLP-C level may be associated with a reduction in CV events in patients with high RLP-C levels.', 'Statins are powerful lipid-lowering drugs, widely used in patients with hyperlipidemia and coronary artery disease. ', 'Patients are frequently treated with lipid-lowering drugs such as resins, fibrates, niacin, statins and cholesterol absorption-inhibiting drugs (ezetimibe). ', 'This study sought to investigate the effect of daily glucose fluctuation on coronary plaque properties in patients with coronary artery disease (CAD) pre-treated with lipid-lowering therapy.There is growing evidence that glucose fluctuation, as a residual risk apart from dyslipidemia, is an important factor contributing to the development of CAD.This prospective study enrolled 70 consecutive CAD patients who were referred for percutaneous coronary intervention and whose low-density lipoprotein cholesterol level was <120 mg/dl under statin treatment or <100 mg/dl without statins', 'To investigate the impact of lipid lowering therapy by different means on skin microvascular function in patients with dysglycaemia and coronary artery disease (CAD).Thirty-six patients were randomized to simvastatin 80 mg daily (S80, n = 19) or ezetimibe 10 mg and simvastatin 10 mg daily (E10/S10, n = 17) for 6 weeks', 'Large clinical trials have elucidated that lipid-lowering therapy using statins reduces cardiovascular events in patients with coronary artery disease (CAD)', 'The aim of the present study was to investigate whether LLT (lipid-lowering therapy) with statins could attenuate EPC telomere erosion in patients with CAD (coronary artery disease)', 'Beneficial effects of pravastatin (+/-colestyramine/niacin) initiated immediately after a coronary event (the randomized Lipid-Coronary Artery Disease [L-CAD] Study).']
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['The lipid lowering drugs administered in patients with Coronary Artery Disease (CAD) are:\n1) Statins\n2) Fibrates\n3) Resins\n4) Niacin\n5) Cholesterol absorption-inhibiting drugs.']
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['Statins', 'Fibrates', 'Resins', 'Niacin', 'Cholesterol absorption-inhibiting drugs']
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Can Levoxyl (levothyroxine sodium) cause insomnia?
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["METHODS: Seventy-one patients diagnosed with primary hypothyroidism were randomly allocated into two study groups: the first group received usual dose of levothyroxine and the second group received combination of levothyroxine and liothyronine for at least 4 months. The main outcomes were psychosocial problems (Goldberg's General Health Questionnaire, GHQ-28), bodyweight, heart rate, blood pressure, and serum lipid levels. RESULTS: In both groups serum thyroid-stimulating hormone levels remained unchanged compared with baseline. Psychosocial scores, body weight, heart rate, blood pressure, and lipid profile in the two groups remained constant. The only exception was a small but significant reduction in anxiety/insomnia in combined treatment group as compared with monotherapy. "]
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['Levoxyl monotherapy is associated with increased insomnia compared to a combination of levothyroxine and liothyronine.']
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['yes']
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Which are the clinical symptoms of left ventricular noncompaction?
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['Perioperative management of the patient with LVNC might be challenging due to the clinical symptoms of heart failure, systemic thromboembolic events, and fatal left ventricular arrhythmias.', 'Left ventricular noncompaction cardiomyopathy is a rare type of congenital cardiomyopathy characterized by prematurely arrested compaction of the endocardial and myocardial fibers and the progressive deterioration of left ventricular contractility. ', 'Clinical features associated with LVNC vary in asymptomatic and symptomatic patients, and include the potential for heart failure, conduction defects (eg, left bundle branch block), supraventricular and ventricular arrhythmias, thromboembolic events, and sudden cardiac death. ', 'The clinical presentations are variable ranging from asymptomatic patients to patients who develop ventricular arrhythmias, thromboembolism, heart failure, and sudden cardiac death. ', 'The clinical presentation and the natural history of LVNC are highly variable, ranging from no symptoms to congestive heart failure, arrhythmias, and systemic thromboemboli. ', 'The clinical manifestations of the disease are variable, ranging from no symptoms to signs of heart failure, systemic emboli, and ventricular arrhythmias. ', 'We describe the case of a 62-year-old woman who presented with symptoms of heart failure secondary to left ventricular noncompaction.', 'Multiple left ventricular thrombi in a patient with left ventricular noncompaction.', 'We present three children with myocardial noncompaction: one male with isolated left ventricular noncompaction, another with right ventricular noncompaction and dysplastic tricuspid valve, and the last with left ventricular noncompaction, ventricular septal defect and coarctation of aorta, to stress especially the different clinical forms of the disorder and the importance of early diagnosis, as it may result in a fatal outcome.', 'Left ventricular noncompaction has a heterogeneous clinical presentation that includes arrhythmia and sudden cardiac death.We retrospectively reviewed all children diagnosed with left ventricular noncompaction at Texas Childrens Hospital from January 1990 to January 2009', 'Left ventricular noncompaction is a cardiomyopathy characterized by excessive trabeculation of the left ventricle, progressive myocardial dysfunction, and early mortality', 'We describe the case of a 62-year-old woman who presented with symptoms of heart failure secondary to left ventricular noncompaction. ', 'Left ventricular noncompaction (LVNC) and dilated CMP are the most common cardiac phenotypes reported and can lead to symptoms of heart failure as well as ventricular arrhythmias.', 'Multiple left ventricular thrombi in a patient with left ventricular noncompaction.', 'Left ventricular noncompaction has a heterogeneous clinical presentation that includes arrhythmia and sudden cardiac death.', 'Clinical symptoms include signs of left ventricular systolic dysfunction even to the point of heart failure, ventricular arrhythmias, and embolic events.']
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['The clinical symptoms of left ventricular noncompaction are:\n1) heart failure, \n2) systemic thromboembolic events, \n3) ventricular arrhythmias and\n4) sudden cardiac death.']
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['heart failure', 'systemic thromboembolic events', 'systemic thromboembolism', 'ventricular arrhythmias', 'sudden cardiac death']
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How is volume associated with Glasgow Outcome Score in patients with intracerebral hemorrhage?
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['["Age, Glasgow Coma Scale, ICH location, volume (all P<0.0001), and pre-ICH cognitive impairment (P=0.005) were independently associated with Glasgow Outcome Score>or = 4. The FUNC score was developed as a sum of individual points (0-11) based on strength of association with outcome. ", "Age, Glasgow Coma Scale, ICH location, volume (all P<0.0001), and pre-ICH cognitive impairment (P=0.005) were independently associated with Glasgow Outcome Score>or = 4."]']
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Volume is significantly associated with Glasgow Outcome Score in patients with intracerebral hemorrhage, with a p-value of less than 0.0001.
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[]
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What is ChIPpeakAnno?
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['ChIPpeakAnno: a Bioconductor package to annotate ChIP-seq and ChIP-chip data', 'We have developed ChIPpeakAnno as a Bioconductor package within the statistical programming environment R to facilitate batch annotation of enriched peaks identified from ChIP-seq, ChIP-chip, cap analysis of gene expression (CAGE) or any experiments resulting in a large number of enriched genomic regions', 'ChIPpeakAnno enables batch annotation of the binding sites identified from ChIP-seq, ChIP-chip, CAGE or any technology that results in a large number of enriched genomic regions within the statistical programming environment R. Allowing users to pass their own annotation data such as a different Chromatin immunoprecipitation (ChIP) preparation and a dataset from literature, or existing annotation packages, such as GenomicFeatures and BSgenome, provides flexibility']
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['ChIPpeakAnno is a Bioconductor package within the statistical programming environment R that facilitates batch annotation of enriched peaks identified from ChIP-seq, ChIP-chip, cap analysis of gene expression (CAGE) or any experiments resulting in a large number of enriched genomic regions.']
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Are there any desmins present in plants?
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['Inherited mutations in the gene coding for the intermediate filament protein desmin have been demonstrated to cause severe skeletal and cardiac myopathies.', 'Mutations in the intermediate filament (IF) protein desmin cause severe forms of myofibrillar myopathy characterized by partial aggregation of the extrasarcomeric desmin cytoskeleton and structural disorganization of myofibrils.', 'The family of 70 intermediate filament genes (including those encoding keratins, desmins, and lamins) is now known to be associated with a wide range of diverse diseases, at least 72 distinct human pathologies, including skin blistering, muscular dystrophy, cardiomyopathy, premature aging syndromes, neurodegenerative disorders, and cataract. ', 'Mutations in desmin have been associated with a subset of human myopathies.', 'Characterization of a zebrafish (Danio rerio) desmin cDNA: an early molecular marker of myogenesis.', 'Acute effects of desmin mutations on cytoskeletal and cellular integrity in cardiac myocytes.', 'Desmin is a muscle-specific protein and a constitutive subunit of the intermediate filaments (IF) in skeletal, cardiac and smooth muscles. It is an early marker of skeletal muscle myogenesis. We have characterized a clone of desmin cDNA from an embryonic zebrafish (Danio rerio) cDNA library. ', 'Immunohistochemical investigation showed a positive reaction for smooth muscle actin and desmins in the spindle cells proliferated in the lymph nodes; no cytokeratin positivity was detected. ', 'We have raised monoclonal antibodies (Mab) to the Mr 55,000 desmin polypeptide, electrophoretically purified from cytoskeletal preparations of isolated bovine heart Purkinje fibers. ', 'Mesothelial and ovarian carcinoma cells could not be distinguished by (intermediate) filament typing, using monoclonal antibodies (MAbs) to keratins, vimentins and desmins.', 'A fast and convenient procedure for the purification of polymerization-competent smooth-muscle desmin is described. Desmin from chicken gizzard and hog stomach were compared by fingerprint techniques. ']
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['No. Desmins are type III intermediate filament (IF) proteins that have been identified to date only in metazoa (human, Danio rerio, bovine). Desmins are also associated with severe forms of skeletal, cardiac and myofibrillar myopathies.']
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['no']
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Which syndromes are associated with heterochromia iridum?
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["To our knowledge, this is the first reported case of Ascher's syndrome associated with iris coloboma, heterochromia iridum, and narrowing of horizontal palpebral fissure and decreased outer intercanthal distance secondary to lengthening of lateral canthal ligament.", ' Sensorineural hearing loss (17/20, 85.0%) and heterochromia iridum (20/20, 100.0%) were the most commonly observed clinical features in Chinese WS2 patients. ', 'Waardenburg Syndrome (WS) is an autosomal-dominant disorder characterized by sensorineural hearing loss and pigmentary abnormalities of the eyes, hair, and skin. Microphthalmia-associated transcription factor (MITF) gene mutations account for about 15% of WS type II (WS2) cases. ', "The association of congenital Horner's syndrome and hypochromia iridum without anhidrosis is highly suggestive of sympathetic pathway injury early in life. ", 'The Waardenburg syndrome (WS) consists of at least two distinct autosomal dominant hereditary disorders. WS Type I has been mapped to the distal part of chromosome 2q and the gene identified as PAX3. Other gene(s) are responsible for WS Type II. ', 'Sensorineural hearing loss (77%) and heterochromia iridum (47%) were the two most important diagnostic indicators for WS Type II. ', "WAARDENBURG'S SYNDROME AND HETEROCHROMIA IRIDUM IN A DEAF SCHOOL POPULATION.", "Waardenburg's syndrome consists of lateral displacement of the inner canthi of the eyes (dystopia canthorum), a broad nasal root and confluent eyebrows, heterochromia iridum, a white forelock and congenital deafness.", "To our knowledge, this is the first reported case of Ascher's syndrome associated with iris coloboma, heterochromia iridum, and narrowing of horizontal palpebral fissure and decreased outer intercanthal distance secondary to lengthening of lateral canthal ligament.", 'Sensorineural hearing loss (77%) and heterochromia iridum (47%) were the two most important diagnostic indicators for WS Type II.', 'Sensorineural hearing loss (17/20, 85.0%) and heterochromia iridum (20/20, 100.0%) were the most commonly observed clinical features in Chinese WS2 patients.', 'We present the genetic analyses conducted on a three-generation family (14 individuals) with three members affected with isolated-Hirschsprung disease (HSCR) and one with HSCR and heterochromia iridum (syndromic-HSCR), a phenotype reminiscent of Waardenburg-Shah syndrome (WS4).', "Heterochromia iridis and Horner's syndrome due to paravertebral neurilemmoma.", "[Iris heterochromia in acquired Horner's syndrome].", 'BACKGROUND: Heterochromia iridis, asymmetry of iris pigmentation, has been well described with congenital Horner syndrome.', "A case of heterochromia iridis and Horner's syndrome is reported in a 7-year old girl with paravertebral neurilemmoma.", 'We present the genetic analyses conducted on a three-generation family (14 individuals) with three members affected with isolated-Hirschsprung disease (HSCR) and one with HSCR and heterochromia iridum (syndromic-HSCR), a phenotype reminiscent of Waardenburg-Shah syndrome (WS4)', 'To our knowledge, this is the first reported case of Aschers syndrome associated with iris coloboma, heterochromia iridum, and narrowing of horizontal palpebral fissure and decreased outer intercanthal distance secondary to lengthening of lateral canthal ligament', 'WAARDENBURGS SYNDROME AND HETEROCHROMIA IRIDUM IN A DEAF SCHOOL POPULATION', 'Waardenburgs syndrome consists of lateral displacement of the inner canthi of the eyes (dystopia canthorum), a broad nasal root and confluent eyebrows, heterochromia iridum, a white forelock and congenital deafness', 'Sensorineural hearing loss (17/20, 85.0%) and heterochromia iridum (20/20, 100.0%) were the most commonly observed clinical features in Chinese WS2 patients', 'Sensorineural hearing loss (17/20, 85.0%) and heterochromia iridum (20/20, 100.0%) were the most commonly observed clinical features in Chinese WS2 patients. ', 'A dominantly inherited syndrome associated with hypopigmentation, heterochromia irides, colobomatous eyes and bilateral hearing loss has been ascertained in Fleckvieh cattle (German White Fleckvieh syndrome). ', 'Sensorineural hearing loss (77%) and heterochromia iridum (47%) were the two most important diagnostic indicators for WS Type II.', 'Sensorineural hearing loss (17/20, 85.0%) and heterochromia iridum (20/20, 100.0%) were the most commonly observed clinical features in Chinese WS2 patients.', "WAARDENBURG'S SYNDROME AND HETEROCHROMIA IRIDUM IN A DEAF SCHOOL POPULATION."]
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["The syndromes that are associated with heterochromia iridum are:\n1) Ascher's syndrome\n2) Waardenburg Syndrome type II (WS2)\n3) Horner's syndrome."]
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["Ascher's syndrome", 'Waardenburg Syndrome type II', 'WS2', 'WS Type II', "Horner's syndrome"]
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Are cyclophilins proteins that bind to prolines?
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['Cyclophilins are ubiquitously expressed proteins that bind to prolines and can catalyse cis/trans isomerization of proline residues.', 'a characteristic of the cyclophilin family of proteins that bind prolines and often act as cis-trans peptidyl-prolyl isomerases. ', 'The cyclophilins are widely expressed enzymes that catalyze the interconversion of the cis and trans peptide bonds of prolines. ', ' an immunophilin on the isomerization of critical prolines that are found in the tCHT1 sequence.']
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['Cyclophilins are ubiquitously expressed proteins that bind to prolines.']
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['yes']
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Which growth factors are known to be involved in the induction of EMT?
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['Moreover, recent studies have shown that most EMT cases are regulated by soluble growth factors or cytokines. Among these factors, fibroblast growth factors (FGFs) execute diverse functions by binding to and activating members of the FGF receptor (FGFR) family, including FGFR1-4.', 'Fibroblast growth factor receptor 1 is an oncoprotein that is involved in tumorigenesis, and PD173074 is known to be a selective inhibitor of FGFR1.', 'Fibroblast growth factor receptor 1 was also overexpressed in EMT cell lines compared with non-EMT cell lines.', 'Furthermore, treatment of HOC313 cells with PD173074 suppressed cellular proliferation and invasion and reduced ERK1/2 and p38 activation.', 'In addition, the expression levels of certain matrix metalloproteinases (MMPs), whose genes contain activator protein-1 (AP-1) promoter sites, as well as Snail1 and Snail2 were reduced following PD173074 treatment.', 'Taken together, these data suggest that PD173074 inhibits the MAPK pathway, which regulates the activity of AP-1 and induces MET.', 'egulation of Na,K-ATPase β1-subunit in TGF-β2-mediated epithelial-to-mesenchymal transition in human retinal pigmented epithelial cells', 'The EMT process is mediated via exposure to vitreous cytokines and growth factors such as TGF-β2.', 'Previous studies have shown that Na,K-ATPase is required for maintaining a normal polarized epithelial phenotype and that decreased Na,K-ATPase function and subunit levels are associated with TGF-β1-mediated EMT in kidney cells.', 'loss of Na,K-ATPase β1 is a potential contributor to TGF-β2-mediated EMT in RPE cells.', 'MT (epithelial-mesenchymal transition) is crucial for cancer cells to acquire invasive phenotypes. In A549 lung adenocarcinoma cells, TGF-β elicited EMT in Smad-dependent manner and TNF-α accelerated this process, as confirmed by cell morphology, expression of EMT markers, capacity of gelatin lysis and cell invasion.', 'Comprehensive expression analysis unraveled genes differentially regulated by TGF-β and TNF-α, such as cytokines, chemokines, growth factors and ECM (extracellular matrices), suggesting the drastic change in autocrine/paracrine signals as well as cell-to-ECM interactions. ', 'Our recent studies found that CCN1 plays a critical role in pancreatic carcinogenesis through the induction of EMT and stemness.', 'Here we show that CCN1 regulates the Sonic Hedgehog (SHh) signaling pathway, which is associated with the PDAC progression and poor prognosis.', 'SHh regulation by CCN1 in pancreatic cancer cells is mediated through the active Notch-1.', 'These extensive studies propose that targeting CCN1 can provide a new treatment option for patients with pancreatic cancer since blocking CCN1 simultaneously blocks two critical pathways (i.e. SHh and Notch1) associated with the development of the disease as well as drug resistance.', 'GF-β-induced epithelial-mesenchymal transition', 'The cytokine TGF-β, which is expressed by tumor-infiltrating immune cells, stands out as a master regulator of the pro-invasive tumor microenvironment. TGF-β cooperates with stem cell pathways, such as Wnt and Ras signaling, to induce EMT. In addition, TGF-β contributes to an EMT-permissive microenvironment by switching the phenotypes of tumor-infiltrating immune cells, which thereby mount pro-invasive and pro-metastatic immune responses.', 'In this review, we discuss the role of TGF-β-induced EMT as a link between cancer and inflammation in the context of questions, which from our point of view are key to answer in order to understand the functionality of EMT in tumors.', 'ranscription factors c-Myc and CDX2 mediate E-selectin ligand expression in colon cancer cells undergoing EGF/bFGF-induced epithelial-mesenchymal transition', 'Treatment of HT29 and DLD-1 cells with EGF and/or basic FGF (bFGF) induced EMT and significantly increased sLe(x/a) expression resulting in enhanced E-selectin binding activity.', 'Upon hypoxia, TGFβ addition or EGFRvIII expression, MCF7, A549 and NMuMG epithelial cells acquired a spindle shape and lost cell-cell contacts. Expression of epithelial markers such as E-cadherin decreased, whereas mesenchymal markers such as vimentin and N-cadherin increased.', 'The EMT process can be regulated by a diverse array of cytokines and growth factors, such as transforming growth factor (TGF)-beta, whose activities are dysregulated during malignant tumor progression.', 'Transforming growth factor-beta-induced tubular cell EMT in C1.1 cells was inhibited by MMP-2/9 inhibitor. Our in vitro study provides evidence that MMPs, specifically MMP-9, secreted by effector macrophages can induce tubular cell EMT and thereby contribute to renal fibrosis.', 'nflammatory cytokines augments TGF-beta1-induced epithelial-mesenchymal transition in A549 cells by up-regulating TbetaR-I', 'In this study, we report that cytomix (a mixture of IL-1beta, TNF-alpha and IFN-gamma) significantly enhances TGF-beta1-induced EMT in A549 cells as evidenced by acquisition of fibroblast-like cell shape, loss of E-cadherin, and reorganization of F-actin.', 'IL-1beta or TNF-alpha alone can also augment TGF-beta1-induced EMT. However, a combination of IL-1beta and TNF-alpha or the cytomix is more potent to induce EMT.', 'These results indicate that inflammatory cytokines together with TGF-beta1 may play an important role in the development of fibrosis and tumor progress via the mechanism of epithelial-mesenchymal transition.', 'TGF-beta stimulated epithelial to mesenchyme transdifferentiation (EMT) in the presence of TGF-alpha, as characterized by increased expression of fibronectin and changes in TGF-beta receptor binding.', 'EMT is typically induced by transforming growth factor-beta1 (TGF-beta1) and inhibited by hepatocyte growth factor (HGF).', 'Exposure of MDCK cells to 10 ng/ml TGF-beta1 for 72 h induced EMT as evidenced by conversion to the spindle-like morphology, loss of E-cadherin, and activation of alpha-smooth muscle actin.', 'In contrast, Akt1 down-regulation in IGF-IR-stimulated cells promoted dramatic neomorphic effects characteristic of an epithelial-mesenchymal transition (EMT) and enhanced cell migration induced by IGF-I or EGF stimulation. The phenotypic effects of Akt1 down-regulation were accompanied by enhanced extracellular signal-related kinase (ERK) activation, which contributed to the induction of migration and EMT.', 'ransforming growth factors beta (TGF-betas) inhibit growth of epithelial cells and induce differentiation changes, such as epithelial-mesenchymal transition (EMT).', 'Ha-Ras cooperates with transforming growth factor beta (TGFbeta) to cause epithelial mesenchymal transition (EMT) characterized by spindle-like cell morphology, loss of epithelial markers, and induction of mesenchymal markers.', 'IGF-II induces rapid beta-catenin relocation to the nucleus during epithelium to mesenchyme transition', 'We can show that (1) IGF-II induces a rapid epithelium to mesenchymal transition;', 'Based on the given case of IGF-II and E-cadherin/beta-catenin complex, this study reveals the backbone of a cascade connecting growth factor signaling with cell-cell adhesion during EMT.', 'The NBT-II rat carcinoma cell line exhibits two mutually exclusive responses to FGF-1 and EGF, entering mitosis at cell confluency while undergoing an epithelium-to-mesenchyme transition (EMT) when cultured at subconfluency.', 'EMT requires continuous TGFbeta receptor (TGFbeta-R) and oncogenic Ras signaling and is stabilized by autocrine TGFbeta production', 'EMT seems to be a close in vitro correlate of metastasis, both requiring synergism between TGFbeta-R and Raf/MAPK signaling']
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['EMT is characterized by acquisition of cell motility, modifications of cell morphology, and cell dissociation correlating with the loss of desmosomes from the cellular cortex. A number of growth factors have been shown to be involved in this process. These include fibroblast growth factors (FGFs), TGF-β1, TGF-β2, TNF-α, CCN family, Sonic Hedgehog (SHh), Notch1, GF-β, Wnt, EGF, bFGF, IGF-I and IGF-II.']
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['fibroblast growth factors (FGFs)', 'TGF-β1', 'TGF-β2', 'TNF-α', 'CCN family', 'Sonic Hedgehog (SHh)', 'Notch1', 'GF-β', 'Wnt', 'EGF', 'bFGF', 'IGF-I', 'IGF-II']
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Which mutations in the cardiac isoform of the ryanodine receptor (RyR2) have been found to be related to CPVT?
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['Recently, a novel CPVT RyR2 mutation, G230C, was found to increase the cytosolic, but not the luminal, Ca2+ sensitivity of single RyR2 channels in lipid bilayers.', 'These data suggest that the G230C mutation enhances the propensity for SOICR by sensitizing the channel to luminal and cytosolic Ca2+ activation, and that G230C has an intrinsic structural impact on the N-terminal domains of RyR2.', 'The novel RYR2-S4153R mutation has been implicated as a cause of CPVT and atrial fibrillation. The mutation has been functionally characterized via store-overload-induced Ca(2+) release (SOICR) and tritium-labelled ryanodine ([(3)H]ryanodine) binding assays. The S4153R mutation enhanced propensity for spontaneous Ca(2+) release and reduced SOICR threshold but did not alter Ca(2+) activation of [(3)H]ryanodine binding, a common feature of other CPVT gain-of-function RYR2 mutations. We conclude that the S4153R mutation is a gain-of-function RYR2 mutation associated with a clinical phenotype characterized by both CPVT and atrial fibrillation.', 'To determine the molecular and cellular mechanisms by which a novel RyR2-V2475F mutation associated with CPVT in humans triggers Ca(2+)-dependent arrhythmias in whole hearts and intact mice.', 'The mutation RyR2-V2475F is phenotypically strong among other CPVT mutations and produces heterogeneous mechanisms of RyR2 dysfunction. ', 'We generated 3 knock-in mice with mutations introduced into RyR2 that result in leaky channels and cause exercise induced polymorphic ventricular tachycardia in humans [catecholaminergic polymorphic ventricular tachycardia (CPVT)]. We examined AF susceptibility in these three CPVT mouse models harboring RyR2 mutations to explore the role of diastolic SR Ca2+ leak in AF. AF was stimulated with an intra-esophageal burst pacing protocol in the 3 CPVT mouse models (RyR2-R2474S+/-, 70%; RyR2-N2386I+/-, 60%; RyR2-L433P+/-, 35.71%) but not in wild-type (WT) mice (P<0.05).', 'The RyR2-G230C mutant exhibits similar biophysical defects compared with previously characterized CPVT mutations: decreased binding of the stabilizing subunit calstabin2 and a leftward shift in the Ca(2+) dependence for activation under conditions that simulate exercise, consistent with a "leaky" channel. Both RyR2-G230C and RyR2-P2328S channels exhibit normal luminal Ca(2+) activation. Thus, diastolic sarcoplasmic reticulum Ca(2+) leak caused by reduced calstabin2 binding and a leftward shift in the Ca(2+) dependence for activation by diastolic levels of cytosolic Ca(2+) is a common mechanism underlying CPVT.', 'A novel CPVT mutation, E189D, was identified. The E189D mutation does not alter the affinity of the channel for FKBP12.6, but it increases the propensity for store-overload-induced Ca(2+) release (SOICR). Furthermore, the E189D mutation enhances the basal channel activity of RyR2 and its sensitivity to activation by caffeine. The E189D RyR2 mutation is causative for CPVT and functionally increases the propensity for SOICR without altering the affinity for FKBP12.6.', 'We found that mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice) exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. ', ' Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the brain can cause seizures in mice, independent of cardiac arrhythmias.', 'We screened 12 Finnish CPVT probands for mutations in these genes and identified three novel RYR2 mutations (V2306I, P4902L, R4959Q), which were absent in unaffected and control individuals.', 'RyR2 mutations suggested to cause defective Ca2+ channel function have recently been identified in catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular dysplasia (ARVD) affected individuals. We report expression of three CPVT-linked human RyR2 (hRyR2) mutations (S2246L, N4104K, and R4497C) in HL-1 cardiomyocytes displaying correct targeting to the endoplasmic reticulum. ', 'We developed a conditional knock-in mouse model carrier of the R4496C mutation, the mouse equivalent to the R4497C mutations identified in CPVT families, to evaluate if the animals would develop a CPVT phenotype and if beta blockers would prevent arrhythmias.', 'These data provide the first experimental demonstration that the R4496C RyR2 mutation predisposes the murine heart to VT and VF in response caffeine and/or adrenergic stimulation.', 'We developed a conditional knock-in mouse model carrier of the R4496C mutation, the mouse equivalent to the R4497C mutations identified in CPVT families, to evaluate if the animals would develop a CPVT phenotype and if beta blockers would prevent arrhythmias']
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['Recently, a novel CPVT RyR2 mutation, G230C, was found to increase the cytosolic, but not the luminal, Ca2+ sensitivity of single RyR2 channels in lipid bilayers. The novel RYR2-S4153R mutation has been implicated as a cause of CPVT and atrial fibrillation. A novel RyR2-V2475F mutation is associated with CPVT in humans. 3 CPVT mouse models are: RyR2-R2474S+/-, RyR2-N2386I+/-, and RyR2-L433P+/-. The E189D RyR2 mutation is causative for CPVT. A knock-in mouse model carrier of the R4496C mutation is the mouse equivalent to the R4497C mutations identified in CPVT families. Scanning of 12 Finnish CPVT probands identified three novel RYR2 mutations (V2306I, P4902L, R4959Q), which were absent in unaffected and control individuals. Three CPVT-linked human RyR2 (hRyR2) mutations are: S2246L, N4104K, and R4497C.']
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['RyR2-G230C', 'RyR2-S4153R', 'RyR2-V2475F', 'RyR2-R2474S', 'RyR2-N2386I', 'RyR2-L433P', 'RyR2-E189D', 'RyR2-R4497C (RyR2-R4496C in the mouse)', 'RyR2-V2306I,', 'RyR2-P4902L', 'RyR2-R4959Q', 'RyR2-S2246L', 'RyR2-N4104K']
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SPAG5 was implicated in which cancers?
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['BACKGROUND: We conducted multiple microarray datasets analyses from clinical and xenograft tumor tissues to search for disease progression-driving oncogenes in prostate cancer (PCa). Sperm-associated antigen 5 (SPAG5) attracted our attention. SPAG5 was recently identified as an oncogene participating in lung cancer and cervical cancer progression.', 'CONCLUSION: Our results collectively showed a progression-driving role of SPAG5 in PCa which can be regulated by miR-539, suggesting that miR-539/SPAG5 can serve as a potential therapeutic target for PCa.', 'RESULTS: We identified that SPAG5 expression was gradually increased in PCa progression and its level was significantly associated with lymph node metastasis, clinical stage, Gleason score, and biochemical recurrence. Our results indicated that SPAG5 knockdown can drastically inhibit PCa cell proliferation, migration, and invasion in vitro and supress tumor growth and metastasis in vivo. ', 'miR-539 inhibits prostate cancer progression by directly targeting SPAG5.', 'SPAG5 as a prognostic biomarker and chemotherapy sensitivity predictor in breast cancer: a retrospective, integrated genomic, transcriptomic, and protein analysis.', 'Copy number aberration leading to SPAG5 gain or amplification and high SPAG5 transcript and SPAG5 protein concentrations were associated with shorter overall breast cancer-specific survival (METABRIC cohort [copy number aberration]: hazard ratio [HR]1·50, 95% CI 1·18-1·92, p=0·00010; METABRIC cohort [transcript]: 1·68, 1·40-2·01, p<0·0001; and Nottingham-HES-breast cancer cohort [protein]: 1·68, 1·32-2·12, p<0·0001). In multivariable analysis, high SPAG5 transcript and SPAG5 protein expression were associated with reduced breast cancer-specific survival at 10 years compared with lower concentrations (Uppsala: HR 1·62, 95% CI 1·03-2·53, p=0·036; METABRIC: 1·27, 1·02-1·58, p=0·034; untreated lymph node-negative cohort: 2·34, 1·24-4·42, p=0·0090; and Nottingham-HES: 1·73, 1·23-2·46, p=0·0020). In patients with oestrogen receptor-negative breast cancer with high SPAG5 protein expression, anthracycline-based adjuvant chemotherapy increased breast cancer-specific survival overall compared with that for patients who did not receive chemotherapy (Nottingham-oestrogen receptor-negative-ACT cohort: HR 0·37, 95% CI 0·20-0·60, p=0·0010). Multivariable analysis showed high SPAG5 transcript concentrations to be independently associated with longer distant relapse-free survival after receiving taxane plus anthracycline neoadjuvant chemotherapy (MD Anderson-NeoACT: HR 0·68, 95% CI 0·48-0·97, p=0·031). ', 'INTERPRETATION: SPAG5 is a novel amplified gene on Ch17q11.2 in breast cancer. The transcript and protein products of SPAG5 are independent prognostic and predictive biomarkers that might have clinical utility as biomarkers for combination cytotoxic chemotherapy sensitivity, especially in oestrogen receptor-negative breast cancer.', 'SPAG5 upregulation predicts poor prognosis in cervical cancer patients and alters sensitivity to taxol treatment via the mTOR signaling pathway.', 'Previously, we found that sperm-associated antigen 5 (SPAG5) was upregulated in pelvic lymph node metastasis-positive cervical cancer.', 'In general, SPAG5 upregulation relates to poor prognosis in cervical cancer patients, and SPAG5 is a regulator of mTOR activity during taxol treatment in cervical cancer.', 'RESULTS: We identified novel genes whose expression was upregulated in NSCLC, including SPAG5, POLH, KIF23, and RAD54L, which are associated with mitotic spindle formation, DNA repair, chromosome segregation, and dsDNA break repair, respectively.', 'Another module identified among male breast cancers, regulated by SPAG5, was closely associated with proliferation.', 'In our study, SPAG5 expression in cervical cancer patients was detected using quantitative real-time polymerase chain reaction, western blotting, and immunohistochemistry; cervical cancer cell function with downregulated SPAG5 in vitro was explored using tetrazolium assay, flow cytometry, and colony formation and Transwell assays. ', 'In patients with oestrogen receptor-negative breast cancer with high SPAG5 protein expression, anthracycline-based adjuvant chemotherapy increased breast cancer-specific survival overall compared with that for patients who did not receive chemotherapy (Nottingham-oestrogen receptor-negative-ACT cohort: HR 0·37, 95% CI 0·20-0·60, p=0·0010).', 'We investigated the clinicopathological relevance of SPAG5 gene copy number aberrations, mRNA transcript expression, and protein expression and analysed the associations of SPAG5 copy number aberrations, transcript expression, and protein expression with breast cancer-specific survival, disease-free survival, distant relapse-free survival, pathological complete response, and residual cancer burden in the Nottingham discovery cohort, Uppsala cohort, METABRIC cohort, a pooled untreated lymph node-negative cohort (n=684), a multicentre combined cohort (n=5439), the Nottingham historical early stage breast cancer cohort (Nottingham-HES; n=1650), N', 'In multivariable analysis, high SPAG5 transcript and SPAG5 protein expression were associated with reduced breast cancer-specific survival at 10 years compared with lower concentrations (Uppsala: HR 1·62, 95% CI 1·03-2·53, p=0·036; METABRIC: 1·27, 1·02-1·58, p=0·034; untreated lymph node-negative cohort: 2·34, 1·24-4·42, p=0·0090; and Nottingham-HES: 1·73, 1·23-2·46, p=0·0020).', 'THY1 may thus be a promising novel prognostic marker for male breast cancer. Another module identified among male breast cancers, regulated by SPAG5, was closely associated with proliferation.', 'Furthermore, men with THY1 positive breast cancers had significantly inferior survival. THY1 may thus be a promising novel prognostic marker for male breast cancer. Another module identified among male breast cancers, regulated by SPAG5, was closely associated with proliferation.', 'SPAG5 was recently identified as an oncogene participating in lung cancer and cervical cancer progression.', 'SPAG5 is a novel amplified gene on Ch17q11.2 in breast cancer.', 'Copy number aberration leading to SPAG5 gain or amplification and high SPAG5 transcript and SPAG5 protein concentrations were associated with shorter overall breast cancer-specific survival (METABRIC cohort [copy number aberration]: hazard ratio [HR] 1·50, 95% CI 1·18-1·92, p=0·00010; METABRIC cohort [transcript]: 1·68, 1·40-2·01, p<0·0001; and Nottingham-HES-breast cancer cohort [protein]: 1·68, 1·32-2·12, p<0·0001).']
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['SPAG5 was implicated in prostate cancer, lung cancer and cervical cancer.']
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['prostate cancer', 'lung cancer', 'cervical cancer', 'breast cancer']
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What is the mechanism of action of verubecestat?
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["The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients.", 'We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys.', "Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease.", "Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. ", "Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer's Disease.", "Verubecestat is an inhibitor of β-secretase being evaluated for the treatment of Alzheimer's disease. ", "Verubecestat is an inhibitor of β-secretase being evaluated for the treatment of Alzheimer's disease.", 'After giving an update on the development and current status of new AD therapeutics, this review will focus on BACE inhibitors and, in particular, will discuss the prospects of verubecestat (MK-8931), which has reached phase III clinical trials.', 'Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans.', 'We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys.', "Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease.", 'Chronic treatment of rats and monkeys with verubecestat achieved exposures >40-fold higher than those being tested in clinical trials in AD patients yet did not elicit many of the adverse effects previously attributed to BACE inhibition, such as reduced nerve myelination, neurodegeneration, altered glucose homeostasis, or hepatotoxicity.', 'Expert opinion: Drugs in Phase III clinical development for AD include one inhibitor of the β-secretase cleaving enzyme (BACE) (verubecestat), three anti-Aβ monoclonal antibodies (solanezumab, gantenerumab, and aducanumab), an inhibitor of receptor for advanced glycation end products (RAGE) (azeliragon) and the combination of cromolyn sodium and ibuprofen (ALZT-OP1).', "Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer's Disease.", "The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients.", "Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease.", 'After giving an update on the development and current status of new AD therapeutics, this review will focus on BACE inhibitors and, in particular, will discuss the prospects of verubecestat (MK-8931), which has reached phase III clinical trials.', 'Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans.']
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['Verubecestat (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity).']
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