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The capacity of target silencing by Drosophila PIWI and piRNAs. Although Piwi proteins and Piwi-interacting RNAs (piRNAs) genetically repress transposable elements (TEs), it is unclear how the highly diverse piRNA populations direct Piwi proteins to silence TE targets without silencing the entire transcriptome. To determine the capacity of piRNA-mediated silencing, we introduced reporter genes into Drosophila OSS cells, which express microRNAs (miRNAs) and piRNAs, and compared the Piwi pathway to the Argonaute pathway in gene regulation. Reporter constructs containing several target sites that were robustly silenced by miRNAs were not silenced to the same degrees by piRNAs. However, another set of reporters we designed to enable a large number of both TE-directed and genic piRNAs to bind were robustly silenced by the PIWI/piRNA complex in OSS cells. These reporters show that a bulk of piRNAs are required to pair to the reporter's transcripts and not the reporter's DNA sequence to engage PIWI-mediated silencing. Following our genome-wide study of PIWI-regulated targets in OSS cells, we assessed candidate gene elements with our reporter platform. These results suggest TE sequences are the most direct of PIWI regulatory targets while coding genes are less directly affected by PIWI targeting. Finally, our study suggests that the PIWI transcriptional silencing mechanism triggers robust chromatin changes on targets with sufficient piRNA binding, and preferentially regulates TE transcripts because protein-coding transcripts lack a threshold of targeting by piRNA populations. This reporter platform will facilitate future dissections of the PIWI-targeting mechanism. | Are piRNAs involved in gene silencing? | 56c6f6005795f9a73e000009_019 | yes |
Normalization, bias correction, and peak calling for ChIP-seq. Next-generation sequencing is rapidly transforming our ability to profile the transcriptional, genetic, and epigenetic states of a cell. In particular, sequencing DNA from the immunoprecipitation of protein-DNA complexes (ChIP-seq) and methylated DNA (MeDIP-seq) can reveal the locations of protein binding sites and epigenetic modifications. These approaches contain numerous biases which may significantly influence the interpretation of the resulting data. Rigorous computational methods for detecting and removing such biases are still lacking. Also, multi-sample normalization still remains an important open problem. This theoretical paper systematically characterizes the biases and properties of ChIP-seq data by comparing 62 separate publicly available datasets, using rigorous statistical models and signal processing techniques. Statistical methods for separating ChIP-seq signal from background noise, as well as correcting enrichment test statistics for sequence-dependent and sonication biases, are presented. Our method effectively separates reads into signal and background components prior to normalization, improving the signal-to-noise ratio. Moreover, most peak callers currently use a generic null model which suffers from low specificity at the sensitivity level requisite for detecting subtle, but true, ChIP enrichment. The proposed method of determining a cell type-specific null model, which accounts for cell type-specific biases, is shown to be capable of achieving a lower false discovery rate at a given significance threshold than current methods. | Does Chromatin Immunoprecipitation (ChIP) show a bias for highly expressed loci? | 52ef6da1c8da898910000011_008 | yes |
Role of the phagosomal redox-sensitive TRP channel TRPM2 in regulating bactericidal activity of macrophages. Acidification of macrophage phagosomes serves an important bactericidal function. We show here that the redox-sensitive transient receptor potential (TRP) cation channel TRPM2 is expressed in the phagosomal membrane and regulates macrophage bactericidal activity through the activation of phagosomal acidification. Measurement of the TRPM2 current in phagosomes identified TRPM2 as a functional redox-sensitive cation channel localized in the phagosomal membrane. Simultaneous measurements of phagosomal Ca changes and phagosome acidification in macrophages undergoing phagocytosis demonstrated that TRPM2 was required to mediate the efflux of cations and for phagosomal acidification during the process of phagosome maturation. Acidification in phagosomes was significantly reduced in macrophages isolated from Trpm2 mice as compared to wild type, and acidification was coupled to reduced bacterial clearance in Trpm2 mice. Trpm2 macrophages treated with the vacuolar H-ATPase inhibitor bafilomycin showed reduced bacterial clearance, similar to that in Trpm2 macrophages. Direct activation of TRPM2 using adenosine diphosphate ribose (ADPR) induced both phagosomal acidification and bacterial killing. These data collectively demonstrate that TRPM2 regulates phagosomal acidification, and is essential for the bacterial killing function of macrophages. | The TRPM2 gene is associated with development of spontaneous thromboembolism? | 5ab144fefcf4565872000012_001 | no |
TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease. | Are mutations in the C9orf72 gene associated with macular degeneration? | 58e11bf76fddd3e83e00000c_006 | no |
Sorting nexin Snx41 is essential for conidiation and mediates glutathione-based antioxidant defense during invasive growth in Magnaporthe oryzae. The sorting nexins Atg20/Snx42 and Snx41 regulate membrane traffic and endosomal protein sorting and are essential for Cvt and/or pexophagy in yeast. Previously, we showed that macroautophagy is necessary for conidiation in the rice-blast fungus Magnaporthe oryzae. Here, we analyzed the physiological function(s) of selective autophagy in Magnaporthe through targeted deletion of MGG_12832, an ortholog of yeast SNX41 and ATG20/SNX42. Loss of MGG_12832 (hereafter SNX41) abolished conidia formation and pathogenesis in M. oryzae. Snx41-GFP localized as dynamic puncta or short tubules that are partially associated with autophagosomes and/or autophagic vacuoles. PX domain, but not macroautophagy per se, was required for such localization of Snx41-GFP in Magnaporthe. Although not required for nonselective autophagy, Snx41 was essential for pexophagy in Magnaporthe. We identified Oxp1, an ATP-dependent oxoprolinase in the gamma-glutamyl cycle, as a binding partner and potential retrieval target of Snx41-dependent protein sorting. The substrate of Oxp1, 5-oxoproline, could partially restore conidiation in the snx41Δ. Exogenous glutathione, a product of the gamma-glutamyl cycle, significantly restored pathogenicity in the snx41Δ mutant, likely through counteracting the oxidative stress imposed by the host. We propose that the gamma-glutamyl cycle and glutathione biosynthesis are subject to regulation by Snx41-dependent vesicular trafficking, and mediate antioxidant defense crucial for in planta growth and pathogenic differentiation of Magnaporthe at the onset of blast disease in rice. | Is macroautophagy a selective degradation process? | 51bedaac3148fdcc22da7188_020 | yes |
Presenteeism according to healthy behaviors, physical health, and work environment. The objective of this study is to identify the contribution that selected demographic characteristics, health behaviors, physical health outcomes, and workplace environmental factors have on presenteeism (on-the-job productivity loss attributed to poor health and other personal issues). Analyses are based on a cross-sectional survey administered to 3 geographically diverse US companies in 2010. Work-related factors had the greatest influence on presenteeism (eg, too much to do but not enough time to do it, insufficient technological support/resources). Personal problems and financial stress/concerns also contributed substantially to presenteeism. Factors with less contribution to presenteeism included physical limitations, depression or anxiety, inadequate job training, and problems with supervisors and coworkers. Presenteeism was greatest for those ages 30-49, women, separated/divorced/widowed employees, and those with a high school degree or some college. Clerical/office workers and service workers had higher presenteeism. Managers and professionals had the highest level of presenteeism related to having too much to do but too little time to do it, and transportation workers had the greatest presenteeism because of physical health limitations. Lowering presenteeism will require that employers have realistic expectations of workers, help workers prioritize, and provide sufficient technological support. Financial stress and concerns may warrant financial planning services. Health promotion interventions aimed at improving nutrition and physical and mental health also may contribute to reducing presenteeism. | Is there an association between presenteeism and depression? | 54f49e56d0d681a040000004_004 | yes |
Calcium/calmodulin-dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure. BACKGROUND: Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)delta(C) mice have heart failure and isoproterenol (ISO)-inducible arrhythmias. We hypothesized that CaMKII contributes to arrhythmias and underlying cellular events and that inhibition of CaMKII reduces cardiac arrhythmogenesis in vitro and in vivo. METHODS AND RESULTS: Under baseline conditions, isolated cardiac myocytes from TG mice showed an increased incidence of early afterdepolarizations compared with wild-type myocytes (P<0.05). CaMKII inhibition (AIP) completely abolished these afterdepolarizations in TG cells (P<0.05). Increasing intracellular Ca stores using ISO (10(-8) M) induced a larger amount of delayed afterdepolarizations and spontaneous action potentials in TG compared with wild-type cells (P<0.05). This seems to be due to an increased sarcoplasmic reticulum (SR) Ca leak because diastolic [Ca](i) rose clearly on ISO in TG but not in wild-type cells (+20+/-5% versus +3+/-4% at 10(-6) M ISO, P<0.05). In parallel, SR Ca leak assessed by spontaneous SR Ca release events showed an increased Ca spark frequency (3.9+/-0.5 versus 2.0+/-0.4 sparks per 100 microm(-1).s(-1), P<0.05). However, CaMKII inhibition (either pharmacologically using KN-93 or genetically using an isoform-specific CaMKIIdelta-knockout mouse model) significantly reduced SR Ca spark frequency, although this rather increased SR Ca content. In parallel, ISO increased the incidence of early (54% versus 4%, P<0.05) and late (86% versus 43%, P<0.05) nonstimulated events in TG versus wild-type myocytes, but CaMKII inhibition (KN-93 and KO) reduced these proarrhythmogenic events (P<0.05). In addition, CaMKII inhibition in TG mice (KN-93) clearly reduced ISO-induced arrhythmias in vivo (P<0.05). CONCLUSIONS: We conclude that CaMKII contributes to cardiac arrhythmogenesis in TG CaMKIIdelta(C) mice having heart failure and suggest the increased SR Ca leak as an important mechanism. Moreover, CaMKII inhibition reduces cardiac arrhythmias in vitro and in vivo and may therefore indicate a potential role for future antiarrhythmic therapies warranting further studies. | Is Calcium/Calmodulin dependent protein kinase II (CaMKII) involved in cardiac arrhythmias and heart failure? | 5502abd1e9bde69634000008_008 | yes |
Delayed enhancement of the intraventricular septum following an extraordinary endurance exercise. Cardiac fatigue and elevations in cardiac biomarkers have been described following prolonged exertion in endurance athletes. We comprehensively evaluated a highly trained 46-year-old man attempting a North American transcontinental run in a record time of 45 consecutive days. After running 1460 km and ascending over 2600 m, the run was ended prematurely on day 17 following a leg injury; in support of the event, the subject cycled an additional 1580 km. Echocardiography and biomarker analysis performed pre-event and while running revealed no decrement in systolic function and undetectable levels of troponin I and T. Post-event cardiac MRI demonstrated the interval appearance of delayed enhancement of gadolinium at the inferior insertion of the right ventricle and in the interventricular septum-a novel finding that may represent subtle inflammation secondary to a combined exercise and altitude effect. | Has the presence of delayed enhancement been documented in athletes performing strenuous exercise? | 531d34be267d7dd053000004_002 | yes |
[Titin: some aspects of the largest protein in the body]. Titin, is definitely the largest protein in the body, with a molecular weight of 3 million Dalton and composed of 27,000 amino acids. Paradoxically, this huge structure was elusive until the last decade but, since it was described in muscle tissue, its importance has rapidly emerged. Titin constitutes about 10% of muscle mass, to represent the third most abundant protein in the muscle following actin and myosin. It is estimated that titin acts like a "ruler" that controls the relative positioning of the latter 2 muscle proteins, and regulates the flexibility and "springiness" of the contracting muscle. Titin has also been implicated in the condensation of chromosomes during mitosis, while induced mutations in titin caused enhanced fragility of chromosomes. A recent demonstration of a high titer of autoantibodies to titin in sera of patients diagnosed with myasthenia gravis, is interpreted as a prognostic parameter to indicate a severe course of the disease. | Is Titin the largest single protein molecule found in Nature? | 55030a6ce9bde6963400000f_005 | yes |
A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury. Traumatic brain injury (TBI) affects 1.6 million Americans annually. The injury severity impacts the overall outcome and likelihood for survival. Current treatment of acute TBI includes surgical intervention and supportive care therapies. Treatment of elevated intracranial pressure and optimizing cerebral perfusion are cornerstones of current therapy. These approaches do not directly address the secondary neurological sequelae that lead to continued brain injury after TBI. Depending on injury severity, a complex cascade of processes are activated and generate continued endogenous changes affecting cellular systems and overall outcome from the initial insult to the brain. Homeostatic cellular processes governing calcium influx, mitochondrial function, membrane stability, redox balance, blood flow and cytoskeletal structure often become dysfunctional after TBI. Interruption of this cascade has been the target of numerous pharmacotherapeutic agents investigated over the last two decades. Many agents such as selfotel, pegorgotein (PEG-SOD), magnesium, deltibant and dexanabinol were ineffective in clinical trials. While progesterone and ciclosporin have shown promise in phase II studies, success in larger phase III, randomized, multicentre, clinical trials is pending. Consequently, no neuroprotective treatment options currently exist that improve neurological outcome after TBI. Investigations to date have extended understanding of the injury mechanisms and sites for intervention. Examination of novel strategies addressing both pathological and pharmacological factors affecting outcome, employing novel trial design methods and utilizing biomarkers validated to be reflective of the prognosis for TBI will facilitate progress in overcoming the obstacles identified from previous clinical trials. | Is progesterone effective for treatment of patients with traumatic brain injury based on clinical trial data? | 54cf48acf693c3b16b00000b_005 | no |
Mutation analysis of the EGFR-NRAS-BRAF pathway in melanomas from black Africans and other subgroups of cutaneous melanoma. Earlier studies have shown frequent mutations in the BRAF and NRAS genes in cutaneous melanoma, but these alterations have not been examined in the rare category of melanoma from black Africans. Moreover, the frequency of epidermal growth factor receptor (EGFR) mutations in melanocytic tumors is not known. We therefore examined 165 benign and malignant melanocytic lesions (including 118 invasive melanomas and 18 metastases collected as consecutive cases from various time periods and from two different pathology departments; the 51 nodular melanomas were randomly selected from a larger, consecutive, population-based series of nodular melanomas) with respect to alterations in the EGFR, BRAF and NRAS genes. Mutations in EGFR (exons 18-21) were not detected. EGFR protein expression was observed in a subgroup of melanomas, but without associations with clinicopathologic phenotype or prognosis. Cytoplasmic EGFR expression was, however, significantly increased from benign nevi to melanomas. Mutations in BRAF and NRAS were detected in superficial melanoma (25 and 29%, respectively), nodular melanoma (29 and 28%, respectively) and lentigo maligna melanoma (15 and 16%, respectively). In a series of melanomas from black Africans (n=26), only two BRAF mutations (8%) were found, both being different from the common T1799A substitution. Moreover, melanomas from black Africans exhibited mutations in NRAS exon 1 only (12%), whereas NRAS exon 2 mutations were predominant in melanomas from Caucasians. Thus, the frequencies of BRAF and NRAS mutations were particularly low in melanomas from black Africans, supporting a different pathogenesis of these tumors. | Does melanoma occur in people of African origin ? | 515df6f2298dcd4e5100002d_006 | yes |
[Clinical study on the therapeutic effects and mechanism of progesterone in the treatment for acute severe head injury]. OBJECTIVE: To evaluate the therapeutic effects of Progesterone (PG) on the patients with acute severe traumatic brain injury, and investigate it's neuroprotective mechanisms. METHODS: Fifth-six patients with acute severe traumatic head injury were divided randomly into two groups: 26 cases were treated with PG and 30 cases were control. Neurological outcome of the patients were assessed using Glasgow Coma Scale (GCS), Glasgow Outcome Scale (GOS), verbal and motor functions scale and Karnofsky Performance Scale (KPS). The serum concentrations of PG, TNF-alpha and 15-F(2t)-isoprostane were measured at day 1, 5 and 10 after trauma. RESULTS: In the two groups, There were no significant difference in the mortality, GCS of acute healing phase, GOS and verbal and motor functions at 10th days after treatment (P>0.05); After follow-up for 3 months, GOS, verbal functions and KPSin the PG treatment group were better than those in the control group (P<0.05); In addition, there was no difference of motor functions in the two groups (P>0.05). At 5th day after trauma, serum 15-F(2t)-isoprostane and TNF-alpha levels increased in the control group, but decreased at 10th day after trauma. Compared with the control group serum PG levels increased, serum 15-F(2t)-isoprostane and TNF-alpha levels reduced significantly in the PG treatment group at 5th and 10th day after injury (P<0.05). CONCLUSION: It indicated that successive early application of PG will benefit the patients with acute severe head injury by improving the recovery and reducing the disability, which may be related to its alleviating inflammatory and lipid peroxidation response. | Is progesterone effective for treatment of patients with traumatic brain injury based on clinical trial data? | 54cf48acf693c3b16b00000b_002 | no |
[Expert consensus for the diagnosis and treatment of patients with renal impairment of multiple myeloma]. Renal impairment (RI) is a common complication of multiple myeloma (MM), which is presented as chronic kidney disease (CKD) or acute kidney injury (AKI). The typical pathological feature is cast nephropathy. Presently international system staging (ISS) is used in evaluating MM. Although the classic Durie-Salmon staging system could be still used in clinical practice, it may miss out some patients with renal impairment. For evaluations of RI in MM patients with CKD, it's recommended to assess the estimated glomerular filtration rate (eGFR) by creatinine based formula CKD-epidemiology collaboration (EPI) or modification of diet in renal disease(MDRD) and to stage the renal injuries according to 2013 Kidney Disease Improving Global Outcomes (KDIGO) CKD guidelines. For MM patients with AKI, KDIGO AKI guidelines is recommended for evaluation. Renal biopsy is not a routine procedure in all MM patients. It's necessary for patients presenting with glomerular injuries such as albuminuria > 1 g/24 h to eliminate immunoglobulin associated amyloidosis (AL) and monoclonal immunoglobulin deposition disease (MIDD). The effective treatment of MM can reduce serum light chain concentration and improve renal function. The basis of the RI treatment in MM is bortizomib-based regimen, which does not require dosage adjustment in patients with dialysis or renal insufficiency. Thalidomide and lenalidomide are two major immunomodulators in MM treatment. Thalidomide can be used effectively in RI patients without dosage adjustment while lenalidomide should be used cautiously in patients with mild or moderate RI with dosage adjustment and serum toxicity surveillance. High-dose therapy (HDT) and autologous peripheral blood stem cell transplantation (APBSCT) can be therapeutical options for RI patients younger than 65 y, and they should be considered more prudently in patients with severe renal insufficiency (GFR<30 ml/min). For patients who are not suitable for the treatment mentioned above, they can be treated with conventional chemotherapy, including VAD (vincristine, adriamycin and dexamethasone), MP (mephalan and prednisolone) and high-dose dexamethasone regimen. Adequate hydration (at least 3 litres of fluid intake a day or 2 L·m(-2)·d(-1)) and correcting reversible causes of RI are key points for the supportive care. Renal replacement therapy (more often hemodialysis) should be started in patients with severe AKI and end stage renal disease (ESRD). High flux or high cut-off membrane are recommended because routine hemodialysis could not remove the serum free light chain (sFLC) effectively. Plasmapheresis (PE) is recommended for patients with hyperviscosity syndrome or cast nephropathy presented with AKI, which may help to increase the dialysis-independency. | Can multiple myeloma patients develop hyperviscosity syndrome? | 5a6f829eb750ff4455000054_001 | yes |
Role of glycosylation in cell surface expression and stability of HERG potassium channels. The human ether-à-go-go-related gene (HERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel in the heart. We previously showed that HERG channel protein is modified by N-linked glycosylation. HERG protein sequence contains two extracellular consensus sites for N-linked glycosylation (N598, N629). In this study, we used the approaches of site-directed mutagenesis and biochemical modification to inhibit N-linked glycosylation and studied the role of glycosylation in the cell surface expression and turnover of HERG channels. Our results show that N598 is the only site for N-linked glycosylation and that glycosylation is not required for the cell surface expression of functional HERG channels. In contrast, N629 is not used for glycosylation, but mutation of this site (N629Q) causes a protein trafficking defect, which results in its intracellular retention. Pulse-chase experiments show that the turnover rate of nonglycosylated HERG channel is faster than that of the glycosylated form, suggesting that N-linked glycosylation plays an important role in HERG channel stability. | Does the hERG gene code for a protein which is part of a sodium channel? | 58bdc76102b8c60953000013_004 | no |
Tumor adaptation and resistance to RAF inhibitors. RAF kinase inhibitors have substantial therapeutic effects in patients with BRAF-mutant melanoma. However, only rarely do tumors regress completely, and the therapeutic effects are often temporary. Several mechanisms of resistance to RAF inhibitors have been proposed. The majority of these cause ERK signaling to become insensitive to treatment with RAF inhibitors by increasing the amount of RAF dimers in cells, whereas others bypass the dependence of the tumor on mutant RAF. One motivation for studying mechanisms of drug resistance is that such efforts may suggest new therapeutic targets or rational combination strategies that delay or prevent the emergence of drug-resistant clones. Here, we review the current model of RAF inhibitor resistance with a focus on the implications of this model on ongoing laboratory and clinical efforts to develop more effective therapeutic strategies for patients with BRAF-mutant tumors. | Are BRAF mutations common in melanoma? | 5512c91b6a8cde6b7200000b_001 | yes |
Vortioxetine: a meta-analysis of 12 short-term, randomized, placebo-controlled clinical trials for the treatment of major depressive disorder. BACKGROUND: Vortioxetine was approved by the U.S. Food and Drug Administration (FDA) in September 2013 for treating major depressive disorder (MDD). Thus far, a number of randomized, double-blind, placebo-controlled clinical trials (RCTs) of vortioxetine have been conducted in patients with MDD. We performed a meta-analysis to increase the statistical power of these studies and enhance our current understanding of the role of vortioxetine in the treatment of MDD. METHODS: We performed an extensive search of databases and the clinical trial registry. The mean change in total scores on the 24-item Hamilton Rating Scale for Depression (HAM-D) and the Montgomery- Åsberg Depression Rating Scale (MADRS) from the baseline were the primary outcome measures. The secondary efficacy measures were the response and remission rates, as defined by a 50% or greater reduction in HAM-D/MADRS total scores and as a score of 10 or less in the MADRS and 7 or less in the HAM-D total scores at the end of treatment. RESULTS: We included 7 published and 5 unpublished short-term (6-12 wk) RCTs in our meta-analysis. Vortioxetine was significantly more effective than placebo, with an effect size (standardized mean difference [SMD]) of -0.217 (95% confidence interval [CI] -0.313 to -0.122) and with odds ratios (ORs) for response and remission of 1.652 (95% CI 1.321 to 2.067) and 1.399 (95% CI 1.104 to 1.773), respectively. Those treated with vortioxetine did not differ significantly from those treated with selective norepinephrine reuptake inhibitors/agomelatine with regard to the SMD of the primary outcome measure (0.081, -0.062 to 0.223) or for response (OR 0.815, 95% CI 0.585 to 1.135) and remission (OR 0.843, 95% CI 0.575 to 1.238) rates. Discontinuation owing to lack of efficacy (OR 0.541, 95% CI 0.308 to 0.950) was significantly less common among those treated with vortioxetine than among those who received placebo, whereas discontinuation owing to adverse events (AEs; OR 1.530, 95% CI 1.144 to 2.047) was significantly more common among those treated with vortioxetine than among those receiving placebo. There was no significant difference in discontinuation rates between vortioxetine and comparators owing to inefficacy (OR 0.983, 95% CI 0.585 to 1.650), whereas discontinuation owing to AEs was significantly less common in the vortioxetine than in the comparator group (OR 0.728, 95% CI 0.554 to 0.957). LIMITATIONS: Studies examining the role of vortioxetine in the treatment of MDD are limited. CONCLUSION: Although our results suggest that vortioxetine may be an effective treatment option for MDD, they should be interpreted and translated into clinical practice with caution, as the meta-analysis was based on a limited number of heterogeneous RCTs. | Is vortioxetine effective for treatment of depression? | 589a246878275d0c4a000030_002 | yes |
Otologic impairments in achondroplasia: a nosologic assessment. The AA report a clinical and radiological study performed in 18 achondroplastic patients in order to achieve a nosological settlement of the otological impairments. They found two main otological syndromes; one, a congenital dysplasic syndrome, showing permanent conductive or sensory-neural hearing loss due to malformations of the middle ear or of the inner ear; the other, an inflammatory tubal tympanic syndrome with transient conductive hearing loss, which is relatively frequent in achondroplastic patients, but seems not related to the main disease. | Is Achondroplasia associated with hearing loss? | 52b2efcb4003448f55000005_003 | yes |
Retrospective comparison of chemoradiotherapy followed by adjuvant chemotherapy, with or without prior gliadel implantation (carmustine) after initial surgery in patients with newly diagnosed high-grade gliomas. PURPOSE: Retrospective study of patients treated for high-grade glioma, with or without biodegradable carmustine wafers and according to the Stupp protocol. METHODS AND MATERIALS: Between May 2007 and June 2008, 65 patients underwent surgery for high-grade glioma, 28 had implantation of Gliadel and 37 patients did not. Patients received radiotherapy with concomitant temozolomide followed by 5 consecutive days of temozolomide every month for 6 months. RESULTS: Overall median follow-up was 17.1 months; the median relapse-free survival (RFS) was 14 months with a RFS of 54% at 12 months, and 38% at 24 months. For patient with and without Gliadel, median and 1-year RFS were 12.9 months and 52% vs. 14 months and 42%, respectively (p = 0.89). According to pathology, Gliadel did not influence RFS of patients with Grade III or glioblastoma. However, for all patients, in multivariate analysis, non-methylated methylguanine methyltransferase (MGMT) was the only unfavorable prognostic factor of RFS (p = 0.017; HR 2.8; CI [1.2-7]). Median overall survival (OS) was 20.8 months; the OS rate at 12 months was 78.5%, and at 24 months 35.4%. For patients treated with and without Gliadel, median and 1-year OS were 20.6 months and 78.6% vs. 20.8 months and 78.4%, respectively. According to pathology, Gliadel did not influence OS of patients with Grade III or glioblastoma. For all patients, in multivariate analysis, unfavorable prognosticators for OS were non-methylated MGMT (p = 0.001; HR: 6.5; CI [2-20]) and irradiation dose <60 Gy (p = 0.02; HR: 6.3; CI [2-20]). With carmustine wafers, before irradiation, median gross tumor volume plus edema was 84 mL (27-229), whereas it was 68 mL (10-362) without carmustine (p = nonsignificant). Four cases of Grade 3 thrombopenia occurred, all in the carmustine wafer group. CONCLUSION: In patients with high-grade gliomas, adding Gliadel before performing a Stupp protocol did not improve survival. | Do carmustine wafers improve survival of glioblastoma patients? | 54d630283706e89528000004_014 | yes |
High-flow nasal cannulae in very preterm infants after extubation. BACKGROUND: The use of high-flow nasal cannulae is an increasingly popular alternative to nasal continuous positive airway pressure (CPAP) for noninvasive respiratory support of very preterm infants (gestational age, <32 weeks) after extubation. However, data on the efficacy or safety of such cannulae in this population are lacking. METHODS: In this multicenter, randomized, noninferiority trial, we assigned 303 very preterm infants to receive treatment with either high-flow nasal cannulae (5 to 6 liters per minute) or nasal CPAP (7 cm of water) after extubation. The primary outcome was treatment failure within 7 days. Noninferiority was determined by calculating the absolute difference in the risk of the primary outcome; the margin of noninferiority was 20 percentage points. Infants in whom treatment with high-flow nasal cannulae failed could be treated with nasal CPAP; infants in whom nasal CPAP failed were reintubated. RESULTS: The use of high-flow nasal cannulae was noninferior to the use of nasal CPAP, with treatment failure occurring in 52 of 152 infants (34.2%) in the nasal-cannulae group and in 39 of 151 infants (25.8%) in the CPAP group (risk difference, 8.4 percentage points; 95% confidence interval, -1.9 to 18.7). Almost half the infants in whom treatment with high-flow nasal cannulae failed were successfully treated with CPAP without reintubation. The incidence of nasal trauma was significantly lower in the nasal-cannulae group than in the CPAP group (P=0.01), but there were no significant differences in rates of serious adverse events or other complications. CONCLUSIONS: Although the result for the primary outcome was close to the margin of noninferiority, the efficacy of high-flow nasal cannulae was similar to that of CPAP as respiratory support for very preterm infants after extubation. (Funded by the National Health and Medical Research Council; Australian New Zealand Clinical Trials Network number, ACTRN12610000166077.). | Are high-flow nasal cannulae effective for treatment of preterm infants? | 530cf4c54a5037880c000002_000 | yes |
[Miller Fisher syndrome as the presenting symptom of Wernicke's encephalopathy]. INTRODUCTION: Wernicke's encephalopathy is an acute neuropsychiatric syndrome resulting from a thiamine deficit, which is defined by the characteristic triad of confusion, ophthalmoparesis and ataxia, although rare presentations have been reported that delay its diagnosis. Miller Fisher syndrome is characterised by the triad ophthalmoparesis, ataxia and areflexia and is considered to be a variant of Guillain-Barré syndrome; its differential diagnosis includes Wernicke's encephalopathy. CASE REPORT: A 75-year-old female with chronic digestive disorders, who developed an acute picture of bilateral internuclear ophthalmoplegia, ataxia and areflexia, with proteinocytologic dissociation in cerebrospinal fluid; accordingly, an initial diagnosis of Miller Fisher syndrome was proposed. Results of the neurophysiological studies were normal; anti-GQ1b antibodies were negative; and magnetic resonance imaging of the brain suggested Wernicke's encephalopathy. The response to thiamine was spectacular. CONCLUSIONS: The similarities in the distribution of the lesions of the two conditions, in the signs and symptoms and the lab findings, as well as the influence of certain misleading factors (hyponatremia, advanced age), went to make up a typical syndrome that favoured a wrong presumptive aetiological diagnosis. This was corrected at an early stage, however, in light of the results of certain diagnostic tests and after observing the therapeutic response. In addition to being an atypical presentation for Wernicke's encephalopathy, this case highlights the fact that for there to be an agreement between the syndromic and aetiological diagnoses it is necessary to carry out a correct differential diagnosis based on details from the patient's history, on appropriate complementary tests and on the follow-up study of how the patients progress, even when we come across typical syndromes that are usually related to a predominant aetiopathogenesis. | Is the Miller-Fisher syndrome considered to be a variant of Guillain-Barré? | 571f59cd0fd6f91b68000008_013 | yes |
Paediatric brain tumours: A review of radiotherapy, state of the art and challenges for the future regarding protontherapy and carbontherapy. BACKGROUND AND PURPOSE: Brain tumours are the most frequent solid tumours in children and the most frequent radiotherapy indications in paediatrics, with frequent late effects: cognitive, osseous, visual, auditory and hormonal. A better protection of healthy tissues by improved beam ballistics, with particle therapy, is expected to decrease significantly late effects without decreasing local control and survival. This article reviews the scientific literature to advocate indications of protontherapy and carbon ion therapy for childhood central nervous system cancer, and estimate the expected therapeutic benefits. MATERIALS AND METHODS: A systematic review was performed on paediatric brain tumour treatments using Medline (from 1966 to March of 2014). To be included, clinical trials had to meet the following criteria: age of patients 18 years or younger, treated with radiation, and report of survival. Studies were also selected according to the evidence level. A secondary search of cited references found other studies about cognitive functions, quality of life, the comparison of photon and proton dosimetry showing potential dose escalation and/or sparing of organs at risk with protontherapy; and studies on dosimetric and technical issues related to protontherapy. RESULTS: A total of 7051 primary references published were retrieved, among which 40 clinical studies and 60 papers about quality of life, dose distribution and dosimetry were analysed, as well as the ongoing clinical trials. These papers have been summarized and reported in a specific document made available to the participants of a final 1-day workshop. Tumours of the meningeal envelop and bony cranial structures were excluded from the analysis. Protontherapy allows outstanding ballistics to target the tumour area, while substantially decreasing radiation dose to the normal tissues. There are many indications of protontherapy for paediatric brain tumours in curative intent, either for localized treatment of ependymomas, germ-cell tumours, craniopharyngiomas, low-grade gliomas; or panventricular irradiation of pure non-secreting germinoma; or craniospinal irradiation of medulloblastomas and metastatic pure germinomas. Carbon ion therapy is just emerging and may be studied for highly aggressive and radioresistant tumours, as an initial treatment for diffuse brainstem gliomas, and for relapse of high-grade gliomas. CONCLUSION: Both protontherapy and carbon ion therapy are promising for paediatric brain tumours. The benefit of decreasing late effects without altering survival has been described for most paediatric brain tumours with protontherapy and is currently assessed in ongoing clinical trials with up-to-date proton devices. Unfortunately, in 2015, only a minority of paediatric patients in France can receive protontherapy due to the lack of equipment. | Is there a role of proton beam therapy in medulloblastoma treatment? | 58850ac7e56acf5176000012_004 | yes |
Accentuate the negative: proteome comparisons using the negative proteome database. The availability of complete genome sequence information for diverse organisms including model genetic organisms has ushered in a new era of protein sequence comparisons making it possible to search for commonalities among entire proteomes using the Basic Local Alignment Search Tool (BLAST). Although the identification and analysis of proteins shared by humans and model organisms has proven an invaluable tool to understanding gene function, the sets of proteins unique to a given model organism's proteome have remained largely unexplored. We have constructed a searchable database that allows biologists to identify proteins unique to a given proteome. The Negative Proteome Database (NPD) is populated with pair-wise protein sequence comparisons between each of the following proteomes: Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, Dictyostelium discoideum, Chlamydomonus reinhardti, Escherichia coli K12, Arabidopsis thaliana and Methanoscarcina acetivorans. Our analysis of negative proteome datasets using the NPD has thus far revealed 107 proteins in humans that may be involved in motile cilia function, 1628 potential pesticide target proteins in flies, 659 proteins shared by flies and humans that are not represented in the less neurologically complex worm proteome, and 180 nuclear encoded human disease associated proteins that are absent from the fly proteome. The NPD is the only online resource where users can quickly perform complex negative and positive comparisons of model organism proteomes. We anticipate that the NPD and the adaptable algorithm which can readily be used to duplicate this analysis on custom sets of proteomes will be an invaluable tool in the investigation of organism specific protein sets. | Is the Dictyostelium discoideum proteome known? | 56b39f148525abca1e000004_008 | yes |
Phenotype variation in two-locus mouse models of Hirschsprung disease: tissue-specific interaction between Ret and Ednrb. Clinical expression of Hirschsprung disease (HSCR) requires the interaction of multiple susceptibility genes. Molecular genetic analyses have revealed that interactions between mutations in the genes encoding the RET receptor tyrosine kinase and the endothelin receptor type B (EDNRB) are central to the genesis of HSCR. We have established two locus noncomplementation assays in mice, using allelic series at Ednrb in the context of Ret kinase-null heterozygotes, to understand the clinical presentation, incomplete penetrance, variation in length of aganglionic segment, and sex bias observed in human HSCR patients. Titration of Ednrb in the presence of half the genetic dose of Ret determines the presentation of an enteric phenotype in these strains, revealing or abrogating a sex bias in disease expression depending on the genotype at Ednrb. RET and EDNRB signaling pathways are also critical for the normal development of other tissues, including the kidneys and neural crest-derived melanocytes. Our data demonstrate that interaction between these genes is restricted to the enteric nervous system and does not affect renal, coat color, and retinal choroid development. | Are EDNRB mutations involved in the development of Hirschsprung disease? | 551910c5622b194345000007_021 | yes |
A naturalistic study of paroxetine in premenstrual syndrome: efficacy and side-effects during ten cycles of treatment. Eighteen women with severe premenstrual syndrome (PMS) (premenstrual dysphoric disorder, PMDD) were treated openly with paroxetine for 10 consecutive menstrual cycles. Dosage was flexible (5-30 mg/day); also, the patients were free to chose between continuous medication and medication in the luteal phase only. The rating of premenstrual irritability, depressed mood, increase in appetite, and anxiety/tension was markedly lower during treatment with paroxetine than before, and this reduction in symptomatology appeared unabated for the entire treatment period. Sedation, dry mouth, and nausea were common side-effects but declined during the course of the trial; in contrast, reduced libido and anorgasmia, which were reported by almost 50% of the participants, were not improved with time. The results indicate that the beneficial effects as well as the sexual side-effects of serotonin reuptake inhibitors persist unchanged for at least 10 consecutive cycles of treatment. | Is paroxetine effective for treatment of premenstrual dysphoric disorder? | 514a59c2d24251bc0500005d_012 | yes |
piRNA-mediated silencing in Drosophila germlines. PIWI interacting RNAs (piRNAs) are a subset of small RNAs predominantly expressed in the germlines of various species. In Drosophila, the main sources of piRNAs are transcripts of mobile DNA elements, including active transposons and their wreckage, found on the genome. After maturing from the primary transcripts, piRNAs are specifically loaded onto germline-specific Argonaute proteins - Argonaute3, Aubergine and Piwi - collectively referred to as PIWI proteins. Loss of function of PIWI proteins and/or the piRNA loci on the genome lead to derepression of transposons and causes severe defects in gametogenesis and fertility. The necessity for both PIWI proteins and piRNAs in protecting the genome of the gametes from mischievous mobile genomic elements is thus obvious. There have been extensive biochemical and genetic studies on PIWI proteins and piRNAs. These have shed light not only on the molecular mechanisms of gene silencing mediated by piRNAs and PIWI proteins, but also on their intriguing relationship with cellular genes that have been shown to be important for gametogenesis and fertility. | Are piRNAs involved in gene silencing? | 56c6f6005795f9a73e000009_003 | yes |
Loss of p15/Ink4b accompanies tumorigenesis triggered by complex DNA double-strand breaks. DNA double-strand breaks (DSBs) are the most deleterious lesion inflicted by ionizing radiation. Although DSBs are potentially carcinogenic, it is not clear whether complex DSBs that are refractory to repair are more potently tumorigenic compared with simple breaks that can be rapidly repaired, correctly or incorrectly, by mammalian cells. We previously demonstrated that complex DSBs induced by high-linear energy transfer (LET) Fe ions are repaired slowly and incompletely, whereas those induced by low-LET gamma rays are repaired efficiently by mammalian cells. To determine whether Fe-induced DSBs are more potently tumorigenic than gamma ray-induced breaks, we irradiated 'sensitized' murine astrocytes that were deficient in Ink4a and Arf tumor suppressors and injected the surviving cells subcutaneously into nude mice. Using this model system, we find that Fe ions are potently tumorigenic, generating tumors with significantly higher frequency and shorter latency compared with tumors generated by gamma rays. Tumor formation by Fe-irradiated cells is accompanied by rampant genomic instability and multiple genomic changes, the most interesting of which is loss of the p15/Ink4b tumor suppressor due to deletion of a chromosomal region harboring the CDKN2A and CDKN2B loci. The additional loss of p15/Ink4b in tumors derived from cells that are already deficient in p16/Ink4a bolsters the hypothesis that p15 plays an important role in tumor suppression, especially in the absence of p16. Indeed, we find that reexpression of p15 in tumor-derived cells significantly attenuates the tumorigenic potential of these cells, indicating that p15 loss may be a critical event in tumorigenesis triggered by complex DSBs. | Do DNA double-strand breaks play a causal role in carcinogenesis? | 5162f5b6298dcd4e5100004c_011 | yes |
From inflammation to sickness: historical perspective. The concept of the four cardinal signs of acute inflammation comes from antiquity as rubor et tumor cum calore et dolore, (redness and swelling with heat and pain) extended later by functio laesa (loss of function). The contemporary understanding of this process we owe to 19th-century milestone discoveries by Rudolph Virchow, Julius Cohnheim and Elie Metchnikoff. In the 20th century, the development of potent technological tools allowed the rapid expansion of knowledge of the cells and mediators of inflammatory processes, as well as the molecular mechanisms of their interactions. It turned out that some mediators of inflammation have both local and distant targets, among them the liver (responding by the production of several acute phase reactants) and neurohormonal centers. In the last decades it has become clear that the immune system shares mediators and their receptors with the neurohormonal system of the body; thus, they form a common homeostatic entity. Such an integrative view, introduced by J. Edwin Blalock, when combined with Hans Selye's concept of stress, led to the contemporary understanding of sickness behavior, defined by Robert Dantzer as a highly organized strategy of the organism to fight infections and to respond to other environmental stressors. | Is Loss of function one of the cardinal signs of inflammation? | 5a7a44b4faa1ab7d2e000010_002 | yes |
Chl1 and Ctf4 are required for damage-induced recombinations. Deletion mutants of CHL1 or CTF4, which are required for sister chromatid cohesion, showed higher sensitivity to the DNA damaging agents methyl methanesulfonate (MMS), hydroxyurea (HU), phleomycin, and camptothecin, similar to the phenotype of mutants of RAD52, which is essential for recombination repair. The levels of Chl1 and Ctf4 associated with chromatin increased considerably after exposure of the cells to MMS and phleomycin. Although the activation of DNA damage checkpoint did not affected in chl1 and ctf4 mutants, the repair of damaged chromosome was inefficient, suggesting that Chl1 and Ctf4 act in DNA repair. In addition, MMS-induced sister chromatid recombination in haploid cells, and, more importantly, MMS-induced recombination between homologous chromosomes in diploid cells were impaired in these mutants. Our results suggest that Chl1 and Ctf4 are directly involved in homologous recombination repair rather than acting indirectly via the establishment of sister chromatid cohesion. | Is Ctf4 involved in sister chromatid cohesion establishment? | 553a5a34bc4f83e82800001a_000 | yes |
Origins of the phospholipids in animal mitochondria. As is the case for the assembly of protein components of the membranes in animal mitochondria, the bilayer phospholipids arise from a complicated interplay of intra- and extra-mitochondrial reactions. Our early studies indicated that the bulk of mitochondrial phospholipids (typified by phosphatidylcholine) had their origin in the endoplasmic reticulum and were transported to the mitochondria as complexes with phospholipid-exchange proteins. The polyglycerophosphatides (typified by diphosphatidylglycerol) were apparently synthesized in situ by intramitochondrial membrane-bound enzymes using CDP-diglycerides as intermediates. The case for the precursors in the latter pathway is less clear, although evidence has been presented for dual localization of enzymes for glycerophosphate acylation and CTP:phosphatidate cytidylyl transfer in both mitochondria and microsomes. Phosphatidylethanolamine also shows evidence for two sites of origin: by translocation from its site of synthesis in the endoplasmic reticulum and by translocation of phosphatidylserine followed by decarboxylation within the mitochondria. In the latter case mitochondrial phosphatidylserine decarboxylase may play an important role in the regulation of phospholipid metabolism throughout the cell. | Is diphosphatidylglycerol (cardiolipin) a phospholipid of the mitochondrial membranes? | 58d90f228acda3452900000f_017 | yes |
Influenza virus inhibits RNA polymerase II elongation. The influenza virus RNA-dependent RNA polymerase interacts with the serine-5 phosphorylated carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II (Pol II). It was proposed that this interaction allows the viral RNA polymerase to gain access to host mRNA-derived capped RNA fragments required as primers for the initiation of viral mRNA synthesis. Here, we show, using a chromatin immunoprecipitation (ChIP) analysis, that similar amounts of Pol II associate with Pol II promoter DNAs in influenza virus-infected and mock-infected cells. However, there is a statistically significant reduction in Pol II densities in the coding region of Pol II genes in infected cells. Thus, influenza virus specifically interferes with Pol II elongation, but not Pol II initiation. We propose that influenza virus RNA polymerase, by binding to the CTD of initiating Pol II and subsequent cleavage of the capped 5' end of the nascent transcript, triggers premature Pol II termination. | Can RNAPolII function as an RNA-dependent RNA-polymerase? | 571696d9cb4ef8864c000009_003 | yes |
The complete exosome workflow solution: from isolation to characterization of RNA cargo. Exosomes are small (30-150 nm) vesicles containing unique RNA and protein cargo, secreted by all cell types in culture. They are also found in abundance in body fluids including blood, saliva, and urine. At the moment, the mechanism of exosome formation, the makeup of the cargo, biological pathways, and resulting functions are incompletely understood. One of their most intriguing roles is intercellular communication--exosomes function as the messengers, delivering various effector or signaling macromolecules between specific cells. There is an exponentially growing need to dissect structure and the function of exosomes and utilize them for development of minimally invasive diagnostics and therapeutics. Critical to further our understanding of exosomes is the development of reagents, tools, and protocols for their isolation, characterization, and analysis of their RNA and protein contents. Here we describe a complete exosome workflow solution, starting from fast and efficient extraction of exosomes from cell culture media and serum to isolation of RNA followed by characterization of exosomal RNA content using qRT-PCR and next-generation sequencing techniques. Effectiveness of this workflow is exemplified by analysis of the RNA content of exosomes derived from HeLa cell culture media and human serum, using Ion Torrent PGM as a sequencing platform. | Can exosomes be detected in urine? | 550895c12e93f0133a000002_009 | yes |
Role of the cysteine residues in Arabidopsis thaliana cyclophilin CYP20-3 in peptidyl-prolyl cis-trans isomerase and redox-related functions. Cyps (cyclophilins) are ubiquitous proteins of the immunophilin superfamily with proposed functions in protein folding, protein degradation, stress response and signal transduction. Conserved cysteine residues further suggest a role in redox regulation. In order to get insight into the conformational change mechanism and functional properties of the chloroplast-located CYP20-3, site-directed mutagenized cysteine-->serine variants were generated and analysed for enzymatic and conformational properties under reducing and oxidizing conditions. Compared with the wild-type form, elimination of three out of the four cysteine residues decreased the catalytic efficiency of PPI (peptidyl-prolyl cis-trans isomerase) activity of the reduced CYP20-3, indicating a regulatory role of dithiol-disulfide transitions in protein function. Oxidation was accompanied by conformational changes with a predominant role in the structural rearrangement of the disulfide bridge formed between Cys(54) and Cys(171). The rather negative E(m) (midpoint redox potential) of -319 mV places CYP20-3 into the redox hierarchy of the chloroplast, suggesting the activation of CYP20-3 in the light under conditions of limited acceptor availability for photosynthesis as realized under environmental stress. Chloroplast Prx (peroxiredoxins) were identified as interacting partners of CYP20-3 in a DNA-protection assay. A catalytic role in the reduction of 2-Cys PrxA and 2-Cys PrxB was assigned to Cys(129) and Cys(171). In addition, it was shown that the isomerization and disulfide-reduction activities are two independent functions of CYP20-3 that both are regulated by the redox state of its active centre. | Are cyclophilins ubiquitously expressed? | 56f6ab7009dd18d46b00000d_012 | yes |
[Treatment of amyotrophic lateral sclerosis with TRH]. In view of earlier reports in the literature it was tried to use TRH (thyrotropin releasing hormone) in cases of amyotrophic lateral sclerosis. TRH was given during 3 weeks once daily intravenously in drip infusions in a 0.4 mg dose. For objectivization of the results the muscle power was assessed using a five-grade scale of Lovette. TRH effect on EMG was analysed also. It was found that in only 3 out of 14 patients with moderately progressed disease no improvement was achieved, while in 11 cases the improvement was from 10 to 20%. However, the improvement was transient, and TRH treatment failed to stop the progression of the disease. | Is there any data to suggest that TRH (thyrotropin releasing hormone) administration can improve symptom severity of amyotrophic lateral sclerosis patients? | 54d76ac63706e89528000016_006 | yes |
Expressions of miRNAs in papillary thyroid carcinoma and their associations with the BRAFV600E mutation. OBJECTIVE: Alterations in microRNA (miRNA) expression have been described in thyroid tumors, suggesting a role for miRNAs in thyroid carcinogenesis. BRAF(V600E) is the most frequently identified genetic alteration in papillary thyroid carcinoma (PTC). We investigated the link between BRAF(V600E) status and the expression of miRNAs in PTC and analyzed the associations of these factors with clinicopathological characteristics. DESIGN AND METHODS: Prospective study of patients who underwent thyroid surgery between October 8, 2008 and November 1, 2010. BRAF(V600E) status was determined by mutant allele-specific amplification PCR and direct sequencing of exon 15 of the BRAF gene in 69 PTC tissues and 69 respective paracancerous normal thyroid tissues. Initially, miRNA expression was analyzed in 12 PTC tissues and three associated paracancerous tissues using a miRNA microarray. miRNAs differentially expressed between BRAF(V600E)-positive and -negative PTC tissues were then validated by real-time quantitative PCR on 69 PTC tissues and 69 paracancerous tissues. We also explored the associations between BRAF(V600E) status or differential miRNA expression and clinicopathological characteristics. RESULTS: The mutation rate of BRAF(V600E) in PTC was 47.8%. Twelve miRNAs were upregulated and six were downregulated in PTC tissues, among which miR-15a, 15a*, 34a*, 34b*, 551b, 873, 876-3p, and 1274a were first identified. miR-21* and 203 were significantly dysregulated (P<0.05) in PTC tissues with BRAF(V600E). Additionally, there were significant associations (P<0.05) between BRAF(V600E) and a higher tumor-node-metastasis staging (III/IV), and between miR-21* over-expression and lymph node metastasis. CONCLUSIONS: We identified two miRNAs that are differentially expressed in PTC tissues with BRAF(V600E) and revealed their associations with clinicopathological features. These findings may lead to the development of a potential diagnostic biomarker or prognostic indicator of PTC. | Is miR-21 related to carcinogenesis? | 511a4ec01159fa8212000004_064 | yes |
Selective antagonism to succinylcholine-induced depolarization by alpha-bungarotoxin with respect to the mode of action of depolarizing agents. 1. The interactions of alpha-bungarotoxin or tubocurarine with the neuromuscular block and endplate depolarization induced by succinylcholine (SCh) in the phrenic nerve-diaphragm preparation of mice were studied in order to elucidate the role of depolarization by SCh in the neuromuscular blockade. 2. The SCh concentrations required to depress the indirect twitch response by 20% and the evoked endplate potential in cut muscle preparations by 80% were 10 microm and 6 microM, respectively, while only 2 microM SCh was needed to induce maximal endplate depolarization from -80 mV to about -60 mV. 3. SCh blocked the neuromuscular transmission synergistically with either alpha-bungarotoxin or tubocurarine. There was an initial partial reversal of the neuromuscular inhibition caused by tubocurarine, but not that by alpha-bungarotoxin. 4. alpha-Bungarotoxin (0.025 microM) antagonized SCh (10 microM)-induced depolarization more effectively than it depressed miniature endplate potentials and the antagonism was insurmountable by increasing SCh concentration. By contrast, tubocurarine preferentially depressed miniature endplate potentials and antagonized SCh-depolarization competitively. 5. The above difference was attributed to the irreversible nature of alpha-bungarotoxin binding to acetylcholine receptors, to the slow diffusion of the toxin molecule into the synaptic cleft and thus to the more rapid binding with perijunctional receptors compared with junctional ones. 6. It is concluded that the sustained depolarization of the endplate by SCh results largely from an action on the perijunctional receptor in mice and, unlike cats, the neuromuscular block by SCh is not due to the depolarization per se but rather to a direct attenuation of endplate potential. | Does d-tubocurarine (d-TC) induces irreversible inhibition of nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction? | 554614bcd355485447000004_006 | no |
Trial assessing individualized options for treatment for breast cancer: the TAILORx trial. Novel genetic profiling tests of breast cancer tissue have been shown to be prognostic for overall survival and predictive of local and distant rates of recurrence in breast cancer patients. One of these tests, Oncotype DXtrade mark, is a diagnostic test comprised of a 21-gene assay applied to paraffin-embedded breast cancer tissue, which allows physicians to predict subgroups of hormone-receptor-positive, node-negative patients who may benefit from hormonal therapy alone or require adjuvant chemotherapy to attain the best survival outcome. The results of the assay are converted to a recurrence score (0-100) that has been found to be predictive of 10- and 15-year local and distant recurrence in node-negative, estrogen-receptor-positive breast cancer patients. Previous studies have shown that patients with high recurrence scores benefit from adjuvant chemotherapy, whereas patients with low recurrence scores do not. To evaluate the ability to guide treatment decisions in the group with a mid-range recurrence score, the North American Cooperative Groups developed the Trial Assessing IndiviuaLized Options for Treatment for breast cancer, a randomized trial of chemotherapy followed by hormonal therapy versus hormonal therapy alone on invasive disease-free survival-ductal carcinoma in situ (IDFS-DCIS) survival in women with node-negative, estrogen-receptor-positive breast cancer with a recurrence score of 11-25. The study was initiated in May 2006 and approximately 4500 patients will be randomized. This article describes the rationale, methodology, statistical ana-lysis and implications of the results on clinical practice. | Does the Oncotype DX test work with paraffin embedded tissues? | 514a0f0ad24251bc05000052_002 | yes |
Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. BACKGROUND: The first analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (median follow-up, 33 months) demonstrated that in adjuvant endocrine therapy for postmenopausal patients with early-stage breast cancer, anastrozole was superior to tamoxifen in terms of disease-free survival (DFS), time to recurrence (TTR), and incidence of contralateral breast cancer (CLBC). In the current article, the results of the first efficacy update, based on a median follow-up period of 47 months, are reported along with the results of an updated safety analysis, performed 7 months after the first analysis (median duration of treatment, 36.9 months). METHODS: DFS, TTR, CLBC incidence, and safety were assessed in the same patient group as in the first analysis of the ATAC trial. RESULTS: DFS estimates at 4 years remained significantly more favorable (86.9% vs. 84.5%, respectively) for patients receiving anastrozole compared with those receiving tamoxifen (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76-0.99; P = 0.03). The benefit generated by anastrozole in terms of DFS was even greater in patients with hormone receptor-positive tumors (HR, 0.82; 95% CI, 0.70-0.96; P = 0.014). The HR for TTR also indicated a significant benefit for patients receiving anastrozole compared with those receiving tamoxifen (HR, 0.83; 95% CI, 0.71-0.96; P = 0.015), with additional benefit for patients with hormone receptor-positive tumors (HR, 0.78; 95% CI, 0.65-0.93; P = 0.007). CLBC incidence data also continued to favor anastrozole (odds ratio [OR], 0.62; 95% CI, 0.38-1.02; P = 0.062), and statistical significance was achieved in the hormone receptor-positive subgroup (OR, 0.56; 95% CI, 0.32-0.98; P = 0.042). The updated safety analysis also confirmed the findings of the first analysis, in that endometrial cancer (P = 0.007), vaginal bleeding and discharge (P < 0.001 for both), cerebrovascular events (P < 0.001), venous thromboembolic events (P < 0.001), and hot flashes (P < 0.001) all occurred less frequently in the anastrozole group, whereas musculoskeletal disorders and fractures (P < 0.001 for both) continued to occur less frequently in the tamoxifen group. These results indicated that the safety profile of anastrozole remained consistent. CONCLUSIONS: After an additional follow-up period, anastrozole continues to show superior efficacy, which is most apparent in the clinically relevant hormone receptor-positive population. Furthermore, anastrozole has numerous noteworthy advantages in terms of tolerability compared with tamoxifen. These findings suggest that the benefits of anastrozole are likely to be maintained in the long term and provide further support for the status of anastrozole as a valid treatment option for postmenopausal women with hormone-sensitive early-stage breast cancer. | Could Arimidex (anastrozole) cause hot flashes? | 516523fd298dcd4e51000055_003 | yes |
Monoclonal antibody therapy for prostate cancer. Early detection of prostate cancer (PCa) and advances in hormonal and chemotherapy treatments have provided great clinical benefits to patients with early stages of the disease. However, a significant proportion of patients still progress to advanced, metastatic disease, for which no effective therapies are available. Therefore, there is a critical need for new treatment modalities, ideally targeted specifically to prostate cancer cells. The recent clinical and commercial successes of monoclonal antibodies (MAbs) have made them the most rapidly expanding class of therapeutics being developed for many disease indications, including cancer. PCa is well suited for antibody-based therapy due to the size and location of recurrent and metastatic tumors, and the lack of necessity to avoid targeting the normal prostate, a nonessential organ. These properties have fostered interest in the development and clinical evaluation of therapeutic MAbs directed to both well established and newly discovered targets in PCa. MAbs directed to established targets include those approved for other solid tumors, including anti-human epidermal growth factor receptor-2 (HER2) MAb trastuzumab, anti-epidermal growth factor receptor (EGFR) MAbs cetuximab and panitumumab, and the antivascular endothelial growth factor (VEGF) MAb bevacizumab. Genomics efforts have yielded a large number of novel, clinically relevant targets in PCa with the desirable expression profiling in tumor and normal tissues, and with an implicated role in tumor growth and spread. Growing efforts are directed to the development of naked or payload-conjugated therapeutic antibodies to these targets, and a variety of MAb products are currently progressing through preclinical and various stages of clinical development. The clinical experience with some of the commercialized MAb products points out specific challenges in conducting clinical trials with targeted therapy in PCa. | Is the monoclonal antibody Trastuzumab (Herceptin) of potential use in the treatment of prostate cancer? | 5313b049e3eabad021000013_003 | yes |
Use of propofol infusion in Australian and New Zealand paediatric intensive care units. Despite the risk of propofol infusion syndrome, a rare but often fatal complication of propofol infusion in ventilated children and possibly adults, propofol infusion remains in use in paediatric intensive care units (PICU). This questionnaire study surveys the current pattern of use of this sedative infusion in Australian and New Zealand PICUs. Thirty-three of the 45 paediatric intensive care physicians surveyed (73%), from 12 of the 13 intensive care units, returned completed questionnaires. The majority of practitioners (82%) use propofol infusion in children in PICU, the main indication being for short-term sedation in children requiring procedures. 39% of respondents consider propofol infusion useful in ventilated children requiring longer-term sedation. 67% of paediatric intensivists use maximum infusion doses that may be considered dangerously high (> or = 10 mg/kg/h). Nineteen per cent use propofol infusion for prolonged periods (> 72 hours). A smaller proportion (15%) of respondents indicate that they may use both higher doses and prolonged periods of infusion, a practice likely to lead to a greater chance of serious adverse events. Knowledge of local protocols for the use of propofol infusion is associated with a significantly greater level of monitoring for possible adverse events. We suggest that national guidelines for the use of propofol infusion in children should be developed. These should include clear indications and contraindications to its use, a maximum dose rate and maximum period of infusion, with a ceiling placed on the cumulative dose given and clearly stated minimum monitoring requirements. | Is Propofol used for short-term sedation? | 515d9a42298dcd4e5100000d_017 | yes |
DNA damage regulates alternative splicing through inhibition of RNA polymerase II elongation. DNA damage induces apoptosis and many apoptotic genes are regulated via alternative splicing (AS), but little is known about the control mechanisms. Here we show that ultraviolet irradiation (UV) affects cotranscriptional AS in a p53-independent way, through the hyperphosphorylation of RNA polymerase II carboxy-terminal domain (CTD) and a subsequent inhibition of transcriptional elongation, estimated in vivo and in real time. Phosphomimetic CTD mutants not only display lower elongation but also duplicate the UV effect on AS. Consistently, nonphosphorylatable mutants prevent the UV effect. Apoptosis promoted by UV in cells lacking p53 is prevented when the change in AS of the apoptotic gene bcl-x is reverted, confirming the relevance of this mechanism. Splicing-sensitive microarrays revealed a significant overlap of the subsets of genes that have changed AS with UV and those that have reduced expression, suggesting that transcriptional coupling to AS is a key feature of the DNA-damage response. | Is alternative splicing of apoptotic genes playing a role in the response to DNA or mitochondrial damage? | 5175b97a8ed59a060a00002f_004 | yes |
Reduced endothelin-3 expression in sporadic Hirschsprung disease. BACKGROUND: Enteric aganglionosis in Hirschsprung disease has been linked to genes coding for endothelin-3 (EDN3) and the endothelin B receptor (EDNRB), but there is no such linkage in most patients with sporadic Hirschsprung disease. However, the similarity between the distal colonic aganglionosis in Hirschsprung disease and that due to EDN3 or EDNRB mutations led to the hypothesis that levels of expression of these genes might be affected in the absence of mutation, thus causing the Hirschsprung disease phenotype. The aim of this study was to determine EDN3 and EDNRB messenger RNA (mRNA) levels in tissue samples from patients with sporadic Hirschsprung disease. METHODS: RNA and DNA were isolated from the ganglionic and aganglionic colonic segments of ten children with sporadic Hirschsprung disease, and from the colon of ten age-matched controls. The DNA was analysed for mutations in the genes coding for endothelin-3 (ET-3) and endothelin B receptor (ET-B) proteins. Relative levels of EDN3 and EDNRB mRNA were determined by semi-quantitative transcriptase-polymerase chain reaction. RESULTS: Three children had sequence variants in EDN3 and EDNRB. In the remaining seven patients, EDN3 mRNA levels were reduced in both the ganglionic and aganglionic colon compared with levels in controls; there was no difference in expression of EDNRB between groups. CONCLUSION: In the absence of mutation, EDN3 is downregulated in short-segment Hirschsprung disease, suggesting that this may be a common step leading to aganglionosis. | Are EDNRB mutations involved in the development of Hirschsprung disease? | 551910c5622b194345000007_022 | yes |
Cognitive behavioral therapy for insomnia outcomes in women after primary breast cancer treatment: a randomized, controlled trial. PURPOSE/OBJECTIVES: To examine the effect of cognitive-behavioral therapy for insomnia (CBTI) on sleep improvement, daytime symptoms, and quality of life (QOL) in breast cancer survivors (BCSs) after cancer treatment. DESIGN: A prospective, longitudinal, randomized, controlled trial. SETTING: Oncology clinics, breast cancer support groups, and communities in Colorado. SAMPLE: 56 middle-aged BCSs with chronic insomnia. METHODS: Women were randomly assigned to CBTI or behavioral placebo treatment (BPT) and completed measures of sleep, QOL, functioning, fatigue, and mood at baseline, postintervention, and at three- and six-month follow-ups. MAIN RESEARCH VARIABLES: Sleep outcomes (e.g., sleep efficiency, sleep latency, total sleep time, wake after sleep onset, number of nightly awakenings); secondary variables included sleep medication use, insomnia severity, QOL, physical function, cognitive function, fatigue, depression, anxiety, and sleep attitudes or knowledge. FINDINGS: Sleep efficiency and latency improved more in the CBTI group than the BPT group; this difference was maintained during follow-up. Women in the CBTI group had less subjective insomnia, greater improvements in physical and cognitive functioning, positive sleep attitudes, and increased sleep hygiene knowledge. No group differences in improvement were noted relative to QOL, fatigue, or mood. CONCLUSIONS: Nurse-delivered CBTI appears to be beneficial for BCSs' sleep latency/efficiency, insomnia severity, functioning, sleep knowledge, and attitudes more than active placebo, with sustained benefit over time. IMPLICATIONS FOR NURSING: Oncology nurses are in a unique position to identify insomnia in cancer survivors. When sleep disturbances become chronic, nurses need to make recommendations and referrals. | Can cognitive behavioral therapy improve fatigue in cancer patients? | 54d762653706e89528000014_007 | yes |
A model in vitro system for co-transcriptional splicing. A hallmark of metazoan RNA polymerase II transcripts is the presence of numerous small exons surrounded by large introns. Abundant evidence indicates that splicing to excise introns occurs co-transcriptionally, prior to release of the nascent transcript from RNAP II. Here, we established an efficient model system for co-transcriptional splicing in vitro. In this system, CMV-DNA constructs immobilized on beads generate RNAP II transcripts containing two exons and an intron. Consistent with previous work, our data indicate that elongating nascent transcripts are tethered to RNAP II on the immobilized DNA template. We show that nascent transcripts that reach full length, but are still attached to RNAP II, are efficiently spliced. When the nascent transcript is cleaved within the intron using RNase H, both the 5' and 3' cleavage fragments are detected in the bound fraction, where they undergo splicing. Together, our work establishes a system for co-transcriptional splicing in vitro, in which the spliceosome containing the 5' and 3' exons are tethered to RNAP II for splicing. | Does splicing occur co-transcriptionally? | 533c3871c45e133714000007_008 | yes |
Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. BACKGROUND & AIMS: Alcohol abuse is a major cause of liver injury. The pathologic features of alcoholic liver disease develop over prolonged periods, yet the cellular defense mechanisms against the detrimental effects of alcohol are not well understood. We investigated whether macroautophagy, an evolutionarily conserved cellular mechanism that is commonly activated in response to stress, could protect liver cells from ethanol toxicity. METHODS: Mice were acutely given ethanol by gavage. The effects of ethanol on primary hepatocytes and hepatic cell lines were also studied in vitro. RESULTS: Ethanol-induced macroautophagy in the livers of mice and cultured cells required ethanol metabolism, generation of reactive oxygen species, and inhibition of mammalian target of rapamycin signaling. Suppression of macroautophagy with pharmacologic agents or small interfering RNAs significantly increased hepatocyte apoptosis and liver injury; macroautophagy therefore protected cells from the toxic effects of ethanol. Macroautophagy induced by ethanol seemed to be selective for damaged mitochondria and accumulated lipid droplets, but not long-lived proteins, which could account for its protective effects. Increasing macroautophagy pharmacologically reduced hepatotoxicity and steatosis associated with acute ethanol exposure. CONCLUSIONS: Macroautophagy protects against ethanol-induced toxicity in livers of mice. Reagents that modify macroautophagy might be developed as therapeutics for patients with alcoholic liver disease. | Is macroautophagy a selective degradation process? | 51bedaac3148fdcc22da7188_036 | yes |
Genomes of diverse isolates of the marine cyanobacterium Prochlorococcus. The marine cyanobacterium Prochlorococcus is the numerically dominant photosynthetic organism in the oligotrophic oceans, and a model system in marine microbial ecology. Here we report 27 new whole genome sequences (2 complete and closed; 25 of draft quality) of cultured isolates, representing five major phylogenetic clades of Prochlorococcus. The sequenced strains were isolated from diverse regions of the oceans, facilitating studies of the drivers of microbial diversity-both in the lab and in the field. To improve the utility of these genomes for comparative genomics, we also define pre-computed clusters of orthologous groups of proteins (COGs), indicating how genes are distributed among these and other publicly available Prochlorococcus genomes. These data represent a significant expansion of Prochlorococcus reference genomes that are useful for numerous applications in microbial ecology, evolution and oceanography. | Is Prochlorococcus the most abundant photosynthetic organism? | 58ea659c3e8b6dc87c000013_000 | yes |
Reduction in pain scores and improvement in depressive symptoms in patients with hidradenitis suppurativa treated with adalimumab in a phase 2, randomized, placebo-controlled trial. BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory skin disease with frequent comorbidities of painand depression. Adalimumab treatment for 16 weeks improved HS lesions significantly versus placebo (NCT00918255). OBJECTIVE: The relationship between pain and depressive symptoms and the effects of adalimumab on each was examined in this post hoc analysis. METHODS: Patients with moderate to severe HS (N=154) were randomized 1:1:1 to adalimumab 40 mg weekly (ew), adalimumab 40 mg every other week (eow), or placebo. Skin pain was assessed using a visual analog scale (VAS; 0-100 mm). Depressive symptoms were assessed using the 9-item Patient Health Questionnaire (PHQ-9; score > 10 indicative of depression). RESULTS: At baseline, overall mean±SD pain VAS was 54.3±26.5 mm and 41.8% of patients had PHQ-9 scores > 10. At baseline, VAS pain scores (mean±SD) were significantly higher (P<0.001) for patients with PHQ-9 scores > 10 (63.9±23.3) versus <10 (47.4±26.7). At Week 16, clinically relevant pain reduction was observed for ew-treated patients with baseline PHQ-9 score > 10 (ew, 45.8%; eow, 29.4%; placebo, 23.8%) and <10 (ew, 50.0%; eow, 37.9%; placebo, 29.6%), but did not reach statistical significance. In patients with high baseline pain ( > median VAS score), adalimumab ew significantly decreased depressivesymptoms versus placebo (PHQ-9 scores, -34.03% vs +2.26%; P<0.01). CONCLUSION: Patients with moderate to severe HS had a high degree of pain and depressive symptoms at baseline. Adalimumabtherapy was associated with decreased pain and depressive symptoms compared to baseline. | Is adalimumab effective for hidradenitis suppurativa? | 58847e36e56acf5176000009_010 | yes |
Alu and LINE-1 hypomethylation is associated with HER2 enriched subtype of breast cancer. The changes in DNA methylation status in cancer cells are characterized by hypermethylation of promoter CpG islands and diffuse genomic hypomethylation. Alu and long interspersed nucleotide element-1 (LINE-1) are non-coding genomic repetitive sequences and methylation of these elements can be used as a surrogate marker for genome-wide methylation status. This study was designed to evaluate the changes of Alu and LINE-1 hypomethylation during breast cancer progression from normal to pre-invasive lesions and invasive breast cancer (IBC), and their relationship with characteristics of IBC. We analyzed the methylation status of Alu and LINE-1 in 145 cases of breast samples including normal breast tissue, atypical ductal hyperplasia/flat epithelial atypia (ADH/FEA), ductal carcinoma in situ (DCIS) and IBC, and another set of 129 cases of IBC by pyrosequencing. Alu methylation showed no significant changes during multistep progression of breast cancer, although it tended to decrease during the transition from DCIS to IBC. In contrast, LINE-1 methylation significantly decreased from normal to ADH/FEA, while it was similar in ADH/FEA, DCIS and IBC. In IBC, Alu hypomethylation correlated with negative estrogen receptor (ER) status, and LINE-1 hypomethylation was associated with negative ER status, ERBB2 (HER2) amplification and p53 overexpression. Alu and LINE-1 methylation status was significantly different between breast cancer subtypes, and the HER2 enriched subtype had lowest methylation levels. In survival analyses, low Alu methylation status tended to be associated with poor disease-free survival of the patients. Our findings suggest that LINE-1 hypomethylation is an early event and Alu hypomethylation is probably a late event during breast cancer progression, and prominent hypomethylation of Alu and LINE-1 in HER2 enriched subtype may be related to chromosomal instability of this specific subtype. | Is Alu hypomethylation associated with breast cancer? | 54db1d580f63c58e6e000005_001 | yes |
Treatment of chronic palmoplantar eczema with local bath-PUVA therapy. BACKGROUND: Systemic PUVA therapy may be useful in the treatment of chronic palmoplantar eczema. Topical PUVA-paint avoids some of the unwanted side effects of systemic psoralens and has been used successfully in the treatment of palmoplantar eczema and psoriasis. However, few data are available on the effectiveness of local bath-PUVA therapy in palmoplantar eczema. OBJECTIVE: Our purpose was to assess the effectiveness of local bath-PUVA therapy in 28 patients with chronic palmar or plantar eczema or both who were resistant to conventional topical treatment. METHODS: After fungal or bacterial infection had been excluded in all patients, hands or feet or both were soaked for 15 minutes in warm water containing 1 mg/L 8-methoxypsoralen. Immediately after, the skin was irradiated with increasing doses of UVA, starting with 0.5 J/cm2. PUVA-bath therapy was performed 4 times a week up to a total of 25 treatments. No additional therapy was allowed except emollients. RESULTS: Excellent or good effects were achieved in 93% of the patients with dyshidrotic and in 86% of the patients with hyperkeratotic eczema. In the patients with dyshidrotic eczema, the cumulative doses and the highest single doses of UVA were lower than those in the patients with hyperkeratotic eczema (21.4 vs 27.9 J/cm2 and 2.4 vs 3.0 J/cm2 of UVA), but this was not statistically significant. No phototoxic reactions were observed. CONCLUSION: Local bath-PUVA therapy is of value in the management of chronic palmoplantar eczema resistant to standard modes of topical treatment. Compared with topical PUVA-paint, local bath-PUVA therapy has several advantages, particularly the absence of phototoxic reactions, severe hyperpigmentation, and protracted photosensitivity. | Is PUVA therapy indicated for eczema treatment? | 58bfe70e02b8c60953000019_012 | yes |
Intraoperative remote afterloading endocurietherapy with high-activity 60cobalt for treatment of glioblastoma multiforme. An intraoperative remote afterloading endocurietherapy technique with high-activity 60Co for the treatment of glioblastoma multiforme is described. The technique can be used for initial management of the unresectable tumor or for retreatment of patients with recurrent tumor who have been treated previously with surgery and postoperative radiotherapy. Neither intraoperative nor postoperative complications were encountered in our treatment of 11 patients in this Phase I toxicity study. | Is intraoperative radiotherapy used for treatment of glioblastoma? | 589a245478275d0c4a000022_003 | no |
SSPE: but we thought measles was gone! Subacute sclerosing panencephalitis (SSPE) is a progressive neurodegenerative disease caused by the measles (rubeola) virus and is most often seen in children. Many affected children have a history of measles infection in the first years of life or exposure to the live measles virus vaccine. Typically, there is a rapid onset of neurological symptoms degenerating into a stuporous state in the patient. Four children and their families are reviewed. Their individual courses, medical and nursing problems and interventions, and implications for immunizations with the measles-mumps-rubella (MMR) vaccine will be discussed. | Is subacute sclerosing panencephalitis caused by the Measles vaccine? | 5aa3fa73d6d6b54f79000008_002 | no |
Characteristics and prognostic importance of myocardial fibrosis in patients with dilated cardiomyopathy assessed by contrast-enhanced cardiac magnetic resonance imaging. INTRODUCTION: Dilated cardiomyopathy (DCM) is associated with significant morbidity and mortality. Contrast-enhanced cardiac MRI (CE-CMR) can detect potentially prognostic myocardial fibrosis in DCM. We investigated the role of CE-CMR in New Zealand patients with DCM, both Maori and non-Maori, including the characteristics and prognostic importance of fibrosis. METHODS: One hundred and three patients (mean age 58 ± 13, 78 male) referred for CMR assessment of DCM were followed for 660 ± 346 days. Major adverse cardiac events (MACE) were defined as death, infarction, ventricular arrhythmias or rehospitalisation. CE-CMR used cines for functional analysis, and delayed enhancement to assess fibrosis. RESULTS: Myocardial fibrosis was present in 30% of patients, the majority of which was mid-myocardial (63%). Volumetric parameters were similar in patients with or without fibrosis. At 2 years patients with fibrosis had an increased rate of MACE (HR = 0.77, 95% CI 0.3-2.0). Patients with full thickness or subendocardial fibrosis had the highest MACE, even in the absence of CAD). More Maori had fibrosis on CE-CMR (40% vs. 28% for non-Maori), and the majority (75%) was mid-myocardial. Maori and non-Maori had similar outcomes (25% vs. 24% with events during follow-up). CONCLUSIONS: DCM patients frequently have myocardial fibrosis detected on CE-CMR, the majority of which is mid-myocardial. Fibrosis is associated with worse outcome in the medium term. The information obtained using CE-CMR in DCM may be of incremental clinical benefit. | Is delayed enhancement documented in patients with non-ischemic dilated cardiomyopathy? | 5339ed7bd6d3ac6a34000060_000 | yes |
DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes. Single-nucleotide substitutions are a defining characteristic of cancer genomes. Many single-nucleotide substitutions in cancer genomes arise because of errors in DNA replication, which is spatio-temporally stratified. Here we propose that DNA replication patterns help shape the mutational landscapes of normal and cancer genomes. Using data on five fully sequenced cancer types and two personal genomes, we determined that the frequency of intergenic single-nucleotide substitution is significantly higher in late DNA replication timing regions, even after controlling for a number of genomic features. Furthermore, some substitution signatures are more frequent in certain DNA replication timing zones. Finally, integrating data on higher-order nuclear organization, we found that genomic regions in close spatial proximity to late-replicating domains display similar mutation spectra as the late-replicating regions themselves. These data suggest that DNA replication timing together with higher-order genomic organization contribute to the patterns of single-nucleotide substitution in normal and cancer genomes. | Does replication timing affect the rate of somatic mutations? | 5710dd61cf1c32585100002e_011 | yes |
Genomic profiling of microRNAs and proteomics reveals an early molecular alteration associated with tumorigenesis induced by MC-LR in mice. Studies have demonstrated that microcystins (MCs) can act as potential carcinogens and have caused serious risk to public environmental health. The molecular mechanisms of MC-induced susceptibility to carcinogenesis are largely unknown. In this study, we performed for the first time a comprehensive analysis of changes in microRNAs (miRNAs) and proteins expression in livers of mice treated with MC-LR. Utilizing microarray and two-dimensional gel electrophoresis (2-DE) analysis, we identified 37 miRNAs and 42 proteins significantly altered. Many aberrantly expressed miRNAs were related to various cancers (e.g., miR-125b, hepatocellular carcinoma; miR-21, leukemia; miR-16, chronic lymphocytic leukemia; miR-192, pituitary adenomas; miR-199a-3p, ovarian cancer; miR-34a, pancreatic cancer). Several miRNAs (e.g., miR-34a, miR-21) and proteins (e.g., TGM2, NDRG2) that play crucial roles in liver tumorigenesis were first found to be affected by MC-LR in mouse liver. MC-LR also altered the expression of a number of miRNAs and proteins involved in several pathways related to tumorigenesis, such as glutathione metabolism, VEGF signaling, and MAPK signaling pathway. Integration of post-transcriptomics, proteomics, and transcriptomics reveals that the networks miRNAs and their potential target genes and proteins involved in had a close association with carcinogenesis. These results provide an early molecular mechanism for liver tumorigenesis induced by MCs. | Is miR-21 related to carcinogenesis? | 511a4ec01159fa8212000004_001 | yes |
The impact of cobalt-60 source age on biologically effective dose in high-dose functional Gamma Knife radiosurgery. OBJECTIVE Functional Gamma Knife radiosurgery (GKRS) procedures have been increasingly used for treating patients with tremor, trigeminal neuralgia (TN), and refractory obsessive-compulsive disorder. Although its rates of toxicity are low, GKRS has been associated with some, if low, risks for serious sequelae, including hemiparesis and even death. Anecdotal reports have suggested that even with a standardized prescription dose, rates of functional GKRS toxicity increase after replacement of an old cobalt-60 source with a new source. Dose rate changes over the course of the useful lifespan of cobalt-60 are not routinely considered in the study of patients treated with functional GKRS, but these changes may be associated with significant variation in the biologically effective dose (BED) delivered to neural tissue. METHODS The authors constructed a linear-quadratic model of BED in functional GKRS with a dose-protraction factor to correct for intrafraction DNA-damage repair and used standard single-fraction doses for trigeminal nerve ablation for TN (85 Gy), thalamotomy for tremor (130 Gy), and capsulotomy for obsessive-compulsive disorder (180 Gy). Dose rate and treatment time for functional GKRS involving 4-mm collimators were derived from calibrations in the authors' department and from the cobalt-60 decay rate. Biologically plausible values for the ratio for radiosensitivity to fraction size (α/β) and double-strand break (DSB) DNA repair halftimes (τ) were estimated from published experimental data. The biphasic characteristics of DSB repair in normal tissue were accounted for in deriving an effective τ halftime (fast repair) and τ halftime (slow repair). A sensitivity analysis was performed with a range of plausible parameter values. RESULTS After replacement of the cobalt-60 source, the functional GKRS dose rate rose from 1.48 to 2.99 Gy/min, treatment time fell, and estimated BED increased. Assuming the most biologically plausible parameters, source replacement resulted in an immediate relative BED increase of 11.7% for GKRS-based TN management with 85 Gy, 15.6% for thalamotomy with 130 Gy, and 18.6% for capsulotomy with 180 Gy. Over the course of the 63-month lifespan of the cobalt-60 source, BED decreased annually by 2.2% for TN management, 3.0% for thalamotomy, and 3.5% for capsulotomy. CONCLUSIONS Use of a new cobalt-60 source after replacement of an old source substantially increases the predicted BED for functional GKRS treatments for the same physical dose prescription. Source age, dose rate, and treatment time should be considered in the study of outcomes after high-dose functional GKRS treatments. Animal and clinical studies are needed to determine how this potential change in BED contributes to GKRS toxicity and whether technical adjustments should be made to reduce dose rates or prescription doses with newer cobalt-60 sources. | Is there a role for gamma knife in treatment of Obsessive-Compulsive Disorder? | 5898500478275d0c4a000017_002 | yes |
B-cell activating factor genetic variants in lymphomagenesis associated with primary Sjogren's syndrome. Primary Sjogren's syndrome (pSS) is complicated by B-cell lymphoma in 5-10% of patients. Several clinical and serological features are proposed as adverse predictors for such complication and define a high risk pSS phenotype. We aimed to explore whether previously described polymorphisms of the B-cell activating factor (BAFF) could be related to pSS-related lymphomagenesis. Five single nucleotide polymorphisms (SNPs) of the BAFF gene (rs1224141, rs12583006, rs9514828, rs1041569 and the rs9514827) were evaluated in 111 low risk pSS patients (type II), 82 high risk/lymphoma patients (type I) and 137 healthy controls (HC) by PCR-based assays. The classification of pSS patients into types I and II was based on the presence or absence of risk factors or lymphoma development, respectively. Genotype and haplotype analysis was performed for all variants in the pSS groups. Since the rs1041569 SNP was not in Hardy-Weinberg equilibrium in the HC group (p < 0.001), haplotype analysis was performed in the remaining four out of the five SNPs tested when comparisons with HC individuals were performed. The high risk pSS group was characterized by higher frequency of the minor T allele of the rs9514828 BAFF polymorphism compared to HC. Compared to the low risk pSS patients but not the HC, the high risk pSS group exhibited lower frequencies of the AA genotype of the rs12583006 polymorphism as well as the TACAC and TACC haplotypes and higher frequency of the TTTC haplotype. The low risk pSS group exhibited higher frequency of the minor A allele and AA genotype of the rs12583006 variant compared to HC. Both pSS groups were characterized by increased frequency of the haplotype TATT and GTTC and decreased frequency of the TTCT when compared to HC. Taken together, these findings suggest the implication of the host's genetic background in pSS-related lymphomagenesis. The interaction of pSS-related BAFF gene haplotypes together with distinct BAFF genetic variants appears to contribute to this complication. | Are patients with Sjogren syndrome at increased risk for lymphoma? | 5a6f87c5b750ff4455000056_017 | yes |
Treatment of restless legs syndrome with pregabalin: a double-blind, placebo-controlled study. OBJECTIVES: To assess the therapeutic efficacy, required dose, and tolerability of pregabalin in patients with idiopathic restless legs syndrome (RLS). METHODS: This was a double-blind, placebo-controlled trial with polysomnographic control, providing Class II evidence. Ninety-eight patients underwent a 2-week single-blind period with placebo; 58 were randomized to receive pregabalin or placebo for 12 weeks under a flexible-dose schedule. Endpoints were mean change from baseline in the International Restless Legs Scale (IRLS) total score, Clinical Global Impression (CGI), and RLS-6 scales, as well as changes in periodic limb movements (PLMs) and sleep architecture. RESULTS: Patients under treatment with pregabalin had a greater improvement in IRLS score than under placebo (63% vs 38.2%; p < 0.05). The mean effective dose of pregabalin at the end of treatment was 322.50 mg/day (+/-98.77), although therapeutic effects were already seen at a mean dose of 139 mg/day. Similarly, improvements were observed on the CGI, RLS-6 scale, and the Medical Outcomes Study sleep scale (all p < 0.01) when compared to placebo. Treatment with pregabalin also resulted in a reduction of the mean (+/-SD) PLM index (p < 0.001). Furthermore, there was a marked improvement in sleep architecture with an increase in slow wave sleep (p < 0.01), and decreases in wake after sleep onset and stages 1 and 2 (p < 0.05). Pregabalin was generally well-tolerated. Adverse events were mild but common, and included unsteadiness, daytime sleepiness, and headache. CONCLUSIONS: This study shows significant therapeutic effects of pregabalin on both sensorial and motor symptoms in restless legs syndrome. Treatment with pregabalin was associated with an improvement of sleep architecture and periodic limb movements. Adverse events included unsteadiness and sleepiness and should be screened carefully in the working population, particularly when pregabalin is administered in the afternoon. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that pregabalin is effective for the treatment of restless legs syndrome and improves sleep architecture and periodic limb movements in placebo-unresponsive patients. | Is pregabalin effective for treatment of patients with restless leg syndrome? | 54cf4a0ef693c3b16b00000c_004 | yes |
Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors. The Lmo2 gene encodes a transcriptional cofactor critical for the development of hematopoietic stem cells. Ectopic LMO2 expression causes leukemia in T-cell acute lymphoblastic leukemia (T-ALL) patients and severe combined immunodeficiency patients undergoing retroviral gene therapy. Tightly controlled Lmo2 expression is therefore essential, yet no comprehensive analysis of Lmo2 regulation has been published so far. By comparative genomics, we identified 17 highly conserved noncoding elements, 9 of which revealed specific acetylation marks in chromatin-immunoprecipitation and microarray (ChIP-chip) assays performed across 250 kb of the Lmo2 locus in 11 cell types covering different stages of hematopoietic differentiation. All candidate regulatory regions were tested in transgenic mice. An extended LMO2 proximal promoter fragment displayed strong endothelial activity, while the distal promoter showed weak forebrain activity. Eight of the 15 distal candidate elements functioned as enhancers, which together recapitulated the full expression pattern of Lmo2, directing expression to endothelium, hematopoietic cells, tail, and forebrain. Interestingly, distinct combinations of specific distal regulatory elements were required to extend endothelial activity of the LMO2 promoter to yolk sac or fetal liver hematopoietic cells. Finally, Sfpi1/Pu.1, Fli1, Gata2, Tal1/Scl, and Lmo2 were shown to bind to and transactivate Lmo2 hematopoietic enhancers, thus identifying key upstream regulators and positioning Lmo2 within hematopoietic regulatory networks. | Do Conserved noncoding elements act as enhancers? | 5139ec51bee46bd34c000006_007 | yes |
RelB is required for Peyer's patch development: differential regulation of p52-RelB by lymphotoxin and TNF. Targeted disruption of the Rel/NF-kappaB family members NF-kappaB2, encoding p100/p52, and RelB in mice results in anatomical defects of secondary lymphoid tissues. Here, we report that development of Peyer's patch (PP)-organizing centers is impaired in both NF-kappaB2- and RelB-deficient animals. IL-7-induced expression of lymphotoxin (LT) in intestinal cells, a crucial step in PP development, is not impaired in RelB-deficient embryos. LTbeta receptor (LTbetaR)-deficient mice also lack PPs, and we demonstrate that LTbetaR signaling induces p52-RelB and classical p50-RelA heterodimers, while tumor necrosis factor (TNF) activates only RelA. LTbetaR-induced binding of p52-RelB requires the degradation of the inhibitory p52 precursor, p100, which is mediated by the NF-kappaB-inducing kinase (NIK) and the IkappaB kinase (IKK) complex subunit IKKalpha, but not IKKbeta or IKKgamma. Activation of RelA requires all three IKK subunits, but is independent of NIK. Finally, we show that TNF increases p100 levels, resulting in the specific inhibition of RelB DNA binding via the C-terminus of p100. Our data indicate an important role of p52-RelB heterodimers in lymphoid organ development downstream of LTbetaR, NIK and IKKalpha. | Is p100 the precursor protein molecule of the NF-kappaB transcription factor subunit p50? | 55088e412e93f0133a000001_002 | no |
Peri-infarct depolarizations reveal penumbra-like conditions in striatum. Spreading depression-like peri-infarct depolarizations not only characterize but also worsen penumbra conditions in cortical border zones of experimental focal ischemia. We intended to investigate the relevance of ischemic depolarization in subcortical regions of ischemic territories. Calomel electrodes measured DC potentials simultaneously in the lateral and medial portions of the caudate nucleus (CN) of 11 anesthetized cats after permanent occlusion of the middle cerebral artery. Additionally, platinum electrodes measured cerebral blood flow (CBF) in the CN, and laser Doppler probes CBF in the cortex. Depolarizations (negative DC shifts >10 mV) were obtained in 10 of 11 cats. Further differentiation revealed that short-lasting spreading depression-like depolarizations (SDs; 5 of 10 cats: 5.24 +/- 1.22 min total duration; 23.3 +/- 4.2 mV amplitude) were predominantly found in medial and longer depolarizations (LDs; 4 of 10 cats: 64.7 +/- 47.5 min; 25.0 +/- 11.3 mV) in the lateral CN. Terminal depolarizations (TDs; 6 of 10 cats; without repolarization) occurred immediately after occlusion or at later stages, being then accompanied by elevations of intracranial pressure presumably inducing secondary CBF reduction. CBF tended to be lower in regions with TDs (33.3 +/- 29.9% of control) and LDs (37.3 +/- 22.8%) than in regions with SDs (51.5 +/- 48.0%). We conclude that in focal ischemia, transient peri-infarct depolarizations emerge not only in cortical but also in striatal gray matter, thereby demonstrating the existence of subcortical zones of ischemic penumbra. The generation of these ischemic depolarizations is a multifocal process possibly linked to brain swelling and intracranial pressure rise in the later course of focal ischemia, and therefore a relevant correlate of progressively worsening conditions. | Does cortical spreading depression appear in ischemic penumbra following ischemic stroke? | 514b335dd24251bc05000061_004 | yes |
[General management in intensive care of patient with spontaneous subarachnoid hemorrhage]. Aneurysmal subarachnoid hemorrhage (SAH) is a neurologic emergency and often a neurologic catastrophe. Nontraumatic subarachnoid hemorrhage is characterized by the extravasation of blood into the spaces covering the central nervous system. The leading cause of SAH is rupture of an intracranial aneurysm, which accounts for about 80-85% of cases. Mortality and morbidity can be reduced if SAH is treated urgently. Sudden, explosive headache is a cardinal but nonspecific feature in the diagnosis of SAH; computered tomography (CT) scanning is mandatory in all the patients with symp toms that are suggestive of SAH. Catheter angiography for detecting aneurysms is gradually being replaced by CT angiography. Diagnosing SAH can be challenging and treatment is complex, sophisticated and multidisciplinary. Reble eding is the most imminent danger, which must be prevented by endovascular occlusion with detachable coils (coiling) or by surgical clipping of the aneurysm; the risk of delayed cerebral ischemia is reduced with nimodipine and avoiding hypovolemia; hydrocephalus can be treated by ventricular drainage. Intensive care plays a more important role in the management of SAH than in any other neurological disorder. Excellence in neurologic diagnosis, in operative neurosurgery or neuroradiologic procedures must be accompanied by excellence in Intensive Care. This review emphasizes treatment in the Intensive Care Unit, surgical and endovascular therapeutic options and the current state of treatment of major complications such as rebleeding, cerebral vasospasm and acute hydrocephalus. | Is nimodipine recommended for prevention of vasospasm in aneurysmal subarachnoid hemorrhage patients? | 51490275d24251bc0500003d_002 | yes |
Complete genome sequence and metabolic potential of the quinaldine-degrading bacterium Arthrobacter sp. Rue61a. BACKGROUND: Bacteria of the genus Arthrobacter are ubiquitous in soil environments and can be considered as true survivalists. Arthrobacter sp. strain Rue61a is an isolate from sewage sludge able to utilize quinaldine (2-methylquinoline) as sole carbon and energy source. The genome provides insight into the molecular basis of the versatility and robustness of this environmental Arthrobacter strain. RESULTS: The genome of Arthrobacter sp. Rue61a consists of a single circular chromosome of 4,736,495 bp with an average G + C content of 62.32%, the circular 231,551-bp plasmid pARUE232, and the linear 112,992-bp plasmid pARUE113 that was already published. Plasmid pARUE232 is proposed to contribute to the resistance of Arthrobacter sp. Rue61a to arsenate and Pb2+, whereas the linear plasmid confers the ability to convert quinaldine to anthranilate. Remarkably, degradation of anthranilate exclusively proceeds via a CoA-thioester pathway. Apart from quinaldine utilization, strain Rue61a has a limited set of aromatic degradation pathways, enabling the utilization of 4-hydroxy-substituted aromatic carboxylic acids, which are characteristic products of lignin depolymerization, via ortho cleavage of protocatechuate. However, 4-hydroxyphenylacetate degradation likely proceeds via meta cleavage of homoprotocatechuate. The genome of strain Rue61a contains numerous genes associated with osmoprotection, and a high number of genes coding for transporters. It encodes a broad spectrum of enzymes for the uptake and utilization of various sugars and organic nitrogen compounds. A. aurescens TC-1 is the closest sequenced relative of strain Rue61a. CONCLUSIONS: The genome of Arthrobacter sp. Rue61a reflects the saprophytic lifestyle and nutritional versatility of the organism and a strong adaptive potential to environmental stress. The circular plasmid pARUE232 and the linear plasmid pARUE113 contribute to heavy metal resistance and to the ability to degrade quinaldine, respectively. | Proteomic analyses need prior knowledge of the organism complete genome. Is the complete genome of the bacteria of the genus Arthrobacter available? | 51593dc8d24251bc05000099_000 | yes |
Modulation of cardiac ionic homeostasis by 3-iodothyronamine. 3-iodothyronamine (T(1)AM) is a novel endogenous relative of thyroid hormone, able to interact with trace amine-associated receptors, a class of plasma membrane G protein-coupled receptors, and to produce a negative inotropic and chronotropic effect. In the isolated rat heart 20-25 microM T(1)AM decreased cardiac contractility, but oxygen consumption and glucose uptake were either unchanged or disproportionately high when compared to mechanical work. In adult rat cardiomyocytes acute exposure to 20 microM T(1)AM decreased the amplitude and duration of the calcium transient. In patch clamped cardiomyocytes sarcolemmal calcium current density was unchanged while current facilitation by membrane depolarization was abolished consistent with reduced sarcoplasmic reticulum (SR) calcium release. In addition, T(1)AM decreased transient outward current (I(to)) and I(K1) background current. SR studies involving 20 microM T(1)AM revealed a significant decrease in ryanodine binding due to reduced B(max), no significant change in the rate constant of calcium-induced calcium release, a significant increase in calcium leak measured under conditions promoting channel closure, and no effect on oxalate-supported calcium uptake. Based on these observations we conclude T(1)AM affects calcium and potassium homeostasis and suggest its negative inotropic action is due to a diminished pool of SR calcium as a result of increased diastolic leak through the ryanodine receptor, while increased action potential duration is accounted for by inhibition of I(to) and I(K1) currents. | Does thyroid hormone regulate calcium transient in the myocardium? | 515ac533d24251bc050000a9_001 | yes |
[Cell-free nucleic acid-based non-invasive prenatal diagnosis of fetal aneuploidies]. Prenatal detection of fetal aneuploidies is one of the main goals of the prenatal diagnostic approach. As a benefit of the development of advanced ultrasound equipment and advances in molecular biology in the last decade, there is a significant progress in screening methods for fetal aneuploidies, although invasive methods remain the gold standard for aneuploidy detection. Non-invasive prenatal diagnosis has substantial medical impact as it targets the development of safer and more effective methods to avoid the risk of fetal loss associated with currently used invasive methods. Identification of fetal-specific messenger ribonucleic acids, digital polymerase chain reaction and next-generation sequencing give the real chance for non-invasive prenatal diagnosis of fetal aneuploidies. Although all these methods have both advantages and limitations, some of them are moving closer to clinical implementation. In this review the authors highlight the most recent advances in methods for non-invasive prenatal diagnosis of aneuploidies. | Can fetal aneuploidy be detected with non-invasive prenatal testing? | 57136cbf1174fb1755000007_020 | yes |
Observation of psammoma bodies in cultured meningiomas: analysis of three-dimensional structure using scanning and transmission electron microscopy. In contrast to the inner structure, three-dimensional structure of psammona bodies in meningiomas is not well defined. This study examined three cultured meningiomas, in which surface observation of psammoma bodies might be easier than in the tumor tissues since influence of interposing connective tissue is minimized in tissue culture. Early culture revealed that psammoma bodies with frank calcification were suspended in the tissue culture medium, and so were they collected, centrifuged, and then processed for electron microscopy. Ultrastructurally, psammoma bodies were mostly spherical in shape and composed of a core of dense calcification and surrounding collagen fiber bundles. Apart from psammoma bodies, round bodies with concentric lamination like a transversely cut onion were frequently noted by light microscopy. These bodies were composed mainly of tangles of collagen fibers emerged from surrounding tumor cell processes. The results suggest that psammoma bodies in meningiomas arise in part from meningothelial whorls due to collagen production by tumor cells followed by obliteration and disappearance of tumor cell processes, although some of the alternative pathways for psammoma body formation proposed by other investigators cannot be ruled out by this study. | Are psammoma bodies characteristic to meningiomas? | 514a4679d24251bc0500005b_012 | yes |
Tissue dependent variations of DNA methylation and endoreduplication levels during tomato fruit development and ripening. Tomato fruit cells are characterized by a strong increase in nuclear ploidy during fruit development. Average ploidy levels increased to similar levels (above 50C) in two distinct fruit tissues, pericarp and locular tissue. However, ploidy profiles differed significantly between these two tissues suggesting a tissue-specific control of endoreduplication in tomato fruit. To determine possible relationships between endoreduplication and epigenetic mechanisms, the methylation status of genomic DNA from pericarp and locular tissue of tomato fruit was analysed. Pericarp genomic DNA was characterized by an increase of CG and/or CNG methylation at the 5S and 18S rDNA loci and at gyspsy-like retrotransposon sequences during fruit growth. A sharp decrease of the global DNA methylation level together with a reduction of methylation at the rDNA loci was also observed in pericarp during fruit ripening. Inversely, no major variation of DNA methylation either global or locus-specific, was observed in locular tissue. Thus, tissue-specific variations of DNA methylation are unlikely to be triggered by the induction of endoreduplication in fruit tissues, but may reflect tissue-specific ploidy profiles. Expression analysis of eight putative tomato DNA methyltransferases encoding genes showed that one chromomethylase (CMT) and two rearranged methyltransferases (DRMs) are preferentially expressed in the pericarp during fruit growth and could be involved in the locus-specific increase of methylation observed at this developmental phase in the pericarp. | Are chromomethylases present in animal genomes? | 5171833c8ed59a060a00000f_008 | no |
[Nemaline myopathy as a cause of neonatal hypotonia - with emphasis on personal experiences. Report of a family with two brothers affected]. Nemaline myopathy is a heterogenous form of congenital myopathy characterised by a variable spectrum of clinical features, predominated in the severe form by profound muscle hypotonia and weakness accompanied by respiratory insufficiency. The clinical variability, with differing age of onset and severity of symptoms makes the diagnosis of nemaline myopathy difficult in some cases. Severe forms of nemaline myopathy may be caused by mutation of a number of different genes: skeletal muscle actin (ACTA1), nebulin (NEB) and alpha-tropomyosin (TPM3), all of which encode components of the sarcomeric thin filaments of skeletal muscle. We describe the severe form of nemaline myopathy diagnosed in two brothers who died at the age of 12 days and 9 months, due to respiratory insufficiency caused by severe muscle weakness. Polyhydramnios and weakness of foetal movements in the IIIrd trimester of pregnancy, as well as variable clinical severity were noted in both cases. Microscopically visible significant immaturity of muscle fibers was found in the skeletal muscle biopsy performed in one of the brothers. The diagnosis of nemaline myopathy was confirmed by the presence of nemaline bodies (rods) in sections stained using the Gomori trichrome method. Molecular studies of DNA isolated from blood leucocytes showed no mutation in the ACTA1 or the TPM3 genes. Linkage analysis with polymorphic markers did not rule out linkage to part of the NEB gene locus. Results of the clinical evaluation and the investigations performed in the family members confirm that it is essential to consider congenital myopathies in the differential diagnosis of neonatal and infantile hypotonia with respiratory insufficiency. Molecular verification of the clinical diagnosis is also important for genetic counselling of the families. | Are ACTA1 (alpha actin) and NEB (nebulin) genes related to nemaline myopathy? | 552440452c8b63434a00000b_000 | yes |
Feasibility of using a computer modeling approach to study SUI Induced by landing a jump. Stress urinary incontinence (SUI) occurs due to anatomic and/or neurologic factors involving connective tissues, muscles and nerves. Although SUI is more common in post-menopausal and multiparous women, studies have also shown a high prevalence of SUI in young, physically fit female athletes. With a goal toward dynamic subject-specific mechanical characterization of the interaction between anatomical structures during physical activities that elicit SUI in females during physical or daily activities, a computer aided design (CAD)-based computer model of the female pelvis has been developed to test the feasibility of the computer modeling approach in understanding the measurable differences between stress-continent and stress-incontinent women. In the present study, a fluid-structure interaction analysis was conducted by using the finite element (FE) analysis technique based on the CAD-based computer model of the female pelvis to investigate the urine leakage in females during jumping. To the best of our knowledge, this is the first application of a fluid-structure interaction FE analysis approach in understanding the mechanisms of SUI in females. Through a series of computer simulations, the effects of varying impact forces determined by jumping height and bladder volume were investigated. The dynamic computer simulation results revealed that jumping heights have a significant influence on the volume of urine leakage caused by the landing impact of jumping. Bladder volume did not have a significant influence on leakage when the jumping heights were smaller than 1 ft, which indicates that normal walking (corresponds to a jumping height smaller than 0.1 ft) is not the primary cause of urine leakage for healthy females. The computer simulation results also showed that the deformation difference between the anterior and posterior portion of the female pelvis causes opening of the urethra and resultant urine leakage. The present study demonstrates the feasibility of using a computer modeling approach to study female SUI during physical and daily activities. | Is there increased incidence of incontinence in athletes? | 5361677c7d100faa09000008_004 | yes |
Should we screen newborns for glucose-6-phosphate dehydrogenase deficiency in the United States? Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common X-linked enzymopathy can lead to severe hyperbilirubinemia, acute bilirubin encephalopathy and kernicterus in the United States. Neonatal testing for G6PD deficiency is not yet routine and the American Academy of Pediatrics recommends testing only in jaundiced newborns who are receiving phototherapy whose family history, ethnicity, or geographic origin suggest risk for the condition, or for infants whose response to phototherapy is poor. Screening tests for G6PD deficiency are available, are suitable for use in newborns and have been used in birth hospitals. However, US birth hospitals experience is limited and no national consensus has emerged regarding the need for newborn G6PD testing, its effectiveness or the best approach. Our review of current state of G6PD deficiency screening highlights research gaps and informs specific operational challenges to implement universal newborn G6PD testing concurrent to bilirubin screening in the United States. | Has Glucose-6-phosphate dehydrogenase (G6PD) deficiency an X-linked inheritance? | 58a2da4260087bc10a000005_001 | yes |
Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013. Direct new oral anticoagulants (NOACs) - inhibitors of thrombin or factor Xa - are intended to be used largely in the treatment of venous thromboembolic disease or the prevention of systematic embolism in atrial fibrillation, instead of vitamin K antagonists. Like any anticoagulant treatment, they are associated with spontaneous or provoked haemorrhagic risk. Furthermore, a significant proportion of treated patients are likely to be exposed to emergency surgery or invasive procedures. Given the absence of a specific antidote, the action to be taken in these situations must be defined. The lack of data means that it is only possible to issue proposals rather than recommendations, which will evolve according to accumulated experience. The proposals presented here apply to dabigatran (Pradaxa(®)) and rivaroxaban (Xarelto(®)); data for apixaban and edoxaban are still scarce. For urgent surgery with haemorrhagic risk, the drug plasma concentration should be less or equal to 30ng/mL for dabigatran and rivaroxaban should enable surgery associated with a high bleeding risk. Beyond that, if possible, the intervention should be postponed by monitoring the drug concentration. The course to follow is then defined according to the NOAC and its concentration. If the anticoagulant dosage is not immediately available, worse propositions, based on the usual tests (prothrombin time and activated partial thromboplastin time), are presented. However, these tests do not really assess drug concentration or the risk of bleeding that depends on it. In case of serious bleeding in a critical organ, the effect of anticoagulant therapy should be reduced using a non-specific procoagulant drug as a first-line approach: activated prothrombin complex concentrate (aPCC) (FEIBA(®) 30-50U/kg) or non-activated PCC (50U/kg). In addition, for any other type of severe haemorrhage, the administration of a procoagulant drug, which is potentially thrombogenic in these patients, is discussed according to the NOAC concentration and the possibilities of mechanical haemostasis. | Are there any specific antidotes for rivaroxaban? | 532f08b8d6d3ac6a34000029_015 | no |
Intraoperative hyperthermic intraperitoneal chemotherapy after cytoreductive surgery in ovarian cancer peritoneal carcinomatosis: systematic review of current results. BACKGROUND: Advanced and recurrent ovarian cancer results in extensive spread of tumor on the peritoneal surfaces of the abdomen and pelvis. We collectively review studies in the literature that report the efficacy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer peritoneal carcinomatosis. METHODS: An electronic search of all relevant studies published in peer-reviewed journals before May 2009 was performed on three databases. The quality of each study was independently assessed and classified according to the time point of HIPEC use in various setting of ovarian cancer from the consensus statement of the Peritoneal Surface Oncology Group. Clinical efficacy was synthesized through a narrative review with full tabulation of the results of each included study. RESULTS: Nineteen studies each of more than ten patients reporting treatment results of HIPEC of patients with both advanced and recurrent ovarian cancer were included and data were extracted. All studies were observational case series. The overall rate of severe perioperative morbidity ranged from 0 to 40% and mortality rate varied from 0 to 10%. The overall median survival following treatment with HIPEC ranged from 22 to 64 months with a median disease-free survival ranging from 10 to 57 months. In patients with optimal cytoreduction, a 5-year survival rate ranging from 12 to 66% could be achieved. CONCLUSION: Despite the heterogeneity of the studies reviewed, current evidence suggest that complete CRS and HIPEC may be a feasible option with potential benefits that are comparable with the current standard of care. A randomized trial is required to establish the role of HIPEC in ovarian cancer. | Could Hyperthermic intraperitoneal chemotherapy (HIPEC) be effective for the treatment of recurrent ovarian cancer? | 553fb11fc6a5098552000003_018 | yes |
Mowat-Wilson syndrome. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype (high forehead, frontal bossing, large eyebrows, medially flaring and sparse in the middle part, hypertelorism, deep set but large eyes, large and uplifted ear lobes, with a central depression, saddle nose with prominent rounded nasal tip, prominent columella, open mouth, with M-shaped upper lip, frequent smiling, and a prominent but narrow and triangular pointed chin), moderate-to-severe intellectual deficiency, epilepsy and variable congenital malformations including Hirschsprung disease (HSCR), genitourinary anomalies (in particular hypospadias in males), congenital heart defects, agenesis of the corpus callosum and eye anomalies. The prevalence of MWS is currently unknown, but 171 patients have been reported so far. It seems probable that MWS is under-diagnosed, particularly in patients without HSCR. MWS is caused by heterozygous mutations or deletions in the Zinc finger E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1). To date, over 100 deletions/mutations have been reported in patients with a typical phenotype; they are frequently whole gene deletions or truncating mutations, suggesting that haploinsufficiency is the main pathological mechanism. Studies of genotype-phenotype analysis show that facial gestalt and delayed psychomotor development are constant clinical features, while the frequent and severe congenital malformations are variable. In a small number of patients, unusual mutations can lead to an atypical phenotype. The facial phenotype is particularly important for the initial clinical diagnosis and provides the hallmark warranting ZEB2 mutational analysis, even in the absence of HSCR. The majority of MWS cases reported so far were sporadic, therefore the recurrence risk is low. Nevertheless, rare cases of sibling recurrence have been observed. Congenital malformations and seizures require precocious clinical investigation with intervention of several specialists (including neonatologists and pediatricians). Psychomotor development is delayed in all patients, therefore rehabilitation (physical therapy, psychomotor and speech therapy) should be started as soon as possible. | Have mutations in the ZEB2 gene been found in any human syndrome? | 53552ed7f1005d6b58000001_003 | yes |
Isolation and expression analysis of genes encoding DNA methyltransferase in wheat (Triticum aestivum L.). DNA methylation of cytosine residues, catalyzed by DNA methyltransferases, is suggested to play important roles in regulating gene expression and plant development. In this study, we isolated four wheat cDNA fragments and one cDNA with open reading frame encoding putative DNA methyltransferase and designated TaMET1, TaMET2a, TaMET2b, TaCMT, TaMET3, respectively. BLASTX searches and phylogenetic analysis suggested that five cDNAs belonged to four classes (Dnmt1, Dnmt2, CMT and Dnmt3) of DNA methyltransferase genes. TaMET2a encoded a protein of 376 aa and contained eight of ten conserved motifs characteristic of DNA methyltransferase. Genomic sequence of TaMET2a was obtained and found to contain ten introns and eleven exons. The expression analysis of the five genes revealed that they were expressed in developing seed, during germination and various vegetative tissues, but in quite different abundance. It was interesting to note that TaMET1 and TaMET3 mRNAs were clearly detected in dry seeds. Moreover, the differential expression patterns of five genes were observed between wheat hybrid and its parents in leaf, stem and root of jointing stage, some were up-regulated while some others were down-regulated in the hybrid. We concluded that multiple wheat DNA methyltransferase genes were present and might play important roles in wheat growth and development. | Are there any DNMT3 proteins present in plants? | 511a16f9df1ebcce7d000005_001 | yes |
Control of brown and beige fat development. Brown and beige adipocytes expend chemical energy to produce heat and are therefore important in regulating body temperature and body weight. Brown adipocytes develop in discrete and relatively homogenous depots of brown adipose tissue, whereas beige adipocytes are induced to develop in white adipose tissue in response to certain stimuli - notably, exposure to cold. Fate-mapping analyses have identified progenitor populations that give rise to brown and beige fat cells, and have revealed unanticipated cell-lineage relationships between vascular smooth muscle cells and beige adipocytes, and between skeletal muscle cells and brown fat. In addition, non-adipocyte cells in adipose tissue, including neurons, blood vessel-associated cells and immune cells, have crucial roles in regulating the differentiation and function of brown and beige fat. | Do brown fat cells produce heat? | 58ca906a02b8c6095300002e_023 | yes |
Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. The RAS/RAF/MEK/ERK pathway has been reported to be activated in over 80% of all cutaneous melanomas, making it the focus of many scientific studies in the melanoma field. Discoveries of mutations and aberrant expression of components in this cascade, in particular, BRAF and NRAS render a deeper understanding of the mechanisms responsible for oncogenesis and provide new therapeutic strategies for this deadly disease. This review starts with a comprehensive discussion on the role of this pathway in initiation and progress of melanoma. Mechanistically, mutated BRAF and NRAS exert most of the oncogenic effects through the activation of the MAPK pathway, which both drive the uncontrolled growth of melanoma cells and regulate the cell survival. In a subsequent section, clinical efficacy of targeted small-molecule inhibitors is highlighted. BRAF-targeted therapies (e.g., vemurafenib, dabrafenib) have showed impressive results in systemic therapy for melanoma harboring activating BRAF V600E mutations. MEK inhibitors show limited activity in phase I trials, and inhibitors directly targeting mutated NRAS, to date, have not been realized. Furthermore, the emerging mechanisms underlying both intrinsic and acquired drug resistance as well as approaches to prevent or abrogate the onset of therapeutic escape are addressed. Finally, the promising vistas and major challenges involving small-molecule inhibitors targeting this MAPK pathway in melanoma therapy are briefly discussed. It can be envisaged that disseminated melanoma is no longer such a bleak prognosis in future given the research and development of new signal transduction inhibitors based on our evolving understanding of melanoma genetics and intracellular signaling. | Are BRAF mutations common in melanoma? | 5512c91b6a8cde6b7200000b_014 | yes |
Cystatin D (CST5): An ultra-early inflammatory biomarker of traumatic brain injury. Traumatic brain injury (TBI) is set to become the leading cause of neurological disability across all age groups. Currently, no reliable biomarkers exist to help diagnose the severity of TBI to identify patients who are at risk of developing secondary injuries. Thus, the discovery of reliable biomarkers for the management of TBI would improve clinical interventions. Inflammatory markers are particularly suited for biomarker discovery as TBI leads to very early alterations in inflammatory proteins. Using the Proseek Multiplex Inflammation assay, we measured in patients that had suffered mild TBI (n = 10) or severe TBI (n = 10) with extra-cranial injury or extracranial injury only (EC) (n = 10), 92 inflammation-associated proteins in serum obtained: <1 hr (within 1-hour), 4-12 hr and 48-72 hr post injury. Changes were compared to healthy volunteers (HV). Our results identified CST5, AXIN1 and TRAIL as novel early biomarkers of TBI. CST5 identified patients with severe TBI from all other cohorts and importantly was able to do so within the first hour of injury. AXIN1 and TRAIL were able to discriminate between TBI and HV at <1 hr. We conclude that CST5, AXIN1 and TRAIL are worthy of further study in the context of a pre-hospital or pitch-side test to detect brain injury. | Is Cystatin D a biomarker? | 5a9d9ab94e03427e73000003_000 | yes |
Identification and removal of low-complexity sites in allele-specific analysis of ChIP-seq data. MOTIVATION: High-throughput sequencing technologies enable the genome-wide analysis of the impact of genetic variation on molecular phenotypes at unprecedented resolution. However, although powerful, these technologies can also introduce unexpected artifacts. RESULTS: We investigated the impact of library amplification bias on the identification of allele-specific (AS) molecular events from high-throughput sequencing data derived from chromatin immunoprecipitation assays (ChIP-seq). Putative AS DNA binding activity for RNA polymerase II was determined using ChIP-seq data derived from lymphoblastoid cell lines of two parent-daughter trios. We found that, at high-sequencing depth, many significant AS binding sites suffered from an amplification bias, as evidenced by a larger number of clonal reads representing one of the two alleles. To alleviate this bias, we devised an amplification bias detection strategy, which filters out sites with low read complexity and sites featuring a significant excess of clonal reads. This method will be useful for AS analyses involving ChIP-seq and other functional sequencing assays. AVAILABILITY: The R package abs filter for library clonality simulations and detection of amplification-biased sites is available from http://updepla1srv1.epfl.ch/waszaks/absfilter | Does Chromatin Immunoprecipitation (ChIP) show a bias for highly expressed loci? | 52ef6da1c8da898910000011_007 | yes |
Multiplex PCR assay for simultaneous detection and differentiation of Mycobacterium tuberculosis, Mycobacterium avium complexes and other Mycobacterial species directly from clinical specimens. AIMS: Polymerase chain reaction (PCR) is the most rapid and sensitive method for diagnosing mycobacterial infections and identifying the aetiological Mycobacterial species in order to administer the appropriate therapy and for better patient management. METHODS AND RESULTS: Two hundred and thirty-five samples from 145 clinically suspected cases of tuberculosis were processed for the detection of Mycobacterial infections by ZN (Ziehl Neelsen) smear examination, L-J & BACTEC MGIT-960 culture and multiplex PCR tests. The multiplex PCR comprised of genus-specific primers targeting hsp65 gene, Mycobacterium tuberculosis complex-specific primer targeting cfp10 (Rv3875, esxB) region and Mycobacterium avium complex-specific primer pairs targeting 16S-23S Internal Transcribed Spacer sequences. The multiplex PCR developed had an analytical sensitivity of 10 fg (3-4 cells) of mycobacterial DNA. The multiplex PCR test showed the highest (77.24%) detection rate, while ZN smear examination had the lowest (20%) detection rate, which was bettered by L-J culture (34.4%) and BACTEC MGIT-960 culture (50.34%) methods. The mean isolation time for M. tuberculosis was 19.03 days in L-J culture and 8.7 days in BACTEC MGIT-960 culture. Using the multiplex PCR, we could establish M. tuberculosis + M. avium co-infection in 1.3% HIV-negative and 2.9% HIV-positive patients. The multiplex PCR was also highly useful in diagnosing mycobacteraemia in 38.09% HIV-positive and 15.38% HIV-negative cases. CONCLUSIONS: The developed in-house multiplex PCR could identify and differentiate the M. tuberculosis and M. avium complexes from other Mycobacterial species directly from clinical specimens. SIGNIFICANCE AND IMPACT OF THE STUDY: The triplex PCR developed by us could be used to detect and differentiate M. tuberculosis, M. avium and other mycobacteria in a single reaction tube. | Is Mycobacterium avium less susceptible to antibiotics than Mycobacterium tuberculosis? | 5710a650cf1c32585100002b_002 | yes |
Adipose tissue as a regulator of energy balance. Adipose tissue plays an active role in energy balance because it is not only a lipid storing and mobilizing tissue but consists of functionally specialized tissues able to produce heat (in brown adipose tissue) and to produce or release a vast number of so called adipokines or adipocytokines. These consist of polypeptides but also non-protein factors and are metabolically active molecules belonging to different functional categories like immunity (complement factors, haptoglobin), endocrine function (leptin, sex steroids, various growth factors), metabolic function (fatty acids, adiponectin, resistin), and cardiovascular function (angiotensinogen, PAI-1). Recent advances using genomic and proteomic approaches have identified numerous new adipocyte secreted factors whose function remain to be established. Too little as well as too much adipose tissue leads to metabolic disturbances like insulin resistance. Visceral obesity is especially strongly correlated with the development of diabetes, hypertension and cardio-vascular disease. Thermogenesis in brown adipose tissue is a means to dissipate excess energy, but in adult humans brown fat is very scarce and probably not functional. However, human white adipose tissue contains mesenchymal stem cells, and if these could be stimulated to differentiate into brown adipocytes, increased energy expenditure in white fat could help to shift energy balance towards a more negative state. | Do brown fat cells produce heat? | 58ca906a02b8c6095300002e_013 | yes |
Pharmaco-miR: linking microRNAs and drug effects. MicroRNAs (miRNAs) are short regulatory RNAs that down-regulate gene expression. They are essential for cell homeostasis and active in many disease states. A major discovery is the ability of miRNAs to determine the efficacy of drugs, which has given rise to the field of 'miRNA pharmacogenomics' through 'Pharmaco-miRs'. miRNAs play a significant role in pharmacogenomics by down-regulating genes that are important for drug function. These interactions can be described as triplet sets consisting of a miRNA, a target gene and a drug associated with the gene. We have developed a web server which links miRNA expression and drug function by combining data on miRNA targeting and protein-drug interactions. miRNA targeting information derive from both experimental data and computational predictions, and protein-drug interactions are annotated by the Pharmacogenomics Knowledge base (PharmGKB). Pharmaco-miR's input consists of miRNAs, genes and/or drug names and the output consists of miRNA pharmacogenomic sets or a list of unique associated miRNAs, genes and drugs. We have furthermore built a database, named Pharmaco-miR Verified Sets (VerSe), which contains miRNA pharmacogenomic data manually curated from the literature, can be searched and downloaded via Pharmaco-miR and informs on trends and generalities published in the field. Overall, we present examples of how Pharmaco-miR provides possible explanations for previously published observations, including how the cisplatin and 5-fluorouracil resistance induced by miR-148a may be caused by miR-148a targeting of the gene KIT. The information is available at www.Pharmaco-miR.org. | Have microRNAs been implicated in pharmacogenomics? | 5162a089298dcd4e51000043_004 | yes |
Gadd45beta promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling. In the liver, the JNK cascade is induced downstream of TNF receptors (TNFRs) in response to inflammatory, microbial, and toxic challenges. Sustained activation of JNK triggers programmed cell death (PCD), and hepatocyte survival during these challenges requires induction of the NF-kappaB pathway, which antagonizes this activation by upregulating target genes. Thus, modulation of JNK activity is crucial to the liver response to TNFR-mediated challenge. The basis for this modulation, however, is unknown. Here, we investigated the role of the NF-kappaB target Gadd45b in the regulation of hepatocyte fate during liver regeneration after partial hepatectomy. We generated Gadd45b(-/-) mice and found that they exhibited decreased hepatocyte proliferation and increased PCD during liver regeneration. Notably, JNK activity was markedly increased and sustained in livers of Gadd45b(-/-) mice compared with control animals after partial hepatectomy. Furthermore, imposition of a Jnk2-null mutation, attenuating JNK activity, completely rescued the regenerative response in Gadd45b(-/-) mice. Interestingly, Gadd45beta ablation did not affect hepatotoxic JNK signaling after a TNFR-mediated immune challenge, suggesting specificity in the inducible hepatic program for JNK restraint activated during distinct TNFR-mediated challenges. These data provide a basis for JNK suppression during liver regeneration and identify Gadd45beta as a potential therapeutic target in liver diseases. | Is the JNK pathway activated during liver regeneration? | 53455e0caeec6fbd0700000f_011 | yes |
Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. In a screen designed to identify novel inducers of autophagy, we discovered that STAT3 inhibitors potently stimulate the autophagic flux. Accordingly, genetic inhibition of STAT3 stimulated autophagy in vitro and in vivo, while overexpression of STAT3 variants, encompassing wild-type, nonphosphorylatable, and extranuclear STAT3, inhibited starvation-induced autophagy. The SH2 domain of STAT3 was found to interact with the catalytic domain of the eIF2α kinase 2 EIF2AK2, best known as protein kinase R (PKR). Pharmacological and genetic inhibition of STAT3 stimulated the activating phosphorylation of PKR and consequent eIF2α hyperphosphorylation. Moreover, PKR depletion inhibited autophagy as initiated by chemical STAT3 inhibitors or free fatty acids like palmitate. STAT3-targeting chemicals and palmitate caused the disruption of inhibitory STAT3-PKR interactions, followed by PKR-dependent eIF2α phosphorylation, which facilitates autophagy induction. These results unravel an unsuspected mechanism of autophagy control that involves STAT3 and PKR as interacting partners. | Is STAT3 involved in EIF2AK2-dependent suppression of autophagy? | 56cdf3995795f9a73e00003a_001 | yes |
Siltuximab (Sylvant). Castleman's disease: good symptomatic efficacy in some patients. Multicentric Castleman's disease is a rare lymphoproliferative disorder characterised by disseminated lymphadenopathy. Symptoms and outcomes differ widely from one patient to another. The median survival time is about 2.5 years. There is no consensus on treatment. Siltuximab, a monoclonal antibody that antagonises interleukin-6, has been authorised in the European Union for patients with multicentric Castleman's disease who are not infected with HIV or HHV-8. In a randomised, double-blind trial in 79 patients, most of whom had mild or moderate symptoms, the estimated one-year survival rate was 100% in the siltuximab group versus 92% in the placebo group after a median follow-up of 60 weeks. However, half of the patients in the placebo group received siltuximab after disease progression. Symptoms disappeared for at least 18 weeks in one-quarter of patients in the siltuximab group versus none of those in the placebo group; the median symptom-free period in the siltuximab group was about 16 months. The known adverse effects of siltuximab are related to its immunosuppressive effect. They include frequent infections, neutropenia and thrombocytopenia. Reactions can occur during the infusion, and mouth sores have been reported. Other adverse events that appear to be more frequent with siltuximab include cutaneous disorders, oedema, renal and cardiac disorders, and peripheral neuropathy. Cases of gastrointestinal perforation have been reported in trials in other clinical settings. Siltuximab can mask the signs and symptoms of acute inflammation, in particular by suppressing fever and acute-phase markers such as C-reactive protein. Interleukin-6 is a cytochrome P450 inhibitor. Siltuximab activates its isoenzymes and can thus reduce the effectiveness of the numerous drugs that are substrates of this enzyme system. This risk of interactions is likely to persist up to several weeks after siltuximab withdrawal, because of its long plasma elimination half-life (about 16 days). In practice, the only available trial suggests that siltuximab has a marked impact on the symptoms of mild or moderate multicentric Castleman's disease in patients who are not infected with HIV or HHV-8. Siltuximab seems to be a reasonable option in this setting, despite its numerous adverse effects, provided patients are fully informed of the many unknowns and are closely monitored. | Is siltuximab effective for Castleman disease? | 5896d3e278275d0c4a000012_000 | yes |
Cohesin Loss Eliminates All Loop Domains. The human genome folds to create thousands of intervals, called "contact domains," that exhibit enhanced contact frequency within themselves. "Loop domains" form because of tethering between two loci-almost always bound by CTCF and cohesin-lying on the same chromosome. "Compartment domains" form when genomic intervals with similar histone marks co-segregate. Here, we explore the effects of degrading cohesin. All loop domains are eliminated, but neither compartment domains nor histone marks are affected. Loss of loop domains does not lead to widespread ectopic gene activation but does affect a significant minority of active genes. In particular, cohesin loss causes superenhancers to co-localize, forming hundreds of links within and across chromosomes and affecting the regulation of nearby genes. We then restore cohesin and monitor the re-formation of each loop. Although re-formation rates vary greatly, many megabase-sized loops recovered in under an hour, consistent with a model where loop extrusion is rapid. | Are loop domains preserved upon cohesin loss? | 5a6e4814b750ff445500004a_000 | no |
[Hemophilia C, a deficiency of a contact phase protein which may involve a risk of hemorrhage]. Factor XI deficiency, also called hemophilia C, was first described in 1953. It is thought to constitute 7% of all disorders of the intrinsic pathway of blood coagulation. It represents the only deficiency of a contact phase protein associated with a bleeding tendency with widely variable expression. Eighteen members of 5 families with this deficiency have been investigated; only 3 exhibited a hemorrhagic diathesis: 2/4 homozygous (hemorrhages after surgical procedures and hematomas and after minor traumatism) and 1/10 heterozygous individuals (hematomas, epistaxis). All homozygotes had a prolongation of the PTT. The hemorrhagic tendency was higher among homozygous individuals (with very low factor XI activity), but 2 were asymptomatic. Heterozygotes may also bleed. This deficiency is found mainly in an Ashkenazy Jewish population. Our study shows that it occurs in an apparently autochthonous Swiss population. A detailed history and studies of other family members are necessary if there is suspicion of factor XI deficiency. | Is factor XI deficient in Hemophilia C? | 51588c1ad24251bc05000094_002 | yes |
Urinary incontinence in elite nulliparous athletes. OBJECTIVE: To determine the prevalence of the symptom of urinary incontinence during athletic endeavors among a group of nulliparous, elite college varsity female athletes. METHODS: All women currently participating in varsity athletics at a large state university were asked to fill out a questionnaire about the occurrence of urinary incontinence while participating in their sport and during activities of daily life. One hundred forty-four of 156 eligible women (92%) responded. RESULTS: The mean age was 19.9 years, and all women were nulliparous. Overall, 40 athletes (28%) reported urine loss while participating in their sport. The proportions in different sports were: gymnastics 67%, basketball 66%, tennis 50%, field hockey 42%, track 29%, swimming 10%, volleyball 9%, softball 6%, and golf 0%. Two-thirds of the women who noted urine loss during athletics were incontinent more often than rarely. There were no statistically significant relations between incontinence and amenorrhea, weight, hormonal therapy, or duration of athletic activity. Activities most likely to provoke incontinence included jumping, high-impact landings, and running. Forty percent and 17% of the women first noted incontinence during their sport while in high school and junior high school, respectively. CONCLUSIONS: Incontinence during physical stresses is common in young, highly fit, nulliparous women. This suggests that there is a continence threshold which, when exceeded, can result in urine loss, even in the absence of known risk factors for incontinence. | Is there increased incidence of incontinence in athletes? | 5361677c7d100faa09000008_008 | yes |
The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. The identification of ultraconserved noncoding sequences in vertebrates has been associated with developmental regulators and DNA-binding proteins. One of the first of these was identified in the intergenic region between the Dlx-5 and Dlx-6 genes, members of the Dlx/dll homeodomain-containing protein family. In previous experiments, we showed that Sonic hedgehog treatment of forebrain neural explants results in the activation of Dlx-2 and the novel noncoding RNA (ncRNA), Evf-1. In this report, we show that the Dlx-5/6 ultraconserved region is transcribed to generate an alternatively spliced form of Evf-1, the ncRNA Evf-2. Evf-2 specifically cooperates with Dlx-2 to increase the transcriptional activity of the Dlx-5/6 enhancer in a target and homeodomain-specific manner. A stable complex containing the Evf-2 ncRNA and the Dlx-2 protein forms in vivo, suggesting that the Evf-2 ncRNA activates transcriptional activity by directly influencing Dlx-2 activity. These experiments identify a novel mechanism whereby transcription is controlled by the cooperative actions of an ncRNA and a homeodomain protein. The possibility that a subset of vertebrate ultraconserved regions may function at both the DNA and RNA level to control key developmental regulators may explain why ultraconserved sequences exhibit 90% or more conservation even after 450 million years of vertebrate evolution. | Are ultraconserved elements often transcribed? | 553a8d78f321868558000003_007 | yes |
ASF1 binds to a heterodimer of histones H3 and H4: a two-step mechanism for the assembly of the H3-H4 heterotetramer on DNA. The first step in the formation of the nucleosome is commonly assumed to be the deposition of a histone H3-H4 heterotetramer onto DNA. Antisilencing function 1 (ASF1) is a major histone H3-H4 chaperone that deposits histones H3 and H4 onto DNA. With a goal of understanding the mechanism of deposition of histones H3 and H4 onto DNA, we have determined the stoichiometry of the Asf1-H3-H4 complex. We have established that a single molecule of Asf1 binds to an H3-H4 heterodimer using gel filtration, amino acid, reversed-phase chromatography, and analytical ultracentrifugation analyses. We demonstrate that Asf1 blocks formation of the H3-H4 heterotetramer by a mechanism that likely involves occlusion of the H3-H3 dimerization interface. | Does the histone chaperone ASF1 interact with histones H1/H2? | 58dcbb8c8acda34529000021_012 | no |
Activating transcription factor 4 promotes angiogenesis of breast cancer through enhanced macrophage recruitment. Angiogenesis plays an important role in the progression of tumor. Besides being regulated by tumor cells per se, tumor angiogenesis is also influenced by stromal cells in tumor microenvironment (TME), for example, tumor associated macrophages (TAMs). Activating transcription factor 4 (ATF4), a member of the ATF/CREB family, has been reported to be related to tumor angiogenesis. In this study, we found that exogenous overexpression of ATF4 in mouse breast cancer cells promotes tumor growth via increasing tumor microvascular density. However, ATF4 overexpression failed to increase the expression level of a series of proangiogenic factors including vascular endothelial growth factor A (VEGFA) in tumor cells in this model. Thus, we further investigated the infiltration of proangiogenic macrophages in tumor tissues and found that ATF4-overexpressing tumors could recruit more macrophages via secretion of macrophage colony stimulating factor (M-CSF). Overall, we concluded that exogenous overexpression of ATF4 in breast cancer cells may facilitate the recruitment of macrophages into tumor tissues and promote tumor angiogenesis and tumor growth indirectly. | Has ATF4 transcription factor been linked to cancer and neoplastic transformation? | 5a773c50faa1ab7d2e000002_001 | yes |
Cytoplasmic RNA: a case of the tail wagging the dog. The addition of poly(A) tails to eukaryotic nuclear mRNAs promotes their stability, export to the cytoplasm and translation. Subsequently, the balance between exonucleolytic deadenylation and selective re-establishment of translation-competent poly(A) tails by cytoplasmic poly(A) polymerases is essential for the appropriate regulation of gene expression from oocytes to neurons. In recent years, surprising roles for cytoplasmic poly(A) polymerase-related enzymes that add uridylyl, rather than adenylyl, residues to RNA 3' ends have also emerged. These terminal uridylyl transferases promote the turnover of certain mRNAs but also modify microRNAs, their precursors and other small RNAs to modulate their stability or biological functions. | Is polyadenylation a process that stabilizes a protein by adding a string of Adenosine residues to the end of the molecule? | 5a8714e261bb38fb24000005_015 | no |
Plasma levels of 8-methoxypsoralen after topical paint PUVA. BACKGROUND: Topical PUVA therapy has become a useful alternative for patients who cannot tolerate the systemic side effects of nausea and headache or are concerned about the ophthalmologic risk associated with oral PUVA therapy. However, there is no study to date on the systemic absorption of psoralen after the localized application of topical paint PUVA. OBJECTIVE: This study was designed to assess the plasma level of 8-methoxypsoralen (8-MOP) after paint PUVA therapy for patients with palmoplantar psoriasis or eczema. METHODS: Reverse-phase high-pressure liquid chromatography was used to determine 8-MOP plasma levels in eight patients with palmoplantar psoriasis and two with eczema. Three patients receiving oral PUVA therapy served as the control group. RESULTS: Plasma levels of 8-MOP taken 1, 6, and 24 hours after topical PUVA treatments of patients with palmoplantar psoriasis were undetectable. One patient with hand eczema consistently had detectable 8-MOP levels 1 hour after topical PUVA treatments. CONCLUSION: This report indicates that there is minimal, if any, systemic absorption of 8-MOP after topical PUVA treatment of patients with palmoplantar psoriasis. | Is PUVA therapy indicated for eczema treatment? | 58bfe70e02b8c60953000019_002 | yes |
Paroxetine: current status in psychiatry. Paroxetine is a selective serotonin reuptake inhibitor (SSRI) with antidepressant and anxiolytic properties. It is commercially available in both an immediate-release (paroxetine) and a controlled-release formulation (paroxetine CR). The latter product was developed to improve gastrointestinal tolerability. Paroxetine is the most potent inhibitor of the reuptake of serotonin among the available SSRIs. It has approved indications for the treatment of major depression, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, post-traumatic stress disorder and social phobia in adults. Paroxetine CR is approved for the treatment of major depression, social anxiety disorder, panic disorder and premenstrual dysphoric disorder in adults. While the overall efficacy of paroxetine appears to be comparable with other SSRIs in the treatment of major depression, it is approved for use in a wider variety of anxiety disorders than any other antidepressant. Long-term data suggest that paroxetine is effective in preventing relapse or recurrence of depression for up to 1 year. Limited data show that paroxetine maintains a therapeutic response over 1 year in obsessive-compulsive disorder and up to 6 months in panic disorder. The side-effect profile of paroxetine is largely similar to that of the other SSRIs, although paroxetine tends to be more sedating and constipating in some patients, perhaps due to its anticholinergic activity. The potential for discontinuation syndrome and weight gain appears to be slightly higher with paroxetine than with other SSRIs. This review focuses on the immediate release and controlled-release formulations of paroxetine. It summarizes the efficacy and tolerability data for both formulations, with a particular emphasis on paroxetine CR which was introduced in 2002. It also discusses emerging evidence in other clinical areas and recent data that have led to modifications in the safety profile of paroxetine. | Is paroxetine effective for treatment of premenstrual dysphoric disorder? | 514a59c2d24251bc0500005d_005 | yes |
A novel TRB@/NOTCH1 fusion gene in T-cell lymphoblastic lymphoma with t(7;9)(q34;q34). BACKGROUND: In T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL), activating mutations of NOTCH1 are observed in more than 50% of cases, whereas the t(7;9)(q34;q34) involving NOTCH1 at 9q34 and TRB@ at 7q34 is an extremely rare but recurrent translocation. PATIENT: A 41-year-old male with a large mediastinal mass, pleural effusion, and lymphadenopathy was diagnosed as having T-LBL. Lymphoma cells were positive for CD4, CD8, CD2, CD3, CD5, CD7, CD10, and TdT. RESULTS: G-banding and spectral karyotyping of pleural effusion cells showed 47,XY,dup(1)(q21q32),t(7;9)(q34;q34),+20. Genomic polymerase chain reaction (PCR) revealed that the 5' end of TRB@ J1-5 was connected with the middle of NOTCH1 exon 25 (434 bp downstream from its 5' end) in a 'head-to-head' configuration on the der(9)t(7;9), although nine extra bases were inserted between the two genes. Reverse transcription-PCR confirmed expression of the TRB@/NOTCH1 fusion transcripts. Similarly, the 5' end of J1-5 was fused to the shortened exon 25 with nine extra bases. The NOTCH1 breakpoint in exon 25 was very close to transcription start sites of deleted Notch1 in murine T-ALL. CONCLUSIONS: The TRB@/NOTCH1 fusion gene with a NOTCH1 breakpoint in exon 25, which has not previously been detected in four other reported cases with t(7;9), could lead to aberrant expression of the truncated NOTCH1 by TRB@ enhancer elements. The resultant NOTCH1 receptor deleting most of the extracellular domain may be implicated in the pathogenesis of T-LBL by ligand-independent, constitutive activation of the NOTCH1 pathway, suggesting avenues for future therapy with γ-secretase inhibitors. | Are Notch mutations related to T-cell Acute Lymphoblastic Leukemia (T-ALL)? | 5522fadb7b523f2123000001_012 | yes |
Curcumin augments the efficacy of antitumor drugs used in leukemia by modulation of heat shock proteins via HDAC6. Heat shock proteins (HSPs) and histone deacetylase 6 (HDAC6) are induced under oxidative stress, which promotes oncogenesis. HSPs are regulated by heat shock factor1 (HSF1). HDAC6, a class IIb deacetylase, plays an essential role in tumorigenesis and cell stress response. HSPs, HSF1 and HDAC6 are up-regulated in cancer. In the present study, we explored the effect of curcumin, a phytochemical, on HSPs (27, 70, 90), HSF1 and HDAC6 in two different leukemia cell lines (K-562 and HL-60). The association between HDAC6, HSPs, and intrinsic oxidative stress was also investigated. Overexpression of HSPs (27, 70, 90), HSF1, and HDAC6 in leukemia cells were down-regulated by curcumin, and the effects on HSPs 27and 70 were less than that on HSP 90. This resulted in cell cycle arrest at the G2/M stage, leading to apoptosis. Different cell cycle regulatory proteins (p53, p21, cyclin B1, CDK1, Cdc25C) and some apoptosis-related proteins (Bcl-2, Bax, Bid, Bad, Apaf1, AIF and Cyt c) were altered by curcumin. Increased ROS levels in leukemia cells were quenched by curcumin. A probable association between high ROS level and the overexpression of the tumor markers was established in this study. Thus, curcumin enhanced the efficacy of anti-tumor drugs imatinib-mesylate and cytarabine through the inhibition of the tumor markers. | Is curcumin a phytochemical? | 56b0eb3b0a360a5e45000019_002 | yes |
T-Cell Responses Are Associated with Survival in Acute Melioidosis Patients. BACKGROUND: Melioidosis is an increasingly recognised cause of sepsis and death across South East Asia and Northern Australia, caused by the bacterium Burkholderia pseudomallei. Risk factors include diabetes, alcoholism and renal disease, and a vaccine targeting at-risk populations is urgently required. A better understanding of the protective immune response in naturally infected patients is essential for vaccine design. METHODS: We conducted a longitudinal clinical and immunological study of 200 patients with melioidosis on admission, 12 weeks (n = 113) and 52 weeks (n = 65) later. Responses to whole killed B. pseudomallei were measured in peripheral blood mononuclear cells (PBMC) by interferon-gamma (IFN-γ) ELIspot assay and flow cytometry and compared to those of control subjects in the region with diabetes (n = 45) and without diabetes (n = 43). RESULTS: We demonstrated strong CD4+ and CD8+ responses to B. pseudomallei during acute disease, 12 weeks and 52 weeks later. 28-day mortality was 26% for melioidosis patients, and B. pseudomallei-specific cellular responses in fatal cases (mean 98 IFN-γ cells per million PBMC) were significantly lower than those in the survivors (mean 142 IFN-γ cells per million PBMC) in a multivariable logistic regression model (P = 0.01). A J-shaped curve association between circulating neutrophil count and mortality was seen with an optimal count of 4000 to 8000 neutrophils/μl. Melioidosis patients with known diabetes had poor diabetic control (median glycated haemoglobin HbA1c 10.2%, interquartile range 9.2-13.1) and showed a stunted B. pseudomallei-specific cellular response during acute illness compared to those without diabetes. CONCLUSIONS: The results demonstrate the role of both CD4+ and CD8+ T-cells in protection against melioidosis, and an interaction between diabetes and cellular responses. This supports development of vaccine strategies that induce strong T-cell responses for the control of intracellular pathogens such as B. pseudomallei. | Is Melioidosis caused by the bacterium Burkholderia pseudomallei? | 58caf88c02b8c60953000031_008 | yes |
Mutated cylindromatosis gene affects the functional state of dendritic cells. Cylindromatosis gene (CYLD) is a ubiquitously expressed deubiquitinating enzyme, which interacts with members of the NF-κB signaling pathway and attenuates NF-κB and JNK signaling. Here, we report that DC derived from transgenic mice, which solely express a naturally occurring CYLD isoform (CYLD(ex7/8)), display a higher content of nuclear RelB and express elevated levels of NF-κB family members as well as of known NF-κB-target genes comprising costimulatory molecules and pro-inflammatory cytokines, as compared with WT DC. Accordingly, unstimulated CYLD(ex7/8) DC exhibited a significantly higher primary allogenic T-cell stimulatory capacity than WT DC and exerted no tolerogenic activity. Transduction of unstimulated CYLD(ex7/8) DC with relB-specific shRNA reduced their T-cell stimulatory capacity. Treatment with the synthetic glucocorticoid dexamethasone known to inhibit NF-κB and AP-1 activity reverted the pro-immunogenic phenotype and function of CYLD(ex7/8) DC and re-established their tolerogenic function. DC derived from CYLD knockout mice showed no functional alterations compared with WT DC. Therefore, although complete loss of CYLD may be compensated for by other endogenous NF-κB inhibitors, CYLD(ex7/8) acts in a dominant negative manner. Our findings raise the question of whether genetic defects associated with increased NF-κB activity may result in disturbed maintenance of peripheral tolerance. | Is the protein product of the cylindromatosis gene (CYLD) a deubiquitinating enzyme? | 550aef0ec2af5d5b7000000a_013 | yes |
Is thrombophilia a risk factor for placenta-mediated pregnancy complications? PURPOSE: To determine if thrombophilia is a risk factor for placenta-mediated pregnancy complications (PMPC) (i.e., preeclampsia, intrauterine growth restriction (IUGR), placental abruption, intrauterine fetal death and recurrent pregnancy loss). METHODS: A 5-year retrospective cohort study. Ongoing pregnancies in women with an antecedent PMPC with thrombophilia were compared with the pregnancies in similar women without thrombophilia. The main outcome measures were mean birth weight deviations, corrected for gestational age, and recurrence of PMPC. Low-molecular-weight heparin (LMWH) was employed for thromboprophylaxis only. Mann-Whitney's, Fisher's and Chi-square tests were employed for comparison. RESULTS: PMPC recurred in 10/43 (23 %) in the thrombophilia group and in 7/41 (17 %) in the non-thrombophilia group, P < 0.059. The mean birth weight deviations were not significantly different either: -7.2 versus -3.0 %, respectively. LMWH, as could be expected, was used more often in thrombophilia patients (39/43 vs. 10/41, P < 0.001). CONCLUSION: Thrombophilia does hardly increase the risk of IUGR/PMPC or if so, it can be prevented by LMWH. | Is thrombophilia related to increased risk of miscarriage? | 513cdc38bee46bd34c000007_003 | yes |
Dupilumab for the treatment of atopic dermatitis: A clinical trial review. INTRODUCTION: Current treatment options for moderate-to-severe atopic dermatitis (AD) are limited and have potentially dangerous side effects. Dupilumab is a novel monoclonal antibody that was recently studied in adult patients with moderate-to-severe AD. Dupilumab inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling and was previously found to be effective in asthma. Considering that both AD and asthma are Th2 cell-mediated inflammatory processes, it is reasonable to suspect that dupilumab would be beneficial in AD.` AREAS COVERED: This article is a review of the one major clinical trial that assessed the efficacy of dupilumab in patients with AD. Its goal is to provide a comparison to the current modalities for the treatment of AD and expert insight regarding future studies. EXPERT OPINION: The results of this study are a significant therapeutic advancement. Dupilumab was shown to provide a mean percent change in Eczema Area and Severity Index score of -74% ± 3.6, in addition to, statistically and clinically significant reductions the severity, symptomatology, and morbidity associated with AD. However, the small sample size makes it difficult to assess the magnitude of this effect. As a result, dupilumab will likely be reserved for cases of severe AD unresponsive to traditional modalities. | Is Dupilumab used for treatment of atopic dermatitis? | 58df3e408acda3452900002d_003 | yes |
Tuberous sclerosis. BACKGROUND AND DESIGN: Tuberous sclerosis (TS) is a genetic disease with prominent cutaneous and brain involvement whose clinical and molecular genetics are reviewed. OBSERVATIONS: Tuberous sclerosis is a systemic disorder (incidence one in 10,000) characterized by benign growths (hamartias and hamartomas) in multiple organ systems. Involvement of the brain can result in persistent seizures and mental retardation; skin involvement includes facial angiofibromas, subungual fibromas, hypomelanotic macules, forehead fibrous plaques, and Shagreen's patches. Approximately 60% of TS occurs as apparent sporadic cases. In families, it has autosomal dominant inheritance with high penetrance (approximately 95%), with careful clinical and radiologic evaluation. Genetic linkage analysis indicates that about half of all TS families show linkage to chromosome 9q34, and about half to chromosome 16p13. There are no distinguishing features in the two groups of families showing linkage to the two genomic regions, nor strong evidence for a third causative gene. Positional cloning efforts for both chromosomal regions have limited the region containing the gene to about 1 to 2 million bases. CONCLUSIONS: Identification of the two TS genes should illuminate the pathogenesis of TS and provide opportunities for genetic counseling, prenatal diagnosis, and therapeutic intervention. | Is Tuberous Sclerosis a genetic disease? | 52b06a68f828ad283c000005_007 | yes |
Safety and potential benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in peritoneal carcinomatosis from primary or recurrent ovarian cancer. OBJECTIVES: To analyze the outcomes of cytoreductive surgery and HIPEC in patients with peritoneal carcinomatosis from ovarian cancer. METHODS: Fifty-three patients with peritoneal carcinomatosis from primary (45 cases) and recurrent (8 cases) ovarian cancer were previously treated by systemic chemotherapy with platinum and taxanes and then submitted to surgical cytoreduction and HIPEC (cisplatin and mitomycin-C) with a closed abdomen technique. The median follow-up period was 27 months (range: 3-107). RESULTS: At the end of operation a complete cytoreduction (CCR-0) was obtained in 37 patients (70%). Major morbidity occurred in 12 patients (23%); reoperation was necessary in 2 patients (4%), and no postoperative mortality was observed. Overall 5-year survival probability was 55%; it was 71% in CCR-0, 44% in CCR-1, and none in patients with CCR-2 or CCR-3 residual tumor (log-rank test: P = 0.017). The cumulative risk of recurrence in 37 CCR-0 cases was 54% at 5 years from operation. CONCLUSIONS: The results of our study indicate the feasibility and the potential benefit of a protocol including systemic chemotherapy, surgical cytoreduction and HIPEC in patients with peritoneal carcinomatosis from ovarian cancer. A phase III trial to compare this approach with conventional treatment is needed. | Could Hyperthermic intraperitoneal chemotherapy (HIPEC) be effective for the treatment of recurrent ovarian cancer? | 553fb11fc6a5098552000003_009 | yes |
Computational discovery of human coding and non-coding transcripts with conserved splice sites. MOTIVATION: Long non-coding RNAs (lncRNAs) resemble protein-coding mRNAs but do not encode proteins. Most lncRNAs are under lower sequence constraints than protein-coding genes and lack conserved secondary structures, making it hard to predict them computationally. RESULTS: We introduce an approach to predict spliced lncRNAs in vertebrate genomes combining comparative genomics and machine learning. It is based on detecting signatures of characteristic splice site evolution in vertebrate whole genome alignments. First, we predict individual splice sites, then assemble compatible sites into exon candidates, and finally predict multi-exon transcripts. Using a novel method to evaluate typical splice site substitution patterns that explicitly takes the species phylogeny into account, we show that individual splice sites can be accurately predicted. Since our approach relies only on predicted splice sites, it can uncover both coding and non-coding exons. We show that our predicted exons and partial transcripts are mostly non-coding and lack conserved secondary structures. These exons are of particular interest, since existing computational approaches cannot detect them. Transcriptome sequencing data indicate tissue-specific expression patterns of predicted exons and there is evidence that increasing sequencing depth and breadth will validate additional predictions. We also found a significant enrichment of predicted exons that form multi-exon transcript parts, and we experimentally validate such a novel multi-exon gene. Overall, we obtain 336 novel multi-exon transcript predictions from human intergenic regions. Our results indicate the existence of novel human transcripts that are conserved in evolution and our approach contributes to the completion of the human transcript catalog. AVAILABILITY AND IMPLEMENTATION: Predicted human splice sites, exons and gene structures together with a Perl implementation of the tree-based log-odds scoring and a supplementary PDF file containing additional figures and tables are available at: http://www.bioinf.uni-leipzig.de/publications/supplements/10-010. The five experimentally confirmed partial transcript isoforms have been deposited in GenBank under accession numbers HM587422-HM587426. | Are long non coding RNAs spliced? | 535d292a9a4572de6f000003_004 | yes |