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GCMS-based metabolomic study in mice with colitis induced by dextran sulfate sodium. BACKGROUND: Metabolomics provides data about all the metabolic processes of a cell or organism. So far, the changes that occur in the levels of metabolites during the development of colitis have not been fully elucidated. Here we examined the changes of metabolite levels in the serum and colon tissue of colitis mice using gas chromatography mass spectrometry (GC/MS) with the aim of achieving a detailed understanding of the pathogenesis of inflammatory bowel disease (IBD). METHODS: To induce colitis, C57BL/6J mice were administered 3.0% dextran sulfate sodium (DSS) in their drinking water for 5 days and were subsequently given drinking water alone. RESULTS: A total of 77 and 92 metabolites were detected in serum and colon tissue, respectively, and among the metabolites the compositions of TCA cycle intermediates and amino acids changed depending on the degree of colitis. Then, partial least square discriminant analysis (PLS-DA), a multiple classification analysis, showed distinct clustering and clear separation of the groups according to the degree of colitis. Furthermore, PLS-DA loadings plots revealed that succinic acid, indole-3-acetic acid, glutamic acid, and glutamine were the main contributors to the separation of each stage of colitis. In addition, it was revealed that supplementation with glutamine, the level of which was significantly decreased in the acute phase of colonic inflammation, attenuated colitis induced by DSS. CONCLUSIONS: Our results suggest that metabolomics is capable of representing the various degrees of colitis, and our findings will aid in the discovery of therapeutic agents for IBD and other inflammatory disorders by metabolomic approaches. | Is the tricarboxylic acid (TCA) cycle affected in inflammation? | 56c4a217b04e159d0e000001_007 | yes |
PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis. PTPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease. The effect of the R-to-W conversion on the phosphatase activity of PTPN22 protein and the impact of the minor T allele of the C1858T SNP on the activation of T cells has remained controversial. In addition, how the overall activity of PTPN22 is regulated and how the R-to-W conversion contributes to rheumatoid arthritis is still poorly understood. Here we report the identification of an alternative splice form of human PTPN22, namely PTPN22.6. It lacks the nearly entire phosphatase domain and can function as a dominant negative isoform of the full length PTPN22. Although conversion of R620 to W620 in the context of PTPN22.1 attenuated T cell activation, expression of the tryptophan variant of PTPN22.6 reciprocally led to hyperactivation of human T cells. More importantly, the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis. Our data depict a model that can reconcile the conflicting observations on the functional impact of the C1858T SNP and also suggest that PTPN22.6 is a novel biomarker of rheumatoid arthritis. | Is the PTPN22 gene a biomarker for rheumatoid arthritis? | 52ffb5d12059c6d71c00007c_009 | yes |
The role of heat shock proteins in Amyotrophic Lateral Sclerosis: The therapeutic potential of Arimoclomol. Arimoclomol is a hydroxylamine derivative, a group of compounds which have unique properties as co-inducers of heat shock protein expression, but only under conditions of cellular stress. Arimoclomol has been found to be neuroprotective in a number of neurodegenerative disease models, including Amyotrophic Lateral Sclerosis (ALS), and in mutant Superoxide Dismutase 1 (SOD1) mice that model ALS, Arimoclomol rescues motor neurons, improves neuromuscular function and extends lifespan. The therapeutic potential of Arimoclomol is currently under investigation in a Phase II clinical trial for ALS patients with SOD1 mutations. In this review we summarize the evidence for the neuroprotective effects of enhanced heat shock protein expression by Arimoclomol and other inducers of the Heat Shock Response. ALS is a complex, multifactorial disease affecting a number of cell types and intracellular pathways. Cells and pathways affected by ALS pathology and which may be targeted by a heat shock protein-based therapy are also discussed in this review. For example, protein aggregation is a characteristic pathological feature of neurodegenerative diseases including ALS. Enhanced heat shock protein expression not only affects protein aggregation directly, but can also lead to more effective clearance of protein aggregates via the unfolded protein response, the proteasome-ubiquitin system or by autophagy. However, compounds such as Arimoclomol have effects beyond targeting protein mis-handling and can also affect additional pathological mechanisms such as oxidative stress. Therefore, by targeting multiple pathological mechanisms, compounds such as Arimoclomol may be particularly effective in the development of a disease-modifying therapy for ALS and other neurodegenerative disorders. | Is arimoclomol a co-inducer of the heat shock response? | 56f7d9dd09dd18d46b000014_000 | yes |
Fanconi anemia is characterized by delayed repair kinetics of DNA double-strand breaks. Among patients with bone marrow failure (BMF) syndrome, some are happened to have underlying Fanconi anemia (FA), a genetically heterogeneous disease, which is characterized by progressive pancytopenia and cancer susceptibility. Due to heterogeneous nature of the disease, a single genetic test, as in vitro response to DNA cross-linking agents, usually is not enough to make correct diagnosis. The aim of this study was to evaluate whether measuring repair kinetics of radiation-induced DNA double-strand breaks (DSBs) can distinguish Fanconi anemia from other BMF patients. An early step in repair of DSBs is phosphorylation of the histone H2AX, generating gamma-H2AX histone, which extends over mega base-pair regions of DNA from the break site and is visualised as foci (gamma-H2AX foci) with specific antibodies. The primary fibroblasts, established from FA patients, were exposed to gamma-rays, a dose of 2 Gy ((60)Co), incubated for up to 24 hours under repair-permissive conditions, and assayed for the level of gamma-H2AX foci and apoptosis at different recovery times after the treatment. Cell lines originating from FA patients displayed a significant delay in the repair of radiation-induced DNA DSBs relative to non-FA bone marrow failure (non-FA BMF) and control cell lines. The delay is especially evident at recovery time of 24 hours, and is seen as about 8-fold increase of residual gamma-H2AX foci compared to self-state before irradiation. The delay in repair kinetics of FA cells represents the unique feature of FA cellular phenotype, which should be exploited to distinguish FA cellular phenotype. | Is Fanconi anemia presented as a genetically and clinically heterogeneous disease entity? | 54ede5c394afd61504000006_007 | yes |
CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Alternative splicing of pre-messenger RNA is a key feature of transcriptome expansion in eukaryotic cells, yet its regulation is poorly understood. Spliceosome assembly occurs co-transcriptionally, raising the possibility that DNA structure may directly influence alternative splicing. Supporting such an association, recent reports have identified distinct histone methylation patterns, elevated nucleosome occupancy and enriched DNA methylation at exons relative to introns. Moreover, the rate of transcription elongation has been linked to alternative splicing. Here we provide the first evidence that a DNA-binding protein, CCCTC-binding factor (CTCF), can promote inclusion of weak upstream exons by mediating local RNA polymerase II pausing both in a mammalian model system for alternative splicing, CD45, and genome-wide. We further show that CTCF binding to CD45 exon 5 is inhibited by DNA methylation, leading to reciprocal effects on exon 5 inclusion. These findings provide a mechanistic basis for developmental regulation of splicing outcome through heritable epigenetic marks. | Are transcription and splicing connected? | 517395b98ed59a060a00001a_006 | yes |
Expression levels of transcribed ultraconserved regions uc.73 and uc.388 are altered in colorectal cancer. OBJECTIVES: The development of colorectal cancer (CRC) is characterized by multiple genetic alterations. Transcribed ultraconserved regions (T-UCRs) are a subset of 481 sequences longer than 200 bp, which are absolutely conserved between orthologous regions of human, rat and mouse genomes, and are actively transcribed. It has recently been proven in cancer systems that differentially expressed T-UCRs could alter the functional characteristics of malignant cells. Genome-wide profiling revealed that T-UCRs have distinct signatures in human leukemia and carcinoma. METHODS: In our study, we examined the expression levels of uc.43, uc.73, uc.134, uc.230, uc.339, uc.388 and uc.399 in 54 samples of primary colorectal carcinomas and 15 samples of non-tumoral adjacent tissues by real-time PCR. T-UCR expression levels were also correlated with commonly used clinicopathological features of CRC. RESULTS: Expression levels of uc.73 (p = 0.0139) and uc.388 (p = 0.0325) were significantly decreased in CRC tissue, and uc.73 indicated a positive correlation with overall survival (p = 0.0315). The lower expression of uc.388 was associated with the distal location of CRC (p = 0.0183), but no correlation of any evaluated T-UCR with clinical stage, grade and tumor diameter was observed. CONCLUSION: Our preliminary results suggest that uc.73 and uc.388 could be potential diagnostic and prognostic biomarkers in CRC patients. | Are alterations in ultraconserved elements associated with colorectal adenocarcinoma? | 587e1e57fc7e8dd84f000003_002 | yes |
Predicting functional residues in Plasmodium falciparum plasmepsins by combining sequence and structural analysis with molecular dynamics simulations. Plasmepsins are aspartic proteases involved in the initial steps of the hemoglobin degradation pathway, a critical stage in the Plasmodium falciparum life cycle during human infection. Thus, they are attractive targets for novel therapeutic compounds to treat malaria, which remains one of the world's biggest health problems. The three-dimensional structures available for P. falciparum plasmepsins II and IV make structure-based drug design of antimalarial compounds that focus on inhibiting plasmepsins possible. However, the structural flexibility of the plasmepsin active site cavity combined with insufficient knowledge of the functional residues and of those determining the specificity of parasitic enzymes is a drawback when designing specific inhibitors. In this study, we have combined a sequence and structural analysis with molecular dynamics simulations to predict the functional residues in P. falciparum plasmepsins. The careful analysis of X-ray structures and 3D models carried out here suggests that residues Y17, V105, T108, L191, L242, Q275, and T298 are important for plasmepsin function. These seven amino acids are conserved across the malarial strains but not in human aspartic proteases. Residues V105 and T108 are localized in a flap of an interior pocket and they only establish contacts with a specific non-peptide achiral inhibitor. We also observed a rapid conformational change in the L3 region of plasmepsins that closes the active site of the enzyme, which explains earlier experimental findings. These results shed light on the role of V105 and T108 residues in plasmepsin specificities, and they should be useful in structure-based design of novel, selective inhibitors that may serve as antimalarial drugs. | Could plasmepsins be used as targets for developing anti-malaria drugs? | 58a6d89660087bc10a00002b_017 | yes |
Hemarthrosis revealing congenital factor XI deficiency. Congenital factor XI deficiency (also known as the Rosenthal syndrome or hemophilia C) manifests as minor bleeding, usually after trauma or surgery. We report a case in which bilateral knee hemarthrosis was the first manifestation. The patient presented at 32 years of age with a 2-year history of mechanical pain and intermittent swelling in both knees. Knee aspiration recovered blood-tinged fluid. The laboratory workup showed severe factor XI deficiency. Replacement therapy with fresh frozen plasma was effective. Tests in the family showed factor XI deficiency in the patient's sister. | Is factor XI deficient in Hemophilia C? | 51588c1ad24251bc05000094_004 | yes |
Down regulation of the L-type Ca2+ channel, GRK2, and phosphorylated phospholamban: protective mechanisms for the denervated failing heart. We previously found that a canine model of selective surgical ventricular denervation (VD), which does not permit increased sympathetic tone during the pathogenesis of heart failure (HF), tolerated the development of HF better than controls. To investigate the cellular mechanisms, we examined cellular contraction and L-type Ca(2+) channel currents (I(Ca)) and their responses to beta-adrenergic receptor (beta-AR) stimulation in left ventricular myocytes from 1) control, 2) VD, 3) HF induced by rapid pacing, and 4) HF induced in VD (VD-HF) dogs. The magnitude of myocyte contraction and rate of relaxation in VD were similar to control but were depressed in both HF and VD-HF. These changes were associated with reduced protein expression of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) and protein kinase A phosphorylated phospholamban (PLB), which was reduced in HF, but essentially abolished in VD-HF. beta-AR kinase (GRK2) was increased in HF but reduced in VD-HF. Basal I(Ca) density did not differ among control, VD, and HF groups, but VD-HF myocytes showed a markedly reduced I(Ca) density (approximately 40%). Compared to controls, the sensitivity of I(Ca) to isoproterenol (ISO), was significantly higher in VD, but reduced in HF. While I(Ca) responses to ISO in VD-HF were maintained at control levels, the amplitude of the ISO-stimulated I(Ca) was significantly smaller (approximately 50%) compared with HF myocytes. The relative decrease in Ca(2+) influx due to downregulation of I(Ca) density may contribute to the cardioprotective effects in VD-HF hearts by preventing Ca(2+) overload during the development of HF. These findings, in combination with the virtual abolition of phosphorylated PLB in VD-HF and the decrease in GRK2, may explain, in part, why VD dogs tolerate the development of HF better than control dogs. | Is phospholamban phosphorylated by Protein kinase A? | 54da0c524b1fd0d33c00000b_001 | yes |
Reversal of target-specific oral anticoagulants. The target-specific oral anticoagulants represent the first new oral anti-thrombotic therapy in over 50 years and have the potential to make therapy easier and hence more accessible to many patients. Like any new therapy, the potential benefits must be weighed against the potential challenges and one of the most concerning aspects of the new target-specific oral anticoagulants is the lack of a proven method to reverse their effect. Unlike the vitamin K antagonist, i.e. warfarin, there is no specific antidote for these medications. This paper will review the limited data on the use of non-specific therapies to reverse anticoagulation for the new agents. We hope to prepare clinicians who are faced with a patient who has serious bleeding or needs emergent surgery while taking dabigatran, rivaroxaban or apixaban. | Are there any specific antidotes for rivaroxaban? | 532f08b8d6d3ac6a34000029_014 | no |
New oral anticoagulants in the ED setting: a review. BACKGROUND: Emergency department (ED) clinicians are not typically involved in the long-term management of patients' anticoagulation therapy, but they are responsible for decision making for emergency conditions requiring anticoagulation, such as acute venous thromboembolism (VTE). In addition, emergency physicians are often faced with patients who present first to the ED with conditions that may prompt long-term anticoagulation upon hospital discharge, such as atrial fibrillation (AF), or who have acute or potential bleeding complications from anticoagulation. OBJECTIVE: In this review, clinical trials of new oral anticoagulants evaluated for treatment of VTE and stroke prophylaxis in AF, as well as practical management aspects, will be discussed. In addition, clinical trials evaluating the adjunctive use of the new oral anticoagulants with antiplatelet therapy in patients who have experienced acute coronary syndrome will be explored. DISCUSSION: Both dabigatran etexilate and rivaroxaban have successfully completed phase III trials for acute VTE treatment and are currently approved for the reduction of risk of stroke and systemic embolism in patients with nonvalvular AF. In a recently completed phase III trial, apixaban also demonstrated promising efficacy and safety in that indication. Rivaroxaban represents the only new anticoagulant to date to have shown promising phase III results as an adjunct to antiplatelet therapy after acute coronary syndrome. CONCLUSION: Knowledge of the appropriate clinical use and safety concerns of the new anticoagulants is imperative as they become more frequently prescribed, and their potential uses in the ED setting represent an important aspect of continuing education for emergency physicians. | Is apixaban effective for treatment of acute venous thromboembolism? | 52fc94572059c6d71c000070_003 | yes |
Clinical use of the FemAssist device in female urinary incontinence. OBJECTIVE: We sought to determine the safety and effectiveness of a new, simple noninvasive device, "FemAssist" for women suffering from urinary incontinence. METHODS: The "FemAssist" is a dome-shaped medical grade silicon device intended to be worn over the external urethral meatus and held in place by suction and an adhesive gel. Thirty eight women with varying degrees of genuine stress urinary incontinence (GSUI) or mixed incontinence on multichannel urodynamic testing were fitted with one of two sizes of "FemAssist" with regard to their anatomy and dexterity. RESULTS: Thus far, of the 38 women who have completed the study, there have been no reported significant increases in bacteriuria or urinary tract infection rates. Over half of the women reported an improvement in the quality of life including comfort, convenience, and overall satisfaction. The device was worn for a total of 886 days by the group; 82% of these were dry days. CONCLUSION: Our preliminary study suggests that the "FemAssist" device is safe and effective for some women with urinary incontinence. | Has silicon been used in treatment of incontinence ? | 536172d17d100faa09000009_007 | yes |
The physiology of cardiac calcium handling. Cardiac calcium (Ca(2+)) handling subsumes the mechanisms maintaining the myocardial Ca(2+) homeostasis that contribute essentially to cardiac performance. This review addresses the interaction of transplasmalemmal and transsarcoplasmic Ca(2+) flux, its potential modifications due to β-adrenergic stimulation and its implications on cardiac action potential. | Is Calcium homeostasis important in cardiac physiology and pathophysiology? | 54c26e29f693c3b16b000003_001 | yes |
NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II Trials. BACKGROUND AND PURPOSE: In animal models of acute ischemic stroke (AIS), the free radical-trapping agent NXY-059 showed promise as a neuroprotectant. SAINT I and II were randomized, placebo-controlled, double-blind trials to investigate the efficacy of NXY-059 in patients with AIS. METHODS: Patients with AIS received an infusion of intravenous NXY-059 or placebo within 6 hours from the onset of stroke symptoms. A pooled individual patient analysis was prespecified to assess the overall efficacy and to examine subgroups. The primary end point was the distribution of disability scores measured on the modified Rankin scale (mRS) at 90 days. Neurologic and activities of daily living scores were investigated as secondary end points. We also evaluated whether treatment with NXY-059 would reduce alteplase-related intracranial hemorrhages. Finally, we evaluated possible predictors of good or poor outcome. RESULTS: An intent-to-treat efficacy analysis was based on 5028 patients. Baseline parameters and prognostic factors were well balanced between treatment groups. The distribution of scores on the mRS was not different in the group treated with NXY-059 (n=2438) compared with the placebo group (n=2456): odds ratio for limiting disability=1.02; 95% CI, 0.92 to 1.13 (P=0.682, Cochran-Mantel-Haenszel test). Comparisons at each level of the mRS confirmed an absence of benefit. There was no evidence of efficacy in prespecified subgroups or from the secondary outcome analyses. Mortality was equal in the 2 groups (16.7% vs 16.5%), and adverse event rates were similar. Among patients treated with alteplase, there was no decrease in rates of symptomatic or asymptomatic hemorrhage associated with NXY-059 treatment versus placebo. Subgroup analyses identified National Institutes of Health Stroke Scale score, age, markers of inflammation, blood glucose, and right-sided infarct as predictors of poor outcome. CONCLUSIONS: NXY-059 is ineffective for treatment of AIS within 6 hours of symptom onset. This is also true for subgroups and the prevention of alteplase-associated hemorrhage. | Can NXY-059 be used for treatment of acute ischemic stroke patients? | 54d62faf3706e89528000003_012 | no |
CTCF and cohesin cooperatively mediate the cell-type specific interchromatin interaction between Bcl11b and Arhgap6 loci. CCCTC-binding factor (CTCF) is a master organizer of genome spatial organization and plays an important role in mediating extensive chromatin interactions. Circular chromosome conformation capture (4C) is a high-throughput approach that allows genome-wide screening for unknown potential interaction partners. Using a conserved CTCF binding site on the Bcl11b locus as bait, an interaction partner at the Arhgap6 locus on a different chromosome was identified by 4C. Additional experiments verified that the interchromatin interaction between the Bcl11b and Arhgap6 loci was cell-type specific, which was cooperatively mediated by CTCF and cohesin. Functional analysis showed that the interchromatin interaction partners were repressing regulatory elements. These results indicate that interaction chromatin loops regulate the expression of the relevant genes. | Does the CTCF protein co-localize with cohesin? | 5344310baeec6fbd0700000c_004 | yes |
Associations of light, moderate, and vigorous intensity physical activity with longevity. The Harvard Alumni Health Study. Physical activity is associated with better health; however, the optimal intensity of activity remains unclear. A total of 13,485 men (mean age, 57.5 years) from the Harvard Alumni Health Study reported their walking, stair climbing, and sports/recreation in 1977. Between 1977 and 1992, 2,539 died. After adjusting for the different activity components, distance walked and storeys climbed independently predicted longevity (p, trend = 0.004 and <0.001, respectively). 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 provide some support for current recommendations that emphasize moderate intensity activity; they also clearly indicate a benefit of vigorous activity. | Is intense physical activity associated with longevity? | 518ccac0310faafe0800000b_000 | yes |
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. We compared the distribution of ZFHX1B transcripts during mouse and human embryogenesis as well as in adult mice and humans. This showed that this gene is strongly transcribed at an early stage in the developing peripheral and central nervous systems of both mice and humans, in all neuronal regions of the brains of 25-week human fetuses and adult mice, and at varying levels in numerous nonneural tissues. Northern blot analysis suggested that ZFHX1B undergoes tissue-specific alternative splicing in both species. These results strongly suggest that ZFHX1B determines the transcriptional levels of target genes in various tissues through the combinatorial interactions of its isoforms with different Smad proteins. Thus, as well as causing neural defects, ZFHX1B mutations may also cause other malformations. | Have mutations in the ZEB2 gene been found in any human syndrome? | 53552ed7f1005d6b58000001_018 | yes |
Transcapillary escape rate of albumin is increased and related to haemodynamic changes in normo-albuminuric type 1 diabetic patients. OBJECTIVE: An increase in urinary albumin excretion (UAE) in type 1 diabetic patients might reflect changes in vascular permeability and/or local haemodynamic factors. Indeed, transcapillary escape of albumin (TERalb), a measure of systemic capillary efflux, is increased in diabetic patients, even in those with a modest increase of albuminuria. In normo-albuminuric type 1 diabetic patients, systemic capillary and glomerular flow is increased. We hypothesized that these haemodynamic changes contribute to an elevated TERalb, even in the phase preceding micro-albuminuria. METHODS: We measured TERalb in 39 normo-albuminuric type 1 diabetic patients and 46 healthy controls. TERalb was calculated from the disappearance curve of 125I-albumin. Renal and systemic haemodynamics were measured by standard techniques. Forearm blood flow (FBF) was measured by plethysmography. Endothelial function was assessed by intra-arterial infusion of acetylcholine. The structural integrity of the vessel wall was determined by the post-occlusive reactive hyperaemia test. RESULTS: TERalb was increased in diabetic patients (5.53+/-0.40 versus 4.39+/-0.21 %/h, P = 0.01). Patients were divided into tertiles with respect to their TERalb. There were no differences in UAE, blood pressure, metabolic parameters, endothelial function or maximal vasodilatation after occlusion between the groups. However, filtration fraction and FBF were significantly increased in the group of diabetic patients with the highest levels of TERalb. Overall, in diabetic patients, FBF was significantly correlated with TERalb. CONCLUSIONS: TERalb is increased in normo-albuminuric type 1 diabetic patients. In these patients with an increased capillary permeability, there is no evidence of endothelial dysfunction or vessel wall damage. However, both FBF and filtration fraction are increased. Therefore, the increased vascular permeability in the early phase of type 1 diabetes is associated with general haemodynamic alterations. Notably, such an increase in vascular permeability is not necessarily reflected by abnormal UAE. This could be due to either a lack of change in glomerular permeability or due to the fact that the threshold for tubular reabsorption of albumin has not been exceeded. | Is transcapillary albumin escape altered in diabetic patients? | 5321b4959b2d7acc7e000007_002 | yes |
MPE-seq, a new method for the genome-wide analysis of chromatin structure. The analysis of chromatin structure is essential for the understanding of transcriptional regulation in eukaryotes. Here we describe methidiumpropyl-EDTA sequencing (MPE-seq), a method for the genome-wide characterization of chromatin that involves the digestion of nuclei withMPE-Fe(II) followed by massively parallel sequencing. Like micrococcal nuclease (MNase), MPE-Fe(II) preferentially cleaves the linker DNA between nucleosomes. However, there are differences in the cleavage of nuclear chromatin by MPE-Fe(II) relative to MNase. Most notably, immediately upstream of the transcription start site of active promoters, we frequently observed nucleosome-sized (141-190 bp) and subnucleosome-sized (such as 101-140 bp) peaks of digested chromatin fragments with MPE-seq but not with MNase-seq. These peaks also correlate with the presence of core histones and could thus be due, at least in part, to noncanonical chromatin structures such as labile nucleosome-like particles that have been observed in other contexts. The subnucleosome-sized MPE-seq peaks exhibit a particularly distinct association with active promoters. In addition, unlike MNase, MPE-Fe(II) cleaves nuclear DNA with little sequence bias. In this regard, we found that DNA sequences at RNA splice sites are hypersensitive to digestion by MNase but not by MPE-Fe(II). This phenomenon may have affected the analysis of nucleosome occupancy over exons. These findings collectively indicate that MPE-seq provides a unique and straightforward means for the genome-wide analysis of chromatin structure with minimal DNA sequence bias. In particular, the combined use of MPE-seq and MNase-seq enables the identification of noncanonical chromatin structures that are likely to be important for the regulation of gene expression. | Is there a sequence bias in MNase digestion patterns? | 5a4e1882966455904c00000f_002 | yes |
Effectiveness of pelvic muscle exercises in reducing urge incontinence among community residing elders. 1. Urinary incontinence is a costly and prevalent problem, affecting 15% to 39% of all community residing elders. 2. Some elders suffering from urge incontinence prefer pelvic muscle exercises to bladder training as the behavioral intervention of choice. 3. Although pelvic muscle exercises are frequently associated as an intervention for stress incontinence, they have been found to be effective in significantly reducing urge incontinence. 4. Nurses are in a key position to identify and treat urinary incontinence among the elderly, and should incorporate continence restoration interventions into their practice. | Is Bladder training an effective method to treat urge incontinence ? | 515df98f298dcd4e51000030_013 | yes |
FGFR mutations and plagiocephaly. FGFR genes have important effects on bone development, and mutations in 4 "hot spot" exons of FGFR1-3 are found in many patients with craniosynostosis and some with synostotic plagiocephaly. To test the hypothesis that sequence variation in those exons predisposes toward developmental bone deformation, we assayed 160 children with nonsynostotic plagiocephaly by temporal temperature gradient gel electrophoresis. No sequence variation was found, indicating that mutations in the "hot spot" exons are not associated with this common developmental condition; however, we did not assay most of the exons or related genes. | Is there an association between FGFR3 mutation and plagiocephaly? | 56c1f042ef6e394741000056_003 | yes |
[Carcinoid heart disease. Report of a case with triple valvular lesion (author's transl)]. A case of carcinoid syndrome, stemming from a tumor of the large intestine with hepatic metastases, is reported. Clinical features included cardiac disease with triple valvular lesion: tricuspid insufficiency with stenosis, pulmonary artery stenosis and mitral insufficiency. More recent views about the pathogenesis of the cardiac involvement in the carcinoid syndrome are reported, and the cardiac therapy is discussed. | Is there an association between carcinoid syndrome and mitral valve disease? | 5a67a550b750ff4455000009_002 | yes |
Assessment of pelvic floor muscle pressure in female athletes. OBJECTIVE: To evaluate the pressure of the pelvic floor muscles in female athletes and the associated signs and symptoms of stress urinary incontinence. DESIGN: A prospective observational study. SETTING: An academic institution, primary level of clinical care. PARTICIPANTS: Forty women between 18 and 30 years of age divided into 4 groups: 10 volleyball players, 10 handball players, 10 basketball players, and 10 nonathletes. METHODS: The measurement of intracavity pressure was performed with use of a perineometer. The volunteers were instructed to perform 3 maximum isometric contractions of the perineum, held for 4 seconds. Data regarding specific training and urinary symptoms were collected through a questionnaire. MAIN OUTCOME MEASUREMENTS: Statistical analysis was performed by analysis of variance, with a significance level of 5%. The Spearman correlation was used to verify the degree of association between variables related to training, urinary symptoms, and perineal pressure. RESULTS: The average (standard deviation) perineal pressure for nonathletes was 6.73 ± 1.91 mm Hg. The average perineal pressure for handball players was 5.55 ± 1.43 mm Hg; for volleyball players, 4.36 ± 1.43 mm Hg; and for basketball players, 3.65 ± 1.35 mm Hg. Statistically significant differences were found in the perineal pressure of volleyball (P = .009) and basketball players (P = .039) compared with nonathletes. The number of games per year, strength training, and on-court workout correlated significantly with perineal pressure (Spearman correlation coefficient [Rs] of -0.512 for the 3 variables). Urine leakage through effort and nocturia correlated moderately with perineal pressure (Rs of -0.51 and -0.54, respectively). A strong correlation was found between urinary frequency and perineal pressure (Rs of -0.85). CONCLUSIONS: Analysis of these data suggests that perineal pressure is decreased in female athletes compared with nonathlete women. A lower perineal pressure correlates with increased symptoms of urinary incontinence and pelvic floor dysfunction. | Is there increased incidence of incontinence in athletes? | 5361677c7d100faa09000008_016 | yes |
Actopaxin (α-parvin) phosphorylation is required for matrix degradation and cancer cell invasion. Dysregulation of cell adhesion and motility is known to be an important factor in the development of tumor malignancy. Actopaxin (α-parvin) is a paxillin, integrin-linked kinase, and F-actin binding focal adhesion protein with several serine phosphorylation sites in the amino terminus that contribute to the regulation of cell spreading and migration. Here, phosphorylation of actopaxin is shown to contribute to the regulation of matrix degradation and cell invasion. Osteosarcoma cells stably expressing wild type (WT), nonphosphorylatable (Quint), and phosphomimetic (S4D/S8D) actopaxin demonstrate that actopaxin phosphorylation is necessary for efficient Src and matrix metalloproteinase-driven degradation of extracellular matrix. Rac1 was found to be required for actopaxin-induced matrix degradation whereas inhibition of myosin contractility promoted degradation in the phosphomutant-expressing Quint cells, indicating that a balance of Rho GTPase signaling and regulation of cellular tension are important for the process. Furthermore, actopaxin forms a complex with the Rac1/Cdc42 GEF β-PIX and Rac1/Cdc42 effector PAK1, to regulate actopaxin-dependent matrix degradation. Actopaxin phosphorylation is elevated in the invasive breast cancer cell line MDA-MB-231 compared with normal breast epithelial MCF10A cells. Expression of the nonphosphorylatable Quint actopaxin in MDA-MB-231 cells inhibits cell invasion whereas overexpression of WT actopaxin promotes invasion in MCF10A cells. Taken together, this study demonstrates a new role for actopaxin phosphorylation in matrix degradation and cell invasion via regulation of Rho GTPase signaling. | Is Rac1 involved in cancer cell invasion? | 5319abc9b166e2b80600002d_014 | yes |
Telephone cognitive-behavioral therapy for subthreshold depression and presenteeism in workplace: a randomized controlled trial. BACKGROUND: Subthreshold depression is highly prevalent in the general population and causes great loss to society especially in the form of reduced productivity while at work (presenteeism). We developed a highly-structured manualized eight-session cognitive-behavioral program with a focus on subthreshold depression in the workplace and to be administered via telephone by trained psychotherapists (tCBT). METHODS: We conducted a parallel-group, non-blinded randomized controlled trial of tCBT in addition to the pre-existing Employee Assistance Program (EAP) versus EAP alone among workers with subthreshold depression at a large manufacturing company in Japan. The primary outcomes were depression severity as measured with Beck Depression Inventory-II (BDI-II) and presenteeism as measured with World Health Organization Health and Work Productivity Questionnaire (HPQ). In the course of the trial the follow-up period was shortened in order to increase acceptability of the study. RESULTS: The planned sample size was 108 per arm but the trial was stopped early due to low accrual. Altogether 118 subjects were randomized to tCBT+EAP (n = 58) and to EAP alone (n = 60). The BDI-II scores fell from the mean of 17.3 at baseline to 11.0 in the intervention group and to 15.7 in the control group after 4 months (p<0.001, Effect size = 0.69, 95%CI: 0.32 to 1.05). However, there was no statistically significant decrease in absolute and relative presenteeism (p = 0.44, ES = 0.15, -0.21 to 0.52, and p = 0.50, ES = 0.02, -0.34 to 0.39, respectively). CONCLUSION: Remote CBT, including tCBT, may provide easy access to quality-assured effective psychotherapy for people in the work force who present with subthreshold depression. Further studies are needed to evaluate the effectiveness of this approach in longer terms. The study was funded by Sekisui Chemicals Co. Ltd. TRIAL REGISTRATION: ClinicalTrials.gov NCT00885014. | Is there an association between presenteeism and depression? | 54f49e56d0d681a040000004_023 | yes |
Telomere length and dynamics predict mortality in a wild longitudinal study. Explaining variation in life expectancy between individuals of the same age is fundamental to our understanding of population ecology and life history evolution. Variation in the length and rate of loss of the protective telomere chromosome caps has been linked to cellular lifespan. Yet, the extent to which telomere length and dynamics predict organismal lifespan in nature is still contentious. Using longitudinal samples taken from a closed population of Acrocephalus sechellensis (Seychelles warblers) studied for over 20 years, we describe the first study into life-long adult telomere dynamics (1-17 years) and their relationship to mortality under natural conditions (n = 204 individuals). We show that telomeres shorten with increasing age and body mass, and that shorter telomeres and greater rates of telomere shortening predicted future mortality. Our results provide the first clear and unambiguous evidence of a relationship between telomere length and mortality in the wild, and substantiate the prediction that telomere length and shortening rate can act as an indicator of biological age further to chronological age when exploring life history questions in natural conditions. | Can chronological age be predicted by measuring telomere length? | 56d34fbcf22319765a000009_000 | no |
A natural history of athleticism, health and longevity. Longitudinal observations on the sports play, social habits and health status of 52,000 men who entered Harvard College or the University of Pennsylvania between 1916 and 1950 have afforded means of identifying causes of disease and death. These observations were then translated into the eff ect of sports and physical exercise on health and longevity. Student sports play in college predicted a decreased risk of developing cardiovascular disease (CVD) at least up to age 50 years. Questionnaire surveys showed physical exercise (sports play, walking and stair climbing) in middle age to be inversely related to the later development of CVD and early death. In a 10-year follow-up between 1962 and 1972, alumni aged 35-74 years who expended greater than or equal to > 2000 kcal week(-1) (8.4 MJ week -1 ) in such activities had a 25% reduced risk of CVD and death compared with less active men. But, the 'protective eff ect' of early athleticism waned unless a physically active life was maintained. In contrast, sedentary students who took up an active life were at a lower risk of CVD and death than former student athletes who gave up or reduced their physical activities in middle age. A total of 17,815 Harvard alumni aged 45-84 years were followed from a 1977 questionnaire survey through 1992, with 4399 deaths occurring. 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. Over the age range, in the 16-year follow-up, Harvard alumni playing moderately vigorous or more intense sports gained 1.5 years by age 90 compared with less active men. | Is intense physical activity associated with longevity? | 518ccac0310faafe0800000b_003 | yes |
Compensatory role of thyroid hormone receptor (TR) alpha 1 in resistance to thyroid hormone: study in mice with a targeted mutation in the TR beta gene and deficient in TR alpha 1. Resistance to thyroid hormone (RTH) is caused by mutations of the thyroid hormone receptor beta (TR beta) gene. Almost all RTH patients are heterozygous with an autosomal dominant pattern of inheritance. That most are clinically euthyroid suggests a compensatory role of the TR alpha1 isoform in maintaining the normal functions of thyroid hormone (T3) in these patients. To understand the role of TR alpha1 in the manifestation of RTH, we compared the phenotypes of mice with a targeted dominantly negative mutant TR beta (TR betaPV) with or without TR alpha1. TR betaPV mice faithfully recapitulate RTH in humans in that these mice demonstrate abnormalities in the pituitary-thyroid axis and impairment in growth. 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. Furthermore, abnormal expression patterns of T3-target genes in TR betaPV mice were altered by the lack of TR alpha1. 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. This compensatory role may be especially crucial for postnatal growth. | Are thyroid hormone receptor alpha1 mutations implicated in thyroid hormone resistance syndrome? | 52f7c4bd2059c6d71c00002d_000 | yes |
[Intestinal microflora of autistic children]. Autistic behavior is often accompanied by numerous disturbing symptoms on the part of gastrointestinal system, such as abdominal pain, constipation or diarrhea. These problems are often connected with deregulation of physiological microflora in intestine. The aim of this study was to determine differences in intestinal microflora of autistic and healthy children. Strains of Clostridium spp. and enterococci were isolated more frequently from stool samples of autistic children and rarely lactobacilli. Quantitative differences were observed maliny among staphylococci, Candida spp. and Clostridium perfringens. Monitoring and stabilization of intestinal microflora and knowledge about role of particular strains in etiology of autistic disorders can increase the chances for appropriate therapy. | Is abdominal pain a common symptom in autism? | 515debe7298dcd4e51000026_005 | yes |
Downregulation of G3BPs inhibits the growth, migration and invasion of human lung carcinoma H1299 cells by suppressing the Src/FAK-associated signaling pathway. G3BP is a RasGAP binding protein that is overexpressed in many human cancers. We previously reported that downregulation of G3BP suppressed cell growth and induced apoptosis in HCT116 cells. Here we report that both transient and stable knockdown of G3BP suppressed the growth, migration and invasion capability of human lung carcinoma H1299 cells. Moreover, downregulation of G3BP significantly inhibited the phosphorylation of Src, FAK and ERK, and the levels of NF-κB were also markedly decreased in H1299 cells. Knockdown of G3BP also decreased the expression of matrix metalloproteinase-2 (MMP-2), MMP-9 and plasminogen activator (uPA), and in vivo data demonstrated that downregulation of G3BP markedly inhibited the growth of H1299 tumor xenografts. Together, these data revealed that knockdown of G3BP inhibited the migration and invasion of human lung carcinoma cells through the inhibition of Src, FAK, ERK and NF-κB and decreased levels of MMP-2, MMP-9 and uPA. | Is the protein FAK (Focal Adhesion Kinase) phosphorylated? | 54f4c382d0d681a040000006_011 | yes |
SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. CONTEXT: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. A recent report described a patient with an abdominal paraganglioma, immunohistochemically negative for SDHA, and identified a causal germline mutation in SDHA. OBJECTIVE: In this study, we evaluated the significance of SDHA immunohistochemistry in the identification of new patients with SDHA mutations. SETTING: This study was performed in the Erasmus Medical Center in Rotterdam (The Netherlands) and the Université Paris Descartes in Paris (France). METHODS: We investigated 316 pheochromocytomas and paragangliomas for SDHA expression. Sequence analysis of SDHA was performed on all tumors that were immunohistochemically negative for SDHA and on a subset of tumors immunohistochemically positive for SDHA. RESULTS: Six tumors were immunohistochemically negative for SDHA. Four tumors from Dutch patients showed a germline c.91C → T SDHA gene mutation (p.Arg31X). Another tumor (from France) carried a germline SDHA missense mutation c.1753C → T (p.Arg585Trp). Loss of the wild-type SDHA allele was confirmed by loss of heterozygosity analysis. Sequence analysis of 35 SDHA immunohistochemically positive tumors did not reveal additional SDHA mutations. CONCLUSIONS: Our results demonstrate that SDHA immunohistochemistry on paraffin-embedded tumors can reveal the presence of SDHA germline mutations and allowed the identification of SDHA-related tumors in at least 3% of patients affected by apparently sporadic (para)sympathetic paragangliomas and pheochromocytomas. | Is the SDHAF2 gene encoding a protein necessary for flavination of SDHA? | 571e06447de986d80d000016_000 | yes |
Measles Virus: Identification in the M Protein Primary Sequence of a Potential Molecular Marker for Subacute Sclerosing Panencephalitis. Subacute Sclerosing Panencephalitis (SSPE), a rare lethal disease of children and young adults due to persistence of measles virus (MeV) in the brain, is caused by wild type (wt) MeV. Why MeV vaccine strains never cause SSPE is completely unknown. Hypothesizing that this phenotypic difference could potentially be represented by a molecular marker, we compared glycoprotein and matrix (M) genes from SSPE cases with those from the Moraten vaccine strain, searching for differential structural motifs. We observed that all known SSPE viruses have residues P64, E89, and A209 (PEA) in their M proteins whereas the equivalent residues for vaccine strains are either S64, K89, and T209 (SKT) as in Moraten or PKT. Through the construction of MeV recombinants, we have obtained evidence that the wt MeV-M protein PEA motif, in particular A209, is linked to increased viral spread. Importantly, for the 10 wt genotypes (of 23) that have had their M proteins sequenced, 9 have the PEA motif, the exception being B3, which has PET. Interestingly, cases of SSPE caused by genotype B3 have yet to be reported. In conclusion, our results strongly suggest that the PEA motif is a molecular marker for wt MeV at risk to cause SSPE. | Is subacute sclerosing panencephalitis caused by the Measles vaccine? | 5aa3fa73d6d6b54f79000008_021 | no |
Magnesium sulfate administration in subarachnoid hemorrhage. Magnesium offers theoretic vascular and neuroprotective benefits for patients with subarachnoid hemorrhage. An electronic literature search was conducted to identify original research studies describing intravenous magnesium treatment in patients with SAH published in English between January 1990 and October 2010. Seventeen articles were identified and reviewed, including one phase III randomized-controlled clinical trial and six phase II randomized-controlled trials. Study quality was low for most of the included studies, with the phase III trial considered to be of moderate quality. Due to inconsistently reported benefits and the occurrence of side effects, phase II data suggested that intravenous magnesium for SAH provided either no overall net benefit or uncertain trade-offs. Benefit was likewise not supported in the single phase III clinical trial. | Does magnesium sulfate improve outcomes of subarachnoid hemorrhage patients? | 54d62ede3706e89528000002_015 | no |
Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). BACKGROUND: Apremilast works intracellularly to regulate inflammatory mediators. OBJECTIVE: ESTEEM 1 evaluated efficacy/safety of apremilast at 30 mg twice a day for moderate to severe plaque psoriasis. METHODS: This phase III, multicenter, double-blind, placebo-controlled study randomized adults (2:1) to apremilast or placebo. At week 16, the placebo group switched to apremilast through week 32, followed by a randomized treatment withdrawal phase to week 52. Binary end points were analyzed using χ(2) test; continuous end points used analysis of covariance. RESULTS: In all, 844 patients were randomized (n = 282, placebo; n = 562, apremilast). At week 16, significantly more patients taking apremilast achieved 75% or greater reduction from baseline Psoriasis Area and Severity Index score (PASI-75) (33.1%) versus placebo (5.3%, P < .0001; primary end point). Most (61.0%) patients rerandomized to apremilast at week 32 achieved PASI-75 at week 52 versus 11.7% rerandomized to placebo. Of patients rerandomized to apremilast at week 32, mean percentage change from baseline PASI score was -88% to -81% (weeks 32-52). During the placebo-controlled period, 55.7% and 69.3% of patients randomized to placebo and apremilast, respectively, had 1 or more adverse events. Most adverse events were mild/moderate in severity. No new significant adverse events emerged with continued apremilast exposure versus the placebo-controlled period. LIMITATIONS: Data were limited to 52 weeks and may not generalize to nonplaque psoriasis. CONCLUSIONS: Apremilast was effective in moderate to severe plaque psoriasis. | Is apremilast effective for psoriasis? | 589a246d78275d0c4a000033_009 | yes |
Severe and critical cases of H1N1 influenza in pregnancy: a Chinese perspective. CONTEXT: In 2009, an outbreak of A/H1N1 influenza spread worldwide. Following the start of winter in Liaoning province in China, the number of pregnant women infected with influenza increased significantly. Some of them developed respiratory failure and multiple organ failure. AIMS: The aim of this study was to determine the high-risk factors associated with the development of critical illness in the hospitalized pregnant women with A/H1N1 infection. SETTINGS AND DESIGN: This retrospective cohort study was carried out in the tertiary care obstetric department of a large general hospital. MATERIALS AND METHODS: The clinical data of H1N1 pregnant women hospitalized from November 2009 to January 2010 was reviewed. We classified these cases into severe and critical grades according to H1N1 influenza treatment guidelines. We selected maternal age, gestational age, and the time interval between symptom-onset and hospital admission as related factors of critical illness. STATISTICAL ANALYSIS: Logistic regression analyses to determine the relevance and importance of factors significantly associated with critical illness. RESULTS: Eighteen cases of H1N1 influenza pregnant women were admitted. Ten pregnant women were severe cases and eight pregnant women were critical cases. The maternal age (OR=0.979, 95% CI: 0.749~1.279)and the time interval between symptom-onset and hospital admission (OR=1.41, 95% CI: 0.917~2.169) were not found to be risk factors for critical cases. The significant risk factor associated with critical illness is gestational age (OR=53.726, 95% CI: 131.165~2477.918). The risk varied by weeks of gestation, with an odds ratio of 1.034 (95% CI: 0.968-1.106) during the first trimester, 9.667 (95% CI: 0.750-124.59) during the second trimester, and 87 (95% CI: 6.750-1121.39) during the third trimester. CONCLUSIONS: Gestational age is associated with the risk of developing critical infection. The risk increases with increasing weeks of gestation. | Is pregnancy an additional risk during during H1N1 infection? | 531a3fe3b166e2b806000038_010 | yes |
Mutational spectrum of semaphorin 3A and semaphorin 3D genes in Spanish Hirschsprung patients. Hirschsprung disease (HSCR, OMIM 142623) is a developmental disorder characterized by the absence of ganglion cells along variable lengths of the distal gastrointestinal tract, which results in tonic contraction of the aganglionic colon segment and functional intestinal obstruction. The RET proto-oncogene is the major gene associated to HSCR with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. In addition, many other genes have been described to be associated with this pathology, including the semaphorins class III genes SEMA3A (7p12.1) and SEMA3D (7q21.11) through SNP array analyses and by next-generation sequencing technologies. Semaphorins are guidance cues for developing neurons implicated in the axonal projections and in the determination of the migratory pathway for neural-crest derived neural precursors during enteric nervous system development. In addition, it has been described that increased SEMA3A expression may be a risk factor for HSCR through the upregulation of the gene in the aganglionic smooth muscle layer of the colon in HSCR patients. Here we present the results of a comprehensive analysis of SEMA3A and SEMA3D in a series of 200 Spanish HSCR patients by the mutational screening of its coding sequence, which has led to find a number of potentially deleterious variants. RET mutations have been also detected in some of those patients carrying SEMAs variants. We have evaluated the A131T-SEMA3A, S598G-SEMA3A and E198K-SEMA3D mutations using colon tissue sections of these patients by immunohistochemistry. All mutants presented increased protein expression in smooth muscle layer of ganglionic segments. Moreover, A131T-SEMA3A also maintained higher protein levels in the aganglionic muscle layers. These findings strongly suggest that these mutants have a pathogenic effect on the disease. Furthermore, because of their coexistence with RET mutations, our data substantiate the additive genetic model proposed for this rare disorder and further support the association of SEMAs genes with HSCR. | Is RET the major gene involved in Hirschsprung disease? | 5503121de9bde69634000019_011 | yes |
Mutation characteristics in type I collagen genes in Chinese patients with osteogenesis imperfecta. Osteogenesis imperfecta is normally caused by an autosomal dominant mutation in the type I collagen genes COL1A1 and COL1A2. The severity of osteogenesis imperfecta varies, ranging from perinatal lethality to a very mild phenotype. Although there have been many reports of COL1A1 and COL1A2 mutations, few cases have been reported in Chinese people. We report on five unrelated families and three sporadic cases. The mutations were detected by PCR and direct sequencing. Four mutations in COL1A1 and one in COL1A2 were found, among which three mutations were previously unreported. The mutation rates of G>C at base 128 in intron 31 of the COL1A1 gene and G>A at base 162 in intron 30 of the COL1A2 gene were higher than normal. The patients' clinical characteristics with the same mutation were variable even in the same family. We conclude that mutations in COL1A1 and COL1A2 also have an important role in osteogenesis imperfecta in the Chinese population. As the Han Chinese people account for a quarter of the world's population, these new data contribute to the type I collagen mutation map. | Is autosomal dominant inheritanced form of Osteogenesis imperfecta caused by mutations in the genes associated with collagen production? | 5a6f77d7b750ff4455000051_013 | yes |
‘Euglycemic’ Ketoacidosis in a Patient With Type 2 Diabetes Being Treated With Canagliflozin. OBJECTIVE: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, one of a class of
novel antiglycemic agents that are gaining in popularity in the treatment of diabetes. METHODS: We describe a case in which a patient experienced difficult-to-treat metabolic ketoacidosis
in the setting of canagliflozin use. RESULTS: A 52-year-old man with type 2 diabetes mellitus developed profound ketoacidosis without
overt hyperglycemia while taking canagliflozin. Despite initiation of an insulin infusion, the
metabolic acidosis persisted for 3 days. CONCLUSION: Treatment with canagliflozin was associated with development of euglycemic ketoacidosis. | Can canagliflozin cause euglycemic diabetic ketoacidosis? | 5a6f922fb750ff4455000059_007 | yes |
Phosphorylation of skeletal muscle calsequestrin enhances its Ca2+ binding capacity and promotes its association with junctin. Calcium signaling, intrinsic to skeletal and cardiac muscle function, is critically dependent on the amount of calcium stored within the sarcoplasmic reticulum. Calsequestrin, the main calcium buffer in the sarcoplasmic reticulum, provides a pool of calcium for release through the ryanodine receptor and acts as a luminal calcium sensor for the channel via its interactions with triadin and junctin. We examined the influence of phosphorylation of calsequestrin on its ability to store calcium, to polymerise and to regulate ryanodine receptors by binding to triadin and junctin. Our hypothesis was that these parameters might be altered by phosphorylation of threonine 353, which is located near the calcium and triadin/junctin binding sites. Although phosphorylation increased the calcium binding capacity of calsequestrin nearly 2-fold, it did not alter calsequestrin polymerisation, its binding to triadin or junctin or inhibition of ryanodine receptor activity at 1 mM luminal calcium. Phosphorylation was required for calsequestrin binding to junctin when calcium concentration was low (100 nM), and ryanodine receptors were activated by dephosphorylated calsequestrin when it bound to triadin alone. These novel data shows that phosphorylated calsequestrin is required for high capacity calcium buffering and suggest that ryanodine receptor inhibition by calsequestrin is mediated by junctin. | Is there a relationship between junctin and ryanodine receptors? | 52b2f3b74003448f5500000c_000 | yes |
[Molecular genetics of the long QT syndrome: clinical aspects]. The long QT syndrome (LQTS) is a heart disorder which is characterised by the prolongation of the QT interval of the surface electrocardiogram and is associated with malignant arrhythmias, syncopal episodes, torsade de pointes form ventricular tachycardias and an increased risk of sudden cardiac death. There are two familial forms of LQTS, the autosomal dominant Romano-Ward syndrome and the autosomal recessive Jervell-Lange-Nielsen syndrome which is associated with congenital senzorineural deaf-mutism. Recent advances in molecular genetics have allowed to identify mutations in four genes, KvLQT1 (11p15.5), HERG (7q35), SCN5A (3p21) and minK (21q22), which cause LQTS. There is a fifth genetic locus known on chromosome 4 (4q25-27), where the disease causing gene has not been identified yet. As LQTS genes code proteins which form sodium and potassium channels of the heart, LQTS can be regarded as the disease of cardiac ion channels. The KvLQT1 and minK genes code the slowly activating, delayed rectifier (Iks) potassium channel, the HERG gene code the rapidly activating, delayed rectifier (Ikr) potassium channel of the heart, while the SCN5A gene codes a cardiac sodium channel. Mutations in KvLQT1, minK and HERG genes affects repolarising, rectifier potassium currents, while SCN5A mutations cause delayed inactivation and reopening of the cardiac sodium channel, which initiates the depolarisation of cardiac cells. Both alterations result in a prolongation of cardiac repolarisation which is represented in the elongation of the QT interval. Elucidation of the genetic base of the disease provided new tools in the clinical management of LQTS. It has been shown that changes in the repolarisation parameters on the ECG may be predictive for the causative gene and different LQTS genes are associated with different clinical picture. More importantly, it is possible to use "gene-specific" therapy in LQTS which specifically targets ion channels affected by given gene mutations. | Does the hERG gene code for a protein which is part of a sodium channel? | 58bdc76102b8c60953000013_010 | no |
Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: a systematic review to update the U.S. Preventive Services Task Force recommendation. BACKGROUND: Mutations in breast cancer susceptibility genes (BRCA1 and BRCA2) are associated with increased risks for breast, ovarian, and other types of cancer. PURPOSE: To review new evidence on the benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women. DATA SOURCES: MEDLINE and PsycINFO between 2004 and 30 July 2013, the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews from 2004 through the second quarter of 2013, Health Technology Assessment during the fourth quarter of 2012, Scopus, and reference lists. STUDY SELECTION: English-language studies about accuracy of risk assessment and benefits and harms of genetic counseling, genetic testing, and interventions to reduce cancer incidence and mortality. DATA EXTRACTION: Individual investigators extracted data on participants, study design, analysis, follow-up, and results, and a second investigator confirmed key data. Investigators independently dual-rated study quality and applicability by using established criteria. DATA SYNTHESIS: Five referral models accurately estimated individual risk for BRCA mutations. Genetic counseling increased the accuracy of risk perception and decreases the intention for genetic testing among unlikely carriers and cancer-related worry, anxiety, and depression. No trials evaluated the effectiveness of intensive screening or risk-reducing medications in mutation carriers, although false-positive rates, unneeded imaging, and unneeded surgeries were higher with screening. Among high-risk women and mutation carriers, risk-reducing mastectomy decreased breast cancer by 85% to 100% and breast cancer mortality by 81% to 100% compared with women without surgery; risk-reducing salpingo-oophorectomy decreased breast cancer incidence by 37% to 100%, ovarian cancer by 69% to 100%, and all-cause mortality by 55% to 100%. LIMITATION: The analysis included only English-language articles;efficacy trials in mutation carriers were lacking. CONCLUSION: Studies of risk assessment, genetic counseling, genetic testing, and interventions to reduce cancer and mortality indicate potential benefits and harms that vary according to risk. | Could BRCA gene test used for breast and ovarian cancer risk? | 58a6bce660087bc10a000029_017 | yes |
Activation of H-Ras and Rac1 correlates with epidermal growth factor-induced invasion in Hs578T and MDA-MB-231 breast carcinoma cells. There is considerable experimental evidence that hyperactive Ras proteins promote breast cancer growth and development including invasiveness, despite the low frequency of mutated forms of Ras in breast cancer. We have previously shown that H-Ras, but not N-Ras, induces an invasive phenotype mediated by small GTPase Rac1 in MCF10A human breast epithelial cells. Epidermal growth factor (EGF) plays an important role in aberrant growth and metastasis formation of many tumor types including breast cancer. The present study aims to investigate the correlation between EGF-induced invasiveness and Ras activation in four widely used breast cancer cell lines. Upon EGF stimulation, invasive abilities and H-Ras activation were significantly increased in Hs578T and MDA-MB-231 cell lines, but not in MDA-MB-453 and T47D cell lines. Using small interfering RNA (siRNA) to target H-Ras, we showed a crucial role of H-Ras in the invasive phenotype induced by EGF in Hs578T and MDA-MB-231 cells. Moreover, siRNA-knockdown of Rac1 significantly inhibited the EGF-induced invasiveness in these cells. Taken together, this study characterized human breast cancer cell lines with regard to the relationship between H-Ras activation and the invasive phenotype induced by EGF. Our data demonstrate that the activation of H-Ras and the downstream molecule Rac1 correlates with EGF-induced breast cancer cell invasion, providing important information on the regulation of malignant progression in mammary carcinoma cells. | Is Rac1 involved in cancer cell invasion? | 5319abc9b166e2b80600002d_009 | yes |
Bubonic and pneumonic plague - Uganda, 2006. Plague is a life-threatening fleaborne disease caused by the bacterium Yersinia pestis. The most common clinical form is bubonic plague, which is characterized by high fever and regional lymphadenitis. Without treatment, infection can spread from lymph nodes to the lungs, resulting in pneumonic plague and the potential for person-to-person transmission through respiratory droplets. In November 2006, the Uganda Ministry of Health received reports of an increase in bubonic plague cases and a possible outbreak of pneumonic plague among residents in the Arua and Nebbi districts. In response, the Uganda Ministry of Health and CDC conducted a joint investigation in the two districts during November 28-December 30, 2006. Overall, 127 clinical plague cases were identified, along with evidence of a focal pneumonic outbreak in Nebbi District. Median age of the patients was 14 years (range: 2 weeks-65 years); 65 (51%) were female. Twenty-eight (22%) of the 127 patients died. Among the 102 patients with documented symptoms, 90 (88%) had bubonic plague, and 12 (12%) had pneumonic plague. The results of this investigation underscore the need to 1) continue efforts to educate residents of rural Uganda regarding the source, signs, and symptoms of plague and the life-saving importance of seeking treatment; 2) strengthen plague surveillance and diagnostic capabilities; and 3) improve emergency response and vector-control capacity, especially in remote regions of the country. | Does Yersinia pestis causes a respiratory infection? | 58caf86f02b8c60953000030_008 | yes |
[Butterfly rash: no lupus]. A 61-year-old male patient presented with petechiae on the arms and legs due to a thrombocytopenia of 3 Gpt/l (3000/microl). A butterfly rash on the patient's face suggested a diagnosis of systemic lupus erythematosus (SLE). The thrombocytopenia was due to autoimmune thrombocytopenia. The diagnosis of SLE could be excluded and the butterfly rash attributed to a laminar hemorrhage, an ecchymosis due to the autoimmune thrombocytopenia. | Is butterfly rash a symptom of Systemic lupus erythematosus? | 58bfeb2b02b8c6095300001a_006 | yes |
A de novo KCNQ2 mutation detected in non-familial benign neonatal convulsions. BACKGROUND: The underlying genetic abnormalities of rare familial idiopathic epilepsy have been identified, such as mutation in KCNQ2, a K(+) channel gene. Yet, few genetic abnormalities have been reported for commoner epilepsy, i.e., sporadic idiopathic epilepsy, which share a phenotype similar to those of familial epilepsy. OBJECTIVE: To search for the genetic cause of seizures in a girl with the diagnosis of non-familial benign neonatal convulsions, and define the consequence of the genetic abnormality identified. METHODS: Genetic abnormality was explored within candidate genes for benign familial neonatal and infantile convulsions, such as KCNQ2, 3, 5, KCNE2, SCN1A and SCN2A. The electrophysiological properties of the channels harboring the identified mutation were examined. Western blotting and immunostaining were employed to characterize the expression and intracellular localization of the mutant channel molecules. RESULTS: A novel heterozygous mutation (c.910-2delTTC or TTT, Phe304del) of KCNQ2 was identified in the patient. The mutation was de novo verified by parentage analysis. The mutation was associated with impaired functions of KCNQ K(+) channel. The mutant channels were expressed on the cell surface. CONCLUSION: The mutant Phe304del of KCNQ2 leads to null function of the KCNQ K(+) channel but the mutation does not alter proper channel sorting onto the cell membrane. Our findings indicate that the genes responsible for rare inherited forms of idiopathic epilepsy could be also involved in sporadic forms of idiopathic epilepsy and expand our notion of the involvement of molecular mechanisms in the more common forms of idiopathic epilepsy. | Is the protein KCNQ2 associated with idiopathic epilepsy? | 56c30ce99d3e5f1412000002_006 | yes |
Analytical validation of the Oncotype DX genomic diagnostic test for recurrence prognosis and therapeutic response prediction in node-negative, estrogen receptor-positive breast cancer. BACKGROUND: Oncotype DX is a clinically validated, high-complexity, multianalyte reverse transcription-PCR genomic test that predicts the likelihood of breast cancer recurrence in early-stage, node-negative, estrogen receptor-positive breast cancer. The Recurrence Score (RS) provides a more accurate, reproducible measure of breast cancer aggressiveness and therapeutic responsiveness than standard measures. Individualized patient management requires strict performance criteria for clinical laboratory tests. We therefore investigated the analytical performance of the assay. METHODS: Assays used a pooled RNA sample from fixed paraffin-embedded tissues to evaluate the analytical performance of a 21-gene panel with respect to amplification efficiency, precision, linearity, and dynamic range, as well as limits of detection and quantification. Performance variables were estimated from assays carried out with sample dilutions. In addition, individual patient samples were used to test the optimized assay for reproducibility and sources of imprecision. RESULTS: Assay results defined acceptable operational performance ranges, including an estimated maximum deviation from linearity of <1 cycle threshold (C(T)) units over a > or =2000-fold range of RNA concentrations, with a mean quantification bias of 0.3% and CVs of 3.2%-5.7%. An analysis of study design showed that assay imprecision contributed by instrument, operator, reagent, and day-to-day baseline variation was low, with SDs of <0.5 C(T). CONCLUSION: The analytical and operational performance specifications defined for the Oncotype DX assay allow the reporting of quantitative RS values for individual patients with an SD within 2 RS units on a 100-unit scale. | Does the Oncotype DX test work with paraffin embedded tissues? | 514a0f0ad24251bc05000052_001 | yes |
Cytogenetic, FISH and array-CGH characterization of a complex chromosomal rearrangement carried by a mentally and language impaired patient. We describe a patient with an abnormal phenotype and a de novo CCR consisting of a reciprocal translocation between chromosomes 1 and 15 and an insertion of an interstitial segment from chromosome 2 within chromosome 1. The CCR was studied by QFQ banding and FISH. The apparently balanced rearrangement was further investigated with array-CGH, that uncovered three cryptic deletions on chromosome 2q. By means of BAC-FISH two deletions were located at the breakpoints of the insertion, at 2q14.3 and 2q31.2, and one at 2q22.2, in the region of 2q translocated on derivative 1. Consequently, in silico analysis of the deleted regions was performed. Among deleted genes, particularly interesting seems to be CNTNAP5, encoding a member of the neurexin superfamily. The three mouse orthologues are highly expressed in adult brain tissues. We speculate that loss of CNTNAP5 might contribute to the developmental language delay of this patient, similar to CNTNAP2, another member of the same protein family, whose alterations have been recently associated with delay in the age at first word in autistic patients. At clinical patient's evaluation, a Mowat-Wilson syndrome (MWS) like appearance was noted. The disease is caused by mutation or deletion of ZEB2 gene, located in our patient 794Kb distally to the 2q22.2 deletion, in the chromosome 2 segment inserted into the derivative 1. The loss of the gene has been excluded by the array-CGH results, but its proximity to the deleted segment and/or its insertion in a different genetic context might influence and consequently impair its expression. Our study confirms that array-CGH is a precious method to identify cryptic imbalances in CCR carriers and underlie the essential role of BAC-FISH as second step of analysis to assess the reciprocal position of the chromosomal segments involved in CCRs and the exact mapping of the imbalances. | Have mutations in the ZEB2 gene been found in any human syndrome? | 53552ed7f1005d6b58000001_034 | yes |
Use of mesenchymal stem cells for therapy of cardiac disease. Despite substantial clinical advances over the past 65 years, cardiovascular disease remains the leading cause of death in America. The past 15 years has witnessed major basic and translational interest in the use 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. The ability of mesenchymal stem cells to differentiate into mesoderm- and nonmesoderm-derived tissues, their immunomodulatory effects, their availability, and their key role in maintaining and replenishing endogenous stem cell niches have rendered them one of the most heavily investigated and clinically tested type of stem cell. 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. Here, we review the biology of mesenchymal stem cells, their interaction with endogenous molecular and cellular pathways, and their modulation of immune responses. Additionally, we discuss factors that enhance their proliferative and regenerative ability and factors that may hinder their effectiveness in the clinical setting. | Are there clinical trials using stem cells for the treatment of cardiac disease? | 56f160a52ac5ed1459000013_003 | yes |
The use of citrullinated peptides for the diagnosis and prognosis of rheumatoid arthritis. Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint inflammation and extra-articular manifestations. To prevent progressive and irreversible structural damage, early diagnosis of RA is of paramount importance. Antibodies directed against citrullinated proteins and peptides (ACPAs) are the most specific serological markers available for diagnosing RA. ACPAs may be detected several years before symptoms appear, and their presence at disease onset is a good predictor of the development of erosive joint lesions. Synthetic peptides can replace cognate proteins in solid-phase assays for specific autoantibody recognition in RA patients. The use of synthetic peptides instead of proteins represents an advantage in terms of the reproducibility of such immunoassays. They give absolute control over the exact epitopes presented. Furthermore, it is difficult to prepare sufficient amounts of high-quality antigenic proteins with a well-defined degree of citrullination. Synthetic citrullinated peptides, in contrast, are easily obtained in a pure form with a well-defined chemical structure and the epitopes can be precisely oriented in the plate by covalent binding of the peptides. We have recently obtained and highlighted the application of chimeric peptides bearing different citrullinated protein domains for the design of RA diagnosis systems. Our results indicate that more than one serological test is required to classify RA patients based on the presence or absence of ACPAs. Each of the target molecules reported (fibrin, vimentin and filaggrin) helps to identify a particular subset of RA patients. | Has protein citrullination been implicated in rheumatoid arthritis? | 54d796f93706e8952800001e_008 | yes |
Excisional surgery versus ablative surgery for ovarian endometriomata. BACKGROUND: Endometriomata are endometriotic deposits within the ovary. The surgical management of these blood filled cysts is controversial. The laparoscopic approach to the management of endometriomata is favoured over a laparotomy approach as it offers the advantage of a shorter hospital stay, faster patient recovery and decreased hospital costs. Currently the commonest procedures for the treatment of ovarian endometriomata are either excision of the cyst capsule or drainage and electrocoagulation of the cyst wall. OBJECTIVES: The objective of this review was to determine the most effective technique of treating an ovarian endometrioma; either excision of the cyst capsule or drainage and electrocoagulation of the cyst wall. The end-points assessed were the relief of pain, recurrence of the endometrioma, recurrence of symptoms and in women desiring to conceive the subsequent pregnancy rate, either spontaneous or as part of fertility treatment. SEARCH STRATEGY: The reviewers searched the Cochrane Menstrual Disorders and Subfertility Group specialised register of trials (searched 3rd March 2007), the Cochrane Register of Controlled Trials (The Cochrane Library, Issue 3, 2007), MEDLINE (1966-August 2007), EMBASE (1980- March 2007) and reference lists of articles, the handsearching of relevant journals and conference proceedings and by contacting leaders in the field of endoscopic surgery throughout the world. The Cochrane Menstrual Disorders and Subfertility Group Trials Register is based on regular searches of MEDLINE, EMBASE, CINHAL and CENTRAL. SELECTION CRITERIA: Randomised controlled trials of excision of the cyst capsule versus drainage and electrocoagulation of the cyst in the management of ovarian endometriomata. DATA COLLECTION AND ANALYSIS: Reviewers assessed eligibility and trial quality. MAIN RESULTS: No randomised studies of the management of endometriomata by laparotomy were found. Two randomised studies of the laparoscopic management of ovarian endometriomata of greater than 3cm in size, for the primary symptom of pain were included. Laparoscopic excision of the cyst wall of the endometrioma was associated with a reduced recurrence rate of the symptoms of dysmenorrhea (OR 0.15 CI 0.06-0.38), dyspareunia (OR 0.08 CI 0.01-0.51) and non-menstrual pelvic pain (OR 0.10 CI 0.02-0.56), a reduced rate of recurrence of the endometrioma (OR 0.41 CI 0.18-0.93) and with a reduced requirement for further surgery (OR 0.21 CI 0.05-0.79) than surgery to ablate the endometrioma. For those women subsequently attempting to conceive it was also associated with a subsequent increased spontaneous pregnancy rate in women who had documented prior sub-fertility (OR 5.21 CI 2.04-13.29). A further randomised study was identified that demonstrated an increased ovarian follicular response to gonadotrophin stimulation for women who had undergone excsional surgery when compared to ablative surgery (WMD 0.6 CI 0.04-1.16). There is insufficient evidence to favour excisional surgery over ablative surgery with respect to the chance of pregnancy after controlled ovarian stimulation and intra-uterine insemination (OR 1.40 CI 0.47-4.15) . AUTHORS' CONCLUSIONS: There is good evidence that excisional surgery for endometriomata provides for a more favourable outcome than drainage and ablation with regard to the recurrence of the endometrioma, recurrence of pain symptoms, and in women who were previously subfertile, subsequent spontaneous pregnancy . Consequently this approach should be the favoured surgical approach. However in women who may subsequently may undergo fertility treatment insufficient evidence exists to determine the favoured surgical approach. | Does surgery for ovarian endometriomas improve fertility? | 54f088ee94afd61504000015_005 | yes |
Decreased quality of life and depression as predictors for shorter survival among patients with low-grade gliomas: a follow-up from 1990 to 2003. OBJECTIVES: To assess the long-term survival of brain tumor patients, and in particular to evaluate the relation of quality of life (QOL) to survival among low-grade glioma patients. METHODS: The postoperative survival of 101 brain tumor patients was followed from surgery (1990-1992) until the end of the year 2003. Depression was evaluated by the Beck Depression Inventory (BDI) and QOL with Sintonen's 15D scale before operation and at one year as well as at five years after operation. RESULTS: The mean survival times in years (SD) were significantly related to tumor malignancy, being the shortest, 1.9 (0.6), for patients with high-grade gliomas, while patients with low-grade gliomas or a benign brain tumor had mean survival times of 9.1 (1.0) and 11.6 (0.5), respectively. At all follow-ups, depressed low-grade glioma patients had a significantly shorter survival time, 3.3-5.8 years, compared to non-depressed low-grade glioma patients, 10.0-11.7 years. A decreased level of QOL in low-grade glioma patients was significantly related to the shorter survival. CONCLUSIONS: The results suggest that depression and decreased QOL among low-grade glioma patients is related to shorter survival at long-term follow-up. Decreased QOL may serve as an indicator for poor prognosis in low-grade glioma patients. | Is depression associated with poor prognosis of brain tumor patients? | 514cc8dcd24251bc05000066_001 | yes |
Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30% of HGGs). To identify additional driver mutations in HGGs, we investigated a cohort of 60 pediatric HGGs using whole-exome sequencing (WES) and compared them to 543 exomes from non-cancer control samples. We identified mutations in SETD2, a H3K36 trimethyltransferase, in 15% of pediatric HGGs, a result that was genome-wide significant (FDR = 0.029). Most SETD2 alterations were truncating mutations. Sequencing the gene in this cohort and another validation cohort (123 gliomas from all ages and grades) showed SETD2 mutations to be specific to high-grade tumors affecting 15% of pediatric HGGs (11/73) and 8% of adult HGGs (5/65) while no SETD2 mutations were identified in low-grade diffuse gliomas (0/45). Furthermore, SETD2 mutations were mutually exclusive with H3F3A mutations in HGGs (P = 0.0492) while they partly overlapped with IDH1 mutations (4/14), and SETD2-mutant tumors were found exclusively in the cerebral hemispheres (P = 0.0055). SETD2 is the only H3K36 trimethyltransferase in humans, and SETD2-mutant tumors showed a substantial decrease in H3K36me3 levels (P < 0.001), indicating that the mutations are loss-of-function. These data suggest that loss-of-function SETD2 mutations occur in older children and young adults and are specific to HGG of the cerebral cortex, similar to the H3.3 G34R/V and IDH mutations. Taken together, our results suggest that mutations disrupting the histone code at H3K36, including H3.3 G34R/V, IDH1 and/or SETD2 mutations, are central to the genesis of hemispheric HGGs in older children and young adults. | Is there an association between Histone H3.3 mutations and glioma? | 5890ede0621ea6ff7e000007_005 | yes |
Biophysical interaction between phospholamban and protein phosphatase 1 regulatory subunit GM. Regulation of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA 2a) depends on the phosphorylation state of phospholamban (PLB). When PLB is phosphorylated, its inhibitory effect towards SERCA 2a is relieved, leading to an enhanced myocardial performance. This process is reversed by a sarcoplasmic reticulum (SR)-associated type 1 protein phosphatase (PP1) composed of a catalytic subunit PP1C and a regulatory subunit GM. Human GM and PLB have been produced in an in vitro transcription/translation system and used for co-immunoprecipitation and biosensor experiments. The detected interaction between the two partners suggests that cardiac PPI is targeted to PLB via GM and we believe that this process occurs with the identified transmembrane domains of the two proteins. Thus, the interaction between PLB and GM may represent a specific way to modulate the SR function in human cardiac muscle. | Is phospholamban a regulatory/inhibitory protein of the Ca ATPase SERCA? | 5501b3b3e9bde69634000007_003 | yes |
Cocaine, pregnancy, and postpartum intracerebral hemorrhage. An increase in cocaine abuse by pregnant women has been associated with a range of maternal/fetal cardiovascular complications. Intracerebral hemorrhage has been reported as a cocaine-related complication, but has not previously been associated with pregnancy. We report a case of cocaine-associated intracerebral hemorrhage in the postpartum period which complicated the differential diagnosis and management of hypertension and seizures. | Is cocaine use associated with increased risk for intracerebral hemorrhage? | 5159b990d24251bc050000a3_002 | yes |
[Type 1 diabetes impairs compensatory response after myocardial infarction; role of tissue hypothyroidism and effects of thyroid hormone administration]. Type 1 diabetes (TOD) increases the risk of coronary artery disease and myocardial infarction and is characterized by baseline cardiac dysfunction. We investigated the influence of TOD in post-infarct remodeling (REM) and the role of thyroid hormone (TH) signaling in this response. Acute myocardial infarction (AMI) was induced in rats with type I diabetes (TOD) and in non diabetic rats (NTOD-AMI), sham-operated rats serving as controls (SHAM). AMI resulted in tissue hypothyroidism due to significant downregulation of the TH receptors TRa1 and TRbeta1 in the TOD myocardium, while no change in plasma T3 or T4 was observed This response was associated with increased expression of beta-MHC and distinct changes in cardiac function and geometry: EF % was decreased in TOD-AMI as compared to NTOD-AMI. Systolic and diastolic chamber dimensions were increased, with no concomitant increase in wall thickness. Thus, WTI (the ratio of LVIDd/2 x posterior wall thickness), an index of wall stress, was significantly increased in TOD-AMI. The absence of wall thickening in TOD-AMI hearts was associated with changes in stretch-induced kinase hypertrophic signaling: phosporylated (p) ERK and p-p38 MAPK levels were not changed in TOD-AMI in comparison with non infarcted hearts (TOD-SHAM) and NTOD-A MI hearts. 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. | Does thyroid hormone affect cardiac remodeling? | 52efc041c8da89891000001b_002 | yes |
SWI/SNF has intrinsic nucleosome disassembly activity that is dependent on adjacent nucleosomes. The ATP-dependent chromatin remodeling complex SWI/SNF regulates transcription and has been implicated in promoter nucleosome eviction. Efficient nucleosome disassembly by SWI/SNF alone in biochemical assays, however, has not been directly observed. Employing a model system of dinucleosomes rather than mononucleosomes, we demonstrate that remodeling leads to ordered and efficient disassembly of one of the two nucleosomes. An H2A/H2B dimer is first rapidly displaced, and then, in a slower reaction, an entire histone octamer is lost. Nucleosome disassembly by SWI/SNF did not require additional factors such as chaperones or acceptors of histones. Observations in single molecules as well as bulk measurement suggest that a key intermediate in this process is one in which a nucleosome is moved toward the adjacent nucleosome. SWI/SNF recruited by the transcriptional activator Gal4-VP16 preferentially mobilizes the proximal nucleosome and destabilizes the adjacent nucleosome. | Is nucleosome eviction ATP-dependent? | 532ff558d6d3ac6a34000037_000 | yes |
[Fatal cerebral hemorrhage in young amphetamine addicts]. Abuse of amphetamine, cocaine and related compounds has become an important risk factor for intracerebral haemorrhage in young adults. Five fatal cases of intracerebral haemorrhage following use of amphetamine are described. The symptoms occurred few hours after amphetamine intake, and all patients had considerably increased blood pressure upon admission. Autopsy was performed on four of the patients and did not reveal any predisposing factors for haemorrhage, such as trauma, vascular malformations or vasculitis. Cerebral CT should always be performed when severe headache and/or altered consciousness occur in relation to abuse of amphetamine-like compounds. Intracerebral haemorrhage in young adults may indicate abuse of psychoactive drugs. | Is cocaine use associated with increased risk for intracerebral hemorrhage? | 5159b990d24251bc050000a3_019 | yes |
IL-27 inhibits epithelial-mesenchymal transition and angiogenic factor production in a STAT1-dominant pathway in human non-small cell lung cancer. BACKGROUND: Interleukin-27 signaling is mediated by the JAK-STAT pathway via activation of STAT1 and STAT3, which have tumor suppressive and oncogenic activities, respectively. Epithelial-mesenchymal transition (EMT) and angiogenesis are key processes in carcinogenesis. Although IL-27 has been shown to have potent anti-tumor activity in various cancer models, the role of IL-27 in EMT and angiogenesis is poorly understood. In this study, we investigated the role of IL-27 in regulating EMT and angiogenesis through modulation of the STAT pathways in human non-small cell lung carcinoma (NSCLC) cells. METHODS: STAT activation following IL-27 exposure was measured in human NSCLC cell lines. Expression of epithelial (E-cadherin, γ-catenin) and mesenchymal (N-cadherin, vimentin) markers were assessed by Western blot analysis. Production of pro-angiogenic factors (VEGF, IL-8/CXCL8, CXCL5) were examined by ELISA. Cell motility was examined by an in vitro scratch and transwell migration assays. Selective inhibitors of STAT1 (STAT1 siRNAs) and STAT3 (Stattic) were used to determine whether both STAT1 and STAT3 are required for IL-27 mediated inhibition of EMT and secretion of angiogenic factors. RESULTS: Our results demonstrate that IL-27 stimulation in NSCLC resulted in 1) STAT1 and STAT3 activation in a JAK-dependent manner, 2) development of epithelial phenotypes, including a decrease in the expression of a transcriptional repressor for E-cadherin (SNAIL), and mesenchymal marker (vimentin) with a reciprocal increase in the expression of epithelial markers, 3) inhibition of cell migration, and 4) reduced production of pro-angiogenic factors. STAT1 inhibition in IL-27-treated cells reversed the IL-27 effect with resultant increased expression of Snail, vimentin and the pro-angiogenic factors. The inhibition of STAT3 activation had no effect on the development of the epithelial phenotype. CONCLUSION: IL-27 induces mesenchymal to epithelial transition and inhibits the production of pro-angiogenic factors in a STAT1-dominant pathway. These findings highlight the importance of STAT1 in repressing lung carcinogenesis and describe a new anti-tumor mechanism of IL-27. | Is signal transducer and activator of transcription-3 (STAT3) critical for tumor angiogenesis progression? | 533d0f44c45e13371400000e_005 | yes |
Aspartic proteases of Plasmodium vivax are highly conserved in wild isolates. The plasmepsins are the aspartic proteases of malaria parasites. Treatment of aspartic protease inhibitor inhibits hemoglobin hydrolysis and blocks the parasite development in vitro suggesting that these proteases might be exploited their potentials as antimalarial drug targets. In this study, we determined the genetic variations of the aspartic proteases of Plasmodium vivax (PvPMs) of wild isolates. Two plasmepsins (PvPM4 and PvPM5) were cloned and sequenced from 20 P. vivax Korean isolates and two imported isolates. The sequences of the enzymes were highly conserved except a small number of amino acid substitutions did not modify key residues for the function or the structure of the enzymes. The high sequence conservations between the plasmepsins from the isolates support the notion that the enzymes could be reliable targets for new antimalarial chemotherapeutics. | Could plasmepsins be used as targets for developing anti-malaria drugs? | 58a6d89660087bc10a00002b_016 | yes |
Progesterone for acute traumatic brain injury. BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability. Progesterone is a potential neuroprotective drug to treat patients with TBI. OBJECTIVES: To assess the effectiveness and safety of progesterone in people with acute TBI. SEARCH METHODS: We searched: the Cochrane Injuries Group's Specialised Register (13 July 2012), Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 7, 2012), MEDLINE (Ovid) (1950 to August week 1, 2012), EMBASE (Ovid) (1980 to week 32 2012), LILACS (12 August 2012), Zetoc (13 July 2012), Clinicaltrials.gov (12 August 2012), Controlled-trials.com (12 August 2012). SELECTION CRITERIA: We included published and unpublished randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of people with acute TBI. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results to identify the full texts of potentially relevant studies for inclusion. From the results of the screened searches two review authors independently selected trials meeting the inclusion criteria, with no disagreement. MAIN RESULTS: Three studies were included with a total of 315 people. Two included studies were of high methodological quality, with low risk of bias in allocation concealment, blinding and incomplete outcome data. One study did not use blinding and had unclear risk of bias in allocation concealment and incomplete outcome data. All three studies reported the effects of progesterone on mortality. The pooled risk ratio (RR) for mortality at end of follow-up was 0.61, 95% confidence interval (CI) 0.40 to 0.93. Three studies measured disability and found the RR of death or severe disability in patients treated with progesterone to be 0.77, 95% CI 0.62 to 0.96. Data from two studies showed no difference in mean intracranial pressure or the rate of adverse and serious adverse events among people in either group. One study presented blood pressure and temperature data, and there were no differences between the people in the progesterone or control groups. There was no substantial evidence for the presence of heterogeneity. AUTHORS' CONCLUSIONS: Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required. | Is progesterone effective for treatment of patients with traumatic brain injury based on clinical trial data? | 54cf48acf693c3b16b00000b_012 | no |
Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury. RNA interference has tremendous yet unrealized potential to treat a wide range of illnesses. Innovative solutions are needed to protect and selectively deliver small interfering RNA (siRNA) cargo to and within a target cell to fully exploit siRNA as a therapeutic tool in vivo. Herein, we describe ammonium-functionalized carbon nanotube (fCNT)-mediated transport of siRNA selectively and with high efficiency to renal proximal tubule cells in animal models of acute kidney injury (AKI). fCNT enhanced siRNA delivery to tubule cells compared to siRNA alone and effectively knocked down the expression of several target genes, includingTrp53,Mep1b,Ctr1, andEGFP A clinically relevant cisplatin-induced murine model of AKI was used to evaluate the therapeutic potential of fCNT-targeted siRNA to effectively halt the pathogenesis of renal injury. Prophylactic treatment with a combination of fCNT/siMep1band fCNT/siTrp53significantly improved progression-free survival compared to controls via a mechanism that required concurrent reduction of meprin-1β and p53 expression. The fCNT/siRNA was well tolerated, and no toxicological consequences were observed in murine models. Toward clinical application of this platform, fCNTs were evaluated for the first time in nonhuman primates. The rapid and kidney-specific pharmacokinetic profile of fCNT in primates was comparable to what was observed in mice and suggests that this approach is amenable for use in humans. The nanocarbon-mediated delivery of siRNA provides a therapeutic means for the prevention of AKI to safely overcome the persistent barrier of nephrotoxicity during medical intervention. | Are there RNAi approaches considered for the treatment of kidney injury? | 5a74a4be0384be9551000004_000 | yes |
Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling. Activating mutations in genes of the Ras-mitogen-activated protein kinase (MAPK) pathway occur in approximately 30% of all human cancers; however, mutation of Ras alone is rarely sufficient to induce tumour development. Scribble is a polarity regulator recently isolated from a Drosophila screen for events that cooperate with Ras mutation to promote tumour progression and cell invasion. In mammals, Scribble regulates directed cell migration and wound healing in vivo; however, no role has been identified for mammalian Scribble in oncogenic transformation. Here we show that in human epithelial cells expressing oncogenic Ras or Raf, loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system. Further, we show that the mechanism by which this occurs is in the regulation of MAPK signalling by Scribble. The suppression of MAPK signalling is a highly conserved function of Scribble as it also prevents Raf-mediated defects in Drosophila wing development. Our data identify Scribble as an important mediator of MAPK signalling and provide a molecular basis for the observation that Scribble expression is decreased in many invasive human cancers. | Does SCRIB deregulation promote cancer? | 53314c98d6d3ac6a3400003b_008 | yes |
The Pla protease of Yersinia pestis degrades fas ligand to manipulate host cell death and inflammation. Pneumonic plague is a deadly respiratory disease caused by Yersinia pestis. The bacterial protease Pla contributes to disease progression and manipulation of host immunity, but the mechanisms by which this occurs are largely unknown. Here we show that Pla degrades the apoptotic signaling molecule Fas ligand (FasL) to prevent host cell apoptosis and inflammation. Wild-type Y. pestis, but not a Pla mutant (Δpla), degrades FasL, which results in decreased downstream caspase-3/7 activation and reduced apoptosis. Similarly, lungs of mice challenged with wild-type Y. pestis show reduced levels of FasL and activated caspase-3/7 compared to Δpla infection. Consistent with a role for FasL in regulating immune responses, Δpla infection results in aberrant proinflammatory cytokine levels. The loss of FasL or inhibition of caspase activity alters host inflammatory responses and enables enhanced Y. pestis outgrowth in the lungs. Thus, by degrading FasL, Y. pestis manipulates host cell death pathways to facilitate infection. | Does Yersinia pestis causes a respiratory infection? | 58caf86f02b8c60953000030_001 | yes |
Apremilast: A Phosphodiesterase 4 Inhibitor for the Treatment of Psoriatic Arthritis. INTRODUCTION: Psoriatic arthritis (PsA) is a spondyloarthritis that occurs in up to 30% of psoriasis patients. Patients with PsA are at risk for decreased quality of life due to both joint and skin symptoms, impaired physical function and disease progression. Treatments include non-steroidal anti-inflammatory drugs, conventional systemic disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate, and biologic agents, including tumor necrosis factor-α inhibitors. The most recently introduced treatment option is apremilast, an oral phosphodiesterase 4 inhibitor. METHODS: This review provides an in-depth discussion of apremilast's mechanism of action, and evidence of its clinical efficacy and safety from the Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) phase III pivotal clinical trials (PALACE 1, 2, and 3). RESULTS: These trials demonstrate that apremilast is effective for the treatment of active PsA, despite prior conventional DMARDs or biologic treatment. The primary efficacy end point, a 20% improvement from baseline in modified American College of Rheumatology response criteria at Week 16, was achieved by significantly greater proportions of patients treated with apremilast 20 mg twice daily (BID) and apremilast 30 mg BID versus placebo in PALACE 1, 2, and 3. Improvements in this and other clinical and patient-reported end points, including swollen and tender joint counts, Psoriasis Area and Severity Index score, physical function, and quality of life, were maintained, extending over 52 weeks of treatment among patients initially randomized to apremilast. Apremilast's safety profile has been acceptable, with diarrhea and nausea being the most common adverse events, with no evidence for an increased risk of infection or need for laboratory monitoring. The PALACE pivotal data indicate that apremilast presents a new option for the treatment of PsA that may be appropriate for use early in the treatment ladder. Ongoing PALACE open-label extension trials of up to 4 years will characterize the long-term clinical effects and safety of apremilast therapy. FUNDING: Celgene Corporation, Summit, NJ, USA. | Is apremilast effective for psoriatic arthritis? | 5896e22078275d0c4a000014_002 | yes |
Lenalidomide in combination with dexamethasone for the treatment of multiple myeloma after one prior therapy. PURPOSE: Lenalidomide (CC-5013, Revlimid; Celgene Corporation, Summit, NJ), a thalidomide analogue, was granted approval by the U.S. Food and Drug Administration (FDA) on June 29, 2006, for use in combination with dexamethasone in patients with multiple myeloma (MM) who have received at least one prior therapy. The FDA approved lenalidomide with a restricted distribution program, RevAssist. EXPERIMENTAL DESIGN: In two randomized, double-blind, multicenter studies, the combination of lenalidomide and dexamethasone (LD) was compared with placebo and dexamethasone (PD) in patients with MM who had received at least one prior therapy. The primary endpoint was time to progression (TTP). RESULTS: Following a prespecified interim analysis of TTP, an independent data-monitoring committee advised the sponsor to halt the two studies. For both studies, the interim analysis for efficacy revealed a statistically significant longer TTP with LD than with PD. The most clinically relevant grade 3 and 4 adverse events that occurred more frequently in the LD arm were neutropenia, thrombocytopenia, deep vein thrombosis, pulmonary embolism, and atrial fibrillation. Thrombotic or thromboembolic events, including deep vein thrombosis, pulmonary embolism, thrombosis, and intracranial venous sinus thrombosis were reported more frequently in patients treated with LD than with PD. CONCLUSIONS: The FDA approved lenalidomide based on interim results from two multicenter, placebo-controlled, randomized trials comparing the combination of LD with PD that revealed a longer TTP with LD than with PD. The major toxicity observed during these trials was myelosuppression. The serious toxicities included thromboembolic events. Lenalidomide is only available under the RevAssist Program. | Has Revlimid been approved by the US Food and Drug Administration? | 56ed0ba22ac5ed1459000007_005 | yes |
Three dimensional structural studies of alpha-N-acetylgalactosaminidase (alpha-NAGA) in alpha-NAGA deficiency (Kanzaki disease): different gene mutations cause peculiar structural changes in alpha-NAGAs resulting in different substrate specificities and clinical phenotypes. BACKGROUND: Kanzaki disease (OMIM#104170) is attributable to a deficiency in alpha-N-acetylgalactosaminidase (alpha-NAGA; E.C.3.2.1.49), which hydrolyzes GalNAcalpha1-O-Ser/Thr. Missense mutations, R329W or R329Q were identified in two Japanese Kanzaki patients. Although they are on the same codon, the clinical manifestation was more severe in R329W because an amino acid substitution led to protein instability resulting in structural change, which is greater in R329W than in R329Q. OBJECTIVE: To examine whether the different clinical phenotypes are attributable to the two mutations. METHODS: Plasma alpha-NAGA activity and urinary excreted glycopeptides were measured and three-dimensional models of human alpha-NAGA and its complexes with GalNAcalpha1-O-Ser and GalNAcalpha1-O-Thr were constructed by homology modeling. RESULTS: Residual enzyme activity was significantly higher in the R329Q- than the R329W mutant (0.022+/-0.005 versus 0.005+/-0.001 nmol/h/ml: p<0.05); the urinary ratios of GalNAcalpha1-O-Ser:GalNAcalpha1-O-Thr were 2:10 and 8:10, respectively. GalNAcalpha1-O-Ser/Thr fit tightly in a narrow space of the active site pocket of alpha-NAGA. GalNAcalpha1-O-Thr requires a larger space to associate with alpha-NAGA because of the side chain (CH3) of the threonine residue. CONCLUSION: Our findings suggest that the association of alpha-NAGA with its substrates is strongly affected by the amino acid substitution at R329 and that the association with GalNAcalpha1-O-Thr is more highly susceptible to structural changes. The residual mutant enzyme in R329W could not associate with GalNAcalpha1-O-Thr and GalNAcalpha1-O-Ser. However, the residual mutant enzyme in R329Q catalyzed GalNAcalpha1-O-Ser to some extent. Therefore, the urinary ratio of GalNAcalpha1-O-Ser:GalNAcalpha1-O-Thr was lower and the clinical phenotype was milder in the R329Q mutation. Structural analysis revealed biochemical and phenotypic differences in these Kanzaki patients with the R329Q and R329W mutation. | Is Kanzaki disease associated with deficiency in alpha-N-acetylgalactosaminidase? | 56f7c44109dd18d46b000013_001 | yes |
Visceral hypersensitivity in endometriosis: a new target for treatment? OBJECTIVE: In women presenting to gynaecological clinics with lower abdominal pain, the cause is frequently attributed to endometriosis irrespective of whether it is found to be minimal or extensive at laparoscopy. Irritable bowel syndrome (IBS) is also common in this setting, and it was speculated that the visceral hypersensitivity associated with this condition might be amplifying the symptoms of endometriosis. METHODS: Visceral sensitivity to balloon distension, symptoms and psychological status were assessed following laparoscopy in 20 women with minimal to mild endometriosis, 20 with moderate to severe endometriosis, 20 with laparoscopy negative abdominal pain and 20 asymptomatic women undergoing laparoscopic sterilisation who acted as controls, and compared with 20 women with IBS. RESULTS: Compared with controls, patients with minimal to mild and moderate to severe endometriosis had a higher prevalence of symptoms consistent with IBS (0% vs 65% and 50%, respectively, p<0.001) with significantly lower mean pain thresholds (39.5 mm Hg (95% CI 36.0 to 43.0) vs 28.1 mm Hg (95% CI 24.5 to 31.6), p=0.001 and 28.8 mm Hg (95% CI 24.9 to 32.6), p=0.002) not explained by differences in rectal compliance. Patients with laparoscopy negative pain had symptoms and visceral sensitivity similar to patients with IBS. Controls undergoing laparoscopy had normal sensitivity, indicating that the laparoscopic procedure was not inducing hypersensitivity. CONCLUSION: Visceral hypersensitivity is extremely common in endometriosis and could be intensifying the pain. This finding might explain why mildly affected individuals often complain of severe symptoms out of proportion to the extent of their disease. This study has introduced a completely new concept into the understanding of pain in endometriosis and could open up new opportunities for treatment. | Is irritable bowel syndrome more common in women with endometriosis? | 54f08d4a94afd61504000016_003 | yes |
Effects of sorafenib on energy metabolism in breast cancer cells: role of AMPK-mTORC1 signaling. In this study, we investigated the effects and the underlying molecular mechanisms of the multi-kinase inhibitor sorafenib in a panel of breast cancer cell lines. Sorafenib inhibited cell proliferation and induced apoptosis through the mitochondrial pathway. These effects were neither correlated with modulation of MAPK and AKT pathways nor dependent on the ERα status. Sorafenib promoted an early perturbation of mitochondrial function, inducing a deep depolarization of mitochondrial membrane, associated with drop of intracellular ATP levels and increase of ROS generation. As a response to this stress condition, the energy sensor AMPK was rapidly activated in all the cell lines analyzed. In MCF-7 and SKBR3 cells, AMPK enhanced glucose uptake by up-regulating the expression of GLUT-1 glucose transporter, as also demonstrated by AMPKα1 RNA interference, and stimulated aerobic glycolysis thus increasing lactate production. Moreover, the GLUT-1 inhibitor fasentin blocked sorafenib-induced glucose uptake and potentiated its cytotoxic activity in SKBR3 cells. Persistent activation of AMPK by sorafenib finally led to the impairment of glucose metabolism both in MCF-7 and SKBR3 cells as well as in the highly glycolytic MDA-MB-231 cells, resulting in cell death. This previously unrecognized long-term effect of sorafenib was mediated by AMPK-dependent inhibition of the mTORC1 pathway. Suppression of mTORC1 activity was sufficient for sorafenib to hinder glucose utilization in breast cancer cells, as demonstrated by the observation that the mTORC1 inhibitor rapamycin induced a comparable down-regulation of GLUT-1 expression and glucose uptake. The key role of AMPK-dependent inhibition of mTORC1 in sorafenib mechanisms of action was confirmed by AMPKα1 silencing, which restored mTORC1 activity conferring a significant protection from cell death. This study provides insights into the molecular mechanisms driving sorafenib anti-tumoral activity in breast cancer, and supports the need for going on with clinical trials aimed at proving the efficacy of sorafenib for breast cancer treatment. | Can sorafenib activate AMPK? | 56c8318f5795f9a73e00000f_001 | yes |
A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55). BACKGROUND: Autosomal recessive hereditary spastic paraplegias (AR-HSP) constitute a heterogeneous group of neurodegenerative diseases involving pyramidal tracts dysfunction. The genes responsible for many types of AR-HSPs remain unknown. We attempted to identify the gene responsible for AR-HSP with optic atrophy and neuropathy. METHODS: The present study involved two patients in a consanguineous Japanese family. Neurologic examination and DNA analysis were performed for both patients, and a skin biopsy for one. We performed genome-wide linkage analysis involving single nucleotide polymorphism arrays, copy-number variation analysis, and exome sequencing. To clarify the mitochondrial functional alteration resulting from the identified mutation, we performed immunoblot analysis, mitochondrial protein synthesis assaying, blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis, and respiratory enzyme activity assaying of cultured fibroblasts of the patient and a control. RESULTS: We identified a homozygous nonsense mutation (c.394C>T, p.R132X) in C12orf65 in the two patients in this family. This C12orf65 mutation was not found in 74 Japanese AR-HSP index patients without any mutations in previously known HSP genes. This mutation resulted in marked reduction of mitochondrial protein synthesis, followed by functional and structural defects in respiratory complexes I and IV. CONCLUSIONS: This novel nonsense mutation in C12orf65 could cause AR-HSP with optic atrophy and neuropathy, resulting in a premature stop codon. The truncated C12orf65 protein must lead to a defect in mitochondrial protein synthesis and a reduction in the respiratory complex enzyme activity. Thus, dysfunction of mitochondrial translation could be one of the pathogenic mechanisms underlying HSPs. | Have C12orf65 mutations been associated with axonal neuropathy and optic atrophy? | 5713c7dd1174fb1755000014_001 | yes |
Scalp fibroblasts have a shared expression profile in monogenic craniosynostosis. BACKGROUND: Craniosynostosis can be caused by both genetic and environmental factors, the relative contributions of which vary between patients. Genetic testing identifies a pathogenic mutation or chromosomal abnormality in ∼ 21% of cases, but it is likely that further causative mutations remain to be discovered. OBJECTIVE: To identify a shared signature of genetically determined craniosynostosis by comparing the expression patterns in three monogenic syndromes with a control group of patients with non-syndromic sagittal synostosis. METHODS: Fibroblasts from 10 individuals each with Apert syndrome (FGFR2 substitution S252W), Muenke syndrome (FGFR3 substitution P250R), Saethre-Chotzen syndrome (various mutations in TWIST1) and non-syndromic sagittal synostosis (no mutation detected) were cultured. The relative expression of ∼ 47,000 transcripts was quantified on Affymetrix arrays. RESULTS: 435, 45 and 46 transcripts were identified in the Apert, Muenke and Saethre-Chotzen groups, respectively, that differed significantly from the controls. Forty-six of these transcripts were shared between two or more syndromes and, in all but one instance, showed the same direction of altered expression level compared with controls. Pathway analysis showed over-representation of the shared transcripts in core modules involving cell-to-cell communication and signal transduction. Individual samples from the Apert syndrome cases could be reliably distinguished from non-syndromic samples based on the gene expression profile, but this was not possible for samples from patients with Muenke and Saethre-Chotzen syndromes. CONCLUSIONS: Common modules of altered gene expression shared by genetically distinct forms of craniosynostosis were identified. Although the expression profiles cannot currently be used to classify individual patients, this may be overcome by using more sensitive assays and sampling additional tissues. | Is there an association between Muenke Syndrome and FGFR3 gene mutation? | 5895ec5e7d9090f353000015_000 | yes |
Immunohistochemistry of small round-cell tumors. The term "small round-cell tumor" describes a group of highly aggressive malignant tumors composed of relatively small and monotonous undifferentiated cells with high nuclear to cytoplasmic ratios. This group includes Ewing's sarcoma (ES), peripheral neuroepithelioma (aka, primitive neuroectodermal tumor or extraskeletal ES), peripheral neuroblastoma ("classic-type"), rhabdomyosarcoma, desmoplastic small round-cell tumor, lymphoma, leukemia, small-cell osteosarcoma, small-cell carcinoma (either undifferentiated or neuroendocrine), olfactory neuroblastoma, cutaneous neuroendocrine carcinoma (aka, Merkel-cell carcinoma), small-cell melanoma, and mesenchymal chondrosarcoma. Their clinical presentations often overlap, thus making a definitive diagnosis problematic in some cases. Yet, a clear understanding of their clinicopathologic features usually allows for a confident diagnosis, especially if immunohistochemistry is used. The following is a review of the immunohistochemistry of this small round-cell tumor group. | Is peripheral neuroepithelioma related to Ewing sarcoma? | 552fa6f5bc4f83e828000002_010 | yes |
Clinical follow-up of hydroxyurea-treated adults with sickle cell disease. Hydroxyurea-derived clinical and biological benefits and safety were retrospectively studied for 123 adult patients from 2 sickle cell disease referral centers during a total follow-up of 654 patient-years and total hydroxyurea exposure of 549 patient-years. Fifty-six adverse events occurred (incidence: 12%/patient-year), with leg ulcers being the most frequent. Adverse events could arise at any time and were usually reversible. No malignancy was observed. Clinical and biological benefits of our cohort were similar to those previously reported. Based on this relatively long retrospective study, the risk/benefit ratio for moderate hydroxyurea doses was satisfactory. | Is hydroxyurea usually used to treated infectious disease? | 58dbbdac8acda3452900001e_000 | no |
Apoptotic abscess imaging with 99mTc-HYNIC-rh-Annexin-V. Abscess formation causes systemic and localized up-regulation of neutrophil [polymorphonuclear leukocytes (PMNs)] signaling pathways. In the abscess, following bacterial ingestion or PMN activation by inflammatory mediators, PMN apoptosis is elevated and leads to the externalization of phosphatidylserine. Annexin-V (AnxV) has been shown to have high affinity to externalized phosphatidylserine. We hypothesized that (99m)Tc-AnxV will target high densities of apoptotic PMNs and image abscesses. AnxV, conjugated with hydrazinenicaotinamide (HYNIC), was labeled with reduced (99m)TcO(4)(-) and its purity was determined by instant thin-layer chromatography. Apoptosis was induced in isolated human PMNs by incubation in 2% saline for 17 and 22 h at 37 degrees C. PMNs were then incubated with (99m)Tc-HYNIC-AnxV and associated (99m)Tc was determined. Abscesses were induced in mice by intramuscular injection of bacteria or turpentine. Following intravenous administration of (99m)Tc-HYNIC-AnxV, mice were imaged and tissue distribution studied at 4 and 24 h. Radiochemical purity of (99m)Tc-HYNIC-AnxV was 84.9+/-8.11%. At 17 h, (99m)Tc-HYNIC-AnxV bound to apoptotic PMNs was 71.6+/-0.01% and 48.6+/-0.01% for experimental and control cells, respectively (P=.002). At 22 h, experimental cells retained 74.9+/-0.02% and control cells retained 47.2+/-0.02% (P=.005). (99m)Tc-HYNIC-AnxV associated with bacterial abscesses was 1.25+/-0.09 and 3.75+/-0.83 percent injected dose per gram (%ID/g) at 4 and 24 h compared to turpentine abscesses which was 1.02+/-0.16 and 0.72+/-0.17 %ID/g at 4 (P<or=.05) and 24 h (P<or=.01). (99m)Tc-HYNIC-AnxV represents a minimally invasive and promising agent to image and potentially distinguish between infectious and inflammatory abscesses. | Is Annexin V an apoptotic marker? | 5894597e7d9090f353000004_015 | yes |
Circular RNA: A new star of noncoding RNAs. Circular RNAs (circRNAs) are a novel type of RNA that, unlike linear RNAs, form a covalently closed continuous loop and are highly represented in the eukaryotic transcriptome. Recent studies have discovered thousands of endogenous circRNAs in mammalian cells. CircRNAs are largely generated from exonic or intronic sequences, and reverse complementary sequences or RNA-binding proteins (RBPs) are necessary for circRNA biogenesis. The majority of circRNAs are conserved across species, are stable and resistant to RNase R, and often exhibit tissue/developmental-stage-specific expression. Recent research has revealed that circRNAs can function as microRNA (miRNA) sponges, regulators of splicing and transcription, and modifiers of parental gene expression. Emerging evidence indicates that circRNAs might play important roles in atherosclerotic vascular disease risk, neurological disorders, prion diseases and cancer; exhibit aberrant expression in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC); and serve as diagnostic or predictive biomarkers of some diseases. Similar to miRNAs and long noncoding RNAs (lncRNAs), circRNAs are becoming a new research hotspot in the field of RNA and could be widely involved in the processes of life. Herein, we review the formation and properties of circRNAs, their functions, and their potential significance in disease. | Are circRNAs associated with diseases and traits? | 56b73c7a345adcac48000002_001 | yes |
Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. BACKGROUND: Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known. METHODS: We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib. RESULTS: Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia. CONCLUSIONS: Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.). | Is selumetinib effective in thyroid cancer? | 56c1f00aef6e39474100003d_000 | yes |
Myocardial response to a triathlon in male athletes evaluated by Doppler tissue imaging and biochemical parameters. The aim of this study was to examine cardiac dysfunction following ultra-endurance exercise in male athletes. Fourteen athletes (mean+/-SD, age 39+/-8 years) were evaluated before and after the European Championship in Triathlon 2003 using echocardiogram (ECG), cardiac markers [cardiac troponin T (cTnT) and pro-brain natriuretic peptide (pro-BNP)] and echocardiography. Conventional echocardiography techniques and new Doppler tissue imaging (DTI) modalities were applied before and immediately after the competition. Blood samples were drawn 1 week before, immediately after and 12-24 h post-competition. CTnT significantly increased immediately, but decreased to within normal limits 12-24 h post-competition. Pro-BNP was significantly increased immediately post-race (27+/-21 vs 7+/-2 pmol/L pre-race, P < or = 0.007), which 12-24 h later, decreased to 19+/-14 pmol/L (P = 0.07 vs pre-race). During echocardiography, no significant differences were found in regional or global systolic parameters. Early diastolic peak flow velocity (9+/-2, P = 0.04) and E/A ratio (2+/-1, P = 0.004) were increased pre-race and decreased significantly toward normal values. In one athlete, cTnT levels increased significantly and systolic velocities decreased, thus suggesting reversible cardiac fatigue. When using cardiac markers and echocardiographic findings, a triathlon was found to have no significant negative effects on left ventricular function or myocardial tissue in male athletes. | Does BNP increase after intensive exercise in athletes? | 531d2aa5267d7dd053000003_009 | yes |
How cohesin and CTCF cooperate in regulating gene expression. Cohesin is a DNA-binding protein complex that is essential for sister chromatid cohesion and facilitates the repair of damaged DNA. In addition, cohesin has important roles in regulating gene expression, but the molecular mechanisms of this function are poorly understood. Recent experiments have revealed that cohesin binds to the same sites in mammalian genomes as the zinc finger transcription factor CTCF. At a few loci CTCF has been shown to function as an enhancer-blocking transcriptional insulator, and recent observations indicate that this function depends on cohesin. Here we review what is known about the roles of cohesin and CTCF in regulating gene expression in mammalian cells, and we discuss how cohesin might mediate the insulator function of CTCF. | Does the CTCF protein co-localize with cohesin? | 5344310baeec6fbd0700000c_006 | yes |
A pathogenetic role for endothelin-1 in peritoneal dialysis-associated fibrosis. In patients undergoing peritoneal dialysis (PD), chronic exposure to nonphysiologic PD fluids elicits low-grade peritoneal inflammation, leading to fibrosis and angiogenesis. Phenotype conversion of mesothelial cells into myofibroblasts, the so-called mesothelial-to-mesenchymal transition (MMT), significantly contributes to the peritoneal dysfunction related to PD. A number of factors have been described to induce MMT in vitro and in vivo, of which TGF-β1 is probably the most important. The vasoconstrictor peptide endothelin-1 (ET-1) is a transcriptional target of TGF-β1 and mediates excessive scarring and fibrosis in several tissues. This work studied the contribution of ET-1 to the development of peritoneal damage and failure in a mouse model of PD. ET-1 and its receptors were expressed in the peritoneal membrane and upregulated on PD fluid exposure. Administration of an ET receptor antagonist, either bosentan or macitentan, markedly attenuated PD-induced MMT, fibrosis, angiogenesis, and peritoneal functional decline. Adenovirus-mediated overexpression of ET-1 induced MMT in human mesothelial cells in vitro and promoted the early cellular events associated with peritoneal dysfunction in vivo. Notably, TGF-β1-blocking peptides prevented these actions of ET-1. Furthermore, a positive reciprocal relationship was observed between ET-1 expression and TGF-β1 expression in human mesothelial cells. These results strongly support a role for an ET-1/TGF-β1 axis as an inducer of MMT and subsequent peritoneal damage and fibrosis, and they highlight ET-1 as a potential therapeutic target in the treatment of PD-associated dysfunction. | Is macitentan an ET agonist? | 56c863385795f9a73e000015_003 | no |
SDH5 mutations and familial paraganglioma: somewhere Warburg is smiling. Paragangliomas have been linked to mutations affecting the succinate dehydrogenase complex. In a recent issue of Science, Rutter and coworkers showed that SDH5 is required for the flavination of SDHA, which is necessary for SDH assembly and function. Moreover, they detected SDH5 mutations in a large kindred with familial paraganglioma. | Is the SDHAF2 gene encoding a protein necessary for flavination of SDHA? | 5717fb557de986d80d000009_002 | yes |
INTRAGO: intraoperative radiotherapy in glioblastoma multiforme - a phase I/II dose escalation study. BACKGROUND: Glioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor in adults. Despite multimodal therapies, almost all GBM recur within a narrow margin around the initial resected lesion. Thus, novel therapeutic intensification strategies must target both, the population of dispersed tumor cells around the cavity and the postoperative microenvironment. Intraoperative radiotherapy (IORT) is a pragmatic and effective approach to sterilize the margins from persistent tumor cells, abrogate post-injury proliferative stimuli and to bridge the therapeutic gap between surgery and radiochemotherapy. Therefore, we have set up INTRAGO, a phase I/II dose-escalation study to evaluate the safety and tolerability of IORT added to standard therapy in newly diagnosed GBM. In contrast to previous approaches, the study involves the application of isotropic low-energy (kV) x-rays delivered by spherical applicators, providing optimal irradiation properties to the resection cavity. METHODS/DESIGN: INTRAGO includes patients aged 50 years or older with a Karnofsky performance status of at least 50% and a histologically confirmed (frozen sections) supratentorial GBM. Safety and tolerability (i.e., the maximum tolerated dose, MTD) will be assessed using a classical 3 + 3 dose-escalation design. Dose-limiting toxicities (DLT) are wound healing deficits or infections requiring surgical intervention, IORT-related cerebral bleeding or ischemia, symptomatic brain necrosis requiring surgical intervention and early termination of external beam radiotherapy (before the envisaged dose of 60 Gy) due to radiotoxicity. Secondary end points are progression-free and overall survival. TRIAL REGISTRATION: The study is registered with clinicaltrials.gov, number: NCT02104882 (Registration Date: 03/26/2014). | Is intraoperative radiotherapy used for treatment of glioblastoma? | 589a245478275d0c4a000022_004 | no |
Proteomic analysis of formalin-fixed prostate cancer tissue. Proteomic analysis of formalin-fixed paraffin-embedded (FFPE) tissue would enable retrospective biomarker investigations of this vast archive of pathologically characterized clinical samples that exist worldwide. These FFPE tissues are, however, refractory to proteomic investigations utilizing many state of the art methodologies largely due to the high level of covalently cross-linked proteins arising from formalin fixation. A novel tissue microdissection technique has been developed and combined with a method to extract soluble peptides directly from FFPE tissue for mass spectral analysis of prostate cancer (PCa) and benign prostate hyperplasia (BPH). Hundreds of proteins from PCa and BPH tissue were identified, including several known PCa markers such as prostate-specific antigen, prostatic acid phosphatase, and macrophage inhibitory cytokine-1. Quantitative proteomic profiling utilizing stable isotope labeling confirmed similar expression levels of prostate-specific antigen and prostatic acid phosphatase in BPH and PCa cells, whereas the expression of macrophage inhibitory cytokine-1 was found to be greater in PCa as compared with BPH cells. | Is it possible to determine the proteome of a formalin fixed and paraffin embedded (FFPE) tissue? | 511a1e12df1ebcce7d000009_001 | yes |
Analysis of leaky viral translation termination codons in vivo by transient expression of improved beta-glucuronidase vectors. Plant RNA viruses commonly exploit leaky translation termination signals in order to express internal protein coding regions. As a first step to elucidate the mechanism(s) by which ribosomes bypass leaky stop codons in vivo, we have devised a system in which readthrough is coupled to the transient expression of beta-glucuronidase (GUS) in tobacco protoplasts. GUS vectors that contain the stop codons and surrounding nucleotides from the readthrough regions of several different RNA viruses were constructed and the plasmids were tested for the ability to direct transient GUS expression. These studies indicated that ribosomes bypass the leaky termination sites at efficiencies ranging from essentially 0 to ca. 5% depending upon the viral sequence. The results suggest that the efficiency of readthrough is determined by the sequence surrounding the stop codon. We describe improved GUS expression vectors and optimized transfection conditions which made it possible to assay low-level translational events. | Is stop codon bypass possible? | 52f77f892059c6d71c00002c_004 | yes |
Urinary calculi and jejunoileal bypass operation. A long-term follow-up. Medical records of 56 patients who had undergone jejunoileal bypass (JIB) surgery because of morbid obesity were reviewed. The follow-up time varied from 3 to 25 years (average 16 years). Twenty-two of the 56 patients (39.3%) were found to have renal calculi. The interval between the operation and the occurrence or knowledge of the first stone formation ranged from some months to 19 years. The mean weight loss at 5 years was 36.5 kg. Renal function investigations showed no evidence that the jejunoileal bypass operation alters the renal function. 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). There was no difference in these respects between stone formers and non-stone formers. | Is oxalate renal excretion increased after bariatric surgery? | 52df887498d023950500000c_003 | yes |
Endocytosis and transcytosis of gliadin peptides. BACKGROUND: Celiac disease (CD) is a frequent inflammatory intestinal disease, with a genetic background, caused by gliadin-containing food. Some gliadin peptides are not digested by intestinal proteases and can have different biological effects. Gliadin peptides can induce innate and adaptive T cell-mediated immune responses. The major mediator of the stress and innate immune response to gliadin peptides (i.e., peptides 31-43 and 31-55) is the cytokine interleukin-15 (IL-15). Other peptides such as the 33 mer containing the P57-68 sequence, after tissue transglutaminase deamidation, are well presented to T cell in the intestine and can induce an adaptive immune response. FINDINGS: In this paper, we review the recent studies on the digestion of gliadin and the peptides released by the digestion process. We will also discuss the mechanisms responsible for the internalization and transcytosis of indigested gliadin peptides in the intestinal epithelium. CONCLUSIONS: Gliadin is not completely digested by the intestinal proteases producing bioactive peptides that have different biological effects. These peptides are internalized in the cells by an active process of endocytosis and can traverse the intestinal mucosa with different kinetics and immunological effects. In vivo findings will also be discussed. | Is celiac disease caused by gliadin-induced transglutaminase-2 (TG2)-dependent events ? | 5a79d195faa1ab7d2e00000e_001 | yes |
Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban. The new oral anticoagulants dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) have predictable pharmacokinetic and pharmacodynamic profiles and are alternatives to warfarin. However, many physicians are wary of these drugs, since there is limited evidence on how to manage bleeding in patients taking them, and since no specific antidote is known to reverse their anticoagulant effect. Management requires careful adherence to first principles of bleeding care. Unapproved and untested reversal strategies may be required in patients with life-threatening bleeding. | Are there any specific antidotes for dabigatran? | 532f08dcd6d3ac6a3400002a_002 | no |
[On the effect of mutations of the fibroblast growth factor receptors as exemplified by three cases of craniosynostoses]. PURPOSE: Craniosynostoses are premature ossifications of cranial sutures. They occur isolated and syndromic. Syndromic craniosynostoses are mainly associated with mutations of the Fibroblast Growth Factor Receptors (FGFR) 1 - 3. This paper gives an overview of the etiology and pathophysiology of isolated and syndromic craniosynostoses and discusses the molecular genetic results in 21 index cases (19 seemingly isolated craniosynostoses, 2 cases with a clinical diagnosis of Crouzon's syndrome). METHOD: Mutation analysis in exons of the FGFR 1 - 3 known to be preferentially affected in craniosynostoses was performed on DNA samples from peripheral blood and bone specimen excised at the time of surgery to correct the craniosynostosis. RESULTS: In a girl with seemingly isolated plagiocephaly we identified a P250L (749C-->T) mutation in FGFR3. Her mother showed minor signs of craniosynostosis when the family was re-evaluated. She was shown to carry the same mutation. In two patients with suspected Crouzon's syndrome 2 different mutations were detected at the same nucleotide (1025G-->A or C) and confirmed the clinical diagnosis. No mutation was found in 18/19 seemingly isolated craniosynostosis cases. CONCLUSION: In contrast to syndromic forms isolated craniosynostoses are rarely associated with mutations in FGFR. The affection of further family members is a strong indication of involvement of FGFR mutations. Because of variable expressivity, parents should be examined carefully in isolated craniosynostoses to identify minor signs. | Is there an association between FGFR3 mutation and plagiocephaly? | 56c1f042ef6e394741000056_005 | yes |
The PACAP-regulated gene selenoprotein T is highly induced in nervous, endocrine, and metabolic tissues during ontogenetic and regenerative processes. Selenoproteins contain the essential trace element selenium whose deficiency leads to major disorders including cancer, male reproductive system failure, or autoimmune thyroid disease. Up to now, 25 selenoprotein-encoding genes were identified in mammals, but the spatiotemporal distribution, regulation, and function of some of these selenium-containing proteins remain poorly documented. Here, we found that selenoprotein T (SelT), a new thioredoxin-like protein, is regulated by the trophic neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) in differentiating but not mature adrenomedullary cells. In fact, our analysis revealed that, in rat, SelT is highly expressed in most embryonic structures, and then its levels decreased progressively as these organs develop, to vanish in most adult tissues. In the brain, SelT was abundantly expressed in neural progenitors in various regions such as the cortex and cerebellum but was undetectable in adult nervous cells except rostral migratory-stream astrocytes and Bergmann cells. In contrast, SelT expression was maintained in several adult endocrine tissues such as pituitary, thyroid, or testis. In the pituitary gland, SelT was found in secretory cells of the anterior lobe, whereas in the testis, the selenoprotein was present only in spermatogenic and Leydig cells. Finally, we found that SelT expression is strongly stimulated in liver cells during the regenerative process that occurs after partial hepatectomy. Taken together, these data show that SelT induction is associated with ontogenesis, tissue maturation, and regenerative mechanisms, indicating that this PACAP-regulated selenoprotein may play a crucial role in cell growth and activity in nervous, endocrine, and metabolic tissues. | Is selenium deficiency involved in autoimmune thyroid disease? | 550c1ca3a103b78016000003_009 | yes |
A novel susceptibility locus for Hirschsprung's disease maps to 4q31.3-q32.3. We report on a multigenerational family with isolated Hirschsprung's disease (HSCR). Five patients were affected by either short segment or long segment HSCR. The family consists of two main branches: one with four patients (three siblings and one maternal uncle) and one with one patient. Analysis of the RET gene, the major gene involved in HSCR susceptibility, revealed neither linkage nor mutations. A genome wide linkage analysis was performed, revealing suggestive linkage to a region on 4q31-q32 with a maximum parametric multipoint LOD score of 2.7. Furthermore, non-parametric linkage (NPL) analysis of the genome wide scan data revealed a NPL score of 2.54 (p = 0.003) for the same region on chromosome 4q (D4S413-D4S3351). The minimum linkage interval spans a region of 11.7 cM (12.2 Mb). No genes within this chromosomal interval have previously been implicated in HSCR. Considering the low penetrance of disease in this family, the 4q locus may be necessary but not sufficient to cause HSCR in the absence of modifying loci elsewhere in the genome. Our results suggest the existence of a new susceptibility locus for HSCR at 4q31.3-q32.3. | Is RET the major gene involved in Hirschsprung disease? | 5503121de9bde69634000019_020 | yes |
A cryptic balanced translocation involving COL1A2 gene disruption cause a rare type of osteogenesis imperfecta. BACKGROUND: Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by low bone mass and recurrent fractures. Most OI cases follow an autosomal dominant pattern of inheritance and are attributed to mutations in genes encoding type I collagen (COL1A1/COL1A2). Genomic structural variations involving type I collagen genes are extremely rare in OI. CASE REPORT: In this study, we characterized a de novo balanced translocation of t(5;7)(q32;q21.3) that caused an extremely rare type of OI in a patient from a non-consanguineous family. The clinical phenotypes of this OI included recurrent fractures, low bone mass, macrocephaly, blue sclera and failure to thrive. Next-generation sequencing was used to identify the translocation, and Sanger sequencing was used to validate and map the breakpoints. The breakpoint on chromosome 7 disrupted the COL1A2 gene in the 17th exon, presumed to affect type I collagen production and give rise to OI. The breakpoint on chromosome 5 disrupted the protein phosphatase 2 regulatory subunit B, beta gene (PPP2R2B) within the first intron. CONCLUSIONS: This is the first report of a copy-neutral structural variant involving COL1A2 that leads to a rare type of OI. This study expands the genotypic spectrum of OI and demonstrates the effectiveness of targeted sequencing for breakpoint mapping. | Is autosomal dominant inheritanced form of Osteogenesis imperfecta caused by mutations in the genes associated with collagen production? | 5a6f77d7b750ff4455000051_009 | yes |
Amantadine, apomorphine and zolpidem in the treatment of disorders of consciousness. Survivors of severe brain injuries may end up in a state of 'wakeful unresponsiveness' or in a minimally conscious state. Pharmacological treatments of patients with disorders of consciousness aim to improve arousal levels and recovery of consciousness. We here provide a systematic overview of the therapeutic effects of amantadine, apomorphine and zolpidem in patients recovering from coma. Evidence from clinical trials using these commonly prescribed pharmacological agents suggests positive changes of the patients' neurological status, leading sometimes to dramatic improvements. These findings are discussed in the context of current hypotheses of these agents' therapeutic mechanisms on cerebral function. In order to improve our understanding of the underlying pathophysiological mechanisms of these drugs, we suggest combining sensitive and specific behavioral tools with neuroimaging and electrophysiological measures in large randomized, double-blind, placebo-controlled experimental designs. We conclude that the pharmacokinetics and pharmacodynamics of amantadine, apomorphine and zolpidem need further exploration to determine which treatment would provide a better neurological outcome regarding the patient's etiology, diagnosis, time since injury and overall condition. | Is amantadine effective for treatment of disorders conciousness? | 530f7cdde3eabad021000001_007 | yes |
Cloning and analysis of the mouse Fanconi anemia group A cDNA and an overlapping penta zinc finger cDNA. Despite the cloning of four disease-associated genes for Fanconi anemia (FA), the molecular pathogenesis of FA remains largely unknown. To study FA complementation group A using the mouse as a model system, we cloned and characterized the mouse homolog of the human FANCA cDNA. The mouse cDNA (Fanca) encodes a 161-kDa protein that shares 65% amino acid sequence identity with human FANCA. Fanca is located at the distal region of mouse chromosome 8 and has a ubiquitous pattern of expression in embryonic and adult tissues. Expression of the mouse cDNA in human FA-A cells restores the cellular drug sensitivity to normal levels. Thus, the expression pattern, protein structure, chromosomal location, and function of FANCA are conserved in the mouse. We also isolated a novel zinc finger protein, Zfp276, which has five C(2)H(2) domains. Interestingly, Zfp276 is situated in the Fanca locus, and the 3'UTR of its cDNA overlaps with the last four exons of Fanca in a tail-to-tail manner. Zfp276 is expressed in the same tissues as Fanca, but does not complement the mitomycin C (MMC)-sensitive phenotype of FA-A cells. The overlapping genomic organization between Zfp276 and Fanca may have relevance to the disease phenotype of FA. | Is there a mouse model for Fanconi anemia? | 54edf05494afd6150400000e_003 | yes |
The neuroprotective effects of progesterone on traumatic brain injury: current status and future prospects. Traumatic brain injury is the leading cause of morbidity and mortality in young adults. The secondary injury in traumatic brain injury consists of a complex cascade of processes that simultaneously react to the primary injury to the brain. This cascade has been the target of numerous therapeutic agents investigated over the last 30 years, but no neuroprotective treatment option is currently available that improve neurological outcome after traumatic brain injury. Progesterone has long been considered merely a female reproductive hormone. Numerous studies, however, show that progesterone has substantial pleiotropic properties as a neuroprotective agent in both animal models and humans. Here, we review the increasing evidence that progesterone can act as a neuroprotective agent to treat traumatic brain injury and the mechanisms underlying these effects. Additionally, we discuss the current progress of clinical studies on the application of progesterone in the treatment of traumatic brain injuries. | Is progesterone effective for treatment of patients with traumatic brain injury based on clinical trial data? | 54cf48acf693c3b16b00000b_011 | no |
Tetrasomy 21 pter-->q22.1 and Down syndrome: molecular definition of the region. Down syndrome is usually caused by complete trisomy 21. Rarely, it is due to partial trisomy of the segment 21q22. We report on a 33-month-old girl with tetrasomy 21 pter-->q22.1 resulting from an extra chromosome idic(21)(q22.1). She has craniofacial traits typical of Down syndrome, including brachycephaly, third fontanel, upward slanting palpebral fissures, round face, and protruding tongue. Speech development is quite delayed whereas motor development is only mildly retarded. The molecular content of the extra isodicentric chromosome was defined by molecular genetic investigations using 13 single copy probes unique to chromosome 21, and SOD1 expression studies. The child was found to have 4 copies of the region defined by D21S16 (21cen) through D21S93 on 21q22.1 and two copies of the remaining region defined by SOD1-->D21S55-->D21S123. In view of the recent assignment of Down syndrome facial characters to the 21q22 region, defined in part by D21S55, it is significant that this child shows a subset of Down syndrome facial manifestations, without duplication of this region. These results suggest that genes contributing to the facial and some of the hand manifestations of Down syndrome also exist in the chromosomal region proximal to D21S55 in band 21q22.1. | Down's syndrome occurs when an individual has an extra copy or part of a copy of chromosome 21, yes or no? | 5a76016683b0d9ea6600000d_005 | yes |
An epidemiological study of the relations between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy and neuropsychological abnormalities in sheep farmers and dippers. OBJECTIVES: To investigate the hypothesis that chronic low level exposure to organophosphates (OPs) in sheep dips is related to clinically detectable measures of polyneuropathy. METHODS: The design was a cross sectional exposure-response study of sheep dippers and other non-exposed groups. The study group consisted of 612 sheep dipping farmers, 53 farmers with no sheep dipping experience, and 107 ceramics workers. Retrospective exposure information was obtained by questionnaire based on stable and easily identifiable features of sheep dipping found during the first phase of the study; in particular, estimates of handling concentrate and splashing with dilute dip. Neurological assessments were based on a standard neuropathy symptoms questionnaire, and thermal and vibration quantitative sensory tests. RESULTS: Adjusted for confounders there was a weak positive association between cumulative exposure to OPs and neurological symptoms, the significance of which was dependent on the inclusion of a few individual workers with extremely high exposure. There was no evidence of an association between cumulative exposure and the thermal or vibration sensory thresholds. However, separating the effects of exposure intensity and duration showed a higher prevalence of symptoms, primarily of a sensory type, among sheep dippers who handled the OP concentrate. There was also evidence that sensory and vibration thresholds were higher among concentrate handlers, the highest exposed group of dippers. CONCLUSIONS: The findings showed a strong association between exposure to OP concentrate and neurological symptoms, but a less consistent association with sensory thresholds. There was only weak evidence of a chronic effect of low dose cumulative exposure to OPs. It is suggested that long term health effects may occur in at least some sheep dippers exposed to OPs over a working life, although the mechanisms are unclear. | Is pesticide exposure associated with polyneuropathy? | 530cefaaad0bf1360c000010_024 | yes |
Identification of methyl violet 2B as a novel blocker of focal adhesion kinase signaling pathway in cancer cells. The focal adhesion kinase (FAK) signaling cascade in cancer cells was profoundly inhibited by methyl violet 2B identified with the structure-based virtual screening. Methyl violet 2B was shown to be a non-competitive inhibitor of full-length FAK enzyme vs. ATP. It turned out that methyl violet 2B possesses extremely high kinase selectivity in biochemical kinase profiling using a large panel of kinases. Anti-proliferative activity measurement against several different cancer cells and Western blot analysis showed that this substance is capable of suppressing significantly the proliferation of cancer cells and is able to strongly block FAK/AKT/MAPK signaling pathways in a dose dependent manner at low nanomolar concentration. Especially, phosphorylation of Tyr925-FAK that is required for full activation of FAK was nearly completely suppressed even with 1nM of methyl violet 2B in A375P cancer cells. To the best of our knowledge, it has never been reported that methyl violet possesses anti-cancer effects. Moreover, methyl violet 2B significantly inhibited FER kinase phosphorylation that activates FAK in cell. In addition, methyl violet 2B was found to induce cell apoptosis and to exhibit strong inhibitory effects on the focal adhesion, invasion, and migration of A375P cancer cells at low nanomolar concentrations. Taken together, these results show that methyl violet 2B is a novel, potent and selective blocker of FAK signaling cascade, which displays strong anti-proliferative activities against a variety of human cancer cells and suppresses adhesion/migration/invasion of tumor cells. | Is the protein FAK (Focal Adhesion Kinase) phosphorylated? | 54f4c382d0d681a040000006_012 | yes |
FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch, Jun, and DEK for degradation. The Fbxw7 (F-box/WD repeat-containing protein 7; also called CDC4, Sel10, Ago, and Fbw7) component of the SCF (Skp1/Cullin/F-box protein) E3 ubiquitin ligase complex acts as a tumor suppressor in several tissues and targets multiple transcriptional activators and protooncogenes for ubiquitin-mediated degradation. To understand Fbxw7 function in the murine intestine, in this study, we specifically deleted Fbxw7 in the murine gut using Villin-Cre (Fbxw7(ΔG)). In wild-type mice, loss of Fbxw7 in the gut altered homeostasis of the intestinal epithelium, resulted in elevated Notch and c-Jun expression, and induced development of adenomas at 9-10 mo of age. In the context of APC (adenomatous polyposis coli) deficiency (Apc(Min/+) mice), loss of Fbxw7 accelerated intestinal tumorigenesis and death and promoted accumulation of β-catenin in adenomas at late but not early time points. At early time points, Fbxw7 mutant tumors showed accumulation of the DEK protooncogene. DEK expression promoted cell division and altered splicing of tropomyosin (TPM) RNA, which may also influence cell proliferation. DEK accumulation and altered TPM RNA splicing were also detected in FBXW7 mutant human colorectal tumor tissues. Given their reduced lifespan and increased incidence of intestinal tumors, Apc(Min/+)Fbxw7(ΔG) mice may be used for testing carcinogenicity and drug screening. | Is protein Fbw7 a SCF type of E3 ubiquitin ligase? | 550ae16bc2af5d5b70000009_003 | yes |
Current advances in non-proteasome inhibitor-based approaches to the treatment of relapsed/refractory multiple myeloma. In the past decade, immunomodulatory drugs have been approved by the US Food and Drug Administration for the treatment of multiple myeloma (MM)-and a number of emerging agents that target the cellular pathways or proteins involved in the pathophysiology of MM are currently in development. Lenalidomide (Revlimid) and pomalidomide induce apoptosis and sensitize MM cells while demonstrating superior efficacy and better tolerability than thalidomide (Thalomid). Several novel classes of drugs, including the histone deacetylase (HDAC) inhibitors, heat shock protein (HSP) inhibitors, and monoclonal antibodies have been shown to have activity in myeloma in early-stage clinical trials. HDAC inhibitors, including vorinostat (Zolinza), panobinostat, and romidepsin (Istodax) are thought to affect multiple pathways involved in MM and correct the deregulation of genes involved in apoptosis and cell cycle arrest, thus potentially sensitizing MM cells to apoptosis. HSP inhibitors (eg, tanespimycin) decrease MM proliferation and suppress the long-term replicative potential of MM cells; they may also sensitize MM cells to other anticancer agents. The humanized monoclonal antibody elotuzumab induces antibody-dependent cell cytotoxicity-mediated apoptosis. It is likely that in the near future the treatment armamentarium for MM will undergo significant expansion as some of these additional target pathways become validated. | Has Revlimid been approved by the US Food and Drug Administration? | 56ed0ba22ac5ed1459000007_004 | yes |
A 'picturesque' case of transition from subcutaneous to oral treatment in neonatal diabetes. We report a case of a 6-week-old infant with diabetes mellitus based on a genetic defect in the sulfonylurea receptor 1 (SUR1), an ATP-sensitive potassium (KATP) channel protein. A spectacular improvement in glucose regulation was shown by real-time continuous glucose monitoring when switching her from insulin to oral glibenclamide. Children with neonatal onset of diabetes deserve genetic testing in order to replace insulin with oral medication. | Can Diabetes be caused by a defect in a potassium chanel? | 58a0a28a78275d0c4a000051_003 | yes |
Mowat-Wilson syndrome detected by using high resolution microarray. 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. This deletion or cytogenetic abnormality has been reported primarily from Europe, Australia and the United States, but not in Korea. Here we report a patient with characteristic facial features of MWS, developmental delay and spasticity. High resolution microarray analysis revealed 0.9 Mb deletion of 2q22.3 involving two genes: ZEB2 and GTDC1. This case shows the important role of high resolution microarray in patients with unexplained psychomotor retardation and/or facial dysmorphism. Knowledge about the most striking clinical signs and implementation of effective molecular tests like microarray could significantly increase the detection rate of new cases of MWS in Korea. This is the first reported case of MWS in Korea. | Is Hirschsprung disease one of the characteristics of the Mowat-Wilson syndrome? | 55001420e9bde69634000005_018 | yes |
Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy (HCM) is a frequent genetic cardiac disease and the most common cause of sudden cardiac death in young individuals. Most of the currently known HCM disease genes encode sarcomeric proteins. Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations. We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene. Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other families. We used a newly designed monoclonal antibody to show that muscle LIM protein (MLP), the protein encoded by CSRP3, is mainly a cytosolic component of cardiomyocytes and not tightly anchored to sarcomeric structures. Our functional data from both in vitro and in vivo analyses suggest that at least one of MLP's mutated forms seems to be destabilized in the heart of HCM patients harbouring a CSRP3 missense mutation. We also present evidence for mild skeletal muscle disease in affected persons. Our results support the view that HCM is not exclusively a sarcomeric disease and also suggest that impaired mechano-sensory stress signalling might be involved in the pathogenesis of HCM. | Is muscle lim protein (MLP) involved in cardiomyopathies? | 54f704b630767eb92e000001_010 | yes |