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Coldog2333

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54e25eaaae9738404b000017

Is the protein Papilin secreted?

Using expression analysis, we identify three genes that are transcriptionally regulated by HLH-2: the protocadherin cdh-3, and two genes encoding secreted extracellular matrix proteins, mig-6/papilin and him-4/hemicentin. We found that mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of DTC migration. Both MIG-6 isoforms have a predicted N-terminal papilin cassette apilins are homologous, secreted extracellular matrix proteins which share a common order of protein domains. The TSR superfamily is a diverse family of extracellular matrix and transmembrane proteins, many of which have functions related to regulating matrix organization, cell-cell interactions and cell guidance. This review samples some of the contemporary literature regarding TSR superfamily members (e.g. F-spondin, UNC-5, ADAMTS, papilin, and TRAP) where specific functions are assigned to the TSR domains. Papilins are extracellular matrix proteins Papilin is an extracellular matrix glycoprotein Collagen IV, laminin, glutactin, papilin, and other extracellular matrix proteins were made primarily by hemocytes and were secreted into the medium. A sulfated glycoprotein was isolated from the culture media of Drosophila Kc cells and named papilin.

yes

535d292a9a4572de6f000003

Are long non coding RNAs spliced?

Our analyses indicate that lncRNAs are generated through pathways similar to that of protein-coding genes, with similar histone-modification profiles, splicing signals, and exon/intron lengths. For alternative exons and long noncoding RNAs, splicing tends to occur later, and the latter might remain unspliced in some cases. bosome-mapping data to identify lncRNAs of Caenorhabditis elegans. We found 170 long intervening ncRNAs (lincRNAs), which had single- or multiexonic structures that did not overlap protein-coding transcripts, and about sixty antisense lncRNAs (ancRNAs), which were complementary to protein-coding transcripts We introduce an approach to predict spliced lncRNAs in vertebrate genomes combining comparative genomics and machine learning. Owing to similar alternative splicing pattern to mRNAs, the concept of lncRNA genes was put forward to help systematic understanding of lncRNAs. Our synthesis of recent studies suggests that neither size, presence of a poly-A tail, splicing, direction of transcription, nor strand specificity are of importance to lncRNA function.

yes

55262a9787ecba3764000009

Is RANKL secreted from the cells?

Osteoprotegerin (OPG) is a soluble secreted factor that acts as a decoy receptor for receptor activator of NF-κB ligand (RANKL) Osteoprotegerin (OPG) is a secreted glycoprotein and a member of the tumor necrosis factor receptor superfamily. It usually functions in bone remodeling, by inhibiting osteoclastogenesis through interaction with a receptor activator of the nuclear factor κB (RANKL). e RANKL/OPG ratio secreted by osteoblasts increased and RANK expression by osteoclasts increased, leading to increased osteoclastogenesis Osteoprotegerin (OPG) is an essential secreted protein in bone turnover due to its role as a decoy receptor for the Receptor Activator of Nuclear Factor-kB ligand (RANKL) in the osteoclasts, thus inhibiting their differentiation We identify a TNFSF11 transcript variant that extends the originally identified transcript encoding secreted RANKL. Activated human T cells express alternative mRNA transcripts encoding a secreted form of RANKL. OPG, on the other hand, is secreted by osteoblast as a decoy receptor for RANKL, prevents RANKL from binding to RANK and thus prevents bone resorption Receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) are cytokines predominantly secreted by osteoblasts and play a central role in differentiation and functional activation of osteoclasts Although B. abortus-activated T cells actively secreted the pro-osteoclastogenic cytokines RANKL and IL-17, osteoclastogenesis depended on IL-17, because osteoclast generation induced by Brucella-activated T cells was completely abrogated when these cells were cultured with BMMs from IL-17 receptor knockout mice. osteoclastogenesis and bone destruction in autoimmune arthritis. We isolated human fibroblasts from RA, pyrophosphate arthropathy (PPA) and osteoarthritis (OA) patients and analyzed their RANKL/OPG expression profile and the capacity of their secreted factors to induce osteoclastogenesis. Osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) are cytokines predominantly secreted by osteoblasts and play critical roles in the differentiation and function of osteoclasts.

yes

51406e6223fec90375000009

Does metformin interfere thyroxine absorption?

LT4 absorption is unchanged by concomitant metformin ingestion. It has been hypothesized that metformin may suppress serum thyrotropin (TSH) concentrations by enhancing LT4 absorption or by directly affecting the hypothalamic-pituitary axis.

no

52bf1db603868f1b06000011

Has Denosumab (Prolia) been approved by FDA?

Denosumab is a RANK-ligand antibody that was approved by the FDA in 2010 for the prevention of skeletal fractures in patients with bone metastases from solid tumors. The authors present the imaging findings and technical report of an attempted percutaneous vertebroplasty in the only patient found to be actively under treatment with denosumab after a retrospective review of the databank of patients with pathological fractures referred to the Department Radiology of the Ohio State University for percutaneous vertebroplasty (a total sample of 20 patients) since the FDA approval of denosumab (November 2010) until June of 2013 (a 30-month period). On the basis of this data, the FDA approved denosumab for the treatment of patients whose GCTB is unresectable, or when surgery is likely to result in severe morbidity. Denosumab (Prolia®) is a fully human monoclonal antibody for RANKL, which selectively inhibits osteoclastogenesis, being recently approved for the treatment of postmenopausal osteoporosis in women at a high or increased risk of fracture by the FDA in the United Sates and by the European Medicines Agency in Europe since June 2010. Recent phase II clinical trials with denosumab in skeletally mature adolescents over age 12 years and adults with GCTB, have shown both safety and efficacy, leading to its accelerated US FDA approval on 13 June 2013. Zoledronic acid (ZA), an intravenously administered bisphosphonate, and Denosumab, a subcutaneously administered inhibitor of nuclear factor B ligand (RANKL), have already been approved by Food and Drug Administration (FDA) for their use in treatment of bone metastases. These results led to the approval of denosumab by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), for the prevention of SREs in adults with bone metastases from solid tumors, including breast cancer. Alendronate, risedronate, zoledronic acid, denosumab, and teriparatide are Food and Drug Administration (FDA)-approved therapeutic options. Several of these therapies have recently been approved by the FDA to treat bone cancer pain (bisphosphonates, denosumab) and others are currently being evaluated in human clinical trials (tanezumab). A fourth agent, denosumab (bone targeted therapy) was also recently approved by the FDA for patients with bone metastasis after showing a reduction in the occurrence of skeletal-related events. AHRQ published an updated review in March 2012 that summarized the benefits and risks of osteoporosis medications in treatment and prevention of osteoporosis, including bisphosphonates (aledronate, risedronate, ibandronate, zoledronic acid), parathyroid hormone, teriparatide, calcitonin, estrogens (for prevention in postmenopausal women), selective estrogen receptor modulators (raloxifene), and denosumab(approved by the FDA in 2010). Four new drugs have received U.S. Food and Drug Administration (FDA)-approval in 2010 and 2011: sipuleucel-T, an immunotherapeutic agent; cabazitaxel, a novel microtubule inhibitor; abiraterone acetate, a new androgen biosynthesis inhibitor; and denosumab, a bone-targeting agent. Recently, the US FDA and the EMA approved denosumab (a fully human monoclonal antibody) to treat skeletal-related events in bone-metastatic prostate cancer. In addition to these new and emerging therapeutic agents, denosumab was approved for the prevention of skeletal complications in patients with bone metastases due to solid tumor malignancies, providing an alternative to zoledronic acid. Recently, denosumab was FDA-approved for prevention of SREs in patients with bone metastases from solid tumors. In the 2010s to date, an additional 3 antibodies (denosumab, belimumab, ipilimumab) have been approved and one antibody-drug conjugate (brentuximab vedotin) is undergoing regulatory review and may be approved in the US by August 30, 2011. We also review the evidence supporting the FDA's approval of denosumab (bone-targeted therapy) as a treatment option for men with CRPC and bony metastases. It has been approved for clinical use by the FDA in the US and by the European Medicines Agency in Europe since June 2010 (trade name Prolia(™), Amgen, Thousand Oaks, CA, USA). The fully human monoclonal antibody denosumab (Prolia(®)) has been recently approved by the European Medical Agency (EMEA) and the Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis. Raloxifene and denosumab are only FDA approved for postmenopausal osteoporosis. The new antiresorptive drug, denosumab, although FDA-approved only for postmenopausal women, has been shown in a study of men on ADT to increase bone density in spine, hip, and forearm and decrease vertebral fractures on x-ray. Since then, an additional six human mAbs have received FDA approval: panitumumab, golimumab, canakinumab, ustekinumab, ofatumumab and denosumab.

yes

517395b98ed59a060a00001a

Are transcription and splicing connected?

, as splicing is often cotranscriptional, a complex picture emerges in which splicing regulation not only depends on the balance of splicing factor binding to their pre-mRNA target sites but also on transcription-associated features such as protein recruitment to the transcribing machinery and elongation kinetics. recent evidence shows that chromatin structure is another layer of regulation that may act through various mechanisms hese span from regulation of RNA polymerase II elongation, which ultimately determines splicing decisions, to splicing factor recruitment by specific histone marks. Chromatin may not only be involved in alternative splicing regulation but in constitutive exon recognition as well Moreover, splicing was found to be necessary for the proper 'writing' of particular chromatin signatures, giving further mechanistic support to functional interconnections between splicing, transcription and chromatin structure. These links between chromatin configuration and splicing raise the intriguing possibility of the existence of a memory for splicing patterns to be inherited through epigenetic modifications. Spliceosome assembly occurs co-transcriptionally, raising the possibility that DNA structure may directly influence alternative splicing. upporting such an association, recent reports have identified distinct histone methylation patterns, elevated nucleosome occupancy and enriched DNA methylation at exons relative to introns Moreover, the rate of transcription elongation has been linked to alternative splicing. ere we provide the first evidence that a DNA-binding protein, CCCTC-binding factor (CTCF), can promote inclusion of weak upstream exons by mediating local RNA polymerase II pausing both in a mammalian model system for alternative splicing, CD45, and genome-wide We recently showed that cotranscriptional splicing occurs efficiently in Drosophila, In recent years it became apparent that splicing is predominantly cotranscriptional To determine the prevalence of cotranscriptional splicing in Drosophila, we sequenced nascent RNA transcripts from Drosophila S2 cells as well as from Drosophila heads. Eighty-seven percent of the introns assayed manifest >50% cotranscriptional splicing. The remaining 13% are cotranscriptionally spliced poorly or slowly, with ∼3% being almost completely retained in nascent pre-mRNA. We estimate that > or =90% of endogenous yeast splicing is posttranscriptional, consistent with an analysis of posttranscriptional snRNP-associated pre-mRNA. Notably, the topoisomerase I inhibitor camptothecin, which stalls elongating Pol II, increased cotranscriptional splicing factor accumulation and splicing in parallel. This provides direct evidence for a kinetic link between transcription, splicing factor recruitment and splicing catalysis. Recent evidence indicates that transcriptional elongation and splicing can be influenced reciprocally: Elongation rates control alternative splicing and splicing factors can, in turn, modulate pol II elongation. The presence of transcription factors in the spliceosome and the existence of proteins, such as the coactivator PGC-1, with dual activities in splicing and transcription can explain the links between both processes and add a new level of complexity to the regulation of gene expression in eukaryotes.

yes

54db1d580f63c58e6e000005

Is Alu hypomethylation associated with breast cancer?

Alu and LINE-1 hypomethylation is associated with HER2 enriched subtype of breast cancer In IBC, Alu hypomethylation correlated with negative estrogen receptor (ER) status In survival analyses, low Alu methylation status tended to be associated with poor disease-free survival of the patients. Alu hypomethylation is probably a late event during breast cancer progression prominent hypomethylation of Alu and LINE-1 in HER2 enriched subtype may be related to chromosomal instability of this specific subtype. DNA methylation for three repetitive elements (LINE1, Sat2 and Alu) were analyzed in invasive ductal carcinoma of the breast, paired adjacent normal tissue and WBC from 40 breast cancer patients DNA methylation for the three repetitive elements was lower in tumor compared to adjacent tissue and WBC DNA.

yes

51593dc8d24251bc05000099

Proteomic analyses need prior knowledge of the organism complete genome. Is the complete genome of the bacteria of the genus Arthrobacter available?

Complete genome sequence of Arthrobacter phenanthrenivorans type strain (Sphe3). Complete genome sequence and metabolic potential of the quinaldine-degrading bacterium Arthrobacter sp. Rue61a. Here, we described the high quality draft genome sequence, annotations and the features ofArthrobactersp. B6. Complete genome sequence of Arthrobacter sp. ZXY-2 associated with effective atrazine degradation and salt adaptation. We announce here the draft genome sequence ofArthrobactersp. strain EpSL27, isolated from the stem and leaves of the medicinal plantEchinacea purpureaand able to inhibit human-pathogenic bacterial strains. We report here the 4.6-Mb genome sequence of a nylon oligomer-degrading bacterium,Arthrobactersp. strain KI72. Arthrobacter alpinusR3.8 is a psychrotolerant bacterial strain isolated from a soil sample obtained at Rothera Point, Adelaide Island, close to the Antarctic Peninsula. Strain R3.8 was sequenced in order to help discover potential cold active enzymes with biotechnological applications.

yes

56bf365eef6e39474100000e

Do mutations of AKT1 occur in meningiomas?

The recent identification of somatic mutations in components of the SHH-GLI1 and AKT1-MTOR signaling pathways indicates the potential for cross talk of these pathways in the development of meningiomas. A mutation in PIK3CA or AKT1 was found in around 9 % of the cases. AKT1E17K mutations cluster with meningothelial and transitional meningiomas and can be detected by SFRP1 immunohistochemistry. AKT1E17K mutations were exclusively seen in meningiomas and occurred in 65 of 958 of these tumors. A strong preponderance was seen in the variant of meningothelial meningioma WHO grade I of basal and spinal localization. In contrast, AKT1E17K mutations were rare in WHO grade II and absent in WHO grade III meningiomas. We observed strong up-regulation of SFRP1 expression in all meningiomas with AKT1E17K mutation and in HEK293 cells after transfection with mutant AKT1E17K, but not in meningiomas and HEK293 cells lacking this mutation. SMO and AKT1 mutations occur in non-NF2 meningiomas. Recurrent mutations in SMO and AKT1 are mutually exclusive with NF2 loss in meningioma. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways. SMO and AKT1 mutations occur in non-NF2 meningiomas The recent identification of somatic mutations in components of the SHH-GLI1 and AKT1-MTOR signaling pathways indicates the potential for cross talk of these pathways in the development of meningiomas A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations Recurrent mutations in SMO and AKT1 are mutually exclusive with NF2 loss in meningioma A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways.

yes

5158644cd24251bc0500008e

Does physical activity influence gut hormones?

Increases in blood PYY(3-36) levels were dependent on the exercise intensity (effect of session: P<0.001 by two-way ANOVA), whereas those in GLP-1 levels were similar between two different exercise sessions. A decrease in serum leptin levels (-48.4%, p < 0.001) was observed after intervention without changes in total peptide YY and insulin levels. ur data suggest that the control of spontaneous physical activity by gut hormones or their neuropeptide targets may represent an important mechanistic component of energy balance regulation Hunger and gut hormones remained unchanged during the bed rest. weight-bearing exercise has a greater exercise-induced appetite suppressive effect compared with non-weight-bearing exercise, and both forms of exercise lowered acylated ghrelin and increased total PYY, but the changes did not differ significantly between exercise modes. Appetite (P < 0.0005) and acylated ghrelin (P < 0.002) were suppressed during exercise but more so during SIE. Peptide YY increased during exercise but most consistently during END (P < 0.05). Acylated ghrelin was lowest in the afternoon of SIE (P = 0.018) despite elevated appetite Following the pre-exercise meal, ghrelin was suppressed ~17% and insulin and PYY were elevated ~157 and ~40%, respectively, relative to fasting (day 7). Following exercise, PYY, ghrelin, and GH were significantly (p < 0.0001) increased by ~11, ~16 and ~813%, respectively. The noted disruption in the typical inverse relationship between ghrelin and PYY following exercise suggests that interaction of these peptides may be at least partially responsible for post-exercise appetite suppression Plasma levels of PYY and GLP-1 were increased by exercise, whereas plasma ghrelin levels were unaffected by exercise These findings suggest ghrelin and PYY may regulate appetite during and after exercise, significant (P < 0.05) interaction effects for hunger, acylated ghrelin, and PYY, indicating suppressed hunger and acylated ghrelin during aerobic and resistance exercise and increased PYY during aerobic exercise 'exercise-induced anorexia' may potentially be linked to increased PYY, GLP-1 and PP levels. Hunger scores and PYY, GLP-1 and PP levels showed an inverse temporal pattern during the 1-h exercise/control intervention Exercise significantly increased mean PYY, GLP-1 and PP levels, and this effect was maintained during the post-exercise period for GLP-1 and PP. No significant effect of exercise was observed on postprandial levels of ghrelin following blood donation the strenuous exercise resulted in a marked reduction in the plasma leptin We conclude that strenuous physical exercise; 1) fails to affect plasma leptin level but when performed after meal but not after blood withdrawal it results in an increase and fall in plasma leptin, and 2) the release of gut hormones (gastrin, CCK and PP) and stress hormones (norepinephrine, cortisol, GH) increase immediately after exercise independently of feeding or blood donation the unrestricted exercise group has a significantly elevated SRIF-LI concentration Exercise has recently been reported to influence ghrelin and PYY concentrations.

yes

54f08d4a94afd61504000016

Is irritable bowel syndrome more common in women with endometriosis?

CONCLUSIONS: Comorbid pain syndromes, mood conditions and asthma are common in adolescents and young women with endometriosis. There are many etiologies of pelvic pain that present with symptoms resembling those of endometriosis-associated pelvic pain that are not diagnosable with laparoscopy, such as interstitial cystitis and irritable bowel syndrome. Often, such patients are labelled with irritable bowel syndrome. Irritable bowel syndrome (IBS) is also common in this setting, and it was speculated that the visceral hypersensitivity associated with this condition might be amplifying the symptoms of endometriosis. RESULTS: Compared with controls, patients with minimal to mild and moderate to severe endometriosis had a higher prevalence of symptoms consistent with IBS (0% vs 65% and 50%, respectively, p<0.001) with significantly lower mean pain thresholds (39.5 mm Hg (95% CI 36.0 to 43.0) vs 28.1 mm Hg (95% CI 24.5 to 31.6), p=0.001 and 28.8 mm Hg (95% CI 24.9 to 32.6), p=0.002) not explained by differences in rectal compliance. Similarly, women with a history of irritable bowel syndrome were twice as likely to develop endometriosis [AOR=1.9, 95% CI (1.03-3.87)]. A weak association between reported family history of endometriosis and history of irritable bowel syndrome and the development of endometriosis was also observed. Irritable bowel syndrome and chronic constipation in patients with endometriosis. Fifteen per cent of the patients with endometriosis also had IBS and 14% of the patients with endometriosis had functional constipation without IBS. CONCLUSION: In patients with endometriosis, 29% also had IBS or constipation. Seventy-six women (21.4%) had previously been diagnosed with irritable bowel syndrome and 79% of them had endometriosis confirmed. Compared with controls, women with endometriosis had increased risks of abdominopelvic pain (OR 5.2 [95% CI: 4.7-5.7]), dysmenorrhoea (OR 8.1 [95% CI: 7.2-9.3]), menorrhagia (OR 4.0 [95% CI: 3.5-4.5]), subfertility (OR 8.2 [95% CI: 6.9-9.9]), dyspareunia and/or postcoital bleeding (OR 6.8 [95% CI: 5.7-8.2]), and ovarian cysts (OR 7.3 [95% CI: 5.7-9.4]), and of being diagnosed with irritable bowel syndrome (IBS) (OR 1.6 [95% CI: 1.3-1.8]) or pelvic inflammatory disease (OR 3.0 [95% CI: 2.5-3.6]). Endometriosis may coexist with or be misdiagnosed as pelvic inflammatory disease or IBS. RESULTS: Compared with the controls, women with endometriosis were 3.5 times more likely to have received a diagnosis of IBS (OR 3.5 [95% CI: 3.1-3.9]). Even after women had been diagnosed with endometriosis, they were still two and a half times more likely to receive a new diagnosis of IBS when compared with the controls (OR 2.5 [95% CI: 2.2-2.8]). CONCLUSIONS: Women with endometriosis are more likely to be diagnosed with IBS and PID than controls, even after a definitive diagnosis of endometriosis has been reached. In women, clinical studies suggest that functional pain syndromes such as irritable bowel syndrome, interstitial cystitis, and fibromyalgia, are co-morbid with endometriosis, chronic pelvic pain, and others diseases. In women, clinical studies suggest that pain syndromes such as irritable bowel syndrome and interstitial cystitis, which are associated with visceral hyperalgesia, are often comorbid with endometriosis and chronic pelvic pain. Depression, anxiety, IBS, FM, CFS, and IC were more common in migraine with EM group than in controls. Intestinal endometriosis can mimic many gastrointestinal diseases, such as irritable bowel syndrome, inflammatory bowel disease, infections and neoplasms. Endometriosis is often associated with other painful conditions such as irritable bowel syndrome, interstitial cystitis and fibromyalgia. CONCLUSIONS: Diagnosis of endometriosis should be considered in women with recurrent monthly abdominal pain and bowel symptoms, especially if accompanied by gynaecologic complaints, even because the significant symptoms overlap with the irritable bowel syndrome (IBS) and makes the differentiation extremely difficult. Intestinal endometriosis is typically asymptomatic; however, when symptoms occur, they can mimic those of irritable bowel syndrome. Similarly, women with a history of irritable bowel syndrome were twice as likely to develop endometriosis [AOR=1. Irritable bowel syndrome (IBS) is also common in this setting, and it was speculated that the visceral hypersensitivity associated with this condition might be amplifying the symptoms of endometriosis. Irritable bowel syndrome (IBS) is also common in this setting, and it was speculated that the visceral hypersensitivity associated with this condition might be amplifying the symptoms of endometriosis.

yes

531d2aa5267d7dd053000003

Does BNP increase after intensive exercise in athletes?

NT-pro-BNP was significantly elevated postexercise in both adults and adolescents and remained above baseline at 24 h in both groups. NT-pro-BNP concentrations increased significantly (28 +/- 17.1 vs 795 +/- 823 ng x L, P < 0.05), whereas postrace cTnT were elevated in just five athletes (20%). [NT-pro-BNP] was observed immediately after the marathon (median [NT-pro-BNP] before: 39.6 pg ml(-1), after: 138.6 pg ml(-1), p=0.003) with a further increase on day one. [BNP] did not increase immediately after the marathon but increased on day one (median [BNP] before: 15 pg ml(-1), day one: 27.35 pg ml(-1), p=0.006). Pro-BNP was significantly increased immediately post-race (27+/-21 vs 7+/-2 pmol/L pre-race, P < or = 0.007), which 12-24 h later, decreased to 19+/-14 pmol/L (P = 0.07 vs pre-race). The relatively high NT-proBNP levels after active recovery when psychophysical stress is higher, because of cycling and cold water immersion, suggest that not only endurance exercise, but also strenuous, stressful short exercise can induce an increase in NT-proBNP concentrations. Running a marathon significantly increases NT-pro-BNP levels in healthy adults. This increase could be partially attributed to cardiac stress. Increases in NT-proBNP can be found in a major part of obviously healthy athletes after prolonged strenuous exercise. The release of BNP during and after exercise may not result from myocardial damage but may have cytoprotective and growth-regulating effects. The different nature of exercise-induced increases in BNP and cardiac troponins has to be elucidated in the future. In healthy cyclists, transient increases in NT-pro-BNP and cTnT are more likely to reflect cardiac fatigue than injury. The rise in BNP in older athletes may reflect a reversible, mainly diastolic left ventricular dysfunction. Plasma BNP concentrations were higher in both the judo and marathon groups than in controls, and positively correlated with LV mass as well as with deceleration time. Such exercise significantly increased ANP and BNP levels in healthy men, and the increases could be partially attributed to myocardial damage during the race.

yes

54fefff26ad7dcbc1200000b

Are there web based self management strategies for chronic pain ?

Fibromyalgia Symptom Reduction by Online Behavioral Self-monitoring, This study aimed to evaluate effects of a web-based, self-monitoring and symptom management system (SMARTLog) that analyzes personal self-monitoring data and delivers data-based feedback over time. Moderate use (3 times weekly x 3 months) increased likelihood of clinically significant improvements in pain, memory, gastrointestinal problems, depression, fatigue, and concentration; heavy use (4.5 times weekly x five months) produced the above plus improvement in stiffness and sleep difficulties. Results suggest that the tailored online chronic pain management program showed promising effects on pain at 1 and 6 months posttreatment and quality of life at 6 months posttreatment in this naturalistic study. Results suggest the potential value of self-management for chronic pain patients and the potential acceptability of web-based delivery of intervention content. Patient involvement can be fostered by web-based applications combining health information with decision support or behaviour change support. These so-called Interactive Health Communication Applications (IHCAs) can reach great numbers of patients at low financial cost and provide information and support at the time, place and learning speed patients prefer. Web-based interventions may also be effective in enhancing self-management for individuals with chronic pain, but little is known about long-term effects. Research on Web-based interventions to support self-management following participation in pain management programs is limited. OBJECTIVE: The aim is to examine the long-term effects of a 4-week smartphone-intervention

yes

571f34ac0fd6f91b68000005

Is Weaver syndrome similar to Sotos?

Overgrowth conditions are a heterogeneous group of disorders characterised by increased growth and variable features, including macrocephaly, distinctive facial appearance and various degrees of learning difficulties and intellectual disability. Among them, Sotos and Weaver syndromes are clinically well defined and due to heterozygous mutations in NSD1 and EZH2, respectively. NSD1 and EZH2 are both histone-modifying enzymes NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key roles in the regulation of transcription through histone modification and chromatin modeling: NSD1 preferentially methylates lysine residue 36 of histone 3 (H3K36) and is primarily associated with active transcription, while EZH2 shows specificity for lysine residue 27 (H3K27) and is associated with transcriptional repression Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap Clinically, Weaver syndrome is closely related to Sotos syndrome, which is frequently caused by mutations in NSD1 Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia. Thus, it is not surprising that prenatal overgrowth occurs in several syndromes, including the Sotos and Weaver syndromes. NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. We conclude therefore that NSD1 mutations account for most cases of Sotos syndrome and a significant number of Weaver syndrome cases in our series. We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes. Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia. Two previous cases of neuroblastoma have been reported in children with Weaver syndrome. Weaver syndrome is closely related to Sotos syndrome, Overgrowth syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome, and Weaver syndrome have an increased risk of neoplasia. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. Clinically, Weaver syndrome is closely related to Sotos syndrome, which is frequently caused by mutations in NSD1.

yes

552fa6f5bc4f83e828000002

Is peripheral neuroepithelioma related to Ewing sarcoma?

The term "small round-cell tumor" describes a group of highly aggressive malignant tumors composed of relatively small and monotonous undifferentiated cells with high nuclear to cytoplasmic ratios. This group includes Ewing's sarcoma (ES), peripheral neuroepithelioma (aka, primitive neuroectodermal tumor or extraskeletal ES), peripheral neuroblastoma ("classic-type"), rhabdomyosarcoma, desmoplastic small round-cell tumor, lymphoma, leukemia, small-cell osteosarcoma, small-cell carcinoma (either undifferentiated or neuroendocrine), olfactory neuroblastoma, cutaneous neuroendocrine carcinoma (aka, Merkel-cell carcinoma), small-cell melanoma, and mesenchymal chondrosarcoma. Their clinical presentations often overlap, thus making a definitive diagnosis problematic in some cases AIMS: To retrospectively study the DNA content in a series of childhood Ewing Family Tumors (EFT), and to investigate its prognostic value. METHODS: The study was performed on a series of 27 EFTs (osseous Ewing's sarcoma, 18 cases; extraosseous Ewing's sarcoma, 2; peripheral neuroepithelioma, 4; Askin Rosai tumors, 3 To improve the prognosis of patients with poor-risk peripheral primitive neuroectodermal tumors (pPNETs; including peripheral neuroepithelioma and Ewing's sarcoma) Large group of small-round-cell tumours of soft tissues and bone represents a complex diagnostic problem for the pathologists. Neuronal nature of many tumours from this group is proven by means of new methods--immunophenotypic analysis, tissue culture, cytogenetics. Peripheral neuroepithelioma, Ewing tumour, primitive neuroectodermal tumour (PNET), Askin tumour belong to these neoplasms Comparison of Ewing's sarcoma of bone and peripheral neuroepithelioma. An immunocytochemical and ultrastructural analysis of two primitive neuroectodermal neoplasms Ewing's sarcoma of bone (ESB) and peripheral neuroepithelioma (PN) are frequently considered to be different tumors. Some researchers have suggested that PN is morphologically a neuroectodermal Ewing's sarcoma. We sought to determine the extent of neuroectodermal features in conventional ESB on direct patient material (25 cases) and to compare these tumors with a similar group of readily diagnosed PNs (10 cases) Neuroectodermal antigens (neuron-specific enolase, Leu-7 [HNK-1], neurofilament 200 kd, and S100) were found in nine of 10 cases of PN and in 17 of 25 cases of ESB These data support the concept that ESB and PN are both peripheral primitive neuroectodermal neoplasms, differing only in extent of neuroectodermal phenotype and morphological differentiation Besides these antigenic features, Ewing sarcoma cells are characterized by a specific t(11;22)(q24;q12) translocation also observed in neuroepithelioma, a neuroectodermal tumor, suggesting a possible evolutionary related origin. Ewings sarcoma (ES) and peripheral neuroepithelioma (PN) are closely related tumors, and it can be difficult to distinguish them from other small-round-cell tumors (SRCTs). The presence of this translocation in Ewing sarcoma and peripheral primitive neuroectodermal tumor has been taken as evidence that these two tumors are related. Besides these antigenic features, Ewing sarcoma cells are characterized by a specific t(11;22)(q24;q12) translocation also observed in neuroepithelioma, a neuroectodermal tumor, suggesting a possible evolutionary related origin. Indistinguishable patterns of protooncogene expression in two distinct but closely related tumors: Ewing's sarcoma and neuroepithelioma. Ewing's sarcoma (ES) and peripheral neuroepithelioma (PN) are related tumors, possibly of neural crest origin, which are cytogenetically characterized by the specific translocation t(11;22)(q24;q12). Ewing's sarcoma/peripheral primitive neuroectodermal tumors (ES/pPNET) are a group of small round cell sarcomas that show varying degrees of neuroectodermal differentiation characterized by translocation involving the EWS gene Ewing's sarcoma (ES) and peripheral neuroepithelioma (PN) are closely related tumors, and it can be difficult to distinguish them from other small-round-cell tumors (SRCTs) Ewing's sarcoma (ES) and peripheral neuroepithelioma (PN) are related tumors, possibly of neural crest origin, which are cytogenetically characterized by the specific translocation t(11;22)(q24;q12) This genetical similarity further supports a nosological concept according to which Askin's tumour, Ewing's sarcoma and peripheral neuroepithelioma represent phenotypic variations of the same tumour, namely the peripheral primitive neuroectodermal tumour. Besides these antigenic features, Ewing sarcoma cells are characterized by a specific t(11;22)(q24;q12) translocation also observed in neuroepithelioma, a neuroectodermal tumor, suggesting a possible evolutionary related origin

yes

5318a955b166e2b806000020

Is c-met involved in the activation of the Akt pathway?

Amplification of MET has been reported in approximately 5%-22% of lung tumors with acquired resistance to small-molecule inhibitors of the epidermal growth factor receptor (EGFR). Resistance to EGFR inhibitors is likely mediated through downstream activation of the phosphoinositide 3-kinase /AKT pathway. Simultaneous treatment of resistant tumors with a MET inhibitor plus an EGFR inhibitor can abrogate activation of downstream effectors of cell growth, proliferation, and survival, thereby overcoming acquired resistance to EGFR inhibitors. HGF mediated both ERK and Akt phosphorylation. ERK/Akt signaling, but not the Smad pathway, may be one of the main processes in HGF-induced EMT, The MAPK/Akt pathway is indispensable in HGF/c-Met signaling. Inhibition of c-Met activation sensitizes osteosarcoma cells to cisplatin via suppression of the PI3K-Akt signaling Specifically, we demonstrated that inhibition of c-Met activity led to suppression of the PI3K-Akt pathway, thus enhancing cisplatin chemosensitivity. Our study clearly suggests that inhibition of c-Met activity can effectively sensitize osteosarcoma cells to cisplatin via suppression of the PI3K-Akt signaling. We found that a dual Met/VEGF receptor 2 kinase inhibitor, E7050, circumvented HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer cell lines by inhibiting the Met/Gab1/PI3K/Akt pathway in vitro. Here, we report that i) treatment of RL95-2 cells with HGF resulted in phosphorylation of the HGF receptor c-Met, activation of Akt and IκB, translocation of NF-κB into the nucleus, and up-regulation of COX-2 mRNA; Our data suggest that HGF possesses chemotactic ability, has anti-apoptosis action, and induces cellular infiltration via the PI3K/Akt pathway; Hepatocyte growth factor-induced c-Src-phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway inhibits dendritic cell activation by blocking IκB kinase activity Activation of c-Src in turn establishes a complex consisting of phosphatidylinositol 3-kinase and c-MET, and promotes downstream activation of the phosphatidylinositol 3-kinase/AKT pathway and mammalian target of rapamycin. Notably, hepatocyte growth factor-stimulated c-Src activation results in induction of phosphatidylinositol 3-kinase complexes p85α/p110α and p85α/p110δ, which is required for activation of mammalian target of rapamycin, and consequent inhibition of IκB kinase and nuclear factor-κB activation. Our findings, for the first time, have identified the c-Src-phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway that plays a pivotal role in mediating the inhibitory effects of hepatocyte growth factor on dendritic cell activation by blocking nuclear factor-κB signaling. Cyr61 siRNA inhibited a second phase of Akt phosphorylation measured 12 hours after cell stimulation with HGF and also inhibited HGF-induced phosphorylation of the Akt target glycogen synthase kinase 3alpha. HGF+EGF treatment increased the duration of ERK1/2 and AKT activation compared to HGF or EGF alone. All these data indicate that a crosstalk between the EGF and HGF pathways in mammary epithelial cells may modulate the development of the mammary gland. Hepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway Consistent with these results, HGF activated Akt, which phosphorylates glycogen synthase kinase-3beta (GSK-3beta) to inactivate it, and reduced phosphorylation of microtubule-associated protein 2 (MAP2), which can promote microtubule polymerization and dendrite elongation when dephosphorylated. Conversely, pharmacological inhibition of c-Met with its specific inhibitor, PHA-665752, or genetic knock-down of c-Met with short hairpin RNAs (shRNAs) suppressed HGF-induced phosphorylation of Akt and GSK-3beta, increased phosphorylation of MAP2, and reduced dendrite number and length in cultured hippocampal neurons. Inhibiting Akt activity with the phosphoinositide-3-kinase inhibitor LY294002 or Akt inhibitor X suppressed HGF-induced phosphorylation of GSK-3beta, increased MAP2 phosphorylation, and blocked the ability of HGF to enhance dendritic length. These observations indicate that HGF and c-Met can regulate the early stages of dendrite maturation via activation of the Akt/GSK-3beta pathway. Involvement of PI3K/Akt signaling pathway in hepatocyte growth factor-induced migration of uveal melanoma cells HGF was found to enhance cell migration, and that HGF-induced migration depends on PI3K/Akt pathway. The activation of PI3K/Akt pathway induced by the HGF/c-Met axis is involved in the downregulation of cell adhesion molecules E-cadherin and beta-catenin, contributing to the attenuation of cell-cell adhesion and promoting the enhanced motility and migration of uveal melanoma cells. HGF protects cultured cortical neurons against hypoxia/reoxygenation induced cell injury via ERK1/2 and PI-3K/Akt pathways HGF stimulated both ERK1/2 and Akt activities in cortical neurons. Inhibition of ERK activation completely abolished the protective effects of HGF, and inhibition of Akt activation reduced, but did not completely eliminate the HGF mediated neuroprotection. It is suggested that the neuroprotection of HGF depend on ERK1/2 pathway, and, to a lesser extent, PI-3K/Akt pathway. Met signals hepatocyte survival by preventing Fas-triggered FLIP degradation in a PI3k-Akt-dependent manner Thus, Met acting on PI3K and Akt ensures high levels of FLIPL, and disruption of this pathway contributes to hepatic apoptosis and possibly to Fas-related liver diseases. The HGF-induced increase in Nkx 2.5 expression was inhibited by co-treatment with the PI3 kinase inhibitors Wortmannin and LY294002, but not by its inactive homolog LY303511, suggesting an involvement of the PI3 kinase/Akt pathway in this effect. X-Linked inhibitor of apoptosis protein expression level in colorectal cancer is regulated by hepatocyte growth factor/C-met pathway via Akt signaling Activation of XIAP expression by HGF was inhibited by siRNA targeting Akt1 and Akt2. Activation of C-MET enhances XIAP through the Akt pathway. Hepatocyte growth factor prevents ventricular remodeling and dysfunction in mice via Akt pathway and angiogenesis A significant reduction in apoptosis in the HGF-treated hearts was observed compared with control hearts, and was strongly associated with increased Akt activation. The antiapoptotic effect of HGF was mediated by activation of PI3-kinase/Akt pathway. The protective effect of HGF/SF against the ADR-induced apoptosis was abolished in the presence of either LY294002, an inhibitor of phosphatidylinositol-3'-OH kinase (PI3-K) or 1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, an inhibitor of Akt, thus implicating the activation of PI3-K-Akt signaling in the antiapoptotic action of HGF/SF. Immunoblotting analysis revealed that HGF/SF stimulated the sustained phosphorylation of Akt for several hours Furthermore, ADR-induced activation of caspase-9, a downstream molecule of Akt, was inhibited for at least 24 h after HGF/SF stimulation, These results indicate that HGF/SF, but not EGF, transmitted protective signals against ADR-induced apoptosis by causing sustained activation of the PI3-K-Akt signaling pathway. Hepatocyte growth factor/scatter factor inhibits UVB-induced apoptosis of human keratinocytes but not of keratinocyte-derived cell lines via the phosphatidylinositol 3-kinase/AKT pathway When we analyzed the signaling pathways initiated by the HGF/SF receptor c-met, we found that the phosphatidylinositol (PI) 3-kinase and its downstream-element AKT and the mitogen-activated protein (MAP) kinase were activated. Inhibition of PI 3-kinase led to a complete abrogation of the anti-apoptotic effect of HGF/SF, whereas blockade of the MAP kinase pathway had no effect. We now show in detached cells a cooperative effect of HGF and FN in the activation of PI 3-kinase and on the phosphorylation of PKB/Akt at serine 473. PI 3-kinase activity is also required for the HGF- and fibronectin-induced survival responses, as well as anchorage-independent colony growth. Together, these results demonstrate that the PI 3-kinase/Akt pathway is a key effector of the HGF- and fibronectin-induced survival response of breast carcinoma cells under detached conditions and corroborate an interaction between integrin and HGF/ Met signalling pathways in the development of invasive breast cancer.

yes

531a3fe3b166e2b806000038

Is pregnancy an additional risk during during H1N1 infection?

H1N1 influenza in pregnancy can be associated with severe complications This case series confirms a high number of complications in pregnant women due to pandemic H1N1/09. Pregnant women might be at increased risk for complications from pandemic H1N1 virus infection. Pregnant women are at increased risk for complications from pandemic influenza H1N1 virus infection. Vaccination of pregnant women against influenza A (H1N1) by Russian subunit formulation (MonoGrippol plus) showed reactogenicity comparable to control group by the level of influence on general metabolic and immunologic homeostasis and on the course of pregnancy, which is an evidence of its safety Pregnancy was identified as a major risk factor for increased mortality and morbidity due to H1N1 influenza in the pandemic of 2009 to 2010 While it is not possible to ascertain retrospectively if myocarditis was caused by either infection with H1N1 virus or as a result of pregnancy (in the absence of endomyocardial biopsies), the significant association with myocardial involvement in both women demonstrates the increased risk of exposure to H1N1 influenza virus in pregnant women. Although limited in size, the fully prospective nature of the safety follow-up of these women vaccinated during pregnancy is unique and offers an important degree of reassurance for the use of the AS03 adjuvanted H1N1 (2009) vaccine in this high risk group for H1N1 infection. During the H1N1 2009 pandemic, pregnant women constituted one of the priority groups for vaccination in many countries, creating a need for close monitoring of the safety of the vaccine in pregnant women Emerging data suggest that pregnancy conveys high risk for severe complications from the 2009 pandemic influenza A virus (2009 H1N1) infection Pregnant women have been identified as a group at risk, both for respiratory complications than for the admissions to the Intensive Care Unit (ICU) during the 2009 H1N1 influenza pandemic This report mitigates substantially the presumed severity of pandemic H1N1/09 influenza infection during pregnancy The results of our study do not indicate a risk for the pregnant woman and the developing embryo/fetus after H1N1 vaccination This large cohort study found no evidence of an increased risk of fetal death associated with exposure to an adjuvanted pandemic A/H1N1 2009 influenza vaccine during pregnancy Our results suggest that second- or third-trimester H1N1 vaccination was associated with improved fetal and neonatal outcomes during the recent pandemic Pregnant women might thus be at increased risk of complications from pandemic H1N1 virus infection, and illness may progress rapidly Pregnant women with H1N1 infection seem to benefit from antiviral therapy. arly identification and treatment were the most important factors in different countries and areas examined. The vaccine and antiviral drugs that have been the most efficient means to control the novel virus appear to be safe but require more extensive study However, there were significant differences between the two groups in relation to mean age, treatment with oseltamivir, schooling, and presence of other risk factors To investigate whether exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was associated with increased risk of adverse fetal outcomes. In this Danish cohort, exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was not associated with a significantly increased risk of major birth defects, preterm birth, or fetal growth restriction Most people affected by the virus, including pregnant women, suffer a mild viral illness, and make a full recovery Pregnant women, because of their altered immunity and physiological adaptations, are at higher risk of developing pulmonary complications, especially in the second and third trimesters The pregnancy outcomes were also poor for women who were affected by the virus with a fivefold increase in the perinatal mortality rate and threefold increase in the preterm delivery rate regnant women were at increased risk for serious outcomes of 2009 pandemic influenza A virus subtype H1N1 (influenza A[H1N1]pdm09) infection, but little is known about the overall impact of the pandemic on neonatal and maternal outcomes In this large, geographically diverse population, A(H1N1)pdm09 infection increased the risk for hospitalization during pregnancy Vaccination during pregnancy with Pandemrix(®) appeared to have no ill effects on the pregnancy. On the contrary, the rate of preterm birth and low birthweight was lower than expected, which agrees with some previous results During the influenza A(H1N1)pmd09 pandemic, although many cases occurred in younger adults, the risk factors identified for severe infections and complications were similar to those for seasonal influenza, including chronic respiratory, renal, liver, and heart diseases. In terms of pregnancy, the studies have shown contradictory results due to variations in methodology and medical care. However, it seems that pregnancy, particularly during the third trimester, increases the risk of complications, and that early antiviral treatment is associated with improved outcomes. Pregnant women with mild clinical illness secondary to 2009 H1N1 were not at a greater risk of adverse pregnancy outcomes However, severely infected women were more likely to deliver SGA infants Gestational age is associated with the risk of developing critical infection. The risk increases with increasing weeks of gestation. Following the start of winter in Liaoning province in China, the number of pregnant women infected with influenza increased significantly regnancy, with or without additional complications, constitutes a high-risk condition for complications of influenza infection and warrants early intervention with neuraminidase inhibitors such as oseltamivir, if influenza is suspected

yes

51757bbb8ed59a060a00002e

Are long non coding RNAs as conserved in sequence as protein coding genes?

Most lncRNAs are under lower sequence constraints than protein-coding genes and lack conserved secondary structures, making it hard to predict them computationally. hey are under stronger selective pressure than neutrally evolving sequences-particularly in their promoter regions, which display levels of selection comparable to protein-coding genes. bout one-third seem to have arisen within the primate lineage.

no

535d75ab7d100faa09000004

Is TENS machine effective in pain?

Transcutaneous electrical nerve stimulation is widely used in pain management but its effectiveness depends on the stimulation being targeted appropriately hypoalgesic effects of transcutaneous electrical nerve stimulation upon experimentally induced ischaemic pain. The results of this study have provided evidence of the hypoalgesic effects of TENS upon experimental ischaemic pain which were found to be frequency specific with the lower frequency used here (4 Hz) demonstrating the only significant effect

yes

56d1d14567f0cb3d66000003

Is there any algorithm for enhancer identification from chromatin state?

RFECS: a random-forest based algorithm for enhancer identification from chromatin state. However, only a limited number of cell types or chromatin marks have previously been investigated for this purpose, leaving the question unanswered whether there exists an optimal set of histone modifications for enhancer prediction in different cell types. Here, we address this issue by exploring genome-wide profiles of 24 histone modifications in two distinct human cell types, embryonic stem cells and lung fibroblasts. We developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer identification from Chromatin States) to integrate histone modification profiles for identification of enhancers, and used it to identify enhancers in a number of cell-types. We show that RFECS not only leads to more accurate and precise prediction of enhancers than previous methods, but also helps identify the most informative and robust set of three chromatin marks for enhancer prediction. We developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer identification from Chromatin States) to integrate histone modification profiles for identification of enhancers, and used it to identify enhancers in a number of cell-types. Here, we address this issue by exploring genome-wide profiles of 24 histone modifications in two distinct human cell types, embryonic stem cells and lung fibroblasts. We developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer identification from Chromatin States) to integrate histone modification profiles for identification of enhancers, and used it to identify enhancers in a number of cell-types. ChromaGenSVM selects optimum combinations of specific histone epigenetic marks to predict enhancers. We developed a Random-Forest based algorithm, RFECS (Random Forest based Enhancer identification from Chromatin States) to integrate histone modification profiles for identification of enhancers, and used it to identify enhancers in a number of cell-types.

yes

553f78c7ab98a37113000008

Are transcribed ultraconserved regions involved in cancer?

Although most cancer research has focused in mRNA, non-coding RNAs are also an essential player in tumorigenesis. In addition to the well-recognized microRNAs, recent studies have also shown that epigenetic silencing by CpG island hypermethylation of other classes of non-coding RNAs, such as transcribed ultraconserved regions (T-UCRs) or small nucleolar RNAs (snoRNAs), also occur in human neoplasia Starting from a genome-wide expression profiling, we demonstrate for the first time a functional link between oxygen deprivation and the modulation of long noncoding transcripts from ultraconserved regions, termed transcribed-ultraconserved regions (T-UCRs). Interestingly, several hypoxia-upregulated T-UCRs, henceforth named 'hypoxia-induced noncoding ultraconserved transcripts' (HINCUTs), are also overexpressed in clinical samples from colon cancer patients Consistent with the hypothesis that T-UCRs have important function in tumor formation The importance of other classes of non-coding RNAs, such as long intergenic ncRNAs (lincRNAs) and transcribed ultraconserved regions (T-UCRs) as altered elements in neoplasia, is also gaining recognition Expression levels of transcribed ultraconserved regions uc.73 and uc.388 are altered in colorectal cancer Transcribed ultraconserved regions (T-UCRs) are a subset of 481 sequences longer than 200 bp, which are absolutely conserved between orthologous regions of human, rat and mouse genomes, and are actively transcribed. It has recently been proven in cancer systems that differentially expressed T-UCRs could alter the functional characteristics of malignant cells. Genome-wide profiling revealed that T-UCRs have distinct signatures in human leukemia and carcinoma Our preliminary results suggest that uc.73 and uc.388 could be potential diagnostic and prognostic biomarkers in CRC patients The transcribed-ultraconserved regions: a novel class of long noncoding RNAs involved in cancer susceptibility This review gives a picture of the state of the art of a novel class of long ncRNA known as transcribed-ultraconserved regions (T-UCRs). Most recent studies show that they are significantly altered in adult chronic lymphocytic leukemias, carcinomas, and pediatric neuroblastomas, leading to the hypothesis that UCRs may play a role in tumorigenesis and promising innovative future T-UCR-based therapeutic approaches CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer We focused on the transcribed-ultraconserved regions (T-UCRs), a subset of DNA sequences that are absolutely conserved between orthologous regions of the human, rat and mouse genomes and that are located in both intra- and intergenic regions. We used a pharmacological and genomic approach to reveal the possible existence of an aberrant epigenetic silencing pattern of T-UCRs by treating cancer cells with a DNA-demethylating agent followed by hybridization to an expression microarray containing these sequences. We observed that DNA hypomethylation induces release of T-UCR silencing in cancer cells. Among the T-UCRs that were reactivated upon drug treatment, Uc.160+, Uc283+A and Uc.346+ were found to undergo specific CpG island hypermethylation-associated silencing in cancer cells compared with normal tissues. The analysis of a large set of primary human tumors (n=283) demonstrated that hypermethylation of the described T-UCR CpG islands was a common event among the various tumor types. Our finding that, in addition to microRNAs, another class of ncRNAs (T-UCRs) undergoes DNA methylation-associated inactivation in transformed cells supports a model in which epigenetic and genetic alterations in coding and non-coding sequences cooperate in human tumorigenesis An integrative genomics screen uncovers ncRNA T-UCR functions in neuroblastoma tumours Different classes of non-coding RNAs, including microRNAs, have recently been implicated in the process of tumourigenesis. In this study, we examined the expression and putative functions of a novel class of non-coding RNAs known as transcribed ultraconserved regions (T-UCRs) in neuroblastoma our results define a T-UCR expression landscape in neuroblastoma and suggest widespread T-UCR involvement in diverse cellular processes that are deregulated in the process of tumourigenesis Moreover, the recent demonstration that other ncRNAs, the ultraconserved genes (UCGs) or transcribed ultraconserved regions (T-UCRs), are involved in human cancerogenesis, suggests that the wider family of ncRNAs (including both miRNAs and UCGs) could contribute to the development of the malignant phenotype. Here we review the main studies investigating the role of miRNAs and UCRs in both normal hemopoiesis and hematological malignancies, and identify the molecular, clinical and therapeutic implications of these recent findings The transcribed-ultraconserved regions: a novel class of long noncoding RNAs involved in cancer susceptibility. Expression levels of transcribed ultraconserved regions uc.73 and uc.388 are altered in colorectal cancer. CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer. Starting from a genome-wide expression profiling, we demonstrate for the first time a functional link between oxygen deprivation and the modulation of long noncoding transcripts from ultraconserved regions, termed transcribed-ultraconserved regions (T-UCRs). The importance of other classes of non-coding RNAs, such as long intergenic ncRNAs (lincRNAs) and transcribed ultraconserved regions (T-UCRs) as altered elements in neoplasia, is also gaining recognition. Moreover, the recent demonstration that other ncRNAs, the ultraconserved genes (UCGs) or transcribed ultraconserved regions (T-UCRs), are involved in human cancerogenesis, suggests that the wider family of ncRNAs (including both miRNAs and UCGs) could contribute to the development of the malignant phenotype. Moreover, the recent demonstration that other ncRNAs, the ultraconserved genes (UCGs) or transcribed ultraconserved regions (T-UCRs), are involved in human cancerogenesis, suggests that the wider family of ncRNAs (including both miRNAs and UCGs) could contribute to the development of the malignant phenotype Starting from a genome-wide expression profiling, we demonstrate for the first time a functional link between oxygen deprivation and the modulation of long noncoding transcripts from ultraconserved regions, termed transcribed-ultraconserved regions (T-UCRs)

yes

56d8b27651531f7e33000003

Do patients with Pendred syndrome present congenital deafness?

Pendred Syndrome can be characterized by the triad composed of familial goitre, abnormal perchlorate discharge and congenital deafness. Pendred syndrome is an autosomal recessive disorder characterized by congenital deafness and goiter. Pendred syndrome comprises congenital sensorineural hearing loss, thyroid goiter, and positive perchlorate discharge test. The cause of the congenital deafness in Pendred syndrome is obscure, although a Mondini type malformation of the cochlea exists in some patients. Pendred syndrome is an autosomal recessive disorder characterized by congenital deafness and goiter. Pendred syndrome is the autosomal recessively transmitted association of familial goiter and congenital deafness. Pendred syndrome (PDS) is an autosomal recessive disorder characterized by congenital deafness, goiter and iodide organification defect. Pendred syndrome is a recessively inherited disorder with the hallmark features of congenital deafness and thyroid goitre. Pendred syndrome, a common autosomal-recessive disorder characterized by congenital deafness and goiter, is caused by mutations of SLC26A4, which codes for pendrin. These studies provide compelling evidence that defects in pendrin cause Pendred syndrome thereby launching a new area of investigation into thyroid physiology, the pathogenesis of congenital deafness and the role of altered sulphate transport in human disease. Mutations in the Pendred syndrome gene have been observed in patients with deafness and vestibular aqueduct dilatation, in the absence of other Pendred syndrome features. The occurrence of congenital deafness, mutism and goitre unassociated with cretinism or mental retardation in euthyroid patients is known as Pendred's Syndrome. The autosomal recessive Pendred's syndrome is defined by congenital sensorineural deafness, goiter, and impaired iodide organification. Pendred's syndrome is an autosomal recessive disease characterized by goiter, impaired iodide organification, and congenital sensorineural deafness. Pendred syndrome is an autosomal recessive disorder characterized by congenital sensorineural deafness, goiter, and impaired iodide organification. Pendred's syndrome is manifested by congenital sensorineural deafness in association with familial goiter due to defective organic binding of iodine in the thyroid gland. Although the textbook view of the Pendred syndrome is that of an autosomal recessive condition characterised by deafness and goitre, it is increasingly clear that not all patients present this classical clinical description. Pendred's syndrome may account for up to 10% of the cases with hereditary hearing loss, and pendrin mutations have also been found in a kindred with non-syndromic deafness. Pendred syndrome comprises the association of severe congenital sensorineural deafness with thyroid pathology. The first one is named Pendred Syndrome (PS) when deafness is associated with thyroid goiter; the second is called DFNB4, when no other symptoms are present. Pendred syndrome is an autosomal recessive disorder characterized by sensorineural deafness, a partial defect in iodide organification, and dyshormonogenetic goiter. Pendred syndrome and non-syndromic recessive deafness associated with enlarged vestibular aqueduct (NSRD with EVA) are caused by mutations in the SLC26A4 (PDS) gene. Although the textbook view of Pendred syndrome is that of an autosomal recessive condition characterized by deafness and goitre, it is increasingly clear that not all such patients present this classical clinical picture. The occurrence of congenital deafness, mutism and goitre unassociated with cretinism or mental retardation in euthyroid patients is known as Pendred's Syndrome. The cause of the congenital deafness in Pendred syndrome is obscure, although a Mondini type malformation of the cochlea exists in some patients. The discovery of mutations in the SLC26A4 gene in patients with Pendred syndrome (congenital deafness, goiter, and defective iodide organification) suggested a possible role for the encoded protein, pendrin, as an apical iodide transporter. Pendred syndrome is a recessively inherited disorder with the hallmark features of congenital deafness and thyroid goitre. Pendred&apos;s syndrome is manifested by congenital sensorineural deafness in association with familial goiter due to defective organic binding of iodine in the thyroid gland. The majority of patients with Pendred&apos;s syndrome are euthyroid. We report on an unusual case of a patient with Pendred&apos;s syndrome presenting with amenorrhea and late-onset hypothyroidism. Although the textbook view of Pendred syndrome is that of an autosomal recessive condition characterized by deafness and goitre, it is increasingly clear that not all such patients present this classical clinical picture. Malformations of the inner ear, specifically enlargement of the vestibular aqueduct, are common in Pendred syndrome and mutations in the PDS (Pendred Syndrome) gene have been recorded in patients presenting with deafness and vestibular aqueduct dilatation only, without other features of Pendred syndrome. The occurrence of congenital deafness, mutism and goitre unassociated with cretinism or mental retardation in euthyroid patients is known as Pendred&apos;s Syndrome. It has been estimated that 4-10 % of children with congenital deafness suffer from this condition. Malformations of the inner ear, specifically enlargement of the vestibular aqueduct, are common in Pendred syndrome and mutations in the PDS (Pendred Syndrome) gene have been recorded in patients presenting with deafness and vestibular aqueduct dilatation only, without other features of Pendred syndrome. Since this is the most common radiological malformation of the cochlea in deaf patients, we investigated what proportion of such cases were due to mutation of the PDS gene. Although the textbook view of Pendred syndrome is that of an autosomal recessive condition characterized by deafness and goitre, it is increasingly clear that not all such patients present this classical clinical picture. Malformations of the inner ear, specifically enlargement of the vestibular aqueduct, are common in Pendred syndrome and mutations in the PDS (Pendred Syndrome) gene have been recorded in patients presenting with deafness and vestibular aqueduct dilatation only, without other features of Pendred syndrome.

yes

552fa32fbc4f83e828000001

Is CD56 useful in Ewing sarcoma prognosis?

Excellent prognosis in a subset of patients with Ewing sarcoma identified at diagnosis by CD56 using flow cytometry There was a highly significant correlation between CD56 expression and progression-free survival (PFS; 69% in low/negative expression versus 30% in high expression groups, P = 0.024) In patients with localized nonpelvic disease, those expressing low/negative CD56 had 100% PFS versus 40% in the high expressing group (P = 0.02) CD56 was found to be an independent prognostic marker with an 11-fold increased risk for relapse in patients with localized disease (P = 0.006) CD56 expression could be used to reveal ES patients with excellent prognosis or patients predisposed to relapse, thus improving treatment stratification and implementation of personalized therapy Excellent prognosis in a subset of patients with Ewing sarcoma identified at diagnosis by CD56 using flow cytometry. Three years after diagnosis the patient presented with severe respiratory difficulty and following resection, the final pathology revealed multiple tumors with foci of high grade sarcoma compatible with primitive neuroectodermal tumor/extraskeletal Ewing sarcoma based on morphology and immunohistochemistry (CD99, CD56). CD56 expression could be used to reveal ES patients with excellent prognosis or patients predisposed to relapse, thus improving treatment stratification and implementation of personalized therapy. Identification of CD56 and CD57 by flow cytometry in Ewing's sarcoma or primitive neuroectodermal tumor. CD56 expression could be used to reveal ES patients with excellent prognosis or patients predisposed to relapse, thus improving treatment stratification and implementation of personalized therapy.

yes

52fa73c62059c6d71c000058

Are there any urine biomarkers for chronic kidney disease?

Kidney and urine proteomic biomarkers are considered as promising diagnostic tools to predict CKD progression early in diabetic nephropathy, facilitating timely and selective intervention that may reduce the related health-care expenditures. Both blood and urine biomarkers are reviewed in this paper and offer a considerable opportunity to enhance the understanding of the pathophysiology and known epidemiology of these recently defined syndromes. Cardiorenal syndromes (CRS) have been subclassified as five defined entities which represent clinical circumstances in which both the heart and the kidney are involved in a bidirectional injury and dysfunction via a final common pathway of cell-to-cell death and accelerated apoptosis mediated by oxidative stress. There is a strong association between both acute and chronic dysfunction of the heart and kidneys with respect to morbidity and mortality. Both blood and urine biomarkers, including the assessment of catalytic iron, a critical element to the generation of oxygen-free radicals and oxidative stress, are reviewed in this paper. Identification of urine biomarkers has proven to be beneficial in recent years because of ease of handling, stability, and the ability to standardize the various markers to creatinine or other peptides generally already present in the urine. Recent markers such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and podocin have garnered a lot of attention. The emergence of these and other biomarkers is largely because of the evolution of novel genomic and proteomic applications in investigations of acute kidney injury and chronic kidney disease.

yes

56c1f029ef6e39474100004a

Is valproic acid effective for glioblastoma treatment?

A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma. PURPOSE: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. CONCLUSIONS: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study. Treatment of GDSCs with histone deacetylase inhibitors, TSA and VPA, significantly reduced proliferation rates of the cells and expression of the stem cell markers, indicating differentiation of the cells. Since differentiation into GBM makes them susceptible to the conventional cancer treatments, we posit that use of histone deacetylase inhibitors may increase efficacy of the conventional cancer treatments for eliminating GDSCs. Several clinical studies have reported that valproic acid could prolong survival of GBM patients. Our meta-analysis confirmed the benefit of using VPA (HR, 0.56; 95% CI, 0.44-0.71). Sub-group analysis shows that patients treated with VPA had a hazard ratio of 0.74 with a 95% confidence interval of 0.59-0.94 vs. patients treated by other-AEDs and a hazard ratio of 0.66 with a 95% confidence interval of 0.52-0.84 vs. patients treated by administration of non-AEDs. .CONCLUSION: The results of our study suggest that glioblastoma patients may experience prolonged survival due to VPA administration. A new and exciting insight is the potential contribution of VPA to prolonged survival, particularly in glioblastomas. Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models Valproic acid use during radiation therapy for glioblastoma associated with improved survival Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT) Valproic acid use during radiation therapy for glioblastoma associated with improved survival. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. PURPOSE: Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT). We investigated whether VA use during RT for GB was associated with overall survival (OS).METHODS AND MATERIALS: Medical records of 544 adults with GB were retrospectively reviewed. Analyses were performed to determine the association of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, seizure history, and concurrent temozolomide (TMZ) and AED use during RT with OS.RESULTS: Seizures before the end of RT were noted in 217 (40%) patients, and 403 (74%) were taking an AED during RT; 29 (7%) were taking VA. When the analysis was restricted to patients who received concurrent TMZ, VA use was marginally associated with OS (P=.057; HR, 0.54; 95% CI, -0.09 to 1.17), independently of RTOG RPA class and seizure history. Patients using VPA in combination with temozolomide showed a longer median survival of 69 weeks (95% confidence interval [CI]: 61.7-67.3) compared with 61 weeks (95% CI: 52.5-69.5) in the group without VPA (hazard ratio, 0.63; 95% CI: 0.43-0.92; P = .016), adjusting for age, extent of resection, and O(6)-DNA methylguanine-methyltransferase promoter methylation status. Use of VPA together with chemoradiation with temozolomide results in a 2-months' longer survival of patients with GBM.

yes

52b2ec744003448f55000001

Can Levoxyl (levothyroxine sodium) cause insomnia?

METHODS: Seventy-one patients diagnosed with primary hypothyroidism were randomly allocated into two study groups: the first group received usual dose of levothyroxine and the second group received combination of levothyroxine and liothyronine for at least 4 months. The main outcomes were psychosocial problems (Goldberg's General Health Questionnaire, GHQ-28), bodyweight, heart rate, blood pressure, and serum lipid levels. RESULTS: In both groups serum thyroid-stimulating hormone levels remained unchanged compared with baseline. Psychosocial scores, body weight, heart rate, blood pressure, and lipid profile in the two groups remained constant. The only exception was a small but significant reduction in anxiety/insomnia in combined treatment group as compared with monotherapy.

yes

530e42e65937551c09000007

Is fatigue prevalent in patients receiving treatment for glioblastoma?

By contrast, fatigue worsened over time, with a difference in mean score of 5.6 points between baseline and 4-month follow-up (P=.02). In the GB cohort, the most common side effects were fatigue (56 %), diarrhea (44 %), neutropenia (31 %), and thrombocytopenia (25 %). A total of 37 patients were treated, and treatment was well tolerated: grade 3, 4 nonhematologic toxicity occurred in 30% of patients and consisted mainly of fatigue (14%) and neuropathy (5%); grade 3, 4 hematologic toxicity occurred in 37% of patients and consisted of thrombocytopenia (30%), lymphopenia (4%), and neutropenia (4%). Nonhematologic Grade 3 toxicity was rare, and included fatigue in 4 patients and cognitive disability in 1 patient. The most common grade 3 events were neutropenia, thrombocytopenia, fatigue, and infection in 25, 20, 13, and 10%, respectively. Analysis of the results of the VAS Norris scale did not demonstrate an increase in emotional fatigue but did show an increase in physical fatigue that did not reach statistical significance. With regards to the MFI 20 tool, analysis of the results demonstrated a significant increase in general (P=0.0260) as well as physical (P=0.0141) fatigue but there was no difference in the other indices. This study demonstrated a progressive increase in physical fatigue in patients with glioblastoma relapse treated with irinotecan-bevacizumab. One patient treated with temozolomide plus isotretinoin plus thalidomide had dose-limiting grade 3 fatigue and rash, and 1 patient receiving all 4 agents had dose-limiting grade 4 neutropenia. The toxicities observed were primarily grade 1 and 2, and the most common were fatigue, hypertension, and headache. Fatigue (41%), rash (62%), and loose stools (58%) constituted the most frequent adverse events, the majority of these being limited to Grade 1/2. The most common grades 3 and 4 nonhematologic toxicities were nausea/vomiting (6.7%) and fatigue (5.8%). Grade 3/4 toxicities included leukopenia (n = 1), lymphopenia (n = 2), thrombocytopenia (n = 1), ALT elevation (n = 3), AST elevation (n = 1), CNS hemorrhage (n = 1), fatigue (n = 1), and thrombotic/embolic events (n = 3); 8 patients required dose reduction. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). Bevacizumab-related toxicity included fatigue (16 patients; 4 grade 3), leukopenia (9; 1 grade 3), anemia (5; 0 grade 3), hypertension (7; 1 grade 3), deep vein thrombosis (4; 1 grade 3) and wound dehiscence (2; 1 grade 3). Tiredness may be caused by the brain injury due to the tumor or the treatment in patients with glioblastoma multiforme (GBM). Some patients describe a sense of tiredness particularly after radiation or oral chemotherapy. Levels of tiredness in patients with GBM were greatly affected by the radiotherapy and oral chemotherapy (temozolomide). The treatment had no negative effect on HRQOL, however, fatigue (P = 0.02) and constipation (P = 0.01) scales worsened over time. This regimen was well tolerated with grade 3/4 toxicities of fatigue, leukopenia, thrombocytopenia and rash requiring dose reductions. The most common atrasentan-related toxicities were grade 1 or 2 rhinitis, fatigue, and edema. One patient developed Grade IV fatigue at the 100 ng/mL dose, but the MTD has not been established. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Some patients suffered from fatigue and weak concentration about three months after the end of radiotherapy, in some cases even the neurologic state was deteriorated. grade 1-2 common toxicities included fever, chills, fatigue, dizziness, nausea, vomiting and headache, neutrophilia and skin painful reactions appeared regularly at levels 3 and 4 (2.5 mg and 3.5 mg). Ten episodes of grade 3/4 adverse events were observed in nine patients, including fatigue (n = 3), thrombocytopenia (n = 4), and myelotoxicity, febrile neutropenia, and pulmonary embolism (each n = 1). Common adverse events were CTCAE grade 1-2 fatigue, loss of appetite, diarrhea, and nausea. The most common grade 3-4 toxicities were venous thrombosis, fatigue, skin reactions, encephalopathy, and neuropathy.

yes

5344310baeec6fbd0700000c

Does the CTCF protein co-localize with cohesin?

To investigate cohesin-non-CTCF (CNC) binding events in vivo we mapped cohesin and CTCF, as well as a collection of tissue-specific and ubiquitous transcriptional regulators using ChIP-seq in primary mouse liver. In contrast to regions of the genome where cohesin and CTCF colocalize, CNC sites coincide with the binding of master regulators and enhancer-markers and are significantly associated with liver-specific expressed genes. Here we report that cohesins colocalize with CTCF at two additional imprinted loci, the Dlk1-Dio3 and the Kcnq1/Kcnq1ot1 loci. By use of human hepatocellular carcinoma cells (HepG2), we found that liver-specific transcription factors colocalize with cohesin independently of CTCF at liver-specific targets that are distinct from those found in breast cancer cells Because cohesin can colocalize with CTCF, we performed chromatin immunoprecipitation for the cohesin subunit Rad21 and found lineage and stage-specific Rad21 recruitment to CTCF in all Ig loci Here we show that zebrafish runx1 is directly bound by cohesin and CCCTC binding factor (CTCF) at the P1 and P2 promoters, and within the intron between P1 and P2. The intronic binding sites for cohesin and CTCF coincide with histone modifications that confer enhancer-like properties, and two of the cohesin/CTCF sites behaved as insulators in an in vivo assay The identified cohesin and CTCF binding sites are likely to be cis-regulatory elements (CREs) for runx1 since they also recruit RNA polymerase II (RNAPII). We have found that CTCF and cohesin are highly enriched at the convergent and partially overlapping transcripts for the LMP1 and LMP2A genes, but it is not yet known how CTCF and cohesin may coordinately regulate these transcripts haracterization of constitutive CTCF/cohesin loci: a possible role in establishing topological domains in mammalian genomes Our analysis revealed: 1) constitutive CTCF loci were located in constitutive open chromatin and often co-localized with constitutive cohesin loci In brain, a third of CTCF and cohesin binding sites coincide, consistent with the potential for many interactions between cohesin and CTCF but also many instances of independent action Here, we focus on the emerging roles of CTCF and the cohesin in coordinating long-range interactions between regulatory elements Chromatin immunoprecipitation for CTCF and the cohesin subunits RAD21 and SMC3 reveals evolutionarily conserved binding sites within unmethylated regions ∼5 kb downstream of the PLAGL1 differentially methylated region and within the PLAGL1 3' untranslated region (UTR) TCF physically links cohesin to chromatin ohesin and CTCF: cooperating to control chromosome conformation? Recently, three groups mapped numerous cohesin-binding sites in mammalian chromosomes and found substantial overlap with the CCCTC-binding factor (CTCF) We found that each site contains a conserved CTCF consensus sequence, binds CTCF, and recruits the cohesin subunit Rad21 in vivo Recent experiments have revealed that cohesin binds to the same sites in mammalian genomes as the zinc finger transcription factor CTCF Here we review what is known about the roles of cohesin and CTCF in regulating gene expression in mammalian cells, and we discuss how cohesin might mediate the insulator function of CTCF Previous studies have shown that this major latency control region is occupied by the cellular chromatin boundary factor CTCF and chromosome structural maintenance proteins SMC1, SMC3, and RAD21, which comprise the cohesin complex Cohesin subunits assembled at the CTCF binding sites and bound CTCF proteins in a cell cycle-dependent manner We propose that the CTCF-cohesin complex plays a critical role in regulating the cell cycle control of viral gene expression during latency and that failure to maintain cell cycle control of latent transcripts inhibits host cell proliferation and survival We used chromosome conformation capture to determine long-range interactions among CTCF/cohesin sites over 2 Mb on human chromosome 11 encompassing the beta-globin locus and flanking olfactory receptor genes These results support a genome-wide role for CTCF/cohesin sites through loop formation that both influences transcription and contributes to cell-type-specific chromatin organization and function Increased methylation at this promoter triggered the dissociation of the insulator protein CTCF as well as the accompanying cohesin from the BDNF locus icotinamide adenine dinucleotide (NAD)-regulated DNA methylation alters CCCTC-binding factor (CTCF)/cohesin binding and transcription at the BDNF locus ecent studies have shown that the protein CTCF, which plays an important role in insulation and in large-scale organization of chromatin within the eukaryotic nucleus, depends for both activities on recruitment of the cohesin complex We show here that the interaction of CTCF with the cohesin complex involves direct contacts between the cohesin subunit SA2 and specific regions of the C-terminal tail of CTCF Taken together, our results demonstrate that specific sites on the C terminus of CTCF are essential for cohesin binding and insulator function The only direct interaction between CTCF and cohesin involves contact with SA2, which is external to the cohesin ring These numerous CTCF/cohesin sites potentially form the bases of the multiloop rosette structures at the Igh locus that compact during Ig heavy chain rearrangement We have previously shown that the Kaposi's Sarcoma-Associated Herpesvirus (KSHV) major latency transcripts encoding LANA, vCyclin, vFLIP, v-miRNAs, and Kaposin are regulated, in part, by a chromatin organizing element that binds CTCF and cohesins Mutation of the CTCF-cohesin binding site reduced or eliminated the chromatin conformation linkages, and deregulated viral transcription and genome copy number control Our findings indicate that KSHV genomes are organized into chromatin loops mediated by CTCF and cohesin interactions, and that these inter-chromosomal linkages coordinate latent and lytic gene control. We show here that GA disrupts an RNA polymerase II (RNAPII) complex that accumulates at the CTCF-cohesin binding site within the first intron of the latency transcript. GA altered the enrichment of the RNAPII pausing complex, along with pausing factors SPT5 and NELF-A, at the intragenic CTCF-cohesin binding sites. GA treatment also inhibited the transcription of some cellular genes, like c-myc, which contain a similar CTCF-cohesin binding site within the first intron. These findings suggest that RNAPII pauses at intragenic CTCF-cohesin binding sites and that abrogation of this pausing by GA leads to loss of proper mRNA production and defects in sister chromatid cohesion, a process important for both viral and cellular chromosome stability. TCF and cohesin cooperatively mediate the cell-type specific interchromatin interaction between Bcl11b and Arhgap6 loci Additional experiments verified that the interchromatin interaction between the Bcl11b and Arhgap6 loci was cell-type specific, which was cooperatively mediated by CTCF and cohesin. enome-wide studies of CCCTC-binding factor (CTCF) and cohesin provide insight into chromatin structure and regulation Recent genome-wide studies mapping the binding sites of CTCF and its interacting partner, cohesin, using chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) revealded that CTCF globally co-localizes with cohesin Here, we show by ChIP-Seq that most human subtelomeres contain a CTCF- and cohesin-binding site within ∼1-2 kb of the TTAGGG repeat tract and adjacent to a CpG-islands implicated in TERRA transcription control. These findings indicate that CTCF and cohesin are integral components of most human subtelomeres, and important for the regulation of TERRA transcription and telomere end protection In addition, we show that this DNA looping requires specific binding of the CTCF/cohesin complex to two symmetrically aligned binding sites in both the transcriptionally active promoters and in one of the enhancers

yes

56c81fd15795f9a73e00000c

Are stress granules involved in the pathogenesis of Amyotrophic Lateral Sclerosis?

SGs have been linked to several pathologies including inflammatory diseases, cancer, viral infection, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Like several other ALS-associated proteins, CREST is recruited to induced stress granules. Our data indicate that CREST and certain other ALS-linked proteins share several features implicated in ALS pathogenesis, namely the ability to aggregate, be recruited to stress granules and alter paraspeckle integrity. A unifying feature of many proteins associated with ALS, including TDP-43 and ataxin-2, is that they localize to stress granules. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis. Amyotrophic lateral sclerosis (ALS)-linked fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is concentrated within cytoplasmic stress granules under conditions of induced stress. Since only the mutants, but not the endogenous wild-type FUS, are associated with stress granules under most of the stress conditions reported to date, the relationship between FUS and stress granules represents a mutant-specific phenotype and thus may be of significance in mutant-induced pathogenesis. Fused in sarcoma (FUS) belongs to the group of RNA-binding proteins implicated as underlying factors in amyotrophic lateral sclerosis (ALS) and certain other neurodegenerative diseases. Multiple FUS gene mutations have been linked to hereditary forms, and aggregation of FUS protein is believed to play an important role in pathogenesis of these diseases. In cultured cells, FUS variants with disease-associated amino acid substitutions or short deletions affecting nuclear localization signal (NLS) and causing cytoplasmic mislocalization can be sequestered into stress granules (SGs). Profilin 1 associates with stress granules and ALS-linked mutations alter stress granule dynamics Here we report that profilin 1 and related protein profilin 2 are novel stress granule-associated proteins in mouse primary cortical neurons and in human cell lines and that ALS-linked mutations in profilin 1 alter stress granule dynamics, providing further evidence for the potential role of stress granules in ALS pathogenesis Furthermore, in response to oxidative stress or heat shock conditions in cultures and in vivo, the ALS-linked FUS mutants, but not wild-type FUS, assembled into perinuclear stress granules in proportion to their cytoplasmic expression levels. Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Our results suggest that the ALS mutations in FUS NLS can impair FUS nuclear localization, induce cytoplasmic inclusions and stress granules, and potentially perturb RNA metabolism. RNA-binding ability of FUS regulates neurodegeneration, cytoplasmic mislocalization and incorporation into stress granules associated with FUS carrying ALS-linked mutations. TDP-43 is an RNA-binding protein linked to amyotrophic lateral sclerosis (ALS) that is known to regulate the splicing, transport, and storage of specific mRNAs into stress granules In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, TAR DNA binding protein 43 (TDP-43) accumulates in the cytoplasm of affected neurons and glia, where it associates with stress granules (SGs) and forms large inclusions Amyotrophic lateral sclerosis (ALS)-linked fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is concentrated within cytoplasmic stress granules under conditions of induced stress Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules Mutations in Fus cause amyotrophic lateral sclerosis (ALS) and the mutant protein forms inclusions that appear to correspond to stress granules Recent work also suggests that TDP-43 associates with cytoplasmic stress granules, which are transient structures that form in response to stress. We found that in response to oxidative stress and to environmental insults of different types TDP-43 is capable to assemble into stress granules (SGs), ribonucleoprotein complexes where protein synthesis is temporarily arrested. Moreover, proteins known to be stress granule markers co-deposit with inclusions in fALS and FTLD-FUS patients, implicating stress granule formation in the pathogenesis of these diseases. We propose that two pathological hits, namely nuclear import defects and cellular stress, are involved in the pathogenesis of FUS-opathies. Amyotrophic lateral sclerosis (ALS)-linked fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is concentrated within cytoplasmic stress granules under conditions of induced stress. Amyotrophic lateral sclerosis-linked FUS/TLS alters stress granule assembly and dynamics. Moreover, proteins known to be stress granule markers co-deposit with inclusions in fALS and FTLD-FUS patients, implicating stress granule formation in the pathogenesis of these diseases. We propose that two pathological hits, namely nuclear import defects and cellular stress, are involved in the pathogenesis of FUS-opathies. . Autophagy regulates amyotrophic lateral sclerosis-linked fused in sarcoma-positive stress granules in neurons However, the role of autophagy in regulation of FUS-positive stress granules (SGs) and aggregates remains unclear. Although co-localized primarily in the nucleus in normal condition, FUS/TLS and PRMT1 were partially recruited to the cytoplasmic granules under oxidative stress, which were merged with stress granules (SGs) markers in SH-SY5Y cell. The effect of PRMT1-mediated arginine methylation on the subcellular localization, stress granules, and detergent-insoluble aggregates of FUS/TLS Stress granules are cytoplasmic inclusions that repress translation of a subset of RNAs in times of cellular stress, and several proteins implicated in neurodegeneration (i.e. Ataxin-2 and SMN) interact with stress granules These findings support a two-hit hypothesis, whereby cytoplasmic mislocalization of FUS protein, followed by cellular stress, contributes to the formation of cytoplasmic aggregates that may sequester FUS, disrupt RNA processing and initiate motor neuron degeneration. Here, we exploited a Drosophila model of ALS and neuronal cell lines to elucidate the role of the RNA-binding ability of FUS in regulating FUS-mediated toxicity, cytoplasmic mislocalization and incorporation into stress granules (SGs). Stress granules as crucibles of ALS pathogenesis

yes

52f5083d2059c6d71c00001e

Does TGF-beta play a role in cardiac regeneration after myocardial infarction?

We then performed a chemical screen and identified several small molecules that increase or reduce cardiomyocyte proliferation during heart development. These compounds act via Hedgehog, Insulin-like growth factor or Transforming growth factor β signaling pathways. Here, we report that the balance between the reparative and regenerative processes is achieved through Smad3-dependent TGFβ signaling. Thus, TGFβ signaling orchestrates the beneficial interplay between scar-based repair and cardiomyocyte-based regeneration to achieve complete heart regeneration. As expected, transforming growth factor (TGF)-beta, a profibrotic cytokine, was dramatically upregulated in MI hearts, but its phosphorylated comediator (pSmad) was significantly downregulated in the nuclei of Cx43-deficient hearts post-MI, suggesting that downstream signaling of TGF-beta is diminished substantially in Cx43-deficient hearts. This diminution in profibrotic TGF-beta signaling resulted in the attenuation of adverse structural remodeling as assessed by echocardiography. Potentially beneficial changes include increases in the HSMP secretory-leucocyte-protease-inhibitor (SLPI) and cytokine transforming growth factor (TGF)-beta(1). Targeting these proteins may mitigate enhanced LV remodeling and dysfunction with aging. After injury, the presence of macrophages, which secreted high levels of transforming growth factor-beta and vascular endothelial growth factor-A, led to rapid removal of cell debris and replacement by granulation tissue containing inflammatory cells and blood vessels, followed by myofibroblast infiltration and collagen deposition. Secretion of transforming growth factor-beta and vascular endothelial growth factor-A as well as neovascularization, myofibroblast infiltration, and collagen deposition decreased. Repression of proinflammatory cytokine and chemokine synthesis, mediated in part through Transforming Growth Factor (TGF)-beta and Interleukin (IL)-10, is critical for resolution of the inflammatory infiltrate and transition to fibrous tissue deposition. TGF-beta conducted the myogenic differentiation of CD117+ stem cells by upregulating GATA-4 and NKx-2.5 expression. Therefore, the intramyocardial implantation of TGF-beta-preprogrammed CD117+ cells effectively assisted the myocardial regeneration and induced therapeutic angiogenesis, contributing to functional cardiac regeneration. These results indicate that TGF-beta/Smad signaling may be involved in the remodeling of the infarct scar after the completion of wound healing per se, via ongoing stimulation of matrix deposition.

yes

52fb4b462059c6d71c00005f

Is DITPA a thyroid hormone analog utilized in experimental and clinical studies

DITPA normalized the elevated serum T(3) and TSH when the dose reached 1 mg/kg · d and T(4) and rT(3) increased to the lower normal range. The identification of 3,5-diiodothyropropionic acid (DITPA) that binds to both α- and β-type TRs with relatively low affinity was unique in that this analog improves left ventricular function in heart failure as well as lowers cholesterol. Treatment with DITPA attenuates the acute inflammatory response and reduces myocardial infarct size. Thus DITPA administration impairs baseline cardiac parameters in mice and can be fatal during in vivo acute myocardial I/R. DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure The results suggested that DITPA can promote a healthy vasculature independently from its thyroid-related metabolic effects. Moreover, DITPA and T(4) were efficacious in preventing effects of hypothyroidism on cardiac function and BVD Both T4 and DITPA had beneficial effects on chamber remodeling, which was most likely due to beneficial changes in cell shape and improved vascular supply. The thyroid analog DITPA enhances endothelial nitric oxide and beta-adrenergic-mediated vasorelaxation by increasing nitric oxide in the vasculature.

yes

5168023b298dcd4e51000061

Is MammaPrint cleared by the United States Food and Drug Administration?

Real-time RT-PCR confirmed the 5-gene prognostic signature that was distinct from an FDA-cleared 70-gene signature of MammaPrint panel and from the Oncotype DX recurrence score assay panel.

yes

530f7cdde3eabad021000001

Is amantadine effective for treatment of disorders conciousness?

We here provide a systematic overview of the therapeutic effects of amantadine, apomorphine and zolpidem in patients recovering from coma. Evidence from clinical trials using these commonly prescribed pharmacological agents suggests positive changes in the neurological status in patients, leading sometimes to dramatic improvements. Pharmaceuticals that act in the oxygen based amino acid systems of the brain include the GABAergic medications zolpidem and baclofen, while those that act in the monoamine axes include the dopaminergic medications L Dopa, amantadine, bromocriptine, apomorphine and methylphenidate, and the noradrenergic and serotonergic medications desipramine, amitriptyline, protriptyline and fluoxetine. Sporadic cases of recovery from a DOC have been reported after the administration of various pharmacological agents (baclofen, zolpidem, amantadine etc.). Amantadine hydrochloride is one of the most commonly prescribed medications for patients with prolonged disorders of consciousness after traumatic brain injury. Preliminary studies have suggested that amantadine may promote functional recovery. During the 4-week treatment period, recovery was significantly faster in the amantadine group than in the placebo group, as measured by the DRS score (difference in slope, 0.24 points per week; P=0.007), indicating a benefit with respect to the primary outcome measure. Amantadine accelerated the pace of functional recovery during active treatment in patients with post-traumatic disorders of consciousness. Sporadic cases of dramatic recovery from DOC after the administration of various pharmacological agents, such as baclofen, zolpidem and amantadine, have been recently supported by intriguing scientific observations. According to the 16 eligible studies, medical management by dopaminergic agents (levodopa, amantadine), zolpidem and median nerve stimulation, or surgical management by deep brain stimulation, extradural cortical stimulation, spinal cord stimulation and intrathecal baclofen have shown to improve the level of consciousness in certain cases. Higher exposure of amantadine (average concentration of amantadine during 6 mg/kg/day > 1.5 mg/L) may be associated with better recovery of consciousness. Based on the preliminary data, higher dosing may be considered in the setting of brain injury. Patients treated with PK-Merz exhibited the more significant restoration of consciousness and better dynamics (regress) of neurological deficit with the most intensive restoration of neurological deficit in the first day that allows to recommend the use of amantadine sulfate in the first hours of ischemic stroke and for the prevention of reperfusion damage in recanalisation therapy of ischemic stroke. There was no significant difference in the slopes of recovery during either arm for the Coma/Near-Coma Scale (P = 0.24) or the Coma Recovery Scale-Revised (P = 0.28), although improvements in consciousness were noted by the physician during weeks when amantadine was given (P = 0.02). This study suggests that amantadine facilitates recovery of consciousness in pediatric acquired brain injury and provides important information necessary to design future more definitive studies. The study has shown a positive effect of this drug at coma emergence, which manifested itself as clinical improvement and a better outcome of the disease. This article will review the evidence for the use of psychostimulants (methylphenidate), antidepressants (amitriptyline, selective serotonin reuptake inhibitors, and buproprion), Parkinson's medications (amantadine, bromocriptine, carbidopa/levodopa), anticonvulsants (valproic acid), modafinil (Provigil), lactate, hyperbaric oxygen chamber, electroconvulsive therapy, and transmagnetic stimulation, in patients following a head injury. Of the psychoactive medications, amantadine hydrochloride was associated with greater recovery and dantrolene sodium was associated with less recovery, in terms of the DRS score at 16 weeks but not the time until commands were followed.

yes

56f3f6b12ac5ed145900001a

Is GAGA associated with nucleosome-free regions (NFR)?

One of the three nuclease hypersensitive sites in the Fab-7 boundary, HS1, contains multiple consensus-binding sequences for the GAGA factor, a protein known to be involved in the formation and/or maintenance of nucleosome-free regions of chromatin. The HS3 sequence contains consensus binding sites for the GAGA factor, a protein implicated in the formation of nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group protein that is related to the mammalian transcription factor YY1. The interactions of GAGA factor and heat shock factor with their binding sites in chromatin occurred in two modes. Their interaction with binding sites in the nucleosome-free regions did not require ATP. In the presence of ATP both factors interacted also with nucleosomal binding sites, causing nucleosome rearrangements and a refinement of nucleosome positions While chromatin remodeling upon transcription factor interaction has previously been interpreted to involve nucleosome disruption, the data suggest energy-dependent nucleosome sliding as main principle of chromatin reorganization. These (CT)n repeats are associated with a nonhistone protein(s) in vivo and are bound by a purified Drosophila protein, the GAGA factor, in vitro. This (CT)n element appears to contribute to formation of the wild-type chromatin structure of hsp26, an organized nucleosome array that leaves the HSEs in nucleosome-free, DNase I-hypersensitive (DH) site The HS3 sequence contains consensus binding sites for the GAGA factor, a protein implicated in the formation of nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group protein that is related to the mammalian transcription factor YY1. One of the three nuclease hypersensitive sites in the Fab-7 boundary, HS1, contains multiple consensus-binding sequences for the GAGA factor, a protein known to be involved in the formation and/or maintenance of nucleosome-free regions of chromatin. The iab-7 polycomb response element maps to a nucleosome-free region of chromatin and requires both GAGA and pleiohomeotic for silencing activity. The HS3 sequence contains consensus binding sites for the GAGA factor, a protein implicated in the formation of nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group protein that is related to the mammalian transcription factor YY1.

yes

5509df4ac2af5d5b70000003

Is amiodarone a class I anti-arrhythmic drug?

Common class I agents are excluded due to the inherent abnormal cardiac structure and function in the setting of cardiogenic shock. Class III drug options include dofetilide and amiodarone. Amiodarone has been used as an anti-arrhythmic drug since the 1970s and has an established role in the treatment of ventricular tachyarrhythmias. Although considered to be a class III anti-arrhythmic, amiodarone also has class I, II and IV actions, which gives it a unique pharmacological and anti-arrhythmic profile. Amiodarone, an iodinated benzofuran derivative, introduced in 1960's as an anti-anginal agent, emerged as a potent anti-arrhythmic agent by 1970's and is currently one of the most commonly prescribed drugs in US for ventricular and atrial arrhythmias. Although amiodarone is considered a class III anti-arrhythmic agent, it also has class I, II, IV actions, making it a unique and effective anti-arrhythmic agent. Amiodarone, a representative class III agent, exerts negative dromotropism by suppressing the fast sodium current responsible for conduction in acute administration (class I effects). Chronic amiodarone causes prolongation of ERP (class III effects), which is sometimes associated with negative dromotropism based on the alteration of passive or active membrane properties. Amiodarone, an iodinated benzofuran derivative with predominantly class III anti-arrhythmic effects, is used to treat supraventricular and ventricular arrhythmias. Although amiodarone is considered a class III anti-arrhythmic agent, it also has class I, II, IV actions, making it a unique and effective anti-arrhythmic agent Amiodarone, a class III antiarrhythmic drug, is one of the most effective drugs used in the treatment of ventricular and paroxysmal supraventricular tachyarrhythmia Although amiodarone is considered a class III anti-arrhythmic agent, it also has class I, II, IV actions, making it a unique and effective anti-arrhythmic agent Although considered to be a class III anti-arrhythmic, amiodarone also has class I, II and IV actions, which gives it a unique pharmacological and anti-arrhythmic profile Amiodarone is a potent class III anti-arrhythmic drug that also possesses beta-blocking properties

no

53386282d6d3ac6a3400005a

Has the protein TIEG1 been associated with apoptosis?

TGF-beta) inducible early gene 1 (TIEG1) is known to induce apoptosis in TGF-beta sensitive pancreatic cancer cells, yet its effect on TGF-beta resistant cancer cells remains unclear overexpression of TIEG1, protected ALL cells against chemotherapy-induced cell death TIEG1 might be involved in mediating this effect from the microenvironment onto the leukemia cells We also demonstrate that TIEG-1 ectopic expression in CGNPs induces cell cycle arrest that can lead to apoptosis but fails to promote differentiation TIEG1 acts as an inducer or repressor of gene transcription to enhance the TGFbeta/Smad pathway, as well at other signaling pathways, to regulate cell proliferation, differentiation, and apoptosis. TGFbeta inducible early gene (TIEG1) mimics TGFbeta action and induces apoptosis the transforming growth factor-beta- (TGF-beta-) inducible early response 1 gene (TIEG1), which plays a pivotal role in TGF-beta-regulated cell growth control and apoptosis Induction of mRNA for Smad4 and the TGF-beta1-regulated apoptosis-inducing transcription factor TGF-beta1-inducible early gene (TIEG1) was detected within the first 6 h of doxazosin treatmen TIEG1 (TGF-beta inducible early gene) is a recently characterized transcription factor regulated by TGF-beta that induces apoptosis when overexpressed in pancreatic adenocarcinoma cell lines Influence of TIEG1 on apoptosis the influence of TIEG1 on apoptosis of HL-60 cells and the expression of Bcl-2/Bax The expression of genes involved in insulin resistance (PDK4, AHSG) is increased, together with expression of TIEG1, a transcription factor that can induce apoptosis via the mitochondrial pathway the overexpression of TIEG1 mediated growth inhibition and apoptosis in TGF-β1-resistant HCC cell lines, On the other hand, KLF10 deficient keratinocytes showed increased proliferation and apoptosis LF10, transforming growth factor-β-inducible early gene 1 IEG1 can induce apoptosis of cancer cells TGF-β inducible early gene 1) plays a significant role in regulating cell proliferation and apoptosis TIEG1) is a Krüppel-like transcription factor (KLF10) that was originally cloned from human osteoblasts as an early response gene to TGF-β treatment Adenoviral delivery of TIEG1 (AdTIEG1) to TIEG1(-/-) cells reversed the RANKL-induced NFATc1 signaling defect in TIEG1(-/-) precursors and eliminated the differentiation and apoptosis defects (TGF)-β inducible early gene (TIEG)-1 is implicated in the control of cell proliferation, differentiation, and apoptosis in some cell types TIEG1 has been shown to mimic the effects of TGF-beta in various carcinoma cells and plays a critical role in the apoptotic cascade (TIEG) is a family of primary response genes induced by TGF-beta, which are well recognized in regulating cellular proliferation and apoptosis In human and murine tissues it has been shown that TIEG1 and TIEG2 induce apoptosis and inhibit cell growth overexpression of TIEG1 in OLI-neu cells induced apoptosis (TGF-beta(1))-inducible transcription factors have recently elicited interest because of their critical role in the regulation of cell proliferation, differentiation, and apoptosis ectopic overexpression of TIEG is sufficient to trigger the apoptotic cell program in these cells

yes

55031650e9bde69634000026

Is PTEN involved in follicular thyroid carcinoma?

Two of the 259 patients (0.8%), with both follicular thyroid carcinoma and macrocephaly, were found to carry a germline mutation in the PTEN gene. The PTEN mutation frequency in unselected cases of follicular thyroid carcinoma was 4.8% The frequency of germline pathogenic PTEN mutations in an unselected series of patients with DTC is relatively low, but it is enriched by considering follicular histology and macrocephaly Similarly, there is increasing evidence demonstrating that mutations leading to activation of the phosphatidylinositol 3- kinase (PI3K)/AKT effectors -PTEN and PI3KCa- are essential for the pathogenesis of follicular thyroid carcinoma (FTC) A single male with follicular thyroid carcinoma from one of these 64 (2%) CS-like families harboured a germline point mutation, c.209T-->C Similarly, there is increasing evidence demonstrating that mutations leading to activation of the phosphatidylinositol 3- kinase (PI3K)/AKT effectors -PTEN and PI3KCa- are essential for the pathogenesis of follicular thyroid carcinoma (FTC). The transcriptional silencing of PTEN was significantly associated with the anaplastic subtype, suggesting that PTEN is involved in the carcinogenesis of highly malignant or late-stage thyroid cancers, whereas this particular mechanism appears to be of minor importance in differentiated follicular thyroid tumors. These results show a high frequency of PTEN promoter hypermethylation, especially in follicular tumors, suggesting its possible role in thyroid tumorigenesis Our findings suggest that the PTEN tumor suppressor gene is occasionally inactivated in sporadic follicular thyroid tumors Germline mutations in the tumor suppressor gene PTEN, which encodes a dual-specificity phosphatase, have been found in up to 80% of patients with Cowden syndrome suggesting a role of PTEN in the pathogenesis of follicular thyroid tumors The most common neoplasms in Cowden disease patients arise in the breast, skin, and thyroid (follicular subtype) The transcriptional silencing of PTEN was significantly associated with the anaplastic subtype, suggesting that PTEN is involved in the carcinogenesis of highly malignant or late-stage thyroid cancers, whereas this particular mechanism appears to be of minor importance in differentiated follicular thyroid tumors

yes

51598b08d24251bc0500009f

Does strenuous physical activity affect thyroid hormone metabolism?

The results of the present study in a unique experimental human model of maximal exposure to altitude and physical exercise demonstrate that extreme HA and strenuous physical exercise are coupled with specific endocrine adaptations. These include increased activity of the GH/IGF-I axis and a low T(3) syndrome 3,5,3'-triiodothyronine (T3) and T4 levels increase during strenuous exercise, and, at the end of the exercise bout, a decrease of T3 and T4 levels, with an increase in TSH during the following 4-5 days, is seen. the obtained results indicate that in intense exercise, causing the rapid development of fatigue, rapid increases in serum levels of hormones of the pituitary-adrenocortical, pituitary-gonadal and pituitary-thyroid systems occur. Mean levels of fasting plasma estradiol, luteinizing hormone, follicle-stimulating hormone, free thyroxine and triiodothyronine were significantly lower in AR compared to ER and SE. Reductions in plasma T4, T3 and T3/T4 ratio are probably due to inhibition of T4 secretion and 5'-monodeiodination with possible conversion of T4 to reverse T3 (rT3). These processes may represent a mechanism for regulation of thyroid hormone metabolism during strenuous and extended flight. Strenuous endurance training seems to have minor changes on the function of the thyroid gland. Depressed T4 levels in runners may rather be due to lowered TBG levels than due to direct effect of training. brief strenuous swimming or moderate bicycle exercise had minor or no effect on thyroid hormone concentrations when consideration was given to the attendant hemoconcentration. thyroxine were determined in 26 men participating in a 90-km cross-country ski race, before, immediately after, and on the following days Total thyroxine and free thyroxine in serum were significantly increased at the end of the race, but had returned to the pre-raced levels during the rest of the observation period. There are controversial results concerning thyroid hormone metabolism during strenuous exercise in adult athletes and only scant data concerning the impact of strenuous exercise on thyroid hormone metabolism in children and adolescents.

yes

56cf50253975bb303a00000b

Is the gene MAOA epigenetically modified by methylation?

Evidence that the methylation state of the monoamine oxidase A (MAOA) gene predicts brain activity of MAO A enzyme in healthy men. We found significant interindividual differences in methylation status and methylation patterns of the core MAOA promoter. In the present study, DNA methylation patterns in the MAOA regulatory and exon 1/intron 1 region were investigated for association with panic disorder with particular attention to possible effects of gender and environmental factors. The present pilot data suggest a potential role of MAOA gene hypomethylation in the pathogenesis of panic disorder particularly in female patients, possibly mediating a detrimental influence of negative life events. The MAOA promoter was hypermethylated immediately upstream of the start codon in cholangiocarcinoma samples and cell lines but not in nonmalignant counterparts. MAOA promoter methylation and susceptibility to carotid atherosclerosis: role of familial factors in a monozygotic twin sample. Because twins reared together share early life experience, which may leave a long-lasting epigenetic mark, aberrant MAOA methylation may represent an early biomarker for unhealthy familial environment. Effects of MAOA promoter methylation on susceptibility to paranoid schizophrenia. In conclusion, abnormalities of DNA methylation at the MAOA promoter may be associated with schizophrenia in males. In our study we analyzed DNA methylation patterns of 14 neuropsychiatric genes (COMT, DAT1, GABRA1, GNB3, GRIN2B, HTR1B, HTR2A, 5-HTT, MAOA, MAOB, NOS1, NR3C1, TPH1 and TH). D Our data suggest that aberrant epigenetic regulation of neuropsychiatric genes may contribute to the pathogenesis of BPD. We conclude that smoking reliably decreases MAOA methylation, but exact characterization of effects on level of methylation depend on genotype, smoking history, current smoking status, gender, and region of the promoter-associated CpG Island examined. Given that DNA methylation is linked to the regulation of gene expression, we hypothesized that epigenetic mechanisms factor into the MAOA expression the extended MAOA regulatory region contains two CpG islands (CGIs), one of which overlaps with the canonical MAOA promoter and the other is located further upstream; both CGIs exhibit sensitivity to differential methylation. Identification and characterization of putative methylation targets in the MAOA locus using bioinformatic approaches. DNA methylation is a key epigenetic mechanism involved in the developmental regulation of gene expression. MAOA methylation is associated with nicotine and alcohol dependence in women. In recent years, the role of epigenetic phenomenon, such as methylation, in mediating vulnerability to behavioral illness has become increasingly appreciated. One prominent locus at which epigenetic phenomena are thought to be in play is the monoamine oxidase A (MAOA) locus. We conclude that methylation of MAOA may play a significant role in common psychiatric illness and that further examination of epigenetic processes at this locus is in order. Analysis of CpG methylation in the MAOA promoter region revealed substantial methylation in females but not in males. Therefore, allelic mRNA expression is affected by genetic and epigenetic events, both with the potential to modulate biogenic amine tone in the CNS.

yes

5713c4a11174fb1755000013

Is glycyl-tRNA synthetase gene involved in the development of Charcot-Marie-Tooth disease?

Charcot-Marie-Tooth disease type 2D (CMT2D) is an autosomal-dominant axonal peripheral neuropathy characterized by impaired motor and sensory function in the distal extremities. Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D Dominant mutations in GARS cause rare forms of Charcot-Marie-Tooth disease and distal spinal muscular atrophy Using exome sequencing she was found to harbor compound heterozygous mutations within the glycyl-tRNA synthetase (GARS) gene mutations of human GlyRS (hGlyRS) were also found to be associated with Charcot-Marie-Tooth disease Dominant mutations in GARS, encoding the essential enzyme glycyl-tRNA synthetase (GlyRS), result in a form of Charcot-Marie-Tooth disease, type 2D (CMT2D), predominantly characterized by lower motor nerve degeneration A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease type 2D with facial and respiratory muscle involvement Here we describe a 45-year-old woman with a long course of motor-dominant neuropathy. Distal weakness appeared in childhood and became worse with age. After a diagnosis of CMT type 2, the symptoms progressed, and in her fourth decade, facial and respiratory muscle weakness appeared, ultimately requiring non-invasive mechanical ventilation. There was no family history of CMT. Comprehensive analysis of known CMT-related genes revealed a novel heterozygous c.815T>A, p.L218Q mutation in glycyl-tRNA synthetase (GARS), a causative gene for both CMT type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS). Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. [A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease type 2D with facial and respiratory muscle involvement]. Glycyl-tRNA synthetase (GARS), which encodes the enzyme responsible for charging tRNA(Gly) with glycine in both the cytoplasm and mitochondria, is implicated to Charcot-Marie-Tooth disease 2D (CMT2D) and distal hereditary motor neuropathy type V (dHMN-V). These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease, the most common heritable disease of the peripheral nervous system. Here, we report the identification of four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V. Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D. Of the many inherited Charcot-Marie-Tooth peripheral neuropathies, type 2D (CMT2D) is caused by dominant point mutations in the gene GARS, encoding glycyl tRNA synthetase (GlyRS). Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS) Charcot-Marie-Tooth disease type 2D is a hereditary axonal and glycyl-tRNA synthetase (GARS)-associated neuropathy that is caused by a mutation in GARS Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease, the most common heritable disease of the peripheral nervous system A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease type 2D with facial and respiratory muscle involvement. Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS). Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D. An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy. We previously implicated mutations in the gene encoding glycyl-tRNA synthetase (GARS) as the cause of CMT2D and dSMA-V. An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model. Charcot-Marie-Tooth disease type 2D is a hereditary axonal and glycyl-tRNA synthetase (GARS)-associated neuropathy that is caused by a mutation in GARS. Dominant mutations in GARS, encoding the essential enzyme glycyl-tRNA synthetase (GlyRS), result in a form of Charcot-Marie-Tooth disease, type 2D (CMT2D), predominantly characterized by lower motor nerve degeneration. Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS). In addition to GARS, mutations in three other tRNA synthetase genes cause similar neuropathies, although the underlying mechanisms are not fully understood. These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease, Charcot-Marie-Tooth disease type 2D (CMT2D) is an autosomal-dominant axonal peripheral neuropathy characterized by impaired motor and sensory function in the distal extremities. Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D. Of the many inherited Charcot-Marie-Tooth peripheral neuropathies, type 2D (CMT2D) is caused by dominant point mutations in the gene GARS, encoding glycyl tRNA synthetase (GlyRS). Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS). Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. These additional functions may explain why dominant mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause Charcot-Marie-Tooth (CMT) disease, the most common heritable disease of the peripheral nervous system. A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease type 2D with facial and respiratory muscle involvement. An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model. Glycyl-tRNA synthetase (GARS), which encodes the enzyme responsible for charging tRNA(Gly) with glycine in both the cytoplasm and mitochondria, is implicated to Charcot-Marie-Tooth disease 2D (CMT2D) and distal hereditary motor neuropathy type V (dHMN-V).

yes

5311cdcce3eabad021000007

Is there any software for automated analysis of FISH images?

he study demonstrated the feasibility of automated FISH signal analysis that applying a CAD scheme to the automated generated 2-D projection images. A color imaging technique, multiplex fluorescent in situ hybridization (M-FISH), has been developed to ease the analysis of the process. Using an M-FISH technique each chromosome class (1,2, …,22,X,Y) is stained with a unique color. However, significant variations between images are observed due to a number of factors such as uneven hybridization and spectral overlap among channels. These types of variations influence the pixel classification accuracy of image classification methods which are supervised and require a set of annotated images for training. In this paper, we present a fully unsupervised M-FISH chromosome image classification methodology. Our main contributions are 1) the assumption that the intensity of a chromosome pixel is sampled from multiple Gaussian components [Gaussian mixture model (GMM)] such that each component corresponds to one chromosome class, and 2) the initialization of the GMM model using the emission information of each chromosome class. This is feasible since prior to the M-FISH image acquirement, we already know which chromosome class is emitting to each of the five M-FISH image channels. The method has been tested on a large number of M-FISH images and an overall accuracy of 89.85% is reported. Our method is unsupervised and presents higher classification accuracy even when it is compared with common supervised based methods. hybridization (FISH) tests provide promising molecular imaging biomarkers to more accurately and reliably detect and diagnose cancers and genetic disorders. Since current manual FISH signal analysis is low-efficient and inconsistent, which limits its clinical utility, developing automated FISH image scanning systems and computer-aided detection (CAD) schemes has been attracting research interests. To acquire high-resolution FISH images in a multi-spectral scanning mode, a huge amount of image data with the stack of the multiple three-dimensional (3-D) image slices is generated from a single specimen. Automated preprocessing these scanned images to eliminate the non-useful and redundant data is important to make the automated FISH tests acceptable in clinical applications. In this study, a dual-detector fluorescence image scanning system was applied to scan four specimen slides with FISH-probed chromosome X. A CAD scheme was developed to detect analyzable interphase cells and map the multiple imaging slices recorded FISH-probed signals into the 2-D projection images. CAD scheme was then applied to each projection image to detect analyzable interphase cells using an adaptive multiple-threshold algorithm, identify FISH-probed signals using a top-hat transform, and compute the ratios between the normal and abnormal cells. To assess CAD performance, the FISH-probed signals were also independently visually detected by an observer. The Kappa coefficients for agreement between CAD and observer ranged from 0.69 to 1.0 in detecting/counting FISH signal spots in four testing samples. In this paper we developed a sparse representation-based classification (SRC) algorithm based on L1-norm minimization for classifying chromosomes from multicolor fluorescence in situ hybridization (M-FISH) images. The algorithm has been tested on a comprehensive M-FISH database that we established, demonstrating improved performance in classification. When compared with other pixel-wise M-FISH image classifiers such as fuzzy c-means (FCM) clustering algorithms and adaptive fuzzy c-means (AFCM) clustering algorithms that we proposed earlier the current method gave the lowest classification error. In order to evaluate the performance of different SRC for M-FISH imaging analysis, three different sparse representation methods, namely, Homotopy method, Orthogonal Matching Pursuit (OMP), and Least Angle Regression (LARS), were tested and compared. Results from our statistical analysis have shown that Homotopy based method is significantly better than the other two methods. Fluorescence in situ hybridization (FISH) is used to study the organization and the positioning of specific DNA sequences within the cell nucleus. Analyzing the data from FISH images is a tedious process that invokes an element of subjectivity. Automated FISH image analysis offers savings in time as well as gaining the benefit of objective data analysis. While several FISH image analysis software tools have been developed, they often use a threshold-based segmentation algorithm for nucleus segmentation. As fluorescence signal intensities can vary significantly from experiment to experiment, from cell to cell, and within a cell, threshold-based segmentation is inflexible and often insufficient for automatic image analysis, leading to additional manual segmentation and potential subjective bias. To overcome these problems, we developed a graphical software tool called FISH Finder to automatically analyze FISH images that vary significantly. By posing the nucleus segmentation as a classification problem, compound Bayesian classifier is employed so that contextual information is utilized, resulting in reliable classification and boundary extraction. This makes it possible to analyze FISH images efficiently and objectively without adjustment of input parameters. Additionally, FISH Finder was designed to analyze the distances between differentially stained FISH probes. The simultaneous detection of protein expression and gene copy number changes in patient samples, like paraffin-embedded tissue sections, is challenging since the procedures of immunohistochemistry (IHC) and Fluorescence in situ Hybridization (FISH) negatively influence each other which often results in suboptimal staining. Therefore, we developed a novel automated algorithm based on relocation which allows subsequent detection of protein content and gene copy number changes within the same cell. METHODS: Paraffin-embedded tissue sections of colorectal cancers were stained for CD133 expression. IHC images were acquired and image coordinates recorded. Slides were subsequently hybridized with fluorescently labeled DNA probes. FISH images were taken at the previously recorded positions allowing for direct comparison of protein expression and gene copy number signals within the same cells/tissue areas. Relocation, acquisition of the IHC and FISH images, and enumeration of FISH signals in the immunophenotyped tumour areas were done in an automated fashion. RESULTS: Automated FISH analysis was performed on 13 different colon cancer samples that had been stained for CD133; each sample was scored for MYC, ZNF217 and Chromosome 6 in CD133 positive and negative glands. From the 13 cases four (31%) showed amplification for the MYC oncogene and seven of 13 (54%) cases were amplified for ZNF217. The simultaneous detection of protein expression and gene copy number changes in patient samples, like paraffin-embedded tissue sections, is challenging since the procedures of immunohistochemistry (IHC) and Fluorescence in situ Hybridization (FISH) negatively influence each other which often results in suboptimal staining.Therefore, we developed a novel automated algorithm based on relocation which allows subsequent detection of protein content and gene copy number changes within the same cell. METHODS: Paraffin-embedded tissue sections of colorectal cancers were stained for CD133 expression. IHC images were acquired and image coordinates recorded. Slides were subsequently hybridized with fluorescently labeled DNA probes. FISH images were taken at the previously recorded positions allowing for direct comparison of protein expression and gene copy number signals within the same cells/tissue areas. Relocation, acquisition of the IHC and FISH images, and enumeration of FISH signals in the immunophenotyped tumour areas were done in an automated fashion. RESULTS: Automated FISH analysis was performed on 13 different colon cancer samples that had been stained for CD133; each sample was scored for MYC, ZNF217 and Chromosome 6 in CD133 positive and negative glands. From the 13 cases four (31%) showed amplification for the MYC oncogene and seven of 13 (54%) cases were amplified for ZNF217. There was no significant difference between CD133 positive tumour and CD133 negative tumour cells. The simultaneous detection of protein expression and gene copy number changes in patient samples, like paraffin-embedded tissue sections, is challenging since the procedures of immunohistochemistry (IHC) and Fluorescence in situ Hybridization (FISH) negatively influence each other which often results in suboptimal staining.Therefore, we developed a novel automated algorithm based on relocation which allows subsequent detection of protein content and gene copy number changes within the same cell.Methods: Paraffin-embedded tissue sections of colorectal cancers were stained for CD133 expression. IHC images were acquired and image coordinates recorded. Slides were subsequently hybridized with fluorescently labeled DNA probes. FISH images were taken at the previously recorded positions allowing for direct comparison of protein expression and gene copy number signals within the same cells/tissue areas. Relocation, acquisition of the IHC and FISH images, and enumeration of FISH signals in the immunophenotyped tumour areas were done in an automated fashion.Results: Automated FISH analysis was performed on 13 different colon cancer samples that had been stained for CD133; each sample was scored for MYC, ZNF217 and Chromosome 6 in CD133 positive and negative glands. From the 13 cases four (31%) showed amplification for the MYC oncogene and seven of 13 (54%) cases were amplified for ZNF217. There was no significant difference between CD133 positive tumour and CD133 negative tumour cells.

yes

54ede5df94afd61504000007

Is there an increased risk for cancer in Dyskeratosis Congenita?

People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis Clinical progression of the disease can lead to aplastic anemia (86% of all patients) and to pulmonary or hepatic complications. These patients also have an increased risk of cancer. Fanconi anaemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anaemia (DBA), and Shwachman-Diamond syndrome (SDS) comprise major inherited bone marrow failure syndromes (IBMFS). Adverse events include severe bone marrow failure (BMF), myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and solid tumours (ST) Patients with FA had earlier onset of cancers, need for stem cell transplant, and death; followed by DC; DBA and SDS were mildest. While FA and DC patients had markedly increased risks of cancer, AML and MDS, there were no cases of leukaemia in DBA or SDS patients The findings demonstrate that both FA and DC are major cancer susceptibility syndromes People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis Patients with dyskeratosis congenita (DC) have an increased risk of cancer, but also exhibit heightened radiation sensitivity. Dyskeratosis congenita (DC) is characterized by the clinical triad of reticular skin pigmentation, oral leukoplakia, and nail dystrophy associated with bone marrow failure (BMF) and an high risk to develop cancer and pulmonary complications. CONCLUSION: Dyskeratosis congenita is a rare condition; however, it is vital to recognise the increased risk of upper aerodigestive tract cancers in these patients. Point mutations in the DKC1 gene that encodes dyskerin cause the rare inherited syndrome called X-linked dyskeratosis congenita, characterized by a failure of proliferating tissues and increased susceptibility to cancer. Dyskeratosis Congenita (DC) also known as Zinsser-Engman-Cole syndrome is a rare multi-system bone marrow failure syndrome characterised by mucocutaneous abnormalities and an increased predisposition to cancer". Dyskeratosis congenita is an inherited syndrome characterised by mucocutaneous features, bone marrow failure, an increased risk of malignancy and other somatic abnormalities. Dyskeratosis congenita is a rare condition; however, it is vital to recognise the increased risk of upper aerodigestive tract cancers in these patients. Epidermal atrophy, hair growth defects, bone marrow failure and increased risk of cancer are also common in DC patients. Telomere dysfunction and tumor suppression responses in dyskeratosis congenita: balancing cancer and tissue renewal impairment. Patients with dyskeratosis congenita (DC) have an increased risk of cancer, but also exhibit heightened radiation sensitivity Dyskeratosis congenita is a rare condition; however, it is vital to recognise the increased risk of upper aerodigestive tract cancers in these patients Dyskeratosis congenita is an inherited syndrome characterised by mucocutaneous features, bone marrow failure, an increased risk of malignancy and other somatic abnormalities While FA and DC patients had markedly increased risks of cancer, AML and MDS, there were no cases of leukaemia in DBA or SDS patients As in Fanconi anemia and dyskeratosis congenita, DBA is both an inherited bone marrow failure syndrome and a cancer predisposition syndrome; cancer risks appear lower in DBA than in Fanconi anemia or dyskeratosis congenita Severe pancytopenia frequently causes early mortality of DC patients, who have an increased risk of developing oropharyngeal squamous cell carcinoma Here different aspects of telomere biology, concerning adult stem cells senescence, tumor suppression and cancer are considered in the context of DC, resulting in two translational models: late onset of DC symptoms in telomere-related mutations carriers is a potential indicator of increased cancer risk and differences in tumor suppression capacities among the genetic subgroups are (at least partial) causes of different clinical manifestations of the disease Point mutations in the DKC1 gene that encodes dyskerin cause the rare inherited syndrome called X-linked dyskeratosis congenita, characterized by a failure of proliferating tissues and increased susceptibility to cancer Dyskeratosis congenita is a cancer-prone bone marrow failure syndrome caused by aberrations in telomere biology.

yes

54f4703764850a5854000008

Does MicroRNA-21 (miR-21) contribute to cardiovascular disease?

The synergistic effect of miR-21 and miR-1 were functionally validated for their significant influences on myocardial apoptosis, cardiac hypertrophy and fibrosis. Taken together, we found a novel reciprocal loop between miR-21 and TGFβRIII in cardiac fibrosis caused by myocardial infarction in mice, and targeting this pathway could be a new strategy for the prevention and treatment of myocardial remodeling. It is still controversial whether microRNA-21 (miR-21) participates in the process of cardiac fibrosis. In mice, myocardial miR-21 overexpression is related to cardiac fibrosis elicited by pressure overload. The myocardial and plasma levels of miR-21 were significantly higher in the AS patients compared with the controls and correlated directly with the echocardiographic mean transvalvular gradients. Our results support the role of miR-21 as a regulator of the fibrotic process that occurs in response to pressure overload in AS patients and underscore the value of circulating miR-21 as a biomarker for myocardial fibrosis. Ad-miR-21 improves LV remodeling and decreases the apoptosis of myocardial cells, suggesting the possible mechanism by which Ad-miR-21 functions in protecting against I/R injury. In the Ad-miR-21 group, LV dimensions, myocardial infarct size, LV/BW, collagen type Ⅰ, type Ⅲ and PCNA positive cells all significantly decreased compared with the Ad-GFP group. While miR-21, -133, -150, -195, and -214 regulate cardiomyocyte hypertrophy, miR-1/-133 and miR-208 have been elucidated to influence myocardial contractile function. In addition, miR-21, -24, -133, -210, -494, and -499 appear to protect myocytes against I/R-induced apoptosis, whereas miR-1, -29, -199a, and -320 promote apoptosis. Myocardial fibrosis can be regulated by the miR-29 family and miR-21. The small regulatory RNA microRNA-21 (miR-21) plays a crucial role in a plethora of biological functions and diseases including development, cancer, cardiovascular diseases and inflammation. During recent years, additional roles of miR-21 in cardiovascular and pulmonary diseases, including cardiac and pulmonary fibrosis as well as myocardial infarction have been described. On the other hand, miR-21, miR-199a, miR-210, and miR-494 have been proven critical for the myocytes' adaptation and survival during hypoxia/ischemia. Studies have shown that several miRs, including miR-1, miR-133, miR-21, miR-126, miR-320, miR-92a, and miR-199a, are regulated after preconditioning and play an active role in protecting the heart against ischemia/reperfusion injury. Studies using various in vivo, ex vivo, and in vitro models have suggested the possible involvement of miR-1, miR-21, miR-29, miR-92a, miR-133, miR-199a, and miR-320 in ischemia-reperfusion injury and/or remodeling after myocardial infarction. MicroRNA-21 (miR-21) is a highly expressed microRNA (miRNA) in cardiovascular system. Recent studies have revealed that its expression is deregulated in heart and vasculature under cardiovascular disease conditions such as proliferative vascular disease, cardiac hypertrophy and heart failure, and ischemic heart disease. miR-21 is found to play important roles in vascular smooth muscle cell proliferation and apoptosis, cardiac cell growth and death, and cardiac fibroblast functions. Accordingly, miR-21 is proven to be involved in the pathogenesis of the above-mentioned cardiovascular diseases as demonstrated by both loss-of-function and gain-of-function approaches. miR-21 might be a novel therapeutic target in cardiovascular diseases. This review article summarizes the research progress regarding the roles of miR-21 in cardiovascular disease. Remarkably, miR-21 was one of most upregulated miRNAs in hearts after IP. In vivo, IP-mediated cardiac protection against ischaemia/reperfusion injury was inhibited by knockdown of cardiac miR-21. In cultured cardiac myocytes, we identified that miR-21 also had a protective effect on hypoxia/reoxygenation-induced cell apoptosis that was associated with its target gene, programmed cell death 4. The protective effect of miR-21 on cardiac cell apoptosis was further confirmed in rat hearts after ischaemia/reperfusion injury in vivo. Lately, some highlight articles revealed that the altered expression of miRNAs such as miR-1, miR-133, miR-21, miR-208 etc in hearts also contributed to cardiovascular diseases, such as heart ischemia, cardiac hypertrophy, and arrhythmias. Remarkably, miR-21 expression was significantly down-regulated in infarcted areas, but was up-regulated in border areas. The down-regulation of miR-21 in the infarcted areas was inhibited by ischemic preconditioning, a known cardiac protective method. Overexpression of miR-21 via adenovirus expressing miR-21 (Ad-miR-21) decreased myocardial infarct size by 29% at 24 h and decreased the dimension of left ventricles at 2 weeks after AMI. Using both gain-of-function and loss-of-function approaches in cultured cardiac myocytes, we identified that miR-21 had a protective effect on ischemia-induced cell apoptosis that was associated with its target gene programmed cell death 4 and activator protein 1 pathway. The protective effect of miR-21 against ischemia-induced cardiac myocyte damage was further confirmed in vivo by decreased cell apoptosis in the border and infarcted areas of the infarcted rat hearts after treatment with Ad-miR-21. The results suggest that miRNAs such as miR-21 may play critical roles in the early phase of AMI. The results suggest that miR-21 is sensitive to H(2)O(2) stimulation. miR-21 participates in H(2)O(2)-mediated gene regulation and functional modulation in cardiac myocytes. miR-21 might play an essential role in heart diseases related to ROS such as cardiac hypertrophy, heart failure, myocardial infarction, and myocardial ischemia/reperfusion injury. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts Myocardial and circulating levels of microRNA-21 reflect left ventricular fibrosis in aortic stenosis patients MicroRNA 21 inhibits left ventricular remodeling in the early phase of rat model with ischemia-reperfusion injury by suppressing cell apoptosis MicroRNA-21 protects against the H(2)O(2)-induced injury on cardiac myocytes via its target gene PDCD4 MicroRNA-21 (miR-21) is a highly expressed microRNA (miRNA) in cardiovascular system. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. MicroRNA-21 (miR-21) is a highly expressed microRNA (miRNA) in cardiovascular system miR-21 might be a novel therapeutic target in cardiovascular diseases MicroRNA-21 as therapeutic target in cancer and cardiovascular disease. These findings reveal that microRNAs can contribute to myocardial disease by an effect in cardiac fibroblasts. Our results validate miR-21 as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.

yes

56b29bf545561f0573000003

Are there any statistical methods for normalizing and identifying differential regions in histone modification ChIP-seq data?

ChIPnorm: a statistical method for normalizing and identifying differential regions in histone modification ChIP-seq libraries. In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. We show that the ChIPnorm method removes most of the noise and bias in the data and outperforms other normalization methods. We correlate the histone marks with gene expression data and confirm that histone modifications H3K27me3 and H3K4me3 act as respectively a repressor and an activator of genes. Compared to what was previously reported in the literature, we find that a substantially higher fraction of bivalent marks in ES cells for H3K27me3 and H3K4me3 move into a K27-only state. We find that most of the promoter regions in protein-coding genes have differential histone-modification sites. In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. We show that the ChIPnorm method removes most of the noise and bias in the data and outperforms other normalization methods. In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. We show that the ChIPnorm method removes most of the noise and bias in the data and outperforms other normalization methods. This problem turns out to be surprisingly difficult, even in simple pairwise comparisons, because of the significant level of noise in ChIP-seq data. In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types.

yes

52ef7170c8da898910000012

Is CD84 genetically associated with arthritis?

The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients) Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity Three members of this gene family, Ly108, Ly9, and CD84, exhibit polymorphisms that strongly influence susceptibility to systemic autoimmunity, notably in mice, but also in some human populations

yes

532f08b8d6d3ac6a34000029

Are there any specific antidotes for rivaroxaban?

Novel oral anticoagulants (NOACs)--apixaban, dabigatran, and rivaroxaban--have a significantly smaller risk of intracerebral hemorrhage (ICH). However, two facts make this situation complicated: First, the risk of hematoma expansion is unknown for NOACs. Second, there is no specific antidote for neither of the NOACs. he new oral anticoagulants dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) have predictable pharmacokinetic and pharmacodynamic profiles and are alternatives to warfarin. However, many physicians are wary of these drugs, since there is limited evidence on how to manage bleeding in patients taking them, and since no specific antidote is known to reverse their anticoagulant effect. Given the absence of a specific antidote, the action to be taken in these situations must be defined. The fact that there is no specific antidote to reverse the anticoagulant action of the new anticoagulants can impair management of hemorrhagic complications; Like any new therapy, the potential benefits must be weighed against the potential challenges and one of the most concerning aspects of the new target-specific oral anticoagulants is the lack of a proven method to reverse their effect. Unlike the vitamin K antagonist, i.e. warfarin, there is no specific antidote for these medications. Two major drawbacks are on the one hand the risk of drug accumulation in kidney and/or liver disease and, on the other hand, the lack of specific antidotes. NOA also have other unresolved problems: drug interactions are still possible, specific coagulation test to assess them must be developed, and no specific antidote is currently available in case of hemorrhagic complication. But they have disadvantages also, they depend on renal clearance, they can interact with other medicaments and they lack a specific antidote. While these trial data are extremely encouraging, several practical issues (e.g., lack of specific antidote, safety of long-term treatment or cost-effectiveness in "real-life" clinical practice) still need to be elucidated. In case of massive bleeding, management is unclear and none of these newer agents has a specific antidote that completely reverses its anticoagulant effect. The short half-life of these new agents compensates for the lack of any specific antidote in many instances. Currently, none of these new agents has a specific antidote, and little advise can be given on how to manage a major bleeding event. Rivaroxaban, which inhibits activated factor X (Xa), is currently in clinical trials and is the most advanced factor Xa inhibitor. The drug offers once-daily oral dosing, with no need for injections, dose titration, or frequent blood tests to monitor the international normalised ratio. It has a rapid onset of action and, although there is no specific antidote, it has a short plasma elimination half-life (about 5-9 hours). Increased use of dabigatran, rivaroxaban, and apixaban as oral anticoagulants for the treatment of atrial fibrillation and acute deep venous thrombosis has increased despite the lack of known antidotes to these medications. There is no antidote for reversal and no reliable laboratory monitoring of the anticoagulant effect for emergency situations. Further concerns about the use of NOAC in the elderly are the high prevalence of renal insufficiency in AF patients >75 years of age, the largely unknown risk of drug-drug and drug-food interactions, the lack of easily available laboratory monitoring tests of anticoagulant activity and the lack of an antidote. Specific antidotes for the reversal of the anticoagulant effect of these drugs, such as monoclonal antibodies against the direct thrombin inhibitor dabigatran or recombinant Xa-analog in the case of factor Xa inhibitors, are still being investigated in early clinical trials. In early 2013 there is no antidote for dabigatran, rivaroxaban or apixaban, nor any specific treatment with proven efficacy for severe bleeding linked to these drugs.

no

54d77f0e3706e8952800001b

Is cytisine superior to nicotine replacement therapy for smoking cessation?

The effectiveness of cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week, 2 months, and 6 months. In a prespecified subgroup analysis of the primary outcome, cytisine was superior to nicotine-replacement therapy among women and noninferior among men. CONCLUSIONS: When combined with brief behavioral support, cytisine was found to be superior to nicotine-replacement therapy in helping smokers quit smoking, but it was associated with a higher frequency of self-reported adverse events.

yes

56c0708eef6e39474100001f

Is the abnormal dosage of ultraconserved elements disfavored in cancer cells?

Abnormal dosage of ultraconserved elements is highly disfavored in healthy cells but not cancer cells. We begin by showing that depletion for UCEs characterizes the most recent large-scale human CNV datasets and then find that even newly formed de novo CNVs, which have passed through meiosis at most once, are significantly depleted for UCEs. In striking contrast, CNVs arising specifically in cancer cells are, as a rule, not depleted for UCEs and can even become significantly enriched. This observation raises the possibility that CNVs that arise somatically and are relatively newly formed are less likely to have established a CNV profile that is depleted for UCEs. Alternatively, lack of depletion for UCEs from cancer CNVs may reflect the diseased state. In support of this latter explanation, somatic CNVs that are not associated with disease are depleted for UCEs. Finally, we show that it is possible to observe the CNVs of induced pluripotent stem (iPS) cells become depleted of UCEs over time, suggesting that depletion may be established through selection against UCE-disrupting CNVs without the requirement for meiotic divisions. Alternatively, lack of depletion for UCEs from cancer CNVs may reflect the diseased state.

no

515ac533d24251bc050000a9

Does thyroid hormone regulate calcium transient in the myocardium?

3-iodothyronamine (T(1)AM) is a novel endogenous relative of thyroid hormone, able to interact with trace amine-associated receptors, a class of plasma membrane G protein-coupled receptors, and to produce a negative inotropic and chronotropic effect In adult rat cardiomyocytes acute exposure to 20 microM T(1)AM decreased the amplitude and duration of the calcium transient. In normal porcine myocardium T3 had no effect on the extent of isometric force generation but accelerated the time course of force development (p < 0.05) and increased the calcium transient (p < 0.001). After induction of myocardial depression by epinephrine exposure T3 accelerated the intracellular calcium transients and reduced diastolic calcium The experimental data showing increased force amplitudes at unaltered amplitudes of the intracellular calcium transient and an even-reduced calcium time integral provide strong evidence for a sensitization of the contractile apparatus for calcium by triiodothyronine hese results indicate that the thyroid state influences the time course of the calcium transient and are consistent with the abbreviation in the duration of contraction that is observed in the hyperthyroid state.

yes

517179718ed59a060a00000e

Are proteasome inhibitors good candidates for treatment of leukemia and solid tumors?

We show that treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model. Our results show that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target We further found that ATO targets AME via both myelodysplastic syndrome 1 (MDS1) and EVI1 moieties and degrades EVI1 via the ubiquitin-proteasome pathway and MDS1 in a proteasome-independent manner. Our results suggest that ATO could be used as a part of targeted therapy for AME-, AML1/MDS1-, MDS1/EVI1-, and EVI1-positive human cancers. Previously we had shown the synergic effect of bortezomib and thiostrepton in breast cancer cells in vitro, where sub-apoptotic concentrations of both proteasome inhibitors resulted in synergic increase in cell death when combined as a treatment. Here, we administered such a combination to MDA-MB-231 xenograft tumors in vivo, and found that the effect of complementary proteasome inhibitors reduced tumor growth rates more efficiently than compared with when administered alone. Addition of a proteasome inhibitor to anti-hormonal therapy resulted in a clinical benefit rate of 22% in a limited number of patients with endocrine resistant and progressive metastatic breast cancer. Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications. Bortezomib has minimal activity as a single-agent in the treatment of recurrent platinum-sensitive EOC/PPC Our study indicates a molecular mechanism by which the sensitivity of thyroid cancer cells is regulated by the level of GRP78 as well as preferential induction of GRP78 or CHOP upon treatment with proteasome inhibitors. Our experiments therefore suggest a novel approach toward sensitization of thyroid cancer cells to proteasome inhibitors. Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. Given the results of this trial, it is safe and reasonable to recommend treatment with PS341 on the schedule used in this trial at 1.56 mg/m2/dose in Phase II trials. Particular care should be taken with patients with preexisting neuropathy The successes of proteasome inhibitors in MM are now being translated to other hematologic malignancies, including acute leukemia Such efforts have led to bortezomib, the first FDA approved proteasome inhibitor now used as a frontline treatment for newly diagnosed multiple myeloma (MM), relapsed/refractory MM and mantle cell lymphoma We recently reported the impact and mechanisms of carfilzomib and oprozomib, second-in-class proteasome inhibitors with higher specificities and reduced toxicities, against head and neck squamous cell carcinoma (HNSCC). Carfilzomib and oprozomib potently inhibit HNSCC cell survival and the growth of HNSCC tumors

yes

553cae13f32186855800000e

Is there any link between CTF4 and CTF18 during sister chromatid cohesion?

Our results suggest that Elg1, Ctf4, and Ctf18 may coordinate the relative movement of the replication fork with respect to the cohesin ring These data defined two cohesion pathways, one containing CSM3, TOF1, CTF4, and CHL1, and the second containing MRC1, CTF18, CTF8, and DCC1 Here we show that three proteins required for sister chromatid cohesion, Eco1, Ctf4, and Ctf18, are found at, and Ctf4 travels along chromosomes with, replication forks. The ring-shaped cohesin complex is loaded onto chromosomes before S phase in an ATP hydrolysis-dependent reaction. Cohesion establishment during DNA replication follows without further cohesin recruitment and without need for cohesin to re-engage an ATP hydrolysis motif that is critical for its initial DNA binding. This provides evidence for cohesion establishment in the context of replication forks and imposes constraints on the mechanism involved Sister-chromatid cohesion mediated by the alternative RF-CCtf18/Dcc1/Ctf8, the helicase Chl1 and the polymerase-alpha-associated protein Ctf4 is essential for chromatid disjunction during meiosis II In budding yeast, a specialized replication factor C called RF-C(Ctf18/Dcc1/Ctf8) and the DNA-polymerase-alpha-associated protein Ctf4 are required to maintain sister-chromatid cohesion in cells arrested for long periods in mitosis We also show that, in contrast to mitosis, RF-C(Ctf18/Dcc1/Cft8), Ctf4 and Chl1 are essential for chromosome segregation during meiosis and for the viability of meiotic products. Ctf8p is a component of Ctf18-RFC, an alternative replication factor C-like complex required for efficient sister chromatid cohesion in Saccharomyces cerevisiae. We performed synthetic genetic array (SGA) analysis with a ctf8 deletion strain as a primary screen to identify other nonessential genes required for efficient sister chromatid cohesion. We then assessed proficiency of cohesion at three chromosomal loci in strains containing deletions of the genes identified in the ctf8 SGA screen. Deletion of seven genes (CHL1, CSM3, BIM1, KAR3, TOF1, CTF4, and VIK1) resulted in defective sister chromatid cohesion Saccharomyces cerevisiae CTF18 and CTF4 are required for sister chromatid cohesion CTF4 and CTF18 are required for high-fidelity chromosome segregation. Both exhibit genetic and physical ties to replication fork constituents. We find that absence of either CTF4 or CTF18 causes sister chromatid cohesion failure and leads to a preanaphase accumulation of cells that depends on the spindle assembly checkpoint. The physical and genetic interactions between CTF4, CTF18, and core components of replication fork complexes observed in this study and others suggest that both gene products act in association with the replication fork to facilitate sister chromatid cohesion. The requirement for CTF4 and CTF18 in robust cohesion identifies novel roles for replication accessory proteins in this process Here we show that three proteins required for sister chromatid cohesion, Eco1, Ctf4, and Ctf18, are found at, and Ctf4 travels along chromosomes with, replication forks. Saccharomyces cerevisiae CTF18 and CTF4 are required for sister chromatid cohesion. We find that absence of either CTF4 or CTF18 causes sister chromatid cohesion failure and leads to a preanaphase accumulation of cells that depends on the spindle assembly checkpoint. In budding yeast, a specialized replication factor C called RF-C(Ctf18/Dcc1/Ctf8) and the DNA-polymerase-alpha-associated protein Ctf4 are required to maintain sister-chromatid cohesion in cells arrested for long periods in mitosis. The physical and genetic interactions between CTF4, CTF18, and core components of replication fork complexes observed in this study and others suggest that both gene products act in association with the replication fork to facilitate sister chromatid cohesion. Sister-chromatid cohesion mediated by the alternative RF-CCtf18/Dcc1/Ctf8, the helicase Chl1 and the polymerase-alpha-associated protein Ctf4 is essential for chromatid disjunction during meiosis II. Genetic analyses revealed that Rmi1 promoted sister chromatid cohesion in a process that was distinct from both the cohesion establishment pathway involving Ctf4, Csm3, and Chl1 and the pathway involving the acetylation of Smc3. The physical and genetic interactions between CTF4, CTF18, and core components of replication fork complexes observed in this study and others suggest that both gene products act in association with the replication fork to facilitate sister chromatid cohesion. Here we show that three proteins required for sister chromatid cohesion, Eco1, Ctf4, and Ctf18, are found at, and Ctf4 travels along chromosomes with, replication forks. We find that absence of either CTF4 or CTF18 causes sister chromatid cohesion failure and leads to a preanaphase accumulation of cells that depends on the spindle assembly checkpoint. In budding yeast, a specialized replication factor C called RF-C(Ctf18/Dcc1/Ctf8) and the DNA-polymerase-alpha-associated protein Ctf4 are required to maintain sister-chromatid cohesion in cells arrested for long periods in mitosis. Here we show that three proteins required for sister chromatid cohesion, Eco1, Ctf4, and Ctf18, are found at, and Ctf4 travels along chromosomes with, replication forks The physical and genetic interactions between CTF4, CTF18, and core components of replication fork complexes observed in this study and others suggest that both gene products act in association with the replication fork to facilitate sister chromatid cohesion We find that absence of either CTF4 or CTF18 causes sister chromatid cohesion failure and leads to a preanaphase accumulation of cells that depends on the spindle assembly checkpoint In addition to Eco1, several other factors contribute to cohesion establishment, including Ctf4, Ctf18, Tof1, Csm3, Chl1 and Mrc1, but little is known about their roles

yes

52f7c4bd2059c6d71c00002d

Are thyroid hormone receptor alpha1 mutations implicated in thyroid hormone resistance syndrome?

This study reports the consequences of LT4 treatment over a prolonged period of time in 2 of the first patients with a heterozygous mutation in TRα1. Here we show that the dysregulation of the pituitary-thyroid axis was worsened by the lack of TR alpha1 in TR betaPV mice, and severe impairment of postnatal growth was manifested in TR betaPV mice deficient in TR alpha1. Heterozygous 2- to 3-week- old mice exhibit a severe retardation of post-natal development and growth, but only a minor reduction in serum thyroxine levels. The data demonstrate a novel array of effects mediated by a dominant negative TRalpha1, and may provide important clues for identification of a potentially unrecognized human disorder and its treatment. No mutations in DNA- and hormone-binding-domains of TRbeta1 and TRalpha1 genes were found in proband, suggesting that the defect could be due to an unknown mutation in either the TR gene or a post receptor abnormality These results demonstrate that the lack of TR alpha1 exacerbates the manifestation of RTH in TR betaPV mice. Therefore, TR alpha1 could play a compensatory role in mediating the functions of T3 in heterozygous patients with RTH.

yes

532673c4d6d3ac6a34000009

Does administration of triiodothyronine improve outcome following coronary artery bypass grafting?

Serum T3 concentrations were significantly higher with fewer patients having T3 concentrations below the normal range in the T3 group than the placebo group throughout the postoperative period. Hemodynamic variables, postoperative inotrope requirement, and outcome variables showed no differences between the groups We conclude that although widespread interest has been shown on the use of thyroid hormones in the perioperative period, and the effect of cardiopulmonary bypass on thyroid hormone metabolism widely studied, there is no substantial evidence to justify routine use of thyroid hormones in patients undergoing coronary artery bypass grafting. Treatment with GIK, T3, and GIK/T3 improves hemodynamic performance and results in reduced cTnI release in patients undergoing on-pump CABG surgery. Perioperative administration of triiodothyronine increased cardiac output slightly and decreased systemic vascular resistance, but it had no effect on operative outcome. Parenteral triiodothyronine given after crossclamp removal during elective coronary artery bypass grafting significantly improved postoperative ventricular function, reduced the need for treatment with inotropic agents and mechanical devices, and decreased the incidence of myocardial ischemia. The incidence of atrial fibrillation was slightly decreased, and the need for postoperative pacemaker support was reduced. Perioperative T3 administration decreased the incidence and need for treatment of postoperative atrial fibrillation. Intravenous T(3) does not have dramatic effects on hemodynamic variables in this setting as has been previously suggested. Raising serum triiodothyronine concentrations in patients undergoing coronary-artery bypass surgery increases cardiac output and lowers systemic vascular resistance, but does not change outcome or alter the need for standard postoperative therapy. No significant differences were noted in the pre and post CPB hemodynamics between the two groups for the most part of the study except that heart rate was increased in T3 group. The haemodynamic parameters were no different between the two groups at any postoperative time point. Likewise, density and affinity of lymphocyte beta-adrenoceptors were not significantly different from pre-operative values in either group.

no

53009f6d2059c6d71c00007e

Is long QT syndrome a cause for sudden cardiac death in athletes?

A diversity of cardiovascular disorders including hypertrophic cardiomyopathy, congenital coronary anomalies, arrhythmogenic right ventricular dysplasia, dilated cardiomyopathy, aortic rupture due to Marfan syndrome, myocarditis, valvular disease and electrical disorders (Wolff-Parkinson-White syndrome, long QT syndrome, Brugada syndrome), as well as commotio cordis represent the common causes of SCD in young athletes. Sudden cardiac death is the leading cause of mortality among young athletes with an incidence of 1-2 per 100,000 athletes per annum. The majority of cases are caused by an underlying structural cardiac abnormality, most commonly hypertrophic cardiomyopathy. More recently, the understanding of non-structural causes such as long QT syndrome and Brugada syndrome has grown and diagnostic criteria have been developed. This review considers in particular the causes of death affecting athletes below 35 years of age. In this age group the largest proportion of deaths are caused by diseases with autosomal dominant inheritance such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT-syndrome, and Marfan's syndrome. Knowledge of sudden cardiac death in young athletes is imperative for all physicians and allied health professionals. In this article, we review several etiologies of sudden cardiac death, including hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, Wolff-Parkinson-White syndrome, long QT syndrome, Brugada syndrome, and commotio cordis. Sudden cardiac death (SCD) in young athletes is generally caused by inherited cardiac disorders. The genetic abnormalities most associated with SCD are hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. The most common cause of sudden cardiac death in athletes is hypertrophic cardiomyopathy. Other reasons are congenital coronary artery anomalies, nivocarditis, dilatative cardiomyopathy, arrhythmogenic cardiomyopathy of the right ventricle, sarcoidosis, mitral valve prolapse, aortic valve stenosis, atherosclerosis, long QT syndrome, and blunt impact to the chest. The congenital long QT syndrome (LQTS) is caused by cardiac ion channel mutations, which predispose young individuals to sudden cardiac death often related to exercise. A group of relatively uncommon but important genetic cardiovascular diseases (GCVDs) are associated with increased risk for sudden cardiac death during exercise, including hypertrophic cardiomyopathy, long-QT syndrome, Marfan syndrome, and arrhythmogenic right ventricular cardiomyopathy. Primary electrical disorders (such as the long QT syndrome) are rarely present in athletes but, so far, are a considerable reason for disqualification from sport activity.

yes

5512cce26a8cde6b7200000c

Is protein M3/6 a dual specificity phosphatase?

Involvement of the dual-specificity phosphatase M3/6 in c-Jun N-terminal kinase inactivation following cerebral ischemia in the rat hippocampus. The results revealed upregulation of dual-specificity phosphatase M3/6 (DUSP8) activity at 4 h of reperfusion in rat hippocampi. This study examines the molecular mechanism underlying JNK dephosphorylation and inactivation evoked by dual-specificity phosphates following cerebral ischemia. Phosphatases play a particularly important role in this respect, by tightly controlling MAPK phosphorylation and activation. M3/6 (DUSP8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of JNK and, to a lesser extent, p38 MAPKs and is found in a complex with these kinases, along with other pathway components, held together by scaffold proteins. Dual-specificity phosphatases (DUSPs) play a very important role in these events by modulating the extent of JNK phosphorylation and activation and thus regulating cellular responses to stress. M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK. M3/6 is a dual-specificity phosphatase selective for JNK [7, 8]. Here we describe two new dual specificity phosphatases of the CL100/MKP-1 family that are selective for inactivating ERK or JNK/SAPK and p38 MAP kinases when expressed in COS-7 cells. M3/6 is the first phosphatase of this family to display highly specific inactivation of JNK/SAPK and p38 MAP kinases. We previously demonstrated that the dual specificity phosphatases (DSPs) MKP7 and M3/6 bind the scaffold JNK-interacting protein-1 (JIP-1) and inactivate the bound subset of JNK (1). the dual-specificity phosphatase M3/6 dual-specificity phosphatase M3/6 (DUSP8) M3/6 (DUSP8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of JNK the M3/6 dual-specificity phosphatase M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK M3/6 is a dual-specificity phosphatase selective for JNK The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases. Phosphorylation of the M3/6 dual-specificity phosphatase enhances the activation of JNK by arsenite. Indeed, expanded polyglutamine impaired the solubility of the dual-specificity JNK phosphatase M3/6. Regulation of dual-specificity phosphatases M3/6 and hVH5 by phorbol esters. M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK. M3/6 is a dual-specificity phosphatase selective for JNK [7, 8] M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK Here we describe how diverse cellular stresses affect differently the stability and activity of a JNK-inactivating dual-specificity threonine-tyrosine phosphatase M3/6 M3/6 is a dual-specificity phosphatase selective for JNK [7, 8] Regulation of dual-specificity phosphatases M3/6 and hVH5 by phorbol esters. Analysis of a delta-like domain. The results revealed upregulation of dual-specificity phosphatase M3/6 (DUSP8) activity at 4 h of reperfusion in rat hippocampi Indeed, expanded polyglutamine impaired the solubility of the dual-specificity JNK phosphatase M3/6 Here we report that JIP-1 also binds the dual-specificity phosphatases MKP7 and M3/6 via a region independent of its JNK binding domain. Differential regulation of M3/6 (DUSP8) signaling

yes

532c0946d6d3ac6a34000019

Are there focused databases from which you can retrieve gene expression data on renal disease?

Proteomics database in chronic kidney disease Naturally occurring human urinary peptides for use in diagnosis of chronic kidney disease

yes

511a16f9df1ebcce7d000005

Are there any DNMT3 proteins present in plants?

De novo DNA methylation in Arabidopsis thaliana is catalyzed by the methyltransferase DRM2, a homolog of the mammalian de novo methyltransferase DNMT3. Here we describe DNA methyltransferase genes from both Arabidopsis and maize that show a high level of sequence similarity to Dnmt3, suggesting that they encode plant de novo methyltransferases. Relative to all known eukaryotic methyltransferases, these plant proteins contain a novel arrangement of the motifs required for DNA methyltransferase catalytic activity. The N termini of these methyltransferases contain a series of ubiquitin-associated (UBA) domains. BLASTX searches and phylogenetic analysis suggested that five cDNAs belonged to four classes (Dnmt1, Dnmt2, CMT and Dnmt3) of DNA methyltransferase genes.

yes

530cf57efe2466f70c000006

Has vitamin D has been shown to reduce incidence of falls in older people in clinical trials?

However, apart from the beneficial effects of 800 IU/d of vitamin D3 for reduction of falls in the elderly, causality remains yet unproven in randomized controlled trials (RCTs). The rate of falls and the number of fallers was significantly reduced in two studies evaluating the effect of medication on preventing falls; one study (85 participants) compared vitamin D versus placebo in institutionalised women after stroke with low vitamin D levels, and the other study (79 participants) evaluated alendronate versus alphacalcidol in hospitalised people after stroke. Two studies testing vitamin D versus placebo and alendronate versus alphacalcidol found a significant reduction in falls and the number of people falling .Overall, vitamin D supplementation does not appear to reduce falls but may be effective in people who have lower vitamin D levels before treatment. Overall, vitamin D did not reduce rate of falls (RaR 1.00, 95% CI 0.90 to 1.11; seven trials; 9324 participants) or risk of falling (RR 0.96, 95% CI 0.89 to 1.03; 13 trials; 26,747 participants), but may do so in people with lower vitamin D levels before treatment. Vitamin D affects bone and muscle health and likely reduces the risk of falls in the elderly. We found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96) This effect was more prominent in patients who were vitamin D deficient at baseline and in studies in which calcium was coadministered with vitamin D. Vitamin D combined with calcium reduces the risk of falls. The majority of the evidence is derived from trials enrolling elderly women. Studies of vitamin D and calcium for fracture prevention have produced inconsistent results, as a result of different vitamin D status and calcium intake at baseline, different doses and poor to adequate compliance. Despite significant increases in the provision of hip protectors and use of vitamin D supplementation in both intervention and control facilities, there was no difference in the number of falls or falls injuries between the intervention and control groups, nor a reduction in falls overall. Beyond fall and fracture prevention, vitamin D may also reduce overall morbidity by multiple mechanisms. There is evidence to suggest that these agents may reduce the incidence of nonvertebral fractures and falls; however, their benefit on vertebral fracture reduction may depend on the type of active vitamin D.

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530cf57efe2466f70c000001

Has depression been shown to be a predictor of frailty?

significant role of frailty as a predictor of depression in a relatively younger old Chinese population significant relationships between frailty and depressive symptoms and mortality at 1 year These findings suggest that malnutrition is a major predictor of frailty or the "failure to thrive" syndrome in older persons. Depression is a major cause of poor nutritional status in older persons. Depressed mood was associated with increased risk of steep strength decline, in particular in older men with low body weight. Low body weight in combination with depressed mood may be an indicator of frailty or severe disease status that leads to accelerated strength loss and disability. Longitudinally, depressed mood was the only independent predictor of decline in cognition, functional ability, physician-rated health, and mortality;

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Is there any association between Jarid2 and miR-155 in Th17 cells?

Jarid2 links MicroRNA and chromatin in Th17 cells. In this issue of Immunity, Escobar et al. (2014) bring microRNAs and chromatin together by showing how activation-induced miR-155 targets the chromatin protein Jarid2 to regulate proinflammatory cytokine production in T helper 17 cells. miR-155 activates cytokine gene expression in Th17 cells by regulating the DNA-binding protein Jarid2 to relieve polycomb-mediated repression. Mir155 was bound by Th17 cell transcription factors and was highly expressed during Th17 cell differentiation. miR-155-deficient Th17 and T regulatory (Treg) cells expressed increased amounts of Jarid2, a DNA-binding protein that recruits the Polycomb Repressive Complex 2 (PRC2) to chromatin. PRC2 binding to chromatin and H3K27 histone methylation was increased in miR-155-deficient cells, coinciding with failure to express Il22, Il10, Il9, and Atf3. Defects in Th17 cell cytokine expression and Treg cell homeostasis in the absence of Mir155 could be partially suppressed by Jarid2 deletion. Thus, miR-155 contributes to Th17 cell function by suppressing the inhibitory effects of Jarid2. Thus, miR-155 contributes to Th17 cell function by suppressing the inhibitory effects of Jarid2. Thus, miR-155 contributes to Th17 cell function by suppressing the inhibitory effects of Jarid2. Defects in Th17 cell cytokine expression and Treg cell homeostasis in the absence of Mir155 could be partially suppressed by Jarid2 deletion. Thus, miR-155 contributes to Th17 cell function by suppressing the inhibitory effects of Jarid2. Thus, miR-155 contributes to Th17 cell function by suppressing the inhibitory effects of Jarid2.

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