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56b8ed4b156496395c000004

Is there any link between conserved noncoding elements and alternative splicing in vertebrates?

Some of the most highly conserved sequences occur in genes encoding RNA binding proteins, particularly the RNA splicing-associated SR genes. Differences in sequence conservation between plants and animals are likely to reflect differences in the biology of the organisms, with plants being much more able to tolerate genomic deletions and whole-genome duplication events due, in part, to their far greater fecundity compared with vertebrates.

yes

57134d511174fb1755000002

Is muscle regeneration possible in mdx mice with the use of induced mesenchymal stem cells?

Purified iMSCs displayed fibroblast-like morphology, formed three-dimensional spheroid structures, and expressed characteristic mesenchymal stem cell surface markers such as CD29, CD33, CD73, CD90, and CD105. Moreover, iMSCs were capable of differentiating into adipogenic, osteogenic, and chondrogenic lineages. Transplanting iMSC cells to tibialis anterior skeletal muscle tissue in mdx mice lowered oxidative damage as evidenced by a reduction in nitrotyrosine levels, and normal dystrophin expression levels were restored This study demonstrates the therapeutic potential of purified iMSCs in skeletal muscle regeneration in mdx mice Flk-1+ adipose-derived mesenchymal stem cells differentiate into skeletal muscle satellite cells and ameliorate muscular dystrophy in mdx mice Within mdx mice, an animal model of DMD, adipose tissue-derived Flk-1(+) MSCs (AD-MSCs) homed to and differentiated into cells that repaired injured muscle tissue. This repair correlated with reconstitution of dystrophin expression on the damaged fibers Flk-1(+) AD-MSC transplants may repair muscular dystrophy This study demonstrates the therapeutic potential of purified iMSCs in skeletal muscle regeneration in mdx mice, and suggests that iPSCs are a viable alternate source for deriving MSCs as needed. Transplanting iMSC cells to tibialis anterior skeletal muscle tissue in mdx mice lowered oxidative damage as evidenced by a reduction in nitrotyrosine levels, and normal dystrophin expression levels were restored This study demonstrates the therapeutic potential of purified iMSCs in skeletal muscle regeneration in mdx mice, and suggests that iPSCs are a viable alternate source for deriving MSCs as needed

yes

571e06447de986d80d000016

Is the SDHAF2 gene encoding a protein necessary for flavination of SDHA?

Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes. the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5) SDHAF2, required for flavination of SDHA At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes. Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. In a recent issue of Science, Rutter and coworkers showed that SDH5 is required for the flavination of SDHA, which is necessary for SDH assembly and function. At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA CONTEXT: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. This gene is co-expressed with a number of genes encoding mitochondrial proteins, including SDH1-1, and has low partial sequence similarity to human SDHAF2, a protein required for flavin-adenine dinucleotide (FAD) insertion into SDH. At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes. Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA.

yes

530cf4fe960c95ad0c00000a

Is zolpidem an antibiotic?

Zolpidem is a short-acting imidazopyridine hypnotic drug that is metabolized mainly by CYP3A4. FGIN-1-27 and alpidem, like the neurosteroid 3 alpha,21-dehydroxy-5 alpha-pregnane-20-one (THDOC), clonazepam and zolpidem (the direct allosteric modulators of gamma-aminobutyric acidA receptors) delay the onset of isoniazid and metrazol-induced convulsions. olpidem is a new, short-acting hypnotic of imidazopyridine structure which binds selectively to a subpopulation of receptors involved in the action of benzodiazepines [omega 1 (BZ1) sites of the gamma-aminobutyric acidA receptors] lpidem is a new, short-acting hypnotic of imidazopyridine structure which binds selectively to a subpopulation of receptors involved in the action of benzodiazepines [omega 1 (BZ1) sites of the gamma-aminobutyric acidA receptors] In contrast, after repeated treatment with zolpidem, there was no change in its ability to produce sedative and anticonvulsant effects. Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects. Zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide hemitartrate] is reported to be a rapid onset, short duration hypnotic that interacts at the benzodiazepine recognition site. The imidazopyridine zolpidem is a short-acting hypnotic chemically distinct from benzodiazepines (BZs). According to its peculiar neuropharmacologic activity (selectivity for the omega 1-BZ receptors), zolpidem is expected to be a pure hypnotic, without the other effects of BZs.

no

530cf4fe960c95ad0c00000c

Can desvenlafaxine be used at a dose of 50mg/day?

Long-term use of desvenlafaxine was safe and well tolerated, with a clinical benefit/risk profile similar to that in other populations. e objective of this study was to evaluate the long-term safety of desvenlafaxine for continuation treatment of major depressive disorder (MDD) in Japanese patients. This was a phase 3, multicenter, 10-month, open-label study with flexible dosing of desvenlafaxine (25, 50, 100 mg/day) n an effort to establish the lowest effective dose of desvenlafaxine (administered as desvenlafaxine succinate), we assessed the efficacy, safety, and tolerability of 10- and 50-mg/day desvenlafaxine vs placebo for the treatment of major depressive disorder Change from baseline to final evaluation in adjusted HAM-D(17) total scores was not significantly different comparing desvenlafaxine 10 mg/day (-9.28) and desvenlafaxine 50 mg/day (-8.92) with placebo (-8.42) Overall rates of treatment-emergent adverse events with both doses were similar to placebo However, in a companion study reported separately, desvenlafaxine 50 mg, but not 25 mg, separated from placebo. Taken together, these studies suggest that 50 mg is the minimum effective dose of desvenlafaxine for the treatment of major depressive disorder. Desvenlafaxine XR was dosed at 50 mg/day for 10 days. Desvenlafaxine therapy is initiated at the therapeutic dose (50 mg/day) without a need for dose titration. Clinical studies have investigated the efficacy of DVS in doses ranging from 50 to 400 mg/day for the treatment of MDD in adult outpatients. The effects of DVS 50 mg/day have been clearly distinguished from placebo in the reduction of MDD symptoms in such clinical trials. No additional therapeutic benefits were found at doses > 50 mg/day. The recommended dose of DVS ranges from 50 to 100 mg. Adult outpatients with major depressive disorder received desvenlafaxine doses ranging from 50-400 mg/day or placebo for 8 weeks At the recommended therapeutic dose of 50 mg/day, discontinuation due to adverse events was similar to placebo atients received fixed (50, 100, 200, or 400 mg/day; n=1,342) or flexible doses (100-400 mg/day; n=463) of desvenlafaxine or placebo (n=1,108) Desvenlafaxine demonstrated short-term efficacy for treating major depressive disorder across the range of doses studied. No evidence of greater efficacy was observed with doses >50 mg/day; a strong dose-response effect on tolerability was observed. To assess the efficacy, safety, and tolerability of 50- and 100-mg/day doses of desvenlafaxine (administered as desvenlafaxine succinate), a serotonin-norepinephrine reuptake inhibitor, for the treatment of major depressive disorder (MDD) Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) MDD and 17-item Hamilton Rating Scale for Depression (HAM-D(17)) scores > or =20 were randomly assigned to double-blind placebo or desvenlafaxine treatment (fixed dose of 50 mg/day or 100 mg/day) for 8 weeks. Desvenlafaxine 50 mg was associated with a significantly greater adjusted mean change from baseline on the HAM-D(17) (-11.5) compared with placebo (-9.5, p=0.018) These results demonstrate efficacy, safety, and tolerability of desvenlafaxine 50 mg/day for treating MDD. CONCLUSIONS: Desvenlafaxine at the recommended dose of 50 mg/d was effective in relapse prevention of depression during a 6-month period in patients who demonstrated stable response after 20 weeks of open-label desvenlafaxine treatment.

yes

530cf4fe960c95ad0c00000d

Can ferric carboxymaltose be used to treat anemia in inflammatory bowel disease patients?

Intravenous iron should be preferred where oral iron is poorly tolerated or where it has failed in moderate to severe anemia, and in combination with erythropoietin Ferric carboxymaltose is much more convenient, and has been shown to be more effective than iron sucrose in a large randomized tria nemia and iron deficiency anemia are very common in inflammatory bowel disease (IBD Ferric carboxymaltose was associated with cost savings of 30-44 % per patient per treatment cycle compared to iron sucrose. Iron deficiency is common in pregnancy, postpartum, inflammatory bowel disease, chronic kidney disease, chronic heart failure, heavy uterine bleeding, cancer and following surgery. We estimate the budget impact (BI) on the Swiss mandatory health insurance associated with substituting iron sucrose (standard) with ferric carboxymaltose (new treatment) using real-life data. reating iron deficiency involves substantial costs to the Swiss MHI which may be reduced by substituting iron sucrose with ferric carboxymaltose. e aim of this study was to observe, in a non-interventional way, how Swedish gastroenterologists adhere to guidelines in IBD outpatients treated with intravenous ferric carboxymaltose (FCM), and the result of treatment FCM lowers platelet counts and platelet activation in patients with IBD-associated secondary thrombocytosis. We performed a randomized, single-blinded placebo-controlled trial testing the effect of ferric carboxymaltose (FCM) in patients with IBD with secondary thrombocytosis (platelets > 450 G/L) e performed a randomized, placebo-controlled trial to determine if administration of ferric carboxymaltose (FCM) prevents anemia in patients with IBD and low levels of serum ferritin FCM prevents recurrence of anemia in patients with IBD, compared with placebo. A subgroup was analyzed regarding efficacy and side effects of iron supplementation with ferric carboxymaltose. Iron deficiency and anemia are frequent in IBD patients. Treatment with ferric carboxymaltose is efficious, safe and well tolerated in iron-deficient IBD patients. Intravenous iron avoids these concerns, especially with the development of ferric carboxymaltose, which allow up to 1000mg to be given rapidly. What is the optimal treatment for anemia in inflammatory bowel disease? We compared the efficacy and safety of a novel fixed-dose ferric carboxymaltose regimen (FCM) with individually calculated iron sucrose (IS) doses in patients with inflammatory bowel disease (IBD) and IDA Study drugs were well tolerated and drug-related adverse events were in line with drug-specific clinical experience The simpler FCM-based dosing regimen showed better efficacy and compliance, as well as a good safety profile, compared with the Ganzoni-calculated IS dose regimen. Ferric carboxymaltose can be rapidly administered in doses of 15 mg/kg body weight, up to a ceiling dose of 1000 mg. A test dose is not required, and it can be used more widely across a spectrum of iron deficiency and iron deficiency anemia indication Intravenous iron offers a rapid means of iron repletion and is superior to oral iron in many circumstances, especially in the presence of anemia of chronic disease, where it appears to overcome the block to absorption of iron from the gastrointestinal tract and immobilization of stored iron. The clinical situations where high doses of iron are commonly required are reviewed. These include nondialysis-dependent chronic kidney disease, inflammatory bowel disease, obstetrics, menorrhagia, and anemia associated with cancer and its treatment. Ferric carboxymaltose can be administered at 15 mg/kg body weight to a maximum dose of 1000 mg, whereas iron isomaltoside 1000 can be administered at 20 mg/kg body weight. The ability to give high doses of iron is important in the context of managing iron deficiency anemia in a number of clinical conditions where demands for iron are high (including chronic blood loss associated with inflammatory bowel disease, menorrhagia, and chronic kidney disease) erric carboxymaltose (FCM, Ferinject) was effective and well tolerated in the treatment of iron-deficiency anemia (IDA) in nine, Phase III, randomized, controlled, multicenter trials in a diverse range of indications, including patients with inflammatory bowel disease (IBD), post-partum anemia (PPA) or abnormal uterine bleeding (AUB), chronic heart failure (CHF), non-dialysis-dependent chronic kidney disease (CKD) and those undergoing hemodialysis (HD In patients with IBD or PPA, improvements in Hb levels were more rapid with FCM than with FeSulf. CM improved patient quality of life to an equivalent extent to oral FeSulf in patients with IBD or PPA, and to a greater extent than oral FeSulf in women with AUB Four different products are principally used in clinical practice, which differ in their pharmacokinetic properties and safety profiles: iron gluconate and iron sucrose (lower single doses), and iron dextran and ferric carboxymaltose (higher single doses). he prevalence of anemia across studies on patients with inflammatory bowel disease (IBD) is high (30%). novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized controlled trial. FeCarb is effective and safe in IBD-associated anemia. It is noninferior to FeSulf in terms of Hb change over 12 wk, and provides a fast Hb increase and a sufficient refill of iron stores. Treatment-related adverse events (AEs) occurred in 28.5% of the FeCarb and 22.2% of the FeSulf groups, with discontinuation of study medication due to AEs in 1.5% and 7.9%, respectively. The median Hb improved from 8.7 to 12.3 g/dL in the FeCarb group and from 9.1 to 12.1 g/dL in the FeSulf group, demonstrating noninferiority (P= 0.6967). Ferric carboxymaltose prevents recurrence of anemia in patients with inflammatory bowel disease. Ferric carboxymaltose (FCM, Ferinject) was effective and well tolerated in the treatment of iron-deficiency anemia (IDA) in nine, Phase III, randomized, controlled, multicenter trials in a diverse range of indications, including patients with inflammatory bowel disease (IBD), post-partum anemia (PPA) or abnormal uterine bleeding (AUB), chronic heart failure (CHF), non-dialysis-dependent chronic kidney disease (CKD) and those undergoing hemodialysis (HD). Ferric carboxymaltose (FCM, Ferinject) was effective and well tolerated in the treatment of iron-deficiency anemia (IDA) in nine, Phase III, randomized, controlled, multicenter trials in a diverse range of indications, including patients with inflammatory bowel disease (IBD), post-partum anemia (PPA) or abnormal uterine bleeding (AUB), chronic heart failure (CHF), non-dialysis-dependent chronic kidney disease (CKD) and those undergoing hemodialysis (HD)

yes

54d63d873706e89528000006

Is there any association of the chromosomal region harboring the gene ITIH3 with schizophrenia?

The most widely shared subset of genes-common to five of six disorders-included ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)). Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. A recent genome-wide analysis indicated that a polymorphism (rs2535629) of ITIH3 showed the strongest association signal with susceptibility to psychiatric disorders in Caucasian populations. We detected a novel association between suicide attempt and the ITIH3/4-region in a combined group of patients with BD, SCZ and related psychosis spectrum disorders. These include variations in chromosomal structure at 16p11.2, rare de novo point mutations at the gene SCN2A, and common single nucleotide polymorphisms (SNPs) mapping near loci encoding the genes ITIH3, AS3MT, CACNA1C and CACNB2. These selected examples point to the challenges to current diagnostic approaches. STAB1 is located in close proximity to PBMR1 and the NEK4-ITIH1-ITIH3-ITIH4 region, which are the top findings from GWAS meta-analyses of mood disorder, and a combined BD and schizophrenia data set. Our findings suggest that rs2535629 influences the susceptibility to psychiatric disorders by affecting the expression level of GLT8D1.

yes

553fbe9fe00431e071000001

Is the regulation of Vsr endonuclease independent of the growth phase of bacteria?

Growth phase-dependent regulation of Vsr endonuclease Vsr endonuclease levels are growth phase dependent. Growth phase-dependent regulation of Vsr endonuclease may contribute to 5-methylcytosine mutational hot spots in Escherichia coli. Using rabbit polyclonal antibodies, we have shown that the Dcm cytosine methylase of Escherichia coli is maintained at a constant level during cell growth, while Vsr endonuclease levels are growth phase dependent. Vsr endonuclease, which initiates very short patch repair, has been hypothesized to regulate mutation in stationary-phase cells. The efficiency of the two pathways changes during the bacterial life cycle; MMR is more efficient during exponential growth and VSP repair is more efficient during the stationary phase. Overexpression of Vsr does dramatically increase the stationary-phase reversion of a Lac- frameshift allele, but the absence of Vsr has no effect. Using rabbit polyclonal antibodies, we have shown that the Dcm cytosine methylase of Escherichia coli is maintained at a constant level during cell growth, while Vsr endonuclease levels are growth phase dependent The efficiency of the two pathways changes during the bacterial life cycle; MMR is more efficient during exponential growth and VSP repair is more efficient during the stationary phase Vsr endonuclease, which initiates very short patch repair, has been hypothesized to regulate mutation in stationary-phase cells

no

56c85f675795f9a73e000013

Are there interactomes available for POU5F1 and SOX2?

The interactomes of POU5F1 and SOX2 enhancers in human embryonic stem cells. We assayed long-range chromosomal interactions on putative enhancers of POU5F1 and SOX2 genes in human embryonic stem cells (hESCs) using 4C-Seq technique. We discovered that their frequent interacting regions mainly overlap with early DNA replication domains. The interactomes are associated with active histone marks and enriched with 5-hydroxymethylcytosine sites. In hESCs, genes within the interactomes have elevated expression. Additionally, some genes associated with the POU5F1 enhancer contribute to pluripotency. Binding sites for multiple DNA binding proteins, including ATF3, CTCF, GABPA, JUND, NANOG, RAD21 and YY1, are enriched in both interactomes.

yes

515ae990d24251bc050000ad

Is Rheumatoid Arthritis related to myopathy?

Prevalence of risk factors for statin-induced myopathy in rheumatoid arthritis patients we describe a patient with rheumatoid arthritis and respiratory failure associated with proximal myopathy secondary to HCQ Occurrence of chloroquine-induced myopathy after low-dose treatment of rheumatoid arthritis for seven years a 75 year old female with rheumatoid arthritis treated with daily doses of 250 mg of chloroquine for four years. The patient visited because of several months history of predominantly proximal progressive tetraparesis with areflexia Myopathy and neuropathy in rheumatoid arthritis with rheumatoid arthritis (RA) have clinical or subclinical evidence of peripheral neuropathy or myopathy The study reveals an increased prevalence of neurogenic but not myogenic changes in patients with RA compared with controls

yes

570908e3cf1c325851000012

Is EZH2 associated with prostate cancer?

The role of EZH2 in the regulation of the activity of matrix metalloproteinases in prostate cancer cells EZH2 plays an active role in this process by repressing the expression of TIMP2 and TIMP3 in prostate cancer cells The TIMP genes are derepressed by knockdown of EZH2 expression in human prostate cancer cells but repressed by overexpression of EZH2 in benign human prostate epithelial cells. Overexpression of EZH2 confers an invasive phenotype on benign prostate epithelial cells EZH2 knockdown markedly reduces the proteolytic activity of MMP-9, thereby decreasing the invasive activity of prostate cancer cells he transcriptional repression of the TIMP genes by EZH2 may be a major mechanism to shift the MMPs/TIMPs balance in favor of MMP activity and thus to promote ECM degradation and subsequent invasion of prostate cancer cells. Expression levels of the novel tumor and metastasis suppressor Raf-1 kinase inhibitor protein (RKIP) have been shown to correlate negatively with those of EZH2 in breast and prostate cell lines as well as in clinical cancer tissues Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer Enhancer of zeste homolog 2 (EZH2), which encodes the histone methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed widely in breast and prostate cancers and epigenetically silences tumor suppressor genes However, the roles and underlying mechanisms of EZH2 in prostate cancer stem cells (PCSCs) remain unknown c-Myc, EZH2 and p27 were defined to modulate the behavior of prostate cancer with pro-tumoral or anti-tumoral effects and had ability in predicting prostate cancer progression, but the research of their co-expression value of prognosis is rarely Composite index of c-Myc, EZH2, and p27 can be valued as powerful prognosis parameter for intermediate-risk prostate cancer patients after the surgery, and postoperative adjuvant therapy can be adopted accordingly. EZH2, an epigenetic driver of prostate cancer. The histone methyltransferase EZH2 has been in the limelight of the field of cancer epigenetics for a decade now since it was first discovered to exhibit an elevated expression in metastatic prostate cancer a comprehensive overview of EZH2 in the context of prostate cancer EZH2 dependent H3K27me3 is involved in epigenetic silencing of ID4 in prostate cancer ChIP data on prostate cancer tissue specimens and cell lines suggested EZH2 occupancy and H3K27Me3 marks on the ID4 promoter Collectively, our data indicate a PRC2 dependent mechanism in ID4 promoter silencing in prostate cancer through recruitment of EZH2 and a corresponding increase in H3K27Me3. Increased EZH2 but decreased ID4 expression in prostate cancer strongly supports this model. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) has recently attracted considerable attention because of its dysregulation in prostate cancer (PCa) and its important function in PCa development. Autoregulatory feedback loop of EZH2/miR-200c/E2F3 as a driving force for prostate cancer development Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. The data show that amplification of the EZH2 gene is rare in early prostate cancer, whereas a fraction of late-stage tumors contains the gene amplification leading to the overexpression of the gene, thus indicating the importance of EZH2 in the progression of prostate cancer. EZH2 expression in prostate cancer correlates with progression to hormone-refractory and metastatic disease, but it is unknown whether EZH2 plays a specific role in the acquisition of an advanced prostate cancer phenotype. Although prior studies in prostate cancer have revealed a number of possible mechanisms of EZH2 upregulation, these changes cannot account for the overexpression EZH2 in many primary prostate cancers, nor in most cases of high grade PIN. As a result, five EZH2 peptides recognized by IgG (EZH2 120-128, EZH2 165-174, EZH2 569-577, EZH2 665-674, and EZH2 699-708) were frequently detected in the plasma of prostate cancer patients. Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression. These results link two major pathways in prostate cancer by providing two additional and complementary Myc-regulated mechanisms by which EZH2 upregulation occurs and is enforced during prostatic carcinogenesis. EZH2 promotes prostate cancer cell proliferation and invasiveness. EZH2 promotes proliferation and invasiveness of prostate cancer cells. The Polycomb Group protein EZH2 is implicated in prostate cancer progression. The polycomb group protein EZH2 is involved in progression of prostate cancer. Mutation screen and association study of EZH2 as a susceptibility gene for aggressive prostate cancer. Expression changes in EZH2, but not in BMI-1, SIRT1, DNMT1 or DNMT3B are associated with DNA methylation changes in prostate cancer. The gene for polycomb group protein enhancer of zeste homolog 2 (EZH2) is amplified in late-stage prostate cancer. Enhancer of zeste homolog 2 (EZH2), a kind of transcriptional repressor, is reportedly over-expressed in metastatic prostate cancer. IgGs reactive to three EZH2 peptides (EZH2-243 to -252, EZH2-291 to -299, and EZH2-735 to -;742) were detected in the plasma of almost half of prostate cancer patients. Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. Overexpression of EZH2 has been associated with the invasion and progression of malignant cancers, especially with the progression of prostate cancer. Antigens overexpressed in metastatic prostate cancer are appropriate targets in anti-cancer immunotherapy, and one candidate is the polycomb group protein enhancer of zeste homolog 2 (EZH2). Cytoplasmic EZH2 is expressed at low levels in benign prostate epithelial cells and over-expressed in prostate cancer cells. Cytoplasmic EZH2 expression levels correlate with nuclear EZH2 expression in prostate cancer samples. DNMT1 or DNMT3B are associated with DNA methylation changes in prostate cancer. EZH2:ECAD status was statistically significantly associated with prostate cancer recurrence in a training set of 103 patients (relative risk [RR] = 2.52, a positive EZH2:ECAD status) was the biomarker combination that was most strongly associated with the recurrence of prostate cancer. PcG proteins EZH2, BMI1, and RING1 are associated with adverse pathologic features and clinical PSA recurrence of prostate cancer. Immunohistochemistry results were evaluated in conjunction with clinical parameters associated with prostate cancer progression, Elevation of the chromatin repression factor enhancer of zeste homolog (EZH2) is associated with progression and poor prognosis in several human cancers including prostate cancer. Various proteins (α2-integrin, α6-integrin, CD117, CD133, EZH2, OCT3/4) are associated with a prostate cancer stem cell phenotype in cell lines and xenografts. Increased expression of EZH2 has been associated previously with invasive growth and aggressive clinical behavior in prostate and breast cancer, EZH2:ECAD status was statistically significantly associated with prostate cancer recurrence after radical prostatectomy and may be useful in defining a cohort of high-risk patients. Immunohistochemistry results were evaluated in conjunction with clinical parameters associated with prostate cancer progression, including tumor stage, Gleason score, and prostate-specific antigen (PSA) level. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. Moderate or strong expression of EZH2 coupled with at most moderate expression of ECAD (i.e., a positive EZH2:ECAD status) was the biomarker combination that was most strongly associated with the recurrence of prostate cancer. Cytoplasmic EZH2 expression levels correlate with nuclear EZH2 expression in prostate cancer samples.

yes

5319a7b2b166e2b806000028

Is there any cross-talk between the Wnt and the Akt pathways?

Our data demonstrate that engaging Wnt signaling at the receptor level by this method leads to necessary crosstalk between multiple signaling pathways including activation of Akt, mTOR, Wnt/β-catenin, PKA/CREB, and inhibition of RhoA/ROCK that substantially increase human β-cell proliferation while maintaining the β-cell phenotype. The cross-talk role of Wnt/β-catenin and PI3K/Akt signaling pathway, with GSK-3β as the key enzyme bridging these pathways, may contribute to the inhibition of cholangiocarcinoma cells by hUC-MSCs. We find that Wnt stimulation leads to phosphorylation of insulin signaling key mediators, including Akt, GSK3β, and ERK1/2, although with a lower fold stimulation and slower time course than observed for insulin. Wnt induces phosphorylation of Akt, ERK1/2, and GSK3β, and this is dependent on insulin/IGF-1 receptors. Pharmacologic inhibition of PI3K resulted in the downregulation of several members of the β-catenin pathway, including Fra-1, c-Myc, and cyclin D1. Similar results were observed in vivo, as intratumoral injection of LY294002 downregulated the expression of the components of the β-catenin pathway and delayed tumor growth in nude mice harboring subcutaneous LN229 xenografts. These results suggest that the PI3K/AKT signaling pathway regulates glioma cell proliferation, in part via repression of the Wnt/β-catenin pathway. Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth Small-molecule inhibitors targeting the PI3K/Akt signaling pathway affected beta-catenin signaling by activation [corrected] of GSK-3beta, [corrected] resulting in cytoplasmic retention of beta-catenin and reduced expression of its target genes cyclin D1 and c-Myc. These findings demonstrate the importance of cross-talk between the PI3K/Akt and beta-catenin pathways in medulloblastoma and rationalize the PI3K/Akt signaling pathway as a therapeutic target in treatment of this disease. Western blot analyses revealed that the recombinant Wnt ligand Wnt-3A increased phosphorylation of AKT and the downstream kinase glycogen synthase kinase (GSK)-3beta as well as accumulation of activated, nuclear beta-catenin. Chemical inhibition of PI3K abolished Wnt-dependent phosphorylation of AKT and GSK-3beta and trophoblast motility but did not affect appearance of activated beta-catenin or Wnt/TCF reporter activity. The data suggest that Wnt-3A may activate canonical Wnt signaling and PI3K/AKT through distinct receptors. Mutational activation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs in a wide variety of tumors, whereas activating Wnt pathway mutants are predominantly found in colon cancer. Because GSK3 is a key component of both pathways, it is widely assumed that active PI3K signaling feeds positively into the Wnt pathway by protein kinase B (PKB)-mediatefd inhibition of GSK3. n addition, PKB has been proposed to modulate the canonical Wnt signaling through direct stabilization and nuclear localization of beta-catenin. Here, we show that compartmentalization by Axin of GSK3 prohibits cross-talk between the PI3K and Wnt pathways and that Wnt-mediated transcriptional activity is not modulated by activation of the PI3K/PKB pathway. Our recent study revealed a second mechanism for Cby-mediated beta-catenin inhibition in which Cby cooperates with 14-3-3 adaptor proteins to facilitate nuclear export of beta-catenin, following phosphorylation of Cby by Akt kinase. Therefore, our findings unravel a novel molecular mechanism regulating the dynamic nucleo-cytoplasmic trafficking of beta-catenin and provide new insights into the cross-talk between the Wnt and Akt signaling pathways. Here, we review recent literature concerning Cby function and discuss our current understanding of the relationship between Wnt and Akt signaling. As inappropriate activation of WNT/CTNNB1 signaling causes late-onset GCT development and cross talk between the PI3K/AKT and WNT/CTNNB1 pathways has been reported, we tested whether these pathways could synergize in GCT. This explains why prostate tumors subjected to androgen ablation experience an increase in Akt phosphorylation, and suggest that the tumor compensates for the loss of one pathway with another. Different modes of interaction between the two pathways, including direct interaction, or regulation via downstream intermediates, such as the wnt/GSK-3beta/beta-catenin pathway, NF-kappaB, and the FOXO family of transcription factors, will be discussed. FGF signals are transduced through FGF receptor to the FRS2-GRB2-GAB1-PI3K-AKT signaling cascade to downregulate GSK3beta activity depending on Ser 9 phosphorylation. Because GSK3beta-dependent phosphorylation of beta-catenin and SNAIL leads to FBXW1 (betaTRCP)-mediated ubiquitination and degradation, GSK3beta downregulation results in the stabilization and the nuclear accumulation of beta-catenin and SNAIL. Bridging the BMP and Wnt pathways by PI3 kinase/Akt and 14-3-3zeta Concurrently, PTEN, an inhibitor of PI3K/Akt pathway, is also primarily inactivated in the ISCs, leading to activation of Akt. Thus, Akt may contribute to activation of beta-catenin in ISCs in coordination with Wnt signaling. Thus, we propose that BMP signaling plays a role in inhibition of ISC self-renewal through suppression of Wnt/beta-catenin signaling in ISC, and this cross-talk is bridged, at least in part, through the PTEN/Akt pathway and further enforced by 14-3-3zeta. In MC3T3-E1 osteoblast-like cultures, dexamethasone (DEX) activates glycogen synthase kinase-3beta (GSK3beta) and inhibits a differentiation-related cell cycle that occurs at a commitment stage immediately after confluence. Here we show that DEX inhibition of the differentiation-related cell cycle is associated with a decrease in beta-catenin levels and inhibition of LEF/TCF-mediated transcription. These inhibitory activities are no longer observed in the presence of lithium, a GSK3beta inhibitor. DEX decreased the serum-responsive phosphorylation of protein kinase B/Akt-Ser(473) within minutes, and this inhibition was also observed after 12 h. When the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was inhibited by wortmannin, DEX no longer inhibited beta-catenin levels. Furthermore, DEX-mediated inhibition of LEF/TCF transcriptional activity was attenuated in the presence of dominant negative forms of either PI3K or protein kinase B/Akt. These results suggest cross-talk between the PI3K/Akt and Wnt signaling pathways. These results suggest that inhibition of a PI3K/Akt/GSK3beta/beta-catenin/LEF axis and stimulation of HDAC1 cooperate to mediate the inhibitory effect of DEX on Wnt signaling and the osteoblast differentiation-related cell cycle. WISP-1 (Wnt-1-induced secreted protein) was identified as an oncogene regulated by the Wnt-1-beta-catenin pathway. Here it is shown that WISP-1 can activate the antiapoptotic Akt/PKB signaling pathway. Our results show that both TGFβ1 and Wnt3a lead to increased accumulation of β-catenin, phosphorylation of AKT and p44/42 MAPK.

yes

5523e8cc7b523f2123000007

Has the protein GFP been used in transgenesis for live protein imaging?

we review recent advancement in the functional studies of the three different GnRH neuron systems, mainly focusing on the electrophysiological analysis of the GnRH-green fluorescent protein (GFP) transgenic animals. founders were found to be transgenic for GFP. GFP expression was detected in a wide range of murine tissues Transgenic Xenopus laevis for live imaging in cell and developmental biology. The stable transgenesis of genes encoding functional or spatially localized proteins, fused to fluorescent proteins such as green fluorescent protein (GFP) or red fluorescent protein (RFP), is an extremely important research tool in cell and developmental biology. GFP-transgenic animals for in vivo imaging: rats, rabbits, and pigs. We have further extended the techniques of genetic engineering to rats, rabbits, and pigs, and have created corresponding GFP-transgenic animals. The results revealed that the 3.6-GFP transgenic animals provide a unique model for direct analysis of cellular and molecular mechanisms of pulp repair and tertiary dentinogenesis in vivo. Long-term effects of PERV-specific RNA interference in transgenic pigs. green fluorescent protein (GFP) as reporter of the vector system were consistently expressed in transgenic animals. The ability to specify the expression levels of exogenous genes inserted in the genomes of transgenic animals is critical for the success of a wide variety of experimental manipulations. Welfare assessment in transgenic pigs expressing green fluorescent protein (GFP). transgenic animals expressing GFP with wildtype animals along various stages of post natal development Production of transgenic chickens expressing a tetracycline-inducible GFP gene. transgenic animals can be readily created to express fluorescently tagged proteins or reporters These findings suggest that mhc2dab:GFP and cd45:DsRed transgenic lines will be instrumental in elucidating the immune response in the zebrafish. f 33 mice born, 28 (81%) carried the transgene DNA and 15 (55.5%) were GFP-positive. Lentiviral vectors containing the green fluorescent protein gene have been successfully used to select transgenic embryos before transfer to a surrogate mother Typically transgenes are generated by placing a promoter upstream of a GFP reporter gene or cDNA of interest, and this often produces a representative expression pattern. Survival and immunogenicity of mesenchymal stem cells from the green fluorescent protein transgenic rat in the adult rat brain. This problem has been lessened by the availability of transgenic animals that express "reporter" genes, such as green fluorescent protein (GFP) full-length GFP fusion proteins was examined, in transgenic animals, Two stable transgenic lines express GFP prior to hair-bundle formation we generated two transgenic pigs by somatic cell nuclear transfer (SCNT) that express green fluorescent protein (GFP) driven by cytomegalovirus (CMV). Fluorescent proteins such as the green fluorescent protein (GFP) have widely been used in transgenic animals as reporter genes. Green Fluorescent Protein (GFP) is used extensively as a reporter for transgene expression in Drosophila and other organisms.

yes

52b2f0d84003448f55000009

Is the Snord116 cluster associated with the Prader-Willi syndrome?

All three deletions included SNORD116, but only two encompassed parts of SNURF-SNRPN, implicating SNORD116 as the major contributor to the Prader-Willi phenotype. Our case adds further information about genotype-phenotype correlation and supports the hypothesis that SNORD116 plays a major role in the pathogenesis of Prader-Willi syndrome These results demonstrate that the AS candidate drug topotecan acts predominantly through stabilizing R loops and chromatin decondensation at the paternally expressed PWS Snord116 locus. Our study holds promise for targeted therapies to the Snord116 locus for both AS and PWS. Prader-Willi syndrome (PWS) is caused by the loss of RNA expression from an imprinted region on chromosome 15 that includes SNRPN, SNORD115, and SNORD116. Recently published data strongly suggest a role for the paternally expressed small nucleolar RNA (snoRNA) cluster, SNORD116, in PWS etiology. Whereas loss of function of the SNORD116 genes appears to be responsible for the major features of PWS, the role of the other genes is less clear. Recent data suggest that snoRNA Snord116 is important for the pathogenesis of Prader-Willi syndrome (PWS) characterized by hyperphagia and obesity. The current study was conducted to assess a potential cellular link between Snord116 and phenotypes of PWS. The imprinted Snurf-Snrpn chromosomal domain contains two large arrays of tandemly repeated, paternally expressed box C/D small-nucleolar RNA (snoRNA) genes: the SNORD115 (H/MBII-52) and SNORD116 (H/MBII-85) gene clusters believed to play key roles in the fine-tuning of serotonin receptor (5-HT2C) pre-mRNA processing and in the etiology of the Prader-Willi Syndrome (PWS), respectively There are multiple imprinted genes in this region, the loss of which contribute to the complete phenotype of Prader-Willi syndrome. However, absence of a small nucleolar organizing RNA gene, SNORD116, seems to reproduce many of the clinical features. Both kits should be made available for accurate characterization of PWS/AS deletion subtypes as well as evaluating for IC and SNORD116 microdeletions. There are multiple imprinted genes in this region, the loss of which contribute to the complete phenotype of Prader-Willi syndrome. However, absence of a small nucleolar organizing RNA gene, SNORD116, seems to reproduce many of the clinical features. Although the SNORD116 gene cluster has become a prime candidate for PWS, it cannot be excluded that other paternally expressed genes in the chromosomal region 15q11q13 contribute to the full phenotype. In addition, recently published data provide strong evidence in support of a role for the snoRNA SNORD116 cluster (HBII-85) in PWS etiology. Identification and characterization of this case provide unequivocal evidence for a critical role for the SNORD116 snoRNA molecules in PWS pathogenesis.

yes

53380000d6d3ac6a34000059

Is poly (ADP- ribosylation) involved in transcriptional control?

Histone phosphorylation, ubiquitylation, SUMOylation and poly-ADP-ribosylation, as well as ATP-dependent nucleosome remodeling complexes, play equally pivotal roles in the maintenance of transcriptional fidelity oly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) is an abundant nuclear protein that is involved in DNA repair, cell cycle control, programmed cell death and transcriptional regulation. Many lines of evidence suggest that poly(ADP-ribose) polymerase-1 (Parp-1) is involved in transcriptional regulation of various genes as a coactivator or a corepressor by modulating chromatin structure These results suggest that Parp-1 is required to maintain transcriptional regulation of a wide variety of genes on a genome-wide scale PARP-1 was identified as a part of the mH2A1.1 nucleosome complex and was found to be associated with the Hsp70.1 promoter Upon heat shock, the Hsp70.1 promoter-bound PARP-1 is released to activate transcription through ADP-ribosylation of other Hsp70.1 promoter-bound proteins Cycloheximide-induced cells were treated with two chemical inhibitors of poly(ADP-ribose) polymerase. 3-Aminobenzamide inhibited 75% of PAP gene induction and 4-hydroxyquinazolone, the highly specific inhibitor of the enzyme, blocked almost completely PAP expression, suggesting that ADP-ribosylation was indeed required for the upregulation of PAP gene expression by cycloheximide inhibitors of poly(ADP-ribose) polymerase suppressed UV-induced HIV-1 gene expression but not tat-mediated expression oly(ADP-ribose) polymerase inhibitors suppress UV-induced human immunodeficiency virus type 1 gene expression

yes

51490275d24251bc0500003d

Is nimodipine recommended for prevention of vasospasm in aneurysmal subarachnoid hemorrhage patients?

This article discusses some of these unresolved issues, including the use of medications such as nimodipine, antifibrinolytics, statins, and magnesium; coiling or clipping for aneurysm securement; and the prevention and treatment of potential complications. The results of this study were as follows: nimodipine demonstrated benefit following aneurysmal SAH; other calcium channel blockers, including nicardipine, do not provide unequivocal benefit; triple-H therapy, fasudil, transluminal balloon angioplasty, thrombolytics, endothelin receptor antagonists, magnesium, statins, and miscellaneous therapies such as free radical scavengers and antifibrinolytics require additional study. The present results suggest that fasudil is equally or more effective than nimodipine for the prevention of cerebral vasospasm and subsequent ischemic injury in patients undergoing surgery for SAH. Three studies (2 meta-analyses and 1 randomized controlled trial) demonstrated that nimodipine use confers benefits (reduced morbidity and mortality) for patients with aneurysmatic subarachnoid hemorrhage. Nimodipine is the only preventative treatment that can be recommended. Nimodipine (Nimotop), HMG Co-A reductase inhibitor (statins) and enoxaparin (Lovenox) were the only drugs with level-1 evidence available for the treatment of vasospasm from aneurysmal subarachnoid hemorrhage as defined by the US Preventative Services Task Force. The calcium antagonist nimodipine has been shown to reduce the incidence of ischemic complications following aneurysmal subarachnoid hemorrhage (SAH). There was no significant difference in the incidence of DINDs (28 vs 30% in the peroral and intravenous groups, respectively) or middle cerebral artery blood flow velocities (> 120 cm/second, 50 vs 45%, respectively). Clinical outcome according to the Glasgow Outcome Scale was the same in both groups, and there was no difference in the number of patients with new infarctions on MR imaging. The results suggest that there is no clinically relevant difference in efficacy between peroral and intravenous administration of nimodipine in preventing DINDs or cerebral vasospasm following SAH. the risk of delayed cerebral ischemia is reduced with nimodipine and avoiding hypovolemia A recommendations (standard) for the prophylaxis and treatment of cerebral vasospasm with oral Nimodipine in good grade patients. Of the 75 patients initially considered for active treatment, 83% underwent surgery within 48 hours of rupture, all received nimodipine, 16% received tissue plasminogen activator to lyse subarachnoid or intraventricular clots, 40% underwent hypertensive treatment, and 7% underwent transluminal balloon angioplasty for vasospasm. All patients with aneurysmal SAH should be treated with the calcium antagonist nimodipine, and in certain circumstances patients should receive anticonvulsants. The following review gives an account of pathophysiological mechanisms; the importance of treatment with calcium antagonists, hypervolaemic haemodilution, and induced arterial hypertension is discussed in light of the current literature. Seven placebo-controlled clinical studies have shown that nimodipine improves the outcome of patients with severe neurological damage due to cerebral vasospasm. In a series of 100 individuals with a ruptured supratentorial aneurysm, who were subjected to aneurysm operation in the acute stage and who subsequently received intravenous treatment with the calcium channel blocker nimodipine, the occurrence of DID with FND was reduced to 5%. There are many possible successful treatment options for preventing vasospasm, delayed ischemic neurologic deficits, and poor neurologic outcome following aneurysmal subarachnoid hemorrhage; however, further multicenter RCTs need to be performed to determine if there is a significant benefit from their use. Nimodipine is the only treatment that provided a significant benefit across multiple studies. Absence of symptomatic vasospasm, occurrence of low density areas associated with vasospasm on CT, and occurrence of adverse events were similar between the two groups. The clinical outcomes were more favorable in the fasudil group than in the nimodipine group (p = 0.040). The proportion of patients with good clinical outcome was 74.5% (41/55) in the fasudil group and 61.7% (37/60) in the nimodipine group. Cerebral vasospasm is the classic cause of delayed neurological deterioration leading to cerebral ischemia and infarction, and thus, poor outcome and occasionally death, after aneurysmal subarachnoid hemorrhage (SAH). Advances in diagnosis and treatment, principally nimodipine, intensive care management, hemodynamic manipulations, and endovascular neuroradiology procedures, have improved the prospects for these patients, but outcomes remain disappointing. Cerebral vasospasm is the classic cause of delayed neurological deterioration after aneurysmal subarachnoid hemorrhage, leading to cerebral ischemia and infarction, and thus to poor outcome and occasionally death. Advances in diagnosis and treatment-principally the use of nimodipine, intensive care management, hemodynamic manipulations and endovascular neuroradiology procedures-have improved the prospects for these patients, but outcomes remain disappointing. Cerebral vasospasm and delayed cerebral ischemia remain common complications of aneurysmal subarachnoid hemorrhage (SAH), and yet therapies for cerebral vasospasm are limited. Despite a large number of clinical trials, only calcium antagonists have strong evidence supporting their effectiveness. The only proven therapy for vasospasm is nimodipine. nimodipine is indicated after SAH and tirilazad is not effective. Fasudil hydrochloride and nimodipine both showed inhibitory effects on cerebral vasospasm. The incidence of symptomatic vasospasm was five of 33 patients in the fasudil group and nine of 32 patients in the nimodipine group. Good recovery evaluated by the Glasgow Outcome Scale was achieved by 23 of 33 patients in the fasudil group and 19 of 34 patients in the nimodipine group. Both drugs significantly improved consciousness levels and neurological deficits such as aphasia. However, fasudil hydrochloride improved motor disturbance more than nimodipine.

yes

56c1f002ef6e394741000038

Is lenvatinib effective for thyroid cancer?

New insights in the treatment of radioiodine refractory differentiated thyroid carcinomas: to lenvatinib and beyond. However, even more impressive responses and progression-free survival benefits were seen in the phase III SELECT trial with lenvatinib, giving even higher hopes for the future management of what was considered just a decade ago an orphan disease. Sorafenib and lenvatinib, small-molecule multikinase inhibitors, were approved for the treatment of progressive, symptomatic, radioactive iodine refractory, advanced differentiated thyroid cancer in 2013 and 2015, respectively. A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment. CONCLUSIONS: In patients with and without prior exposure to VEGF therapy, the encouraging response rates, median time to response, and PFS for lenvatinib have prompted further investigation in a phase 3 trial. Since 2011, four multikinase inhibitors (MKIs) have been approved by the US Food and Drug Administration for thyroid cancer - cabozantinib and vandetanib for medullary thyroid cancer and sorafenib and lenvatinib for differentiated thyroid cancer. Moreover, four of those investigational drugs, vandetanib, cabozantinib, sorafenib and lenvatinib, have reached a phase III clinical trial with favorable results in progression-free survival and overall survival in medullary thyroid carcinoma and differentiated thyroid carcinoma. Since 2011, four multikinase inhibitors (MKIs) have been approved by the US Food and Drug Administration for thyroid cancer - cabozantinib and vandetanib for medullary thyroid cancer and sorafenib and lenvatinib for differentiated thyroid cancer BACKGROUND: Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor �, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131).METHODS: In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine-refractory, differentiated thyroid cancer (RR-DTC).METHODS: Fifty-eight patients with RR-DTC who had disease progression during the previous 12 months received lenvatinib 24 mg once daily in 28-day cycles until disease progression, unmanageable toxicity, withdrawal, or death.

yes

56c0968def6e394741000026

Was tamoxifen tested for treatment of glioma patients?

Tamoxifen might have a role in the initial treatment of high-grade gliomas and should be studied in future Phase II trials building on the newly established platform of concurrent chemoradiotherapy. The addition of high-dose tamoxifen to standard radiotherapy does not improve the survival of patients with diffuse intrinsic pontine glioma. In this study, in which tamoxifen was used in conjunction with radiotherapy, progression free survival was shown to be less good when compared with historical data HR = 3.1 (CI: 1.7-5.7). The addition of high-dose tamoxifen, although well tolerated, confers no clinical benefit to patients treated with diffuse intrinsic pontine glioma treated with standard radiotherapy. CONCLUSIONS: Carboplatin and high dose tamoxifen has similar response rates to other regimens for recurrent malignant gliomas and are probably equivalent to those found using tamoxifen as monotherapy. CONCLUSIONS: Pegylated liposomal doxorubicin administered alone or in combination with tamoxifen is safe and moderately effective in patients with recurrent high-grade glioma. Protein kinase C (PKC) inhibitors such as high-dose tamoxifen and hypericin also have been used in the treatment of malignant gliomas. Considering these facts, polyethylene-glycol-liposomal doxorubicin with and without tamoxifen was evaluated within two sequential Phase II trials performed at our institution. In a parallel phase-II-study investigating post-operative treatment with tamoxifen (TAM), carboplatin and radiation therapy for glioblastomas, 16 of 49 patients (33%) showed multifocal recurrence, which developed after a mean of 46 weeks, raising the question of an association with therapy. Radiation therapy and high-dose tamoxifen in the treatment of patients with diffuse brainstem gliomas: results of a Brazilian cooperative study. Brainstem Glioma Cooperative Group. PURPOSE: The efficacy of radiation therapy (RT) combined with tamoxifen (TX) was tested in patients diagnosed with diffuse brainstem gliomas in a multicenter trial. CONCLUSION: This treatment combination produced no significant change in the overall poor prognosis of these patients. Most tumors responded initially to treatment but recurred as the study progressed. A minority of patients seemed to benefit from the extended use of TX. Tamoxifen, a protein kinase C inhibitor when administered in high dosages, is currently being used as an adjuvant in the treatment of patients with malignant gliomas. We present a patient with a recurrent malignant glioma who was continued on high dose tamoxifen despite radiologic documented doubling of the tumor size and who eventually showed a delayed response to this agent nine months after initiation of treatment. The combination of oral tamoxifen (120 to 240 mg/m2/day) and subcutaneous interferon-alpha [6 x 10(6) U three times per week] was associated with significant neurotoxicity in this group of recurrent glioma patients, resulting in early study closure. A phase I study of high-dose tamoxifen for the treatment of refractory malignant gliomas of childhood. Phase I clinical trial assessing temozolomide and tamoxifen with concomitant radiotherapy for treatment of high-grade glioma. Prolonged treatment with biologic agents for malignant glioma: a case study with high dose tamoxifen. Tamoxifen as a potential treatment of glioma. We tested the efficacy and toxicity of the combination of high-dose tamoxifen and interferon alpha in adults with recurrent glioma in a phase II trial. PURPOSE: The efficacy of radiation therapy (RT) combined with tamoxifen (TX) was tested in patients diagnosed with diffuse brainstem gliomas in a multicenter trial. We tested the efficacy and toxicity of the combination of high-dose tamoxifen and interferon alpha in adults with recurrent glioma in a phase II trial. The efficacy of radiation therapy (RT) combined with tamoxifen (TX) was tested in patients diagnosed with diffuse brainstem gliomas in a multicenter trial. The efficacy of radiation therapy (RT) combined with tamoxifen (TX) was tested in patients diagnosed with diffuse brainstem gliomas in a multicenter trial. We tested the efficacy and toxicity of the combination of high-dose tamoxifen and interferon alpha in adults with recurrent glioma in a phase II trial. Eligible patients had radiographically measurable recurrent gliomas of any grade after initial radiation therapy. Thyroid function was suppressed to reduce IGF-1 levels in glioma patients and high-dose tamoxifen administered. Propylthiouracil was used to induce chemical hypothyroidism in 22 patients with recurrent glioma. Activity against recurrent gliomas has been reported for both tamoxifen and interferon alpha, agents that have more acceptable toxicity profiles and that can be administered in an outpatient setting. We tested the efficacy and toxicity of the combination of high-dose tamoxifen and interferon alpha in adults with recurrent glioma in a phase II trial. Thyroid function was suppressed to reduce IGF-1 levels in glioma patients and high-dose tamoxifen administered. Radiation therapy and high-dose tamoxifen in the treatment of patients with diffuse brainstem gliomas: results of a Brazilian cooperative study. We tested the efficacy and toxicity of the combination of high-dose tamoxifen and interferon alpha in adults with recurrent glioma in a phase II trial. The subsequent in vitro testing of the tumor that was removed after the recurrence of tumor (22 months after the initiation of tamoxifen) revealed loss of sensitivity to tamoxifen. The combination of oral tamoxifen (120 to 240 mg/m2/day) and subcutaneous interferon-alpha [6 x 10(6) U three times per week] was associated with significant neurotoxicity in this group of recurrent glioma patients, resulting in early study closure.

yes

532f0ca1d6d3ac6a3400002f

Are there any animal models for Niemann-Pick C1 disease?

Several animal models were used to analyze the impaired pathways. We investigated components of the surfactant system in both NPC1 mutant mice and felines and in NPC2 mutant mice near the end of their expected life span. Thus far, studies of NPC mice have been performed mainly to study the brain and neurodegeneration, because degeneration in the brain was known as the primary cause of death in NPC mice. the NPC1(-/-) mouse is available serving as an appropriate animal model of the human disease, o examine the onset and progression of neuropathological insults in NPC we have systematically examined the CNS of a mouse model of NPC1 (Npc1(-/-) mice) at different stages of the disease course. We have identified a point mutation in Npc1 that creates a novel mouse model (Npc1(nmf164)) of Niemann-Pick type C1 (NPC) disease Niemann-Pick type C1-deficient mice, which accumulate intracellular free cholesterol. hUCB-MSCs were transplanted into the hippocampus of NPC mice in the early asymptomatic stage. Niemann Pick type C1 mice Three mouse models of glycosphingolipid storage diseases, namely Niemann-Pick type C1, Npc1(-/-) mice, a well-established model of NPC pathology murine model of this disease, the npc1 mouse, NPC1 (Niemann-Pick type C1) knock-out mice We have made transgenic mice which express the Npc1 protein exclusively in fibrillary astrocytes, using the glial fibrillary acidic protein (GFAP) promoter. homozygous affected (NPC1(-/-)) mice heterozygous (NPC1(+/-)) mice npc1(-/-) mice, npc1(-/-) mouse model A murine model of Niemann-Pick type C disease (NPC), the NPC1-deficient [NPC1 (-/-)] mouse,

yes

51542eacd24251bc05000084

Does HER2 under-expression lead to favorable response to trastuzumab?

over-expression of HER2 is reported in approximately 20% of gastric tumours, challenging the use of targeted therapies. In patients with advanced gastric or gastro-oesophageal junction cancer, addition of trastuzumab to chemotherapy significantly improved overall survival compared with chemotherapy alone. Addition of trastuzumab to chemotherapy did not increase the incidence of adverse events. treatment of HER2-overexpressing breast cancer: trastuzumab, Trastuzumab has demonstrated clinical activity in several types of HER2-overexpressing epithelial tumors, such as breast and metastatic gastric or gastroesophageal junction cancer. An example is the established benefit of trastuzumab as adjuvant therapy for breast cancer; a clear definition of HER2-positivity and the assay reproducibility have, however, remained unanswered. Trastuzumab is a monoclonal antibody targeted to the Her2 receptor and approved for treatment of Her2-positive breast cancer. Human epidermal growth factor receptor 2 (HER2/neu) is an important target for the treatment of the breast cancers in which it is overexpressed. However, no approved anti-HER2/neu therapy is available for the majority of breast cancer patients, who express HER2/neu at low levels (with scores of 1+ or 2+/fluorescence in situ hybridization-negative). The humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin) is useful in the treatment of ErbB2-overexpressing breast cancers, HercepTestTM (DAKO A/S, Glostrup, Denmark) is an immunohistochemical assay that detects HER2/neu gene products, and evaluates the overexpression status of the HER2/neu protein in determining eligibility for the Trastuzumab (HerceptinR, Genentech, San Francisco, CA, USA) therapy.

no

52ffb5d12059c6d71c00007c

Is the PTPN22 gene a biomarker for rheumatoid arthritis?

TPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL he HLA locus, particularly HLA-DRB1, is its strongest genetic risk determinant across ethnicities. Several other genes, including PTPN22 and PADI4, show modest association with RA. Several alleles in the epitope-recognition part of the HLA molecule that show the highest association with RA susceptibility, also share a common string of amminoacid residues (the so-called shared-epitope hypothesis). Other variants in potentially pathogenic genes located in non-MHC regions have been implicated by recently performed genome wide analysis studies. These genes include PTPN22, TRAF1-C5, PADI4, STAT4. n particular, genome-wide association studies (GWAS) have provided supportive evidence that RA is a disease with a strong genetic background. Interestingly, a series of candidate genes have been identified outside of the classical major histocompatibility (MHC) locus, which had long been regarded as the major contributor to the pathogenesis of this disease. Among these genes, PTPN22 plays an outstanding role. ssociation of the PTPN22 gene (-1123G > C) polymorphism with rheumatoid arthritis in Chinese patients Eight markers (ie, rs1160542 (AFF3), rs1678542 (KIF5A), rs2476601 (PTPN22), rs3087243 (CTLA4), rs4810485 (CD40), rs5029937 (6q23), rs10760130 (TRAF1/C5) and rs7574865 (STAT4)) were significantly associated with RA by meta-analysis Recent genome-wide association studies (GWAS) on RA identified known and novel susceptibility genes like HLA-DRB1, PTPN22, STAT4, TRAF1/C5, OLIG3/TNFAIP3, CD40, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, IL2RB, and KIF5A-PIP4K2C. This study investigated five confirmed rheumatoid arthritis (RA) susceptibility genes/loci (HLA-DRB1, PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5) for association with susceptibility and severity in an inception cohort After initial completion of the Human Genome Project on the 16th February 2001, significant progress has been made in identifying other than HLA genome regions linked to the increased RA susceptibility. As an effect several new genes have been recognized as an HLA-independent genetic risk factors of RA. PTPN22 gene polymorphism, C5/TRAF1 genes region polymorphism and TNFAIP3-OLIG3 genes region polymorphism(s) are among newly identified and already confirmed genetic risk factors As well as the major susceptibility gene HLA-DRB1, recent genome-wide and candidate-gene studies reported additional evidence for association of single nucleotide polymorphism (SNP) markers in the PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5 loci with RA. Recent advances have led to novel identification of genetic polymorphisms that are associated with susceptibility to rheumatoid arthritis (RA). Currently, 5 loci (HLA, PTPN22, TRAF1/C5, TNFAIP3, and STAT4) have been consistently reported, whereas others have been observed less systematically However, inconsistent results of the contributions of non-HLA susceptibility genes have been described, with the exception of a few genes repeatedly associated with RA-susceptibility, such as PTPN22 gene in populations of European ancestry and PADI4 gene in populations of Asian ancestry, revealing the presence of genetic heterogeneity in RA. In conclusion, we have confirmed that PTPN22 620W allele is associated with Tunisian RA but does not constitute a factor influencing clinical manifestations. After adjusting for smoking and reproductive factors, PTPN22 was associated with RA risk among Caucasian women in these cohorts We found strong evidence of an association of PTPN22 with the development of anti-citrulline antibody-positive RA (odds ratio [OR] 1.49; P=.00002), using previously untested EIRA samples. Although HLA-DRB1 is the main RA gene, it accounts for only part of the familial risk for RA. HLA-DRB1 alleles are neither necessary nor sufficient to cause the development of RA in a given individual. Several genome scans conducted in populations from France, Japan, North America and UK have confirmed the role of the HLA region and suggested several other susceptibility loci. Association studies support a role for several genes, including TNFR2, PADI4, SLC22A4, RUNX1, and PTPN22. the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis PTPN22, PADI-4, and CTLA-4 have been associated with risk for rheumatoid arthritis (RA) progression from undifferentiated arthritis to rheumatoid arthritis: the effect of the PTPN22 1858T-allele In this Dutch cohort of UA-patients, the PTPN22 1858T allele does not markedly improve individual decision-making to predict RA-development challenges in identifying genetic polymorphisms that influence the susceptibility to rheumatoid arthritis are the same as those faced in most complex diseases Recently a number of convincing candidate genes have begun to emerge and an update has been provided for three of these: PTPN22

yes

5314d0e4dae131f84700000e

Can administration of the thyrotropin releasing hormone reduce fatigue in cancer patients?

TRH administration was associated with significant improvement (p < 0.05) in fatigue levels as measured by the Visual Analog Scale-Energy (VAS-E), was associated with significant (p < 0.05) improvement in sleep disturbances and improved quality of life. This decrease in CRP level with TRH administration was associated with improvement in energy levels as measured by the VAS-E. In the present pilot, randomized, placebo-controlled, crossover study, we investigated the efficacy and safety of TRH as a treatment for CF. TRH administration was associated with significant improvement in fatigue level as measured by the VAS-E, the fatigue and vigor subscales of the POMS, and the fatigue subscale of FACIT-F (p < 0.05). TRH administration was efficacious, safe, and tolerable in the treatment of CF with a positive impact on quality of life. These results provide a crucial impetus for pursuing TRH therapeutics to treat CF. Thyrotropin-releasing hormone can relieve cancer-related fatigue: hypothesis and preliminary observations. Global assessment using both subjective and objective parameters showed that TRH exerted clear anti-fatigue effects in four of the six TRH treatments. These initial findings support the proposal that TRH can ameliorate cancer-related fatigue.

yes

56b0eb3b0a360a5e45000019

Is curcumin a phytochemical?

we analyzed turmeric from different agroclimatic regions for influence of various factors on its growth and yield of important phytochemicals The phytochemical, curcumin, has been reported to play many beneficial roles. Curcumin (CUR), the major component in Curcuma longa, has been shown as a potent chemopreventive phytochemical that modulates various signaling pathways. Curcumin (CUR) is a phytochemical that inhibits the xenobiotic ABC efflux transporters implicated in cancer multidrug resistance (MDR), such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins 1 and 5 (MRP1 and MRP5). In this study, we tested the efficacy of combining temozolomide with curcumin, a phytochemical known to inhibit glioblastoma growth, and investigated the mechanisms involved. In the present study, we investigate whether curcumin (cur), a phytochemical compound with potent anti-inflammatory effect the Phytochemicals Curcumin in combination with the phytochemicals curcumin and quercetin Curcumin is a phytochemical derived from rhizome of turmeric Curcuma longa, present in the curry spice. Curcumin, a naturally occurring polyphenolic phytochemical isolated from the medicinal plant Curcuma longa, has anti-inflammatory activities In the present study curcumin (CUR), a known anticancer phytochemical, Curcumin, a natural phytochemical, exhibits potent anticancer activities. hat curcumin, a phytochemical compound with potent anti-inflammatory properties curcumin, a phytochemical

yes

54ede5c394afd61504000006

Is Fanconi anemia presented as a genetically and clinically heterogeneous disease entity?

Fanconi anaemia (FA) is a rare, autosomal recessive, genetically complex, DNA repair deficiency syndrome in man. Patients with FA exhibit a heterogeneous spectrum of clinical features. The most significant and consistent phenotypic characteristics are stem cell loss, causing progressive bone marrow failure and sterility, diverse developmental abnormalities and a profound predisposition to neoplasia. To date, 15 genes have been identified, biallelic disruption of any one of which results in this clinically defined syndrome Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder Significant phenotypic differences were found. FA-G patients had more severe cytopenia and a higher incidence of leukemia. Somatic abnormalities were less prevalent in FA-C, but more common in the rare groups FA-D, FA-E, and FA-F. In FA-A, patients homozygous for null mutations had an earlier onset of anemia and a higher incidence of leukemia than those with mutations producing an altered protein Fanconi anemia (FA), an autosomal recessive disorder characterized by a progressive pancytopenia associated with congenital anomalies and high predisposition to malignancies, is a genetically and clinically heterogeneous disease. At least eight complementation groups (FA-A to FA-H) have been identified Fanconi anemia (FA), an autosomal recessive disorder characterized by a progressive pancytopenia associated with congenital anomalies and high predisposition to malignancies, is a genetically and clinically heterogeneous disease. At least eight complementation groups (FA-A to FA-H) have been identified with their relative prevalence varying among the ethnical backgrounds Fanconi anemia is a rare autosomal recessive disorder characterized clinically by congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancy. FA cells are sensitive to DNA cross-linking agents. Complementation analysis of FA cells using somatic cell fusion has facilitated the identification of eight complementation groups, suggesting that FA is a genetically heterogeneous disorder. Six genes (FANCA, FANCC, FANCD2, FANCE, FANGF, FANCG) have been cloned so far Fanconi anemia (FA), an autosomal recessive disorder characterized by a progressive pancytopenia associated with congenital anomalies and high predisposition to malignancies, is a genetically and clinically heterogeneous disease. Fanconi anemia (FA), an autosomal recessive disorder characterized by a progressive pancytopenia associated with congenital anomalies and high predisposition to malignancies, is a genetically and clinically heterogeneous disease. Among patients with bone marrow failure (BMF) syndrome, some are happened to have underlying Fanconi anemia (FA), a genetically heterogeneous disease, which is characterized by progressive pancytopenia and cancer susceptibility. Fanconi anemia (FA) is a genetically and phenotypically heterogeneous inherited disease. Fanconi anemia is a genetically heterogeneous recessive disease characterized mainly by bone marrow failure and cancer predisposition. INTRODUCTION: Fanconi anemia (FA) is a genetically and phenotypically heterogeneous inherited disease. Fanconi anemia (FA) is a genetically heterogeneous, autosomal recessive disorder characterized by pediatric bone marrow failure and congenital anomalies. Fanconi anemia (FA) is a heterogeneous disease associated with a bone marrow failure, cancer predisposition and hypersensitivity to DNA crosslinking agents. Fanconi anemia is a genetically heterogeneous chromosomal instability syndrome, characterized by multiple congenital anomalies, progressive bone marrow failure, and a predisposition to malignancy. Fanconi anemia (FA) is a heterogeneous disease characterized by spontaneous chromosomal breaks and abnormal DNA repair. Fanconi anemia (FA) is a genetically heterogeneous disease with at least eight genes on the basis of complementation groups (FAA to FAH). Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder. Fanconi anaemia (FA) is a genetically heterogeneous disease with at least eight complementation groups (A-H). FA is a genetically heterogeneous disease with at least seven genes so far identified. Fanconi anemia (FA) is an autosomal recessive rare disease characterized by progressive pancytopenia, congenital malformations and predisposition to acute myeloid leukemia. Fanconi anemia is genetically heterogeneous, with at least eight complementation groups of FA (FAA to FAD2). Fanconi anemia (FA), an autosomal recessive disorder characterized by a progressive pancytopenia associated with congenital anomalies and high predisposition to malignancies, is a genetically and clinically heterogeneous disease Fanconi anemia (FA), an autosomal recessive disorder characterized by a progressive pancytopenia associated with congenital anomalies and high predisposition to malignancies, is a genetically and clinically heterogeneous disease The disease is clinically heterogeneous; eight different complementation groups (FA A-H) and, thus, genetic loci have been discovered The hereditary genetic disorder Fanconi anemia (FA) belongs to the heterogeneous group of diseases associated with defective DNA damage repair The clinical manifestations of FA are heterogeneous, but one common outcome in the majority of patients is the development of life-threatening hematologic disease Fanconi anemia is a genetically heterogeneous chromosomal breakage disorder exhibiting a high degree of clinical variability Fanconi anemia (FA) is a genetically heterogeneous chromosomal instability syndrome associated with multiple congenital abnormalities, aplastic anemia, and cancer Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive syndrome associated with chromosomal instability, hypersensitivity to DNA cross-linking agents, and predisposition to malignancy Fanconi anemia (FA) is a rare autosomal recessive disease characterized by progressive pancytopenia, congenital malformations, and predisposition to acute myeloid leukemia Fanconi anemia (FA) is a heterogeneous disease characterized by spontaneous chromosomal breaks and abnormal DNA repair Fanconi anemia (FA) is a genetically and phenotypically heterogeneous recessive disorder characterized by diverse congenital malformations, progressive pancytopenia and predisposition to both hematologic malignancies and solid tumors Fanconi anemia is a genetically heterogeneous chromosomal instability syndrome, characterized by multiple congenital anomalies, progressive bone marrow failure, and a predisposition to malignancy

yes

56ae71cb0a360a5e45000010

Is there evidence for de novo genesis of enhancers in vertebrates?

De novo genesis of enhancers in vertebrates. Evolutionary innovation relies partially on changes in gene regulation. While a growing body of evidence demonstrates that such innovation is generated by functional changes or translocation of regulatory elements via mobile genetic elements, the de novo generation of enhancers from non-regulatory/non-mobile sequences has, to our knowledge, not previously been demonstrated. Here we show evidence for the de novo genesis of enhancers in vertebrates. For this, we took advantage of the massive gene loss following the last whole genome duplication in teleosts to systematically identify regions that have lost their coding capacity but retain sequence conservation with mammals. We found that these regions show enhancer activity while the orthologous coding regions have no regulatory activity. These results demonstrate that these enhancers have been de novo generated in fish. By revealing that minor changes in non-regulatory sequences are sufficient to generate new enhancers, our study highlights an important playground for creating new regulatory variability and evolutionary innovation. Here we show evidence for the de novo genesis of enhancers in vertebrates. While a growing body of evidence demonstrates that such innovation is generated by functional changes or translocation of regulatory elements via mobile genetic elements, the de novo generation of enhancers from non-regulatory/non-mobile sequences has, to our knowledge, not previously been demonstrated. While a growing body of evidence demonstrates that such innovation is generated by functional changes or translocation of regulatory elements via mobile genetic elements, the de novo generation of enhancers from non-regulatory/non-mobile sequences has, to our knowledge, not previously been demonstrated While a growing body of evidence demonstrates that such innovation is generated by functional changes or translocation of regulatory elements via mobile genetic elements, the de novo generation of enhancers from non-regulatory/non-mobile sequences has, to our knowledge, not previously been demonstrated. Here we show evidence for the de novo genesis of enhancers in vertebrates. For this, we took advantage of the massive gene loss following the last whole genome duplication in teleosts to systematically identify regions that have lost their coding capacity but retain sequence conservation with mammals. Here we show evidence for the de novo genesis of enhancers in vertebrates. While a growing body of evidence demonstrates that such innovation is generated by functional changes or translocation of regulatory elements via mobile genetic elements, the de novo generation of enhancers from non-regulatory/non-mobile sequences has, to our knowledge, not previously been demonstrated. Here we show evidence for the de novo genesis of enhancers in vertebrates.

yes

551c4ffc6b348bb82c000010

Is TNNI3K a cardiac-specific protein?

cardiomyocyte-specific kinase TNNI3K We report that cardiac troponin I-interacting kinase (TNNI3K), a cardiomyocyte-specific kinase, TNNI3K, a cardiac-specific kinase, The cardiac troponin I-interacting kinase (TNNI3K), a novel cardiac specific kinase, is associated with cardiomyocyte hypertrophy Human cardiac troponin I-interacting kinase (TNNI3K) is a novel cardiac-specific functional kinase that can bind to cTnI in a yeast two-hybrid screen. Overexpression of TNNI3K, a cardiac-specific MAPKKK, promotes cardiac dysfunctio Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific kinase whose biological function remains largely unknown Cardiac troponin I-interacting kinase (TNNI3K) is a novel cardiac-specific kinase gene a novel cardiac-specific kinase gene (TNNI3K), TNNI3K is a novel cardiac troponin I-interacting kinase gene and its overexpression may promote cardiac myogenesis, TNNI3K is a new cardiac-specific MAP kinase whose gene is localized to 1p31.1 and that belongs to a tyrosine kinase-like branch in the kinase tree of the human genome. The cardiac ankyrin repeat kinase (CARK) gene, also named TNNI3K for its interaction with cardiac troponin I, is both a unique expression and heart-enriched gene Molecular cloning of cardiac troponin I-interacting kinase (TNNI3K), a novel cardiac-specific protein kinase containing seven N-terminal ankyrin (ANK) repeats followed by a protein kinase domain and a C-terminal Ser-rich domain, has previously been reported. TNNI3K is highly expressed in heart, but is undetectable in other tissues. Immunohistochemical analysis predominantly localized TNNI3K in the nucleus of cardiac myocytes.

yes

51588c1ad24251bc05000094

Is factor XI deficient in Hemophilia C?

Factor XI deficiency is a rare hematologic disorder. Hemophilia C (factor XI deficiency) affects both genders and it is usually asymptomatic, Congenital factor XI deficiency (also known as the Rosenthal syndrome or hemophilia C) rare case of an acute cerebral aneurysm rupture in a patient with a known factor XI deficiency. Aneurysmal subarachnoid hemorrhage (SAH) accounts for a high mortality and morbidity rate. When SAH is associated with an inherited coagulation disorder such as hemophilia C Factor XI deficiency (Hemophilia C) Factor XI deficiency, also called hemophilia C,

yes

551910c5622b194345000007

Are EDNRB mutations involved in the development of Hirschsprung disease?

QTL analysis identifies a modifier locus of aganglionosis in the rat model of Hirschsprung disease carrying Ednrb(sl) mutations As reported previously, when the same null mutation of the Ednrb gene, Ednrb(sl), was introgressed into the F344 strain, almost 60% of F344-Ednrb(sl/sl) pups did not show any symptoms of aganglionosis, appearing healthy and normally fertile. Genetic background strongly modifies the severity of symptoms of Hirschsprung disease, but not hearing loss in rats carrying Ednrb(sl) mutations In this study, we found that the null mutation of the Ednrb gene, thought indispensable for enteric neuron development, is insufficient to result in HSCR disease when bred onto a different genetic background in rats carrying Ednrb(sl) mutations. New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease. The aim of this study was to evaluate the implication of the EDN3 and EDNRB genes in a series of patients with Hirschsprung disease from Spain and determinate their mutational spectrum. A De Novo novel mutation of the EDNRB gene in a Taiwanese boy with Hirschsprung disease Although mutations in eight different genes (EDNRB, EDN3, ECE1, SOX10, RET, GDNF, NTN, SIP1) have been identified in affected individuals, it is now clear that RET and EDNRB are the primary genes implicated in the etiology of HSCR. Mutations in genes of the RET receptor tyrosine kinase and endothelin receptor B (EDNRB) signaling pathways have been shown to be associated in HSCR patients. Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10Dom mouse model of Hirschsprung disease Molecular genetic analyses have revealed that interactions between mutations in the genes encoding the RET receptor tyrosine kinase and the endothelin receptor type B (EDNRB) are central to the genesis of HSCR Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease Thus, genetic interaction between mutations in RET and EDNRB is an underlying mechanism for this complex disorder. EDNRB/EDN3 and Hirschsprung disease type II. Analysis of the RET, GDNF, EDN3, and EDNRB genes in patients with intestinal neuronal dysplasia and Hirschsprung disease wo susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene and the endothelin B receptor (EDNRB) gene. We conclude that Ednrb loss only in neural crest cells is sufficient to produce the Hirschsprungs disease phenotype observed with genomic Ednrb mutations EDNRB mutations were detected in 2 of the 13 short-segment HD The mutations of EDNRB gene and EDN-3 gene are found in the short-segment HD of sporadic Hirschsprung's disease in Chinese population, which suggests that the EDNRB gene and EDN-3 gene play important roles in the pathogenesis of HD Functional characterization of three mutations of the endothelin B receptor gene in patients with Hirschsprung's disease Hirschsprung's disease (HSCR) is one the most common congenital intestinal disease. It leads to aganglionic megacolon in the early childhood. Several susceptibility genes have been identified : RET protooncogene and its ligand, glial cell derived neutrophic factor (GDNF), Sox 10, Endothelin-3 (EDN3) and its receptor B (EDNRB). EDNRB mutations are found in 5% of familial or sporadic HSCR Enteric aganglionosis in Hirschsprung disease has been linked to genes coding for endothelin-3 (EDN3) and the endothelin B receptor (EDNRB) To date, three genes have been identified as susceptibility genes for Hirschsprung's disease (HSCR), the RET proto-oncogene, the endothelin-B receptor gene (EDNRB) and the endothelin-3 gene (EDN3) Our data indicate that RET and EDNRB mutations have a role in the aetiology of some sporadically occurring HSCR Mutations of the endothelin-B receptor and endothelin-3 genes in Hirschsprung's disease The endothelin-B receptor gene (EDNRB) and the endothelin-3 gene (EDN3) have recently been recognized as susceptibility genes for Hirschsprung's disease (HD) These observations confirm that impaired function of the endothelin-B receptor or endothelin-3 is involved in the aetiology of some human HD cases. EDNRB mutations appear to be associated with short-segment HD, in contrast to RET mutations, which are found mainly in long-segment aganglionosis In addition to mutations in the RET and EDNRB genes, embryonic environmental factors and/or other genetic factors appear to be involved in the development of Hirschsprung disease. Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. QTL analysis identifies a modifier locus of aganglionosis in the rat model of Hirschsprung disease carrying Ednrb(sl) mutations. Homozygous mutations in the endothelin-B receptor gene (EDNRB) on 13q22 have been identified in humans and mice with Hirschsprung disease type 2 (HSCR2). A De Novo novel mutation of the EDNRB gene in a Taiwanese boy with Hirschsprung disease. Hitherto however, homozygosity for EDNRB mutations accounted for the HSCR-Waardenburg syndrome (WS) association. These data might suggest that EDNRB mutations could be dosage sensitive: heterozygosity would predispose to isolated HSCR with incomplete penetrance, while homozygosity would result in more complex neurocristopathies associating HSCR and WS features. Highly recurrent RET mutations and novel mutations in genes of the receptor tyrosine kinase and endothelin receptor B pathways in Chinese patients with sporadic Hirschsprung disease. Mutations in genes encoding the RET receptor tyrosine kinase and endothelin receptor type B (EDNRB) are involved in HSCR pathogenesis; however, also important in ENS development are molecules that mediate events that are more restricted than those of RET and EDNRB, act later in development and which might not be HSCR-associated. Several missense mutations of the endothelin-B receptor (EDNRB) associated with Hirschsprung disease have recently been identified. These findings indicate that these missense mutations result in loss of function of EDNRB, and may provide the molecular pathological basis of Hirschsprung disease in some individuals. Manifestation of the disease has been linked to mutations in genes that encode the crucial signals for the development of the enteric nervous system-the RET and EDNRB signalling pathways. In addition to mutations in the RET and EDNRB genes, embryonic environmental factors and/or other genetic factors appear to be involved in the development of Hirschsprung disease In this study, we investigated whether germline mutations of endothelin receptor B (EDNRB), a gene involved in Hirschsprung disease (HSCR), could also predispose for malignant melanoma (MM) However, the similarity between the distal colonic aganglionosis in Hirschsprung disease and that due to EDN3 or EDNRB mutations led to the hypothesis that levels of expression of these genes might be affected in the absence of mutation, thus causing the Hirschsprung disease phenotype Our data strongly suggest that EDNRB is involved in predisposition for two different multigenic disorders, HSCR and melanoma.

yes

5717bacacb4ef8864c00000d

Can the apoptosis regulator BAX trigger the release of cytochrome c?

6-Shogaol reduced the mitochondrial membrane potential (MMP) and released cytochrome c from mitochondria to cytosol via Bax activation. Moreover, overexpression of ERβ prevented Bax activation, cytochrome c release, caspase-3 activation, and PARP cleavage during apoptosis. In this study, we demonstrated that EV71 infection altered Bax conformation and triggered its redistribution from the cytosol to mitochondria in RD cells. Subsequently, cytochrome c was released from mitochondria to cytosol. associated with translocation of Bax from the cytosol to the mitochondrial membrane, cytochrome c release, and caspase activation. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. Our results showed that OC induced a caspase-dependent apoptosis by triggering a series of events in HeLa cells including Bax translocation, cytochrome c release, caspase-3 activation, chromosome fragmentation followed by caspase-8 activation, Bid cleavage and eventually cell death. Bax plays a key role in intrinsic apoptotic signaling in neurons by allowing the release of mitochondrial cytochrome c.

yes

56e0797451531f7e3300000f

Are optogenetics tools used in the study and treatment of epilepsy?

The emerging revolutionary technique of optogenetics enables manipulation of the activity of specific neuronal populations in vivo with exquisite spatiotemporal resolution using light. We used optogenetic approaches to test the role of hippocampal excitatory neurons in the lithium-pilocarpine model of acute elicited seizures in awake behaving rats. This chapter focuses on the development of optogenetics and on-demand technologies for the study of epilepsy and the control of seizures. We then turn to the use of optogenetics, including on-demand optogenetics in the study of epilepsies, which highlights the powerful potential of optogenetics for epilepsy research. Optogenetic techniques provide powerful tools for bidirectional control of neuronal activity and investigating alterations occurring in excitability disorders, such as epilepsy. Therefore, one could optogenetically activate specific or a mixed population of interneurons and dissect their selective or concerted inhibitory action on principal cells. We chose to explore a conceptually novel strategy involving simultaneous activation of mixed populations of interneurons by optogenetics and study their impact on ongoing epileptiform activity in mouse acute hippocampal slices. Our data suggest that global optogenetic activation of mixed interneuron populations is a more effective approach for development of novel therapeutic strategies for epilepsy, but the initial action potential generation in principal neurons needs to be taken in consideration. Recently, a number of experiments have explored the treatments for epilepsy with optogenetic control of neurons. Here, we discuss the possibility that an optogenetic approach could be used to control the release of gliotransmitters and improve astrocyte function such as glutamate and K(+) uptake, and thereby offer a potential strategy to investigate and treat astrocyte-related epilepsy. Optogenetic and designer receptor technologies provide unprecedented and much needed specificity, allowing for spatial, temporal and cell type-selective modulation of neuronal circuits. Using such tools, it is now possible to begin to address some of the fundamental unanswered questions in epilepsy, to dissect epileptic neuronal circuits and to develop new intervention strategies. We then turn to the use of optogenetics, including on-demand optogenetics in the study of epilepsies, which highlights the powerful potential of optogenetics for epilepsy research. Moreover, optogenetics may be considered for developing potential treatment strategies for brain diseases, particularly for excitability disorders such as epilepsy. This chapter focuses on the development of optogenetics and on-demand technologies for the study of epilepsy and the control of seizures. How might novel technologies such as optogenetics lead to better treatments in epilepsy? WONOEP appraisal: optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis. Finally, optogenetic tools allow rapid and reversible suppression of epileptic electroencephalography (EEG) activity upon photoactivation. Our data suggest that epileptiform activity in the hippocampus caused by impaired inhibition may be controlled by optogenetic silencing of principal neurons and potentially can be developed as an alternative treatment for epilepsy. Seizure suppression by high frequency optogenetic stimulation using in vitro and in vivo animal models of epilepsy. Optogenetic techniques provide powerful tools for bidirectional control of neuronal activity and investigating alterations occurring in excitability disorders, such as epilepsy. We first discuss the benefits and caveats to using optogenetic approaches and recent advances in optogenetics related tools. We then turn to the use of optogenetics, including on-demand optogenetics in the study of epilepsies, which highlights the powerful potential of optogenetics for epilepsy research.

yes

54f4627e64850a5854000007

Is micro RNA 1 (miR-1) implicated in cardiac arrhythmias?

Dysfunction of the gap junction protein connexin 43 (Cx43), an established miR-1 target, during cardiac hypertrophy leads to ventricular tachyarrhythmias (VT). miR-1 overexpression may contribute to the increased susceptibility of the heart to AVB, which provides us novel insights into the molecular mechanisms underlying ischemic cardiac arrhythmias. The incidence of AVB was higher in miR-1 Tg mice than that in wild-type (WT) mice. As miR-1 has been shown in animal models and clinical studies to contribute to arrhythmogenesis by regulating pacemaker channel genes, our finding of miR-1 up-regulation in patients with myocardial infarction indicates that it might be responsible for the higher risk for arrhythmias in these patients. 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. MicroRNA-1 (miR-1) reciprocally regulates inwardly rectifying potassium channel (Kir)2.1 expression in coronary disease, contributing to arrhythmogenesis. miR-1 levels are greatly reduced in human AF, possibly contributing to up-regulation of Kir2.1 subunits, leading to increased I(K1). Because up-regulation of inward-rectifier currents is important for AF maintenance, these results provide potential new insights into molecular mechanisms of AF with potential therapeutic implications. The muscle-specific miR-1 has been implicated in cardiac hypertrophy, heart development, cardiac stem cell differentiation, and arrhythmias through targeting of regulatory proteins. We conclude that the beta-adrenergic pathway can stimulate expression of arrhythmogenic miR-1, contributing to ischaemic arrhythmogenesis, and beta-blockers produce their beneficial effects partially by down-regulating miR-1, which might be a novel strategy for ischaemic cardioprotection. MiR-1 influences susceptibility to cardiac arrhythmias after myocardial infarction. Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure. In the presence of isoproterenol, rhythmically paced, miR-1-overexpressing myocytes exhibited spontaneous arrhythmogenic oscillations of intracellular Ca(2+), events that occurred rarely in control myocytes under the same conditions. Here we show that miR-1 is overexpressed in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis. Elimination of miR-1 by an antisense inhibitor in infarcted rat hearts relieved arrhythmogenesis. Thus, miR-1 may have important pathophysiological functions in the heart, and is a potential antiarrhythmic target. MiR-1 influences susceptibility to cardiac arrhythmias after myocardial infarction The muscle-specific miR-1 has been implicated in cardiac hypertrophy, heart development, cardiac stem cell differentiation, and arrhythmias through targeting of regulatory proteins Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure Changes in abundance of muscle-specific microRNA, miR-1, have been implicated in cardiac disease, including arrhythmia and heart failure

yes

516c1041298dcd4e51000070

Does thyroid hormone signaling affect microRNAs expression in the heart?

e show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a. On the other hand, T₃ treatment increased miR-350 expression. Through a bioinformatics screening using TargetScan, we identified thyroid hormone receptor β1 (TRβ1), which negatively regulates β-MHC transcription, as a target of miR-27a hese findings suggested that miR-27a regulates β-MHC gene expression by targeting TRβ1 in cardiomyocytes. We found that a cardiac-specific microRNA (miR-208) encoded by an intron of the alphaMHC gene is required for cardiomyocyte hypertrophy, fibrosis, and expression of betaMHC in response to stress and hypothyroidism. Moreover, miR-27a was demonstrated to modulate β-MHC gene regulation via thyroid hormone signaling and to be upregulated during the differentiation of mouse embryonic stem (ES) cells or in hypertrophic hearts in association with β-MHC gene upregulation.

yes

5547d72ef35db75526000008

Do all archaea possess multiple origins of DNA replication?

Origins differ in number and structure across the three domains of life and their properties determine the dynamics of chromosome replication. Bacteria and some archaea replicate from single origins, whereas most archaea and all eukaryotes replicate using multiple origins. Replication starts at a single Ori site in bacteria, but in eukaryotes multiple Ori sites are used for fast copying across all chromosomes. The situation becomes complex in archaea, where some groups have single and others have multiple origins of replication. Results from this in silico analysis show that the Themococcales have a single origin of replication. Until recently, the only archaeon for which a bona fide origin of replication was reported was Pyrococcus abyssi, where a single origin was identified. Although several in silico analyses have suggested that some archaeal species might contain more than one origin, this has only been demonstrated recently. In bacteria and eukaryotes, replication initiates from single and multiple origins, respectively, while archaea can adopt either of the two modes. Bacteria and some archaea replicate from single origins, whereas most archaea and all eukaryotes replicate using multiple origins. Bacteria and some archaea replicate from single origins, whereas most archaea and all eukaryotes replicate using multiple origins

no

55088e412e93f0133a000001

Is p100 the precursor protein molecule of the NF-kappaB transcription factor subunit p50?

We previously reported that alymphoplasia (aly/aly) mice, which have a natural loss-of-function mutation in the Nik gene, which encodes a kinase essential for the processing of p100 to p52 in the alternative nuclear factor-κB (NF-κB) pathway, show mild osteopetrosis with an increase in several parameters of bone formation: Proteolytic processing of the nuclear factor (NF)-kappaB2 precursor protein p100 generates the active NF-kappaB2 subunit p52, which in turn transcriptionally up-regulates p100 expression. The mammalian Rel/NF-kappaB family of transcription factors, including RelA, c-Rel, RelB, NF-kappaB1 (p50 and its precursor p105), and NF-kappaB2 (p52 and its precursor p100), plays a central role in the immune system by regulating several processes ranging from the development and survival of lymphocytes and lymphoid organs to the control of immune responses and malignant transformation. NF-kappaB functions as a hetero- or homo-dimer which can be formed from five NF-kappaB subunits, NF-kappaB1 (p50 and its precursor p105), NF-kappaB2 (p52 and its precursor p100), RelA (p65), RelB and c-Rel. The non-canonical pathway based on processing of NF-kappaB2 precursor protein p100 to generate p52 plays a critical role in controlling B cell function and lymphoid organogenesis. Processing of NF-kappaB2 precursor protein p100 to generate p52 is tightly controlled, which is important for proper function of NF-kappaB. Processing of NF-kappa B2 precursor protein p100 to generate p52 is tightly regulated. Processing of the NF-kappaB2 precursor protein p100 to generate p52 is an important step of NF-kappaB regulation. Targeted disruption of the Rel/NF-kappaB family members NF-kappaB2, encoding p100/p52, and RelB in mice results in anatomical defects of secondary lymphoid tissues. Here, we show that in T cells infected with the human T-cell leukemia virus (HTLV), IKKalpha is targeted to a novel signaling pathway that mediates processing of the nfkappab2 precursor protein p100, resulting in active production of the NF-kappaB subunit, p52. nfkb2 encodes two members of the NF-kappa B/Rel family of proteins: p52 and p100. The p100 polypeptide has been proposed to serve as a precursor of p52, which corresponds to the N-terminal half of p100. In most cells, small amounts of p52 are produced relative to the levels of p100, unlike the usually balanced production of nfkb1-derived p50 and p105. The alternative or second pathway proceeded via NF-kappaB-inducing kinase (NIK)-, IKKalpha-, and protein synthesis-dependent processing of the inhibitory NF-kappaB2 p100 precursor protein to the p52 form and resulted in a delayed but sustained activation of primarily RelB-containing NF-kappaB dimers. In one exceptional case, generation of the p50 subunit of the transcriptional regulator NF-kappaB, the precursor protein p105 is processed in a limited manner: the N-terminal domain yields the p50 subunit, whereas the C-terminal domain is degraded Proteolytic processing of the p105 precursor (NF-kappa B1) generates the p50 subunit of NF-kappa B p105 (NFKB1) acts in a dual way as a cytoplasmic IkappaB molecule and as the source of the NF-kappaB p50 subunit upon processing The p50 subunit of NF-kappa B is derived from the amino terminus of a 105 kilodalton precursor Regulation of the transcription factor NF-kappaB involves proteasome-mediated processing of the NF-kappaB1 p105 precursor protein, which generates the p50 subunit of NF-kappaB This effort identified NF-kappaB1 (p105), an atypical IkappaB molecule and the precursor of NF-kappaB subunit p50 NF-kappaB functions as a hetero- or homo-dimer which can be formed from five NF-kappaB subunits, NF-kappaB1 (p50 and its precursor p105), NF-kappaB2 (p52 and its precursor p100), RelA (p65), RelB and c-Rel The mammalian Rel/NF-kappaB family of transcription factors, including RelA, c-Rel, RelB, NF-kappaB1 (p50 and its precursor p105), and NF-kappaB2 (p52 and its precursor p100), plays a central role in the immune system by regulating several processes ranging from the development and survival of lymphocytes and lymphoid organs to the control of immune responses and malignant transformation

no

5149b575d24251bc05000047

Is there a difference in the rate between gene fusion and gene fission?

we illustrate arrangement diversity within closely related organisms, estimate arrangement turnover frequency and establish, for the first time, branch-specific rate estimates for fusion, fission, domain addition and terminal loss. Rate and polarity of gene fusion and fission in Oryza sativa and Arabidopsis thaliana We have identified all differentially composite or split genes in 2 fully sequenced plant genomes, Oryza sativa and Arabidopsis thaliana Polarizing these events by outgroup comparison revealed differences in the rate of gene fission but not of gene fusion in the rice and Arabidopsis lineages. Gene fission occurred at a higher rate than gene fusion in the O. sativa lineage and was furthermore more common in rice than in Arabidopsis. Gene fusion and fission are thus rare and slow processes in higher plant genomes; they should be of utility to address deeper evolutionary relationships among plants--and the relationship of plants to other eukaryotic lineages--where sequence-based phylogenies provide equivocal or conflicting results. Primary factors correlating with fusion rates are the presence of transmembrane helices in HKs and the presence of DNA-binding domains in RRs, features that require correct (and separate) spatial location. In the absence of such features, there is a relative abundance of fused genes. We show that indels are the most frequent elementary events and that they occur in most cases at either the N- or C-terminus of the proteins. As revealed by the genomic neighbourhood/context of the corresponding genes, we show that a substantial number of these terminal indels are the consequence of gene fusions/fissions. We provide evidence showing that the contribution of gene fusion/fission to the evolution of multi-domain bacterial proteins is lower-bounded by 27% and upper-bounded by 64%. We conclude that gene fusion/fission is a major contributor to the evolution of multi-domain bacterial proteins. We found that fusion events are approximately four times more common than fission events, and we established that, in most cases, any particular fusion or fission event only occurred once during the course of evolution. Analyzing the most parsimonious pathways, we find 87% of architectures to gain complexity over time through simple changes, among which fusion events account for 5.6 times as many architectures as fission. These trees defined timelines of architectural discovery and revealed remarkable evolutionary patterns, including the explosive appearance of domain combinations during the rise of organismal lineages, the dominance of domain fusion processes throughout evolution, and the late appearance of a new class of multifunctional modules in Eukarya by fission of domain combinations We searched for examples which have arisen by one of the three postulated mechanisms: independent fusion/fission, "duplication/deletion," and plasmid-mediated "cut and paste." We conclude that all three mechanisms can be observed, with the independent fusion/fission being the most frequent.

yes

54d762653706e89528000014

Can cognitive behavioral therapy improve fatigue in cancer patients?

Physical activity, educational interventions, and cognitive-behavioral therapy have the most supportive data and can be recommended to patients with confidence. For women undergoing radiotherapy (3 RCTs), hypnosis combined with cognitive-behavioral therapy improved distress and fatigue. Patients in the CBT group reported a significantly larger decrease in fatigue scores than patients in the waiting list group. However, relative to VCBT-I, PCBT-I was associated with significantly greater improvements of insomnia severity, early morning awakenings, depression, fatigue, and dysfunctional beliefs about sleep. CBT-I may also improve mood, fatigue, and overall quality of life, and can be successfully delivered through a variety of treatment modalities, making it possible to reach a broader range of patients who may not have access to more traditional programs. No group differences in improvement were noted relative to QOL, fatigue, or mood. In case of persistent fatigue, personalized cognitive behavioral therapy can be considered. ONCLUSION: The results support CBTH as an evidence-based intervention to control fatigue in patients undergoing radiotherapy for breast cancer. Severe fatigue after cancer treatment can be treated effectively with cognitive behavioral therapy (CBT), but it is unclear whether CBT has an effect on cognitive functioning. CONCLUSION: CBT for post-cancer fatigue has already been shown to be an effective therapy. Frequently reported side effects include cancer-related fatigue, peripheral neuropathy, and psychological distress. Exercise and cognitive behavioral therapy interventions have counteracted such adverse effects in other cancer populations. There is evidence from methodologically rigorous controlled trials that exercise, psycho-educational interventions, and cognitive-behavioral therapy for insomnia are effective in the treatment of CRF, and a wide range of pharmacologic and nonpharmacologic interventions has shown initial promise in single-arm pilot studies with small, heterogeneous samples. CONCLUSIONS: Physical training combined with cognitive-behavioral therapy and physical training alone had significant and beneficial effects on fatigue compared with no intervention. Physical training was equally effective as or more effective than physical training combined with cognitive-behavioral therapy in reducing cancer-related fatigue, suggesting that cognitive-behavioral therapy did not have additional beneficial effects beyond the benefits of physical training. RESULTS: Imagery/hypnosis and CBT/CST interventions have produced improvement in all the three cancer-related symptoms individually: pain, fatigue, and sleep disturbance. RESULTS: Multilevel modeling indicated that for weekly FACIT fatigue data, there was a significant effect of the CBTH intervention on the rate of change in fatigue (p < .05), such that on average, CBTH participants' fatigue did not increase over the course of treatment, whereas control group participants' fatigue increased linearly. ONCLUSION: The results suggest that CBTH is an effective means for controlling and potentially preventing fatigue in breast cancer radiotherapy patients. Results were consistent with the view that CBTH was effective in managing fatigue and skin discomfort, and increasing relaxation. RESULTS: Participants in the Internet group showed significant improvements at post-assessment compared with those in the control group in overall insomnia severity (F(1,26) = 22.8; p<0.001), sleep efficiency (F(1,24) = 11.45; P = 0.002), sleep onset latency (F(1,24) = 5.18; P = 0.03), soundness of sleep (F(1,24) = 9.34; P = 0.005), restored feeling upon awakening (F(1,24) = 11.95; P = 0.002), and general fatigue (F(1,26) = 13.88; P = 0.001). Cognitive-behavior therapy (CBT) has alleviated fatigue and improved QOL of cancer patients; however, little is known about the effects of nurse-led CBT on breast cancer patients undergoing radiotherapy. Physical training was equally effective as or more effective than physical training combined with cognitive-behavioral therapy in reducing cancer-related fatigue, suggesting that cognitive-behavioral therapy did not have additional beneficial effects beyond the benefits of physical training. Cognitive-behavior therapy (CBT) has alleviated fatigue and improved QOL of cancer patients; however, little is known about the effects of nurse-led CBT on breast cancer patients undergoing radiotherapy. Physical training was equally effective as or more effective than physical training combined with cognitive-behavioral therapy in reducing cancer-related fatigue, suggesting that cognitive-behavioral therapy did not have additional beneficial effects beyond the benefits of physical training. The positive effects of cognitive behavioral therapy in adolescents with chronic fatigue syndrome are sustained after cognitive behavioral therapy

yes

550ae16bc2af5d5b70000009

Is protein Fbw7 a SCF type of E3 ubiquitin ligase?

FBW7 (F-box and WD repeat domain-containing 7) is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligase. However, very few E3 ubiquitin ligases are known to target G-CSFR for ubiquitin-proteasome pathway. Here we identified F-box and WD repeat domain-containing 7 (Fbw7), a substrate recognizing component of Skp-Cullin-F box (SCF) E3 ubiquitin Ligase physically associates with G-CSFR and promotes its ubiquitin-mediated proteasomal degradation. FBW7 is a crucial component of an SCF-type E3 ubiquitin ligase, which mediates degradation of an array of different target proteins. F-box and WD repeat domain-containing 7 (FBW7), the substrate-binding subunit of E3 ubiquitin ligase SCF(FBW7) (a complex of SKP1, cullin-1 and FBW7), plays important roles in various physiological and pathological processes. The tumor suppressor Fbxw7 (also known as Sel-10, hCdc4, hAgo, or Fbw7) is an F-box protein that functions as the substrate-recognition subunit of an SCF ubiquitin ligase complex and targets a group of oncoproteins for degradation. Fbw7 is the substrate recognition component of the Skp1-Cullin-F-box (SCF)-type E3 ligase complex and a well-characterized tumor suppressor that targets numerous oncoproteins for destruction. Fbw7 is a member of F-box family proteins, which constitute one subunit of Skp1, Cul1, and F-box protein (SCF) ubiquitin ligase complex. The F-box protein Fbw7 (also known as Fbxw7, hCdc4 and Sel-10) functions as a substrate recognition component of a SCF-type E3 ubiquitin ligase. SCF(Fbw7) facilitates polyubiquitination and subsequent degradation of various proteins such as Notch, cyclin E, c-Myc and c-Jun. Fbxw7 (also known as Fbw7, SEL-10, hCdc4, or hAgo) is the F-box protein subunit of an Skp1-Cul1-F-box protein (SCF)-type ubiquitin ligase complex that plays a central role in the degradation of Notch family members. The Fbxw7 (F-box/WD repeat-containing protein 7; also called CDC4, Sel10, Ago, and Fbw7) component of the SCF (Skp1/Cullin/F-box protein) E3 ubiquitin ligase complex acts as a tumor suppressor in several tissues and targets multiple transcriptional activators and protooncogenes for ubiquitin-mediated degradation. The F-box protein Fbw7 (also known as Fbxw7, hCdc4 and Sel-10) functions as a substrate recognition component of a SCF-type E3 ubiquitin ligase. We demonstrate here that Fbw7 (F-box and WD repeat domain containing-7), the substrate recognition component of an SCF (complex of SKP1, CUL1 and F-box protein)-type E3 ubiquitin ligase, is a key regulator of NSC/NPC viability and differentiation. The SCF(Fbw7) ubiquitin ligase complex plays important roles in cell growth, survival, and differentiation via the ubiquitin-proteasome-mediated regulation of protein stability. F-box and WD-40 domain protein 7 (Fbw7) provides substrate specificity for the Skp1-Cullin1-F-box protein (SCF) ubiquitin ligase complex that targets multiple oncoproteins for degradation, including cyclin E, c-Myc, c-Jun, Notch, and mammalian target of rapamycin (mTOR). Mammalian Fbw7 (also known as Sel-10, hCdc4, or hAgo) is the F-box protein component of an SCF (Skp1-Cul1-F-box protein-Rbx1)-type ubiquitin ligase, and the mouse Fbw7 is expressed prominently in the endothelial cell lineage of embryos. The F-box protein Fbw7 (also known as Fbxw7, hCdc4 and Sel-10) functions as a substrate recognition component of a SCF-type E3 ubiquitin ligase We demonstrate here that Fbw7 (F-box and WD repeat domain containing-7), the substrate recognition component of an SCF (complex of SKP1, CUL1 and F-box protein)-type E3 ubiquitin ligase, is a key regulator of NSC/NPC viability and differentiation Here we identified F-box and WD repeat domain-containing 7 (Fbw7), a substrate recognizing component of Skp-Cullin-F box (SCF) E3 ubiquitin Ligase physically associates with G-CSFR and promotes its ubiquitin-mediated proteasomal degradation FBW7 is a crucial component of an SCF-type E3 ubiquitin ligase, which mediates degradation of an array of different target proteins

yes

5361677c7d100faa09000008

Is there increased incidence of incontinence in athletes?

Urinary incontinence affects women of all ages, including top female athletes, but is often under-reported. The highest prevalence of urinary incontinence is reported in those participating in high impact sports. The prevalence of female stress urinary incontinence is high, and young adults are also affected, including athletes, especially those involved in "high-impact" sports Analysis of these data suggests that perineal pressure is decreased in female athletes compared with nonathlete women. A lower perineal pressure correlates with increased symptoms of urinary incontinence and pelvic floor dysfunction. Urinary incontinence is a prevalent condition among athletes that is not openly discussed. High-level sport appears to be a significant independent risk factor for AI in healthy young women. The prevalence of LUTS was 54.7%, and 30% for urinary incontinence. LUTS and incontinence are prevalent in female athletes. A relationship between sport or fitness activities and urinary incontinence (UI) previously has been described in women. studies have also shown a high prevalence of SUI in young, physically fit female athletes. There was urinary incontinence in female long-distance runners and a correlation with eating disorders. young female athletes participating in high-impact sports may be at higher risk for urinary incontinence. Results indicated that more than 25% of those completing surveys experienced incontinence and that more than 90% had never told anyone about their problem and had no knowledge of preventive measures; 16% reported incontinence negatively impacted their quality of life. There is a very high prevalence of urinary incontinence in women athletes. Women athletes should be counseled about the increased risk of urinary incontinence with ultra high-impact sports and eating disorders. Stress urinary incontinence is a barrier to women's participation in sport and fitness activities and, therefore, it may be a threat to women's health, self-esteem and well-being. The prevalence during sports among young, nulliparous elite athletes varies between 0% (golf) and 80% (trampolinists). The highest prevalence is found in sports involving high impact activities such as gymnastics, track and field, and some ball games Urinary leakage is common among elite athletes and dancers, particularly during training, but also during daily life activities. There is a high prevalence of stress and urge incontinence in female elite athletes. The frequency of SUI and urge incontinence was significantly higher in eating disordered athletes compared with healthy athletes. High impact sports activities may produce urinary incontinence. Urinary incontinence during physical stresses is common in young nulliparous wome Incontinence during physical stresses is common in young, highly fit, nulliparous women.

yes

56a8adb0a17756b72f000003

Are there enhancer RNAs (eRNAs)?

active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription eRNAs may then facilitate enhancer-promoter interaction or activate promoter-driven transcription Enhancer RNAs: a class of long noncoding RNAs synthesized at enhancers Enhancer RNAs and regulated transcriptional programs enhancers have been found to be broadly transcribed, resulting in the production of enhancer-derived RNAs, or eRNAs The emerging roles of eRNAs in transcriptional regulatory networks we found certain enhancer RNAs (eRNAs) regulate chromatin accessibility of the transcriptional machinery at loci encoding master regulators of myogenesis (i.e., MyoD/MyoG), thus suggesting their significance and site-specific impact in cellular programming Enhancer RNAs: the new molecules of transcription the discovery that distal regulatory elements known as enhancers are transcribed and such enhancer-derived transcripts (eRNAs) serve a critical function in transcriptional activation has added a new dimension to transcriptional regulation eRNAs reach the heart of transcription Recent studies have disclosed the function of enhancer RNAs (eRNAs), which are long non-coding RNAs transcribed from gene enhancer regions, in transcriptional regulation. Since the discovery that many transcriptional enhancers are transcribed into long noncoding RNAs termed "enhancer RNAs" (eRNAs), their putative role in enhancer function has been debated. Recent studies have revealed that active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). Enhancer RNAs (eRNAs) are a class of long noncoding RNAs (lncRNA) expressed from active enhancers, whose function and action mechanism are yet to be firmly established. In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs). In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs). A subset of enhancers are occupied by RNA polymerase II (RNAP II) and transcribed to produce long non-coding RNAs termed eRNAs. Very recent evidence has indicted that some eRNAs play a role in initiating or activating transcription, possibly by helping recruit and/or stabilize binding of the general transcription machinery to the proximal promoter of their target genes. In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs). However, it has remained unclear whether these eRNAs are functional or merely a reflection of enhancer activation. Notably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 monomethylated at lysine 4. The level of eRNA expression at neuronal enhancers positively correlates with the level of messenger RNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis. A function of CBP at enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of enhancers. Notably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 monomethylated at lysine 4. Enhancer RNAs (eRNAs) are a class of long noncoding RNAs (lncRNA) expressed from active enhancers, whose function and action mechanism are yet to be firmly established. Here we show that eRNAs facilitate the transition of paused RNA polymerase II (RNAPII) into productive elongation by acting as a decoy for the negative elongation factor (NELF) complex upon induction of immediate early genes (IEGs) in neurons. Recent studies have disclosed the function of enhancer RNAs (eRNAs), which are long non-coding RNAs transcribed from gene enhancer regions, in transcriptional regulation. Recent studies have revealed that active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription. Enhancer RNAs (eRNAs) are a class of long noncoding RNAs (lncRNA) expressed from active enhancers, In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs). However, it has remained unclear whether these eRNAs are functional or merely a reflection of enhancer activation. Recent studies have revealed that active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription.

yes

56b8a222156496395c000001

Are conserved noncoding elements associated with the evolution of animal body plans?

Here, we discuss the evidence that CNEs are part of the core gene regulatory networks (GRNs) that specify alternative animal body plans. The major animal groups arose>550 million years ago. We propose that the cis-regulatory inputs identified by CNEs arose during the "re-wiring" of regulatory interactions that occurred during early animal evolution. Consequently, different animal groups, with different core GRNs, contain alternative sets of CNEs. Due to the subsequent stability of animal body plans, these core regulatory sequences have been evolving in parallel under strong purifying selection in different animal groups. Conserved noncoding elements and the evolution of animal body plans. Conserved noncoding elements and the evolution of animal body plans

yes

56ae69fb0a360a5e4500000d

Are DNA methylation maps applicable to the diagnosis of non-small-cell lung carcinomas?

Here we present a genome-wide DNA methylation analysis of NSCLC samples and paired lung tissues, where we combine MethylCap and next generation sequencing (MethylCap-seq) to provide comprehensive DNA methylation maps of the tumor and paired lung samples. Analysis of the MethylCap-seq data revealed a strong positive correlation between replicate experiments and between paired tumor/lung samples. We identified 57 differentially methylated regions (DMRs) present in all NSCLC tumors analyzed by MethylCap-seq. While hypomethylated DMRs did not correlate to any particular functional category of genes, the hypermethylated DMRs were strongly associated with genes encoding transcriptional regulators. Furthermore, subtelomeric regions and satellite repeats were hypomethylated in the NSCLC samples. We also identified DMRs that were specific to two of the major subtypes of NSCLC, adenocarcinomas and squamous cell carcinomas. Collectively, we provide a resource containing genome-wide DNA methylation maps of NSCLC and their paired lung tissues, and comprehensive lists of known and novel DMRs and associated genes in NSCLC. Genome-wide DNA methylation profiling of non-small cell lung carcinomas. Genomewide DNA methylation analysis identifies novel methylated genes in non-small-cell lung carcinomas. To identify candidate markers for use in NSCLC diagnosis, we used genomewide DNA methylation maps that we had previously generated by MethylCap and next-generation sequencing and listed the most significant differentially methylated regions (DMRs). The 25 DMRs with highest significance in their methylation scores were selected. The methylation status of these DMRs was investigated in 61 tumors and matching control lung tissues by methylation-specific polymerase chain reaction. We found 12 novel DMRs that showed significant differences between tumor and control lung tissues. We also identified three novel DMRs for each of the two most common NSCLC subtypes, adenocarcinomas and squamous cell carcinomas. We propose a panel of five DMRs, composed of novel and known markers that exhibit high specificity and sensitivity to distinguish tumors from control lung tissues. Here we present a genome-wide DNA methylation analysis of NSCLC samples and paired lung tissues, where we combine MethylCap and next generation sequencing (MethylCap-seq) to provide comprehensive DNA methylation maps of the tumor and paired lung samples. It is a very stable and specific modification and therefore in principle a very suitable marker for epigenetic phenotyping of tumors. Here we present a genome-wide DNA methylation analysis of NSCLC samples and paired lung tissues, where we combine MethylCap and next generation sequencing (MethylCap-seq) to provide comprehensive DNA methylation maps of the tumor and paired lung samples. Here we present a genome-wide DNA methylation analysis of NSCLC samples and paired lung tissues, where we combine MethylCap and next generation sequencing (MethylCap-seq) to provide comprehensive DNA methylation maps of the tumor and paired lung samples. The MethylCap-seq data were validated by bisulfite sequencing and methyl-specific polymerase chain reaction of selected regions. Here we present a genome-wide DNA methylation analysis of NSCLC samples and paired lung tissues, where we combine MethylCap and next generation sequencing (MethylCap-seq) to provide comprehensive DNA methylation maps of the tumor and paired lung samples.

yes

550aef0ec2af5d5b7000000a

Is the protein product of the cylindromatosis gene (CYLD) a deubiquitinating enzyme?

CYLD was originally identified as a tumor suppressor gene mutated in familial cylindromatosis, an autosomal dominant predisposition to multiple benign neoplasms of the skin known as cylindromas. The CYLD protein is a deubiquitinating enzyme that acts as a negative regulator of NF-κB and JNK signaling through its interaction with NEMO and TNFR-associated factor 2. CYLD, a deubiquitinating enzyme (DUB), is a critical regulator of diverse cellular processes, ranging from proliferation and differentiation to inflammatory responses, via regulating multiple key signaling cascades such as nuclear factor kappa B (NF-κB) pathway. CYLD is a lysine 63-deubiquitinating enzyme that inhibits NF-κB and JNK signaling. Tumor suppressor gene CYLD is a deubiquitinating enzyme which negatively regulates various signaling pathways by removing the lysine 63-linked polyubiquitin chains from several specific substrates. The cylindromatosis tumor suppressor (CYLD) is a deubiquitinating enzyme that has been implicated in various aspects of adaptive and innate immune responses. The cylindromatosis gene (CYLD) was identified as a tumor suppressor gene, which is mutated in familial cylindromatosis (Brooke-Spiegler syndrome), an autosomal-dominant predisposition to multiple tumors of the skin appendages. CYLD is a deubiquitinating enzyme acting as a negative regulator of the nuclear factor κB (NF-κB) signaling pathway by removing lysine-63-linked polyubiquitin chains from NF-κB activating proteins. Here, we identify the deubiquitinating enzyme CYLD, the familial cylindromatosis tumor suppressor gene, as a negative regulator of proximal events in Wnt/beta-catenin signaling. CYLD is a tumour-suppressor gene that is mutated in a benign skin tumour syndrome called cylindromatosis. The CYLD gene product is a deubiquitinating enzyme that was shown to regulate cell proliferation, cell survival and inflammatory responses, mainly through inhibiting NF-kappaB signalling. Cyld encodes a 956-amino acid deubiquitinating enzyme (CYLD), which is a negative regulator of nuclear factor kappaB and mitogen-activated protein kinase pathways. The deubiquitinating enzyme CYLD has been identified as a key negative regulator for NF-kappaB. CYLD, a tumor suppressor gene, has deubiquitinating enzyme activity and inhibits the activation of transcription factor NF-kappaB. Loss of the deubiquitinating activity of CYLD is correlated with tumorigenesis. We show that dCYLD encodes a deubiquitinating enzyme that deubiquitinates dTRAF2 and prevents dTRAF2 from ubiquitin-mediated proteolytic degradation. The CYLD gene encodes a deubiquitinating enzyme that removes Lys-63-linked ubiquitin chains from I kappa B kinase signaling components and thereby inhibits NF-kappaB pathway activation. Deubiquitinating enzymes (DUB) form a family of cysteine proteases that digests ubiquitin chains and reverses the process of protein ubiquitination. Despite the identification of a large number of DUBs, their physiological functions remain poorly defined. Here we provide genetic evidence that CYLD, a recently identified DUB, plays a crucial role in regulating the peripheral development and activation of B cells. The cylindromatosis (CYLD) gene was originally identified as a tumor suppressor that is mutated in familial cylindromatosis, an autosomal dominant condition that confers a predisposition to multiple tumors of the skin appendages. CYLD has deubiquitinating enzyme activity and inhibits the activation of transcription factor NF-kappaB. Therefore, loss of CYLD function correlates with tumorigenesis. Cylindromatosis gene (CYLD) is a ubiquitously expressed deubiquitinating enzyme, which interacts with members of the NF-κB signaling pathway and attenuates NF-κB and JNK signaling. The cylindromatosis tumor suppressor gene (Cyld) encodes a deubiquitinating enzyme (CYLD) with immunoregulatory function. The CYLD gene product is a deubiquitinating enzyme that was shown to regulate cell proliferation, cell survival and inflammatory responses, mainly through inhibiting NF-kappaB signalling. Here, we examined the potential role of the deubiquitinating enzyme CYLD (cylindromatosis), mutation of which has been reported to cause familial cylindromatosis. The deubiquitinating enzyme cylindromatosis (CYLD), loss of which was originally reported to cause a benign human syndrome called cylindromatosis, has been identified as a key negative regulator for NF-kappaB in vitro. The CYLD gene product is a deubiquitinating enzyme that was shown to regulate cell proliferation, cell survival and inflammatory responses, mainly through inhibiting NF-kappaB signalling. Cylindromatosis gene (CYLD) is a ubiquitously expressed deubiquitinating enzyme, which interacts with members of the NF-�B signaling pathway and attenuates NF-�B and JNK signaling. Cylindromatosis (CYLD) is a deubiquitinating enzyme that is altered in patients with familial cylindromatosis, a condition characterized by numerous benign adnexal tumors. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Here, we identify the deubiquitinating enzyme CYLD, the familial cylindromatosis tumor suppressor gene, as a negative regulator of proximal events in Wnt/beta-catenin signaling Cylindromatosis gene (CYLD) is a ubiquitously expressed deubiquitinating enzyme, which interacts with members of the NF-κB signaling pathway and attenuates NF-κB and JNK signaling The CYLD gene product is a deubiquitinating enzyme that was shown to regulate cell proliferation, cell survival and inflammatory responses, mainly through inhibiting NF-kappaB signalling The cylindromatosis tumor suppressor gene (Cyld) encodes a deubiquitinating enzyme (CYLD) with immunoregulatory function Cylindromatosis gene (CYLD) is a ubiquitously expressed deubiquitinating enzyme, which interacts with members of the NF-κB signaling pathway and attenuates NF-κB and JNK signaling The cylindromatosis tumor suppressor gene (Cyld) encodes an enzyme (CYLD) with deubiquitinating activity that has been implicated in the regulation of thymocyte selection in an NF-κB-essential-modulator (NEMO)-dependent manner Here, we identify the deubiquitinating enzyme CYLD, the familial cylindromatosis tumor suppressor gene, as a negative regulator of proximal events in Wnt/beta-catenin signaling CYLD is a deubiquitinating enzyme acting as a negative regulator of the nuclear factor κB (NF-κB) signaling pathway by removing lysine-63-linked polyubiquitin chains from NF-κB activating proteins CYLD, a tumor suppressor gene, has deubiquitinating enzyme activity and inhibits the activation of transcription factor NF-kappaB Here, we examined the potential role of the deubiquitinating enzyme CYLD (cylindromatosis), mutation of which has been reported to cause familial cylindromatosis CYLD has deubiquitinating enzyme activity and inhibits the activation of transcription factor NF-kappaB

yes

531d34be267d7dd053000004

Has the presence of delayed enhancement been documented in athletes performing strenuous exercise?

Atypical findings such as marked cardiac dilation, reduced deformation, or small patches of delayed gadolinium enhancement may be commonly encountered in well-trained athletes, but, at present, the prognostic significance of such findings is unknown. On CMR, DGE localized to the interventricular septum was identified in 5 of 39 athletes who had greater cumulative exercise exposure and lower RVEF (47.1 ± 5.9 vs. 51.1 ± 3.7%, P = 0.042) than those with normal CMR. Post-event cardiac MRI demonstrated the interval appearance of delayed enhancement of gadolinium at the inferior insertion of the right ventricle and in the interventricular septum-a novel finding that may represent subtle inflammation secondary to a combined exercise and altitude effect. No evidence of delayed enhancement of the left ventricular myocardium was found on CMR imaging, suggesting that the increase in cardiac biomarkers after the marathon may not have be due to myocardial necrosis. Of the 102 runners, five had a CAD pattern of LGE, and seven had a non-CAD pattern of LGE. The CAD pattern of LGE was located in the territory of the left anterior descending coronary artery more frequently than was the non-CAD pattern (P = .0027, Fisher exact test). The prevalence of LGE in runners was higher than that in age-matched control subjects (12% vs 4%; P = .077, McNemar exact test).

yes

52b2f09f4003448f55000008

Is triadin involved in cardiac function?

Junctin (JCN), a 26-kd sarcoplasmic reticulum (SR) transmembrane protein, forms a quaternary protein complex with the ryanodine receptor, calsequestrin, and triadin in the SR lumen of cardiac muscle. Within this complex, calsequestrin, triadin, and JCN appear to be critical for normal regulation of ryanodine receptor-mediated calcium (Ca) release. Recent studies have uncovered functional roles of both JCN and triadin in the mouse heart, using transgenic overexpression strategies, which exhibit varying phenotypes including mild SR structural alterations, prolongation of Ca transient decay, impaired relaxation, and cardiac hypertrophy and/or heart failure. Triadin is involved in the regulation of cardiac excitation-contraction coupling. Thus the maintenance of triadin expression is essential for normal SR Ca cycling and contractile function. Ca2+ release from the cardiac junctional sarcoplasmic reticulum (SR) is regulated by a complex of proteins, including the ryanodine receptor (RyR), calsequestrin (CSQ), junctin (JCN), and triadin 1 (TRD). Impaired sarcoplasmic reticulum (SR) Ca release has been suggested to contribute to the depressed cardiac function in heart failure. The release of Ca from the SR may be regulated by the ryanodine receptor, triadin, junctin, calsequestrin, and a histidine-rich, Ca-binding protein (HRC).

yes

51487821d24251bc0500002f

Is Mammaprint approved by the United States Food and Drug Administration?

an FDA-cleared 70-gene signature of MammaPrint panel on MammaPrint, the first and only assay for breast cancer management that has been cleared by the FDA. The MammaPrint assay has the advantages of a 510(k) clearance by the US Food and Drug Administration, a larger gene number which may enhance further utility, and the potentially wider patient eligibility including lymph node-positive, ER-negative, The MammaPrint assay has the advantages of a 510(k) clearance by the U.S. Food and Drug Administration, a larger gene number, which may enhance further utility, and a potentially wider patient eligibility, including lymph node-positive, estrogen receptor (ER)-negative, and younger patients being accrued into the prospective trial (Microarray in Node-Negative Disease May Avoid Chemotherapy).

yes

53636e727d100faa0900000d

Are microRNA (miR) regulated through DNA methylation of their promoters?

We found that Tcf3 down-regulation in the context of constitutively active Wnt signaling does not result from promoter DNA methylation but is likely to be caused by a plethora of mechanisms at both the RNA and protein level as shown by the observed decrease in activating histone marks (H3K4me3 and H3-acetylation) and the upregulation of miR-211, a novel Wnt-regulated microRNA that targets Tcf3 and attenuates early neural differentiation in mouse ESCs ene silencing of MIR22 in acute lymphoblastic leukaemia involves histone modifications independent of promoter DNA methylation Whereas a CpG island was identified within the promoter element of MIR22, no promoter DNA methylation was detected in these cells xtensive promoter DNA hypermethylation and hypomethylation is associated with aberrant microRNA expression in chronic lymphocytic leukemia Integration of DNA methylation and miRNA promoter data led to the identification of 128 recurrent miRNA targets for aberrant promoter DNA methylation Together, our findings characterize the role of epigenetic changes in the regulation of miRNA transcription and create a repository of disease-specific promoter regions that may provide additional insights into the pathogenesis of CLL NA methylation of microRNA genes in multiple myeloma Recently, epigenetic dysregulation of tumor-suppressor miRNA genes by promoter DNA methylation has been implicated in human cancers, including multiple myeloma (MM) ethylation of tumor suppressor microRNAs Dysregulation of miRNA expression involved in cancer can be triggered by multiple mechanisms including aberrant DNA methylation of the miRNA gene promoter Of note, DNA methylation of tumor suppressor miRNAs has been implicated in various human cancers Moreover, miRNA silencing mediated by aberrant promoter DNA methylation can potentially be reversed by hypomethylating agents, and hence may pose a new therapeutic target in cancer In this review, the authors will focus on the aberrant methylation of miRNAs in the pathogenesis of lymphoid malignancies including chronic lymphocytic leukemia, multiple myeloma and acute lymphoblastic leukemia Here, we review those miRNAs implicated in AD that are regulated by promoter DNA methylation and/or chromatin modifications and, which frequently direct the expression of constituents of the epigenetic machinery, concluding with the delineation of a complex epigenetic-miRNA regulatory network and its alterations in AD Furthermore, we also discuss epigenetic dysregulation of tumor-suppressor miRNA genes by promoter DNA methylation and the interaction of DNA methylation with miRNAs involved in the regulation of HSC activation and liver fibrosi Instead, the cell type-specific silencing of these genes is due to enhanced p21 mRNA degradation, 14-3-3sigma promoter DNA methylation and reduced processing of the miR-34a primary transcript Some tumor-suppressive miRNAs are known to be epigenetically silenced by promoter DNA methylation in cancer In the present study, we aimed to identify miRNA genes that are silenced by DNA hypermethylation in hepatocellular carcinoma (HCC) It was found that miR-335, which is harbored within an intron of its protein-coding host gene, MEST, was downregulated by aberrant promoter hypermethylation via further methylation assays, including methylation-specific PCR, combined bisulfite and restriction analysis, bisulfite sequencing analysis and 5-aza-2'-deoxycytidine treatment he levels of miR-335/MEST methylation were significantly higher in 18 (90%) out of 20 primary HCC tumors, compared to their non-tumor tissue counterparts (P<0.001) In conclusion, our results indicate that expression of miR-335 is reduced by aberrant DNA methylation in HCC.

yes

513596225274a5fb0700000d

Are nucleosomes positioned at DNA replication origins?

yeast origins are characterized by an asymmetric pattern of positioned nucleosomes flanking the ACS. The origin sequences are sufficient to maintain a nucleosome-free origin; however, ORC is required for the precise positioning of nucleosomes flanking the origin. Here, we identify nucleosome occupancy as a likely candidate to set up ORI distribution we demonstrate that open chromatin domains, characterized by nucleosome depletion, are preferentially permissive for replication Nucleosome assembly of the template prevented DNA replication. Replication of chromosomes was severely inhibited at more than two-thirds of physiological nucleosome density

no

54d901ec4b1fd0d33c000006

Does nimotuzumab improve survival of glioblastoma patients?

The survival times were similar to those seen in historical data of standard therapy. The survival time of a matched population treated at the same hospital with irradiation alone was decreased (median 8.0 and 12.2 mo for GBM and AA patients, respectively) compared with that of the patients who received nimotuzumab and curative-intent radiotherapy. This study, in a poor prognosis population, validates the previous data of survival gain after combining nimotuzumab and radiotherapy, in newly diagnosed high-grade glioma patients. The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. CONCLUSIONS: In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation. Nimotuzumab was well-tolerated and treatment with the antibody yielded a survival benefit: median survival time was 32.66 mo and the 2-y survival rate was 54.2%. This study demonstrated the feasibility of prolonged administration of nimotuzumab and showed preliminary evidence of clinical benefit in HGG patients with poor prognosis. Recent clinical studies show that patients with malignant gliomas could benefit from nimotuzumab treatment. CONCLUSIONS: Nimotuzumab in combination with chemotherapy has moderate activity in patients with malignant gliomas and the toxicities are well tolerable, therefore, worth further investigation. It has been evaluated in malignant brain tumors in adults and children, and shown to be therapeutically safe and effective in terms of increased survival and improved quality of life. Conclusions As used in this study, nimotuzumab demonstrated a broad safety profile, making it acceptable for chronic use, and implied clinical benefits in terms of increased survival and improved functional status in these patients, compared to findings described in the literature. Nimotuzumab prolongs survival in patients with malignant gliomas: A phase I/II clinical study of concomitant radiochemotherapy with or without nimotuzumab. Conclusions As used in this study, nimotuzumab demonstrated a broad safety profile, making it acceptable for chronic use, and implied clinical benefits in terms of increased survival and improved functional status in these patients, compared to findings described in the literature. This study, in a poor prognosis population, validates the previous data of survival gain after combining nimotuzumab and radiotherapy, in newly diagnosed high-grade glioma patients Conclusions As used in this study, nimotuzumab demonstrated a broad safety profile, making it acceptable for chronic use, and implied clinical benefits in terms of increased survival and improved functional status in these patients, compared to findings described in the literature A multicenter exploratory study combining nimotuzumab and radiotherapy showed disease control and an overall patient survival similar to previous experiences along with an improvement in the quality of patient survival and no severe side effects. Combining craniospinal irradiation (CSI) with concurrent temozolomide and nimotuzumab therapy may slightly improve tumor control and overall survival

yes

5321b8a39b2d7acc7e000009

Is there a relation between ANP and transcapillary albumin escape?

Thus, in a large ethnically homogeneous cohort of diabetic subjects, our data show: (1) a significant association of C708/T polymorphism with microalbuminuria in long-term diabetes and with both lower plasma ANP levels and widespread albumin leakage hese results suggest a possible role of PND gene in conferring protection from nephropathy and microvascular damage in type 1 diabetes. Moreover, the increased susceptibility of the glomerular capillaries in diabetics to ANP seems to be part of a more generalized capillary abnormality, because ANP also increases the transcapillary escape of albumin. In summary, low dose ANP infusion in healthy subjects caused a shift of plasma water and electrolytes from the circulation, with albumin escape as a secondary phenomenon.

yes

56d34fbcf22319765a000009

Can chronological age be predicted by measuring telomere length?

Human somatic cells gradually lose telomeric repeats with age. This study investigated if one could use a correlation between telomere length and age, to predict the age of an individual from their DNA. Therefore, telomere length measurement by real-time quantitative PCR cannot be used to predict age of a person, due to the presence of large inter-individual variations in telomere lengths. ur results provide the first clear and unambiguous evidence of a relationship between telomere length and mortality in the wild, and substantiate the prediction that telomere length and shortening rate can act as an indicator of biological age further to chronological age when exploring life history questions in natural conditions.

no

514cbbf9d24251bc05000065

Is there an association between c-reactive protein concentrations and outcomes of subarachnoid hemorrhage patients?

Besides the baseline characteristics, daily interleukin-6 (IL-6), procalcitonin, C-reactive protein levels, and leukocyte counts were prospectively measured until day 14 after subarachnoid hemorrhage. Occurrence of infectious complications and application of therapeutic hypothermia were assessed as confounding factors. The primary end point was outcome after 3 months, assessed by Glasgow Outcome Scale; the secondary end point was the occurrence of DINDs. RESULTS: : During a 3-year period, a total of 138 patients were included. All inflammatory parameters measured were higher in patients with unfavorable outcome (Glasgow Outcome Scale score, 1-3). Twenty-three and 28 patients showed poor outcome and symptomatic vasospasm after SAH, respectively. Both preoperative and postoperative CRP levels were significantly higher in patients with a poor outcome compared with patients with a good outcome (P<0.05). e area under the receiver operating characteristic curve of CRP measured on postoperative day 1 or 2 (CRP POD1-2) for predicting a poor clinical outcome was 0.870, and its cutoff point of 4 mg/dL had a sensitivity of 0.826 and a specificity of 0.843. A high CRP level after aneurysm treatment was associated with severe neurological deterioration on admission, cerebral infarction, intracerebral hemorrhage, and surgical decompression (P<0.05). CRP POD1-2, and not the preoperative CRP, was an independent factor in predicting symptomatic vasospasm (P<0.05). In patients with symptomatic vasospasm, an increase in the postoperative CRP was associated with the time profile of developing symptomatic vasospasm. Postoperative CRP, especially CRP POD1-2, can be a useful prognostic factor for both poor outcome and symptomatic vasospasm in patients with aneurysmal SAH. Serum CRP levels were related to severity of aSAH. Patients with lower GCS scores and higher Hunt and Hess and Fisher grades presented statistically significant higher serum CRP levels. Patients with higher serum CRP levels had a less favorable prognosis. Increased serum CRP levels were strongly associated with worse clinical prognosis in this study. After SAH, the value of C-reactive protein (CRP)--an acute phase sensitive inflammatory marker--as a prognostic factor has been poorly studied, with conflicting results. Admission (18.0 ± 35.7 vs 8.5 ± 8.4 mg/l) and postoperative (41.0 ± 40.2 vs 21.1 ± 24.1 mg/l) CRP levels were higher (p < 0.001) in those with a poor outcome than in those with a favourable outcome, but CRP values did not predict delayed cerebral ischaemia or cerebral infarction. Higher increase in CRP level between admission and postoperative morning, however, independently predicted poor outcome (p = 0.004). CRP levels correlate with outcome but do not seem to predict delayed cerebral ischaemia or infarction after SAH. Systemic oxygen consumption is associated with hsCRP levels in the first 14 days after SAH and is an independent predictor of DCI. Intracranial hypertension was associated with an inflammatory response, indicating activation of the inflammatory cascade in the brain (ECF) and systemic circulation with high IL-6 and C-reactive protein (CRP) plasma levels after SAH, the latter associated with unfavourable outcome. Patients with angiographic vasospasm had higher CRP measurements in serum and CSF, in a statistically significant fashion (p < 0.0001). Additionally, patients with higher CRP levels in serum and CSF had less favorable outcome in this cohort. Furthermore, patients developing angiographically proven vasospasm demonstrated significantly elevated CRP levels in serum and CSF, and increased CRP measurements were strongly associated with poor clinical outcome in this cohort. Finally, serum concentrations of ICAM-1, VCAM-1, and hsCRP during the early (P = .0055, P = .0266, and P = .0266) and late (P = .0423, P = .0041, and P = .0004) period were significantly higher in patients with DIND than in patients without DIND. CONCLUSIONS: Serum levels of ICAM-1, VCAM-1 and hsCRP during the early and late period following SAH correlate with DIND CRP levels on days 5, 6, 7, and 8 were statistically significantly higher in the group of patients developing a DIND (P < 0.025, P < 0.016, P < 0.011, P < 0.0002). Overall CRP values were higher with increasing severity of the initial ictus according to the Hunt and Hess Scale and to the outcome according to the Glasgow Outcome Scale from day 3 on. The presented data do not prove that WBCs and CRP values have a direct contribution to the pathogenesis of ischemic complications following SAH, but it supports the assertion that inflammation may present a common pathogenic pathway in the development of such complications. The CRP and TGF-beta1 levels in CSF are strongly concerned with communicating hydrocephalus after SAH.

yes

53372b66d6d3ac6a34000057

Can RNASeq be used for the analysis of nascent transcripts?

Here, we utilize nascent RNA sequencing to document dosage compensation during transcriptional elongation. Here we show that RNA-seq can also be used for studying nascent RNAs undergoing transcription Conversely, the nuclear fraction shows an enrichment of unprocessed RNA compared with total RNA-seq, making it suitable for analysis of nascent transcripts and RNA processing dynamics.

yes

56e310a151531f7e33000017

Do RNA:DNA hybrids preferentially form in high or low GC regions?

Intrinsic termination signals for multisubunit bacterial RNA polymerases (RNAPs) encode a GC-rich stem-loop structure followed by a polyuridine [poly(U)] tract, and it has been proposed that steric clash of the stem-loop with the exit pore of the RNAP imposes a shearing force on the RNA in the downstream RNA:DNA hybrid, resulting in misalignment of the active site We have observed that transcription through the GC-rich FMR1 5'UTR region favors R-loop formation, with the nascent (G-rich) RNA forming a stable RNA:DNA hybrid with the template DNA strand, thereby displacing the non-template DNA strand. Transcription termination by bacterial RNA polymerase (RNAP) occurs at sequences coding for a GC-rich RNA hairpin followed by a U-rich tract. We used single-molecule techniques to investigate the mechanism by which three representative terminators (his, t500, and tR2) destabilize the elongation complex (EC). In the 5' flanking region, nucleotides -234 to -213 encompass a GC-rich region which exhibits high homology (greater than 70%) to the 5' flanking regions of the genes of all the apolipoproteins published to date, namely, apo-A-II (-497 to -471), apo-A-I (approximately -196 to -179), apo-E (-409 to -391), and apo-C-III (approximately -116 to -103). Recently, we demonstrated that cotranscriptional RNA•DNA hybrids are preferentially formed at GC-rich trinucleotide and tetranucleotide repeat sequences in vitro as well as in human genomic DNA. Considering the extent of transcription through the human genome as well as the abundance of GC-rich and/or non-canonical DNA structure forming tandem repeats, RNA•DNA hybrids may represent a common mutagenic conformation. Recently, we demonstrated that cotranscriptional RNA•DNA hybrids are preferentially formed at GC-rich trinucleotide and tetranucleotide repeat sequences in vitro as well as in human genomic DNA.

yes

56a292ae496b62f23f000001

Are shadow enhancers associated with development?

Critical developmental control genes sometimes contain "shadow" enhancers that can be located in remote positions, including the introns of neighboring genes These results suggest that shadow enhancers represent a novel mechanism of canalization whereby complex developmental processes "bring about one definite end-result regardless of minor variations in conditions" Shadow enhancers flanking the HoxB cluster direct dynamic Hox expression in early heart and endoderm development. This suggests that they function as shadow enhancers to modulate the expression of genes from the HoxB complex during cardiac development. Regulatory analysis of the HoxA complex reveals that it also has enhancers in the 3' flanking region which contain RAREs and have the potential to modulate expression in endoderm and heart tissues This suggests that they function as shadow enhancers to modulate the expression of genes from the HoxB complex during cardiac development. Recent reports have shown that developmental genes often possess multiple discrete enhancer modules that drive transcription in similar spatio-temporal patterns: primary enhancers located near the basal promoter and secondary, or 'shadow', enhancers located at more remote positions. Together, the similarities in their location, enhancer output, and dependence on retinoid signaling suggest that a conserved cis-regulatory cassette located in the 3' proximal regions adjacent to the HoxA and HoxB complexes evolved to modulate Hox gene expression during mammalian cardiac and endoderm development. This suggests that they function as shadow enhancers to modulate the expression of genes from the HoxB complex during cardiac development.

yes

53319653d6d3ac6a3400003e

Does prudent diet reduce cardiovascular risk?

Using this approach, large prospective studies have reported reductions in CVD risk ranging from 10 to 60% in groups whose diets can be variously classified as ‘Healthy’, ‘Prudent’, Mediterranean’ or ‘DASH compliant’. Our findings suggest that a heart healthy dietary pattern is associated with moderately reduced risk of MI, but not related to risk of VTE. The systematically reviewed studies reveal that a high adherence to a Mediterranean type of diet or "prudent diet" is associated with reduced risk of CVD and some types of cancer, even in the elderly. In a large healthy Italian population, non-predefined dietary patterns including foods considered to be rather unhealthy, were associated with higher levels of cardiovascular risk factors, CRP and individual global CVD risk, whereas a "prudent-healthy" pattern was associated with lower levels. We observed an inverse association between the prudent pattern and AMI, with higher levels being protective. After multivariable adjustment, the prudent diet was associated with a 28% lower risk of cardiovascular mortality (95% confidence interval [CI], 13 to 40) and a 17% lower risk of all-cause mortality (95% CI, 10 to 24) when the highest quintile was compared with the lowest quintile. Greater adherence to the prudent pattern may reduce the risk of cardiovascular and total mortality, whereas greater adherence to the Western pattern may increase the risk among initially healthy women. Composite diets (such as DASH diets, Mediterranean diet, 'prudent' diet) have been demonstrated to reduce the risk of hypertension and CHD.

yes

553a54babc4f83e828000019

Are there Conserved Noncoding Elements (CNEs) in plant genomes?

Conservation and functional element discovery in 20 angiosperm plant genomes The detailed view of conservation across angiosperms revealed not only high coding-sequence conservation but also a large set of previously uncharacterized intergenic conservation Conserved noncoding sequences highlight shared components of regulatory networks in dicotyledonous plants Using a comparative genomics approach with four dicotyledonous plant species (Arabidopsis thaliana, papaya [Carica papaya], poplar [Populus trichocarpa], and grape [Vitis vinifera]), we detected hundreds of CNSs upstream of Arabidopsis genes Long identical multispecies elements in plant and animal genomes. Using an alignment-free information-retrieval approach, we have comprehensively identified all long identical multispecies elements (LIMEs), which include both syntenic and nonsyntenic regions, of at least 100 identical base pairs shared by at least two genomes In contrast, among six plant genomes, we only found nonsyntenic LIMEs Although complex LIMEs were found in both animal and plant genomes, they differed significantly in their composition and copy number Ultraconserved elements between the genomes of the plants Arabidopsis thaliana and rice We consequently compared the genomes of Arabidopsis thaliana and rice, which diverged about 200 million years ago, and identified 25 ultraconserved elements that are longer than 100 bp ultraconserved elements in plants tend to occur in clusters and locate at noncoding regions the functions of these plant ultraconserved elements and the reasons why they are practically frozen during the evolution of millions of years remain a mystery Conserved noncoding sequences in the grasses Using a local sequence alignment set to deliver only significant alignments, we found one or more CNSs in the noncoding regions of the majority of genes studied. Grass genes have dramatically fewer and much smaller CNSs than mammalian genes Conserved noncoding sequences among cultivated cereal genomes identify candidate regulatory sequence elements and patterns of promoter evolution Surveys for conserved noncoding sequences (CNS) among genes from monocot cereal species were conducted to assess the general properties of CNS in grass genomes and their correlation with known promoter regulatory elements Comparisons of orthologous maize-rice and maize-sorghum gene pairs identified 20 bp as a minimal length criterion for a significant CNS among grass genes, with few such CNS found to be conserved across rice, maize, sorghum, and barley

yes

530cf4fe960c95ad0c000009

Can tetracycline affect tooth formation?

he results of that study, reported earlier (Rebich et al., 1983), indicated that over one-fifth of the American Indian children had discoloration of the dentition due to ingestion of tetracycline during the years of tooth formatio ale Wistar rats prelabeled with tetracycline to mark surfaces of bone and tooth formation-mineralization were placed into orbit for 18.5 days aboard the Soviet COSMOS-1129 Biosatellit It was concluded that the increased tetracycline incorporation reflected a higher rate of mineralization associated with faster tooth formation in the unimpeded toot n this investigation an attempt has been made to determine the relationship between the staining of permanent teeth by tetracycline administered during the period of tooth formation with the dosage of the drug and the duration of therap definite relationship between total dosage and staining and duration of administration and staining was established; the condition occurred with greater frequency (in more than one-third of the children) when the total dosage exceeded 3 g. or the duration of treatment was longer than 10 days This case report suggests the possibility that discoloration from tetracycline may not be limited to tooth development in the child, but may also affect the adult dentition

yes

530cf4fe960c95ad0c000003

Could Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) cause sudden cardiac death?

Here we refine our approach, and apply it to novel variants found in 2266 patients across two large cohorts with inherited sudden death syndromes, namely catecholaminergic polymorphic ventricular tachycardia (CPVT) or Brugada syndrome (BrS). Calsequestrin-associated catecholaminergic polymorphic ventricular tachycardia (CPVT2) can cause sudden death in young individuals in response to stress. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic cardiac disorder characterized by life-threatening arrhythmias induced by physical or emotional stress, in the absence structural heart abnormalities. The arrhythmias may cause syncope or degenerate into cardiac arrest and sudden death which usually occurs during childhood In many cases the cause of death can be elucidated by medico-legal autopsy, however, a significant number of these cases remain unexplained despite a detailed postmortem investigation and are labeled as sudden unexplained death (SUD). Post-mortem genetic testing, so called molecular autopsy, revealed that primary arrhythmogenic disorders including long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) may account for a certain number of these cases. We report a family with repeat events of sudden cardiac death and recurrent ventricular fibrillation in a teenage girl, where autopsy data and clinical investigations were inconclusive. The diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) was established only following finding a gene mutation in the cardiac ryano Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. In conclusion, patients with CASQ2-associated CPVT should be recommended to receive ICDs to prevent sudden death when medical therapy is not effective. Cardiac channelopathies associated with structurally normal hearts such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) yield no evidence to be found at autopsy, leaving coroners, medical examiners, and forensic pathologists only to speculate that a lethal arrhythmia might lie at the heart of a sudden unexplained death (SUD). Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare adrenergically mediated arrhythmogenic disorder classically induced by exercise or emotional stress and found in structurally normal hearts. It is an important cause of cardiac syncope and sudden death in childhood. We also compare CPVT to other notable cardiomyopathic and channelopathic causes of sudden death in youth including hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, long QT syndrome, short QT syndrome, and Brugada syndrome. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease that can cause sudden cardiac death due to ventricular fibrillation (VF). Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disease that manifests as syncope or sudden death during high adrenergic tone in the absence of structural heart defects. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac channelopathy characterized by altered intracellular calcium handling resulting in ventricular arrhythmias and high risk of cardiac sudden death in young cases with normal structural hearts Early detection of CPVT is crucial because opportune medical intervention prevents sudden cardiac death. If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. Sudden death may be the first manifestation of the disease. Hereditary non-structural diseases such as catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT, and the Brugada syndrome as well as structural disease such as hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) cause a significant percentage of sudden cardiac deaths in the young Patients with CPVT present with exercise-induced syncope and sudden cardiac death but normal resting electrocardiograms. Although structural cardiovascular abnormalities explain most cases of sudden cardiac death in young people, the cause of death remains unexplained after autopsy in 10% to 30% of cases. Potentially lethal ion channel disorders (channelopathies) such as the long QT syndromes (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and the Brugada syndrome (BrS) may account for at least one-third of these unexplained cases. Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exercise-induced sudden cardiac death. The inherited arrhythmogenic diseases associated with the transmembranous ionic channels, anchoring proteins or intracellular calcium regulating proteins are thought to be responsible for sudden cardiac death in infants, children, and young adults who have structurally normal hearts. Recent genetic analyses have identified congenital diseases such as the long-QT syndrome (LQTS), the Jervell and Lange-Nielsen syndrome (JLNS), the Brugada syndrome (BrS), the short-QT syndrome (SQTS), the arrhythmogenic right ventricular cardiomyopathy type 2 (ARVC2), and the catecholamine-induced polymorphic ventricular tachycardia (CPVT) /familial polymorphic ventricular tachycardia (FPVT). At least some cases of sudden, unexplained death in young individuals may be ascribed to CPVT

yes

530cf4fe960c95ad0c000002

Does Apolipoprotein E (ApoE) have anti-inflammatory activity?

have previously reported that apolipoprotein E (apoE), a protein component of very-low-density lipoproteins (VLDL) and high-density lipoproteins and a potent plasma-borne atheroprotective factor, exerts anti-inflammatory activity in macrophages by switching the activation profile from M1 ("classic") to M2 ("alternative") in a process involving signaling via low-density lipoprotein receptor anti-inflammatory activity in macrophages Small peptides corresponding to the receptor-binding region of apoE mimic the anti-inflammatory activity of the apoE Apolipoprotein (apo) E-containing high-density lipoprotein (HDL) has antioxidant, anti-inflammatory and anti-atherogenic properties

yes

530cf4fe960c95ad0c000005

Is the ACE inhibitor indicated for lung cancer treatment?

The angiotensin converting enzyme (ACE) inhibitors are used widely as antihypertensive agents, and it has been suggested that they decrease the risk of some cancers, although available data are conflicting. Using cell viability and fluorescent activated cell sorting analysis tests, we demonstrated that captopril inhibited the viability of LNM35 cells by inducing apoptosis, providing insight about the mechanisms underlying its antitumorigenic activities. In view of these experimental findings, we conclude that captopril could be a promising option for the treatment of lung cancer. In order to determine the mechanism by which captopril inhibited tumor growth, we investigated the impact of this drug on cell proliferation, apoptosis, and angiogenesis. Immunohistochemical analysis demonstrated that captopril treatment significantly reduced the number of proliferating cells (Ki-67) in the tumor samples but was not associated with inhibition of tumor angiogenesis (CD31). Using this model, we demonstrated that daily IP administration of captopril (2.8 mg/mouse) for 3 weeks resulted in a remarkable reduction of tumor growth (58%, P < 0.01) and lymph node metastasis (50%, P= 0.088). Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models ACE inhibitors may decrease the incidence of radiation pneumonitis in patients receiving thoracic radiation for lung cancer.

no

55425615ed966d112c000003

Are genes symmetrically distributed between leading and lagging DNA strand in bacteria?

Genomic DNA is used as the template for both replication and transcription, whose machineries may collide and result in mutagenesis, among other damages. Because head-on collisions are more deleterious than codirectional collisions, genes should be preferentially encoded on the leading strand to avoid head-on collisions, as is observed in most bacterial genomes examined. Most genes in bacteria are encoded on the leading strand of replication. This presumably avoids the potentially detrimental head-on collisions that occur between the replication and transcription machineries when genes are encoded on the lagging strand. The majority of bacterial genes are located on the leading strand genes of some functional categories such as ribosome have higher preferences to be on the leading strands genes of some functional categories such as transcription factor have higher preferences on the lagging strands essential genes are more preferentially situated at the leading strand than at the lagging strand remarkable strand-bias of the distribution of essential genes Head-on encounters between the replication and transcription machineries on the lagging DNA strand can lead to replication fork arrest and genomic instability. To avoid head-on encounters, most genes, especially essential and highly transcribed genes, are encoded on the leading strand such that transcription and replication are co-directional. Replication-associated purine asymmetry may contribute to strand-biased gene distribution. strand-biased gene distribution (SGD) SGD correlates not only with polC, but also with purine asymmetry (PAS) In bacteria, most genes are on the leading strand of replication, a phenomenon attributed to collisions between the DNA and RNA polymerases. genes whose expression is important for fitness are selected to the leading strand because this reduces the duration of these interruptions Among prokaryotic genomes, the distribution of genes on the leading and lagging strands of the replication fork is known to be biased. We show that the evidence they provided is invalid and that the existence of lagging strand encoded genes is explainable by a balance between deleterious mutations that bring genes from the leading to the lagging strand and purifying selection purging such mutants. Based on those experimentally determined for 10 bacteria, we find that essential genes are more preferentially situated at the leading strand than at the lagging strand, for all the 10 genomes studied, confirming previous findings based on either smaller datasets or putatively assigned ones by homology search. The majority of bacterial genes are located on the leading strand, and the percentage of such genes has a large variation across different bacteria. Most genes in bacteria are encoded on the leading strand of replication. This paradox could be explained by assuming that the stronger mutation pressure and selection after inversion preferentially eliminate genes transferred from the leading to the lagging DNA strand. We have shown that the relative number of translocations which have switched positions of genes from the leading to the lagging DNA strand is lower than the number of translocations which have transferred genes from the lagging strand to the leading strand of prokaryotic genomes. Most genes in bacteria are encoded on the leading strand of replication The majority of bacterial genes are located on the leading strand, and the percentage of such genes has a large variation across different bacteria We have shown that the relative number of translocations which have switched positions of genes from the leading to the lagging DNA strand is lower than the number of translocations which have transferred genes from the lagging strand to the leading strand of prokaryotic genomes Using Monte Carlo methods, we have simulated, under experimentally determined directional mutation pressure, the divergence rate and the elimination rate of genes depending on their location in respect to the leading/lagging DNA strands in the asymmetric prokaryotic genome

no

531616bdb166e2b806000003

Is c-myc subject to regulation by the circadian clock?

The current study encompasses the investigation of simultaneous expression of four circadian clock genes (Bmal1, Clock, Per1 and Per2) and three clock-controlled cell cycle genes (Myc, Cyclin D1 and Wee1) Our results suggest that aberrant expression of circadian clock genes can lead to aberrant expression of their downstream targets that are involved in cell proliferation and apoptosis and hence may result in manifestation of CLL. Loss of Bmal1 reduced the expression of per1, per2, per3, wee1 and p53. The expression of p21 and c-myc was also altered in certain cell lines. In particular, the proto-oncogene c-Myc has been documented to be under circadian regulation. The circadian expression of c-MYC is modulated by the histone deacetylase inhibitor trichostatin A in synchronized murine neuroblastoma cells. Our results, using the murine neuroblastoma cell line N2A, show that Per1 and c-Myc steady-state mRNA levels oscillate with the same phase. These experiments demonstrate for the first time that a significant decrease in c-Myc transcript and protein levels can be achieved after a short TSA treatment applied only at specific circadian times. This is also followed by a reduction in the proliferation rate of the cell population. Among the circadian output pathways, the rhythmic sympathetic signaling plays a key role in the central-peripheral timing mechanism that simultaneously activates the cell cycle clock via AP1-controlled Myc induction and p53 via peripheral clock-controlled ATM activation. Jet-lag promptly desynchronizes the central clock-SNS-peripheral clock axis, abolishes the peripheral clock-dependent ATM activation, and activates myc oncogenic potential, leading to tumor development in the same organ systems in wild-type and circadian gene-mutant mice. The results showed that over-expression of Per2 induced not only cell cycle arrest at G2/M phase but also an increase in apoptosis, which was confirmed by characteristic morphological changes, FCM and evident DNA fragmentation. Further experiments confirmed both up-regulation of P53 and down-regulation of CylinB1and C-myc. On the other hand, while P53 was found to be down-regulated. CylinB1 and C-myc were up-regulated. after Per2 knockdown. We also show that BMAL1 epigenetic inactivation impairs the characteristic circadian clock expression pattern of genes such as C-MYC, catalase, and p300 in association with a loss of BMAL1 occupancy in their respective promoters. Per2 mutant (Per2(m/m)) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control. The expression of cell cycle genes such as Wee1, Cyclins, and c-Myc are under circadian control and could be directly under the regulation of the circadian transcriptional complex. Overexpressed mPER2 also altered the expression of apoptosis-related genes. The mRNA and protein levels of c-Myc, Bcl-X(L) and Bcl-2 were downregulated, Temporal expression of genes involved in cell cycle regulation and tumor suppression, such as c-Myc, Cyclin D1, Cyclin A, Mdm-2 and Gadd45alpha is deregulated in mPer2 mutant mice. The temporal expression of genes involved in cell cycle regulation and tumor suppression, such as c-Myc, Cyclin D1, Cyclin A, Mdm-2, and Gadd45alpha, is deregulated in mPer2 mutant mice.

yes

531c380db166e2b80600003f

is there an increase in ultrasound comets after intense exercise?

Healthy athletes developed subclinical increase in pulmonary water content immediately after an Ironman race at sea level, as shown by the increased number of ULCs related to cardiac changes occurring during exercise. Increased EVLW is associated with estimated PCWP and indices of left ventricular systolic and diastolic dysfunction. The additional exercise-induced increase of PCWP, the worsening of left ventricular diastolic function, and extensive wall-motion abnormalities correlate with variations of EVLW. Among them chest ultrasonography can detect and quantify the extravascular lung water, creating "comet-tail" ultrasound artefacts (ULCs) from water-thickened pulmonary interlobular septa. In top-level breath-hold divers, chest sonography frequently reveals an increased number of ULCs after immersion, indicating a relatively high prevalence of (often subclinical) reversible extravascular lung water accumulation.

yes

57135fae1174fb1755000004

Can cffDNA be used for non-invasive testing?

Non-invasive prenatal testing using cell-free fetal DNA in maternal circulation The identification of cell-free fetal DNA (cffDNA) in maternal circulation has made non-invasive prenatal testing (NIPT) possible. In recent years, technical advances in the molecular analysis of fetal DNA (e.g., digital PCR and massively parallel sequencing (MPS)) has enabled the successful implementation of noninvasive testing into clinical practice, such as fetal sex assessment, RhD genotyping, and fetal chromosomal aneuploidy detection.With the ability to decipher the entire fetal genome from maternal plasma DNA, we foresee that an increased number of non-invasive prenatal tests will be available for detecting many single-gene disorders in the near future. This review briefly summarizes the technical aspects of the NIPT and application of NIPT in clinical practice. First identified in 1997, cell-free fetal DNA (cffDNA) has just recently been used to detect fetal aneuploidy of chromosomes 13, 18, and 21, showing its potential to revolutionize prenatal genetic testing as a non-invasive screening tool To determine how adults in the United States view non-invasive prenatal testing using cell-free fetal DNA (cffDNA testing) in order to help estimate uptake Non-invasive prenatal testing of cell-free fetal DNA (cffDNA) in maternal plasma can predict the fetal RhD type in D negative pregnant women The identification of cell-free fetal DNA (cffDNA) in maternal circulation has made non-invasive prenatal testing (NIPT) possible The effectiveness and clinical utility of non-invasive prenatal diagnosis (NIPD) for fetal sex determination using cell-free fetal DNA (cffDNA) was assessed by undertaking a prospective national audit of UK testing The recent release of new, non-invasive prenatal tests for fetal aneuploidy using cell-free fetal DNA (cffDNA) has been hailed as a revolution in prenatal testing and has triggered significant commercial interest in the field Non-invasive prenatal aneuploidy testing that utilizes cell-free fetal DNA (cffDNA) circulating in maternal blood is one example of an innovative technology that promises significant benefits for its intended end users; however, it is currently uncertain whether it will achieve widespread clinical implementation Analysis of cell free fetal (cff) DNA in maternal plasma is used routinely for non invasive prenatal diagnosis (NIPD) of fetal sex determination, fetal rhesus D status and some single gene disorders Non-invasive prenatal diagnosis (NIPD) using cell-free fetal DNA (cffDNA) in maternal plasma is an alternative to invasive prenatal diagnosis (IPD), which carries a 1% risk of miscarriage. The recent release of new, non-invasive prenatal tests for fetal aneuploidy using cell-free fetal DNA (cffDNA) has been hailed as a revolution in prenatal testing and has triggered significant commercial interest in the field. The effectiveness and clinical utility of non-invasive prenatal diagnosis (NIPD) for fetal sex determination using cell-free fetal DNA (cffDNA) was assessed by undertaking a prospective national audit of UK testing. NIFTY (Non-invasive Fetal Trisomy Test) is a non-invasive prenatal test which is used for diagnosing fetal trisomy. The test is based on the analysis of cell free fetal DNA (cffDNA) present in the plasma and serum of a pregnant woman. Using non-invasive method of cffDNAs in the shortest time possible, as well as avoiding invasive tests for early determination of fetal gender, provides the opportunity of deciding and employing early treatment for fetuses at risk of genetic diseases. The identification of cell-free fetal DNA (cffDNA) in maternal circulation has made non-invasive prenatal testing (NIPT) possible. To determine how adults in the United States view non-invasive prenatal testing using cell-free fetal DNA (cffDNA testing) in order to help estimate uptake. Nowadays, new advances in the use of cell free fetal DNA (cffDNA) in maternal plasma of pregnant women has provided the possibility of applying cffDNA in prenatal diagnosis as a non-invasive method. Non-invasive prenatal testing of cell-free fetal DNA (cffDNA) in maternal plasma can predict the fetal RhD type in D negative pregnant women. Prevention of contamination following our anti-contamination criteria is a good practice for certain non-invasive sex determination, using cffDNA.

yes

56cab4c75795f9a73e00001f

Do U6-associated proteins Lsm4 and Lsm6 interact with SMN?

SMN also interacts with at least two of the U6-associated Sm-like (Lsm) proteins, Lsm4 and Lsm6. Interestingly, SMN also interacts with at least two of the U6-associated Sm-like (Lsm) proteins, Lsm4 and Lsm6 Furthermore, we present evidence for two separate binding sites in SMN for Sm/Lsm proteins. Interestingly, SMN also interacts with at least two of the U6-associated Sm-like (Lsm) proteins, Lsm4 and Lsm6. Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B' and the Sm-like protein LSm4, and their interaction with the SMN protein. Interestingly, SMN also interacts with at least two of the U6-associated Sm-like (Lsm) proteins, Lsm4 and Lsm6. Furthermore, the carboxyl-terminal arginine- and glycine-rich domain of Lsm4 directly interacts with SMN. This entity promotes the binding of a set of factors, termed LSm/Sm proteins, onto snRNA to form the core structure of these particles. Toward an assembly line for U7 snRNPs: interactions of U7-specific Lsm proteins with PRMT5 and SMN complexes. In this report, we demonstrate that the coilin C-terminal domain binds directly to various Sm and Lsm proteins via their Sm motifs. We show that the region of coilin responsible for this binding activity is separable from that which binds to SMN. Thus, the ability to interact with free Sm (and Lsm) proteins as well as with intact snRNPs, indicates that coilin and CBs may facilitate the modification of newly formed snRNPs, the regeneration of 'mature' snRNPs, or the reclamation of unassembled snRNP components. Moreover this structure has important consequences for snRNP assembly that is mediated by two complexes containing the PRMT5 methyltransferase and the SMN (survival of motor neurons) protein, respectively. Arginine/glycine (RG)-rich domains in components of the SMN complex interact with Sm, like-Sm (LSm), fibrillarin, RNA helicase A (Gu), and coilin proteins, all of which are antigen targets in a variety of diseases.

yes

56cf2a153975bb303a000004

Does MVIIA and MVIIC bind to the same calcium channel?

We examined the post-pubertal behavioral effects of neonatal (postnatal day 7) medial prefrontal cortex infusion of either vehicle or N-type and P/Q-type presynaptic voltage-dependent calcium channel blockers (omega-conotoxins MVIIA and MVIIC respectively; 6.8 and 45 pmol infused respectively) in rat pups. Additionally, the number of binding sites for radioligands labelling L- ([3H]nitrendipine), N- ([125I]omega-conotoxin MVIIA) and P/Q-type ([125I]omega-conotoxin MVIIC) Ca2+ channels was assessed in the rat retina and, for further comparison, in the rat cortex. Omega-conotoxin MVIIC (MVIIC) blocks P/Q-type calcium channels with high affinity and N-type calcium channels with low affinity, while the highly homologous omega-conotoxin MVIIA blocks only N-type calcium channels. However, omega-conotoxin MVIIC seems to bind to sites different from those recognised by omega-conotoxin GVIA and MVIIA, which are markedly differentiated by their Ca2+ requirements for binding to their receptors. Despite their high sequence homology, the peptide neurotoxins omega-conotoxin MVIIA and MVIIC selectively block N- and P/Q-type calcium channels, respectively. Replacement of the N-terminal half of omega-conotoxin MVIIC, a peptide blocker of P/Q-type calcium channels, with that of omega-conotoxin MVIIA significantly increased the affinity for N-type calcium channels. Omega-conotoxin MVIIC (MVIIC) blocks P/Q-type calcium channels with high affinity and N-type calcium channels with low affinity, while the highly homologous omega-conotoxin MVIIA blocks only N-type calcium channels. We wished to obtain MVIIC analogues more selective for P/Q-type calcium channels than MVIIC to elucidate structural differences among the channels, which discriminate the omega-conotoxins. omega-conotoxin MVIIC seems to bind to sites different from those recognised by omega-conotoxin GVIA and MVIIA,

no

56f7d9dd09dd18d46b000014

Is arimoclomol a co-inducer of the heat shock response?

Arimoclomol is a hydroxylamine derivative, a group of compounds which have unique properties as co-inducers of heat shock protein expression, but only under conditions of cellular stress. In this review we summarize the evidence for the neuroprotective effects of enhanced heat shock protein expression by Arimoclomol and other inducers of the Heat Shock Response. arimoclomol, a co-inducer of the heat shock stress response, The heat-shock response (HSR) was activated in P23H retinae, and this was enhanced with arimoclomol treatment. We also assessed these functions in mice treated with a known heat shock protein inducer, arimoclomol. Under conditions of excessive stress, arimoclomol induces amplification of the cytoprotective heat shock response in order to protect motor neurons from death. Although both arimoclomol and celastrol induced the expression of Hsp70 Arimoclomol, an amplifier of heat shock protein expression involved in cellular stress response, has emerged as a potential therapeutic candidate in amyotrophic lateral sclerosis (ALS) in recent years. The mechanism of action of arimoclomol involves potentiation of the heat shock response, and treatment with arimoclomol increased Hsp70 expression. Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress. Arimoclomol, a coinducer of heat shock proteins, delayed progression of amyotrophic lateral sclerosis (ALS) in a mouse model in which motor neurons in the spinal cord and motor cortex degenerate.

yes

536172d17d100faa09000009

Has silicon been used in treatment of incontinence ?

an artificial anal sphincter. Worldwide, there are two established devices on the market: the artificial bowel sphincter® (ABS) from A. M. S. (Minnetonka, MN, USA) and the soft anal band® from A. M. I. (Feldkirch, Austria). How to implant the artificial anal sphincter? Both devices consist of a silicon cuff which can be filled with fluid. The InVance™ system uses a silicon-coated polyester sling positioned under the bulbar urethra via a perineal incision. Through a perineal incision three titanium screws with a polipropylene suture were inserted in each ischiopubic rami, and a silicon/polipropylene mesh (Invance) is affixed to them, compressing the bulbar urethra surgical treatment of female stress urinary incontinence with a trans-obturator sub-urethral tape of Uratape (Porgés). METHODS: Treatment and follow up of their complication were performed at the CHRU of Lille. RESULTS: In both cases, this complication is related to prolonged vaginal exposition of the tape. Vaginal erosion always occurs next to the silicon coated section of the tape A non-elastic, polypropylene tape (UraTape, Mentor-Porgès) with a silicon coated central part was placed under the mid-urethra. Stress incontinence is a rare complication in men, usually following prostatic surgery. It can be treated conservatively with pelvic floor training and alpha-adrenergic receptor agonists and if necessary surgically with submucosal collagen or silicon injections in the sphincter area or implantation of a sphincter prosthesis The Femassist is a medical-grade silicon dome-shaped device, worn over the urethra and held securely via suction and a commercially available adhesive lotion. To examine the performance of a silicon urinary control device for nonsurgical management of women with genuine stress incontinence The "FemAssist" is a dome-shaped medical grade silicon device intended to be worn over the external urethral meatus and held in place by suction and an adhesive gel. Thirty eight women with varying degrees of genuine stress urinary incontinence (GSUI) or mixed incontinence on multichannel urodynamic testing were fitted with one of two sizes of "FemAssist

yes

56ebfac12ac5ed1459000001

Does the 3D structure of the genome remain stable during cell differentiation?

We identify large, megabase-sized local chromatin interaction domains, which we term 'topological domains', as a pervasive structural feature of the genome organization. The domains are stable across different cell types and highly conserved across species, indicating that topological domains are an inherent property of mammalian genomes Insulators are involved in 3D genome organization at multiple spatial scales and are important for dynamic reorganization of chromatin structure during reprogramming and differentiation. The relation between alterations in chromatin structure and changes in gene expression during cell differentiation has served as a paradigm to understand the link between genome organization and function. Architectural proteins orchestrate higher-order chromatin organization through the establishment of interactions between regulatory elements across multiple spatial scales. The regulation of these proteins, their interaction with DNA, and their co-occurrence in the genome, may be responsible for the plasticity of 3D chromatin architecture that dictates cell and time-specific blueprints of gene expression. The role of 3D genome organisation in the control and execution of lineage-specific transcription programmes during the development and differentiation of multipotent stem cells into specialised cell types remains poorly understood. Chromatin structural states and their remodelling, including higher-order chromatin folding and three-dimensional (3D) genome organisation, play an important role in the control of gene expression Here, we show that substantial remodelling of the higher-order chromatin structure of the epidermal differentiation complex (EDC), a keratinocyte lineage-specific gene locus on mouse chromosome 3, occurs during epidermal morphogenesis. Many studies have suggested a link between the spatial organization of genomes and fundamental biological processes such as genome reprogramming, gene expression, and differentiation. Moreover, we reveal that formation of such highly condensed, transcriptionally repressed heterochromatin promotes transcriptional activation of differentiation genes and loss of pluripotency. The open chromatin of embryonic stem cells (ESCs) condenses into repressive heterochromatin as cells exit the pluripotent state. we find that localized heterochromatin condensation of ribosomal RNA genes initiates establishment of highly condensed chromatin structures outside of the nucleolus We focus on the emerging relationship between genome organization and lineage-specific transcriptional regulation, which we argue are inextricably linked. Cells face the challenge of storing two meters of DNA in the three-dimensional (3D) space of the nucleus that spans only a few microns. The nuclear organization that is required to overcome this challenge must allow for the accessibility of the gene regulatory machinery to the DNA and, in the case of embryonic stem cells (ESCs), for the transcriptional and epigenetic changes that accompany differentiation In this review we summarize some of the recent findings illuminating the 3D structure of the eukaryotic genome, as well as the relationship between genome topology and function from the level of whole chromosomes to enhancer-promoter loops with a focus on features affecting genome organization in ESCs and changes in nuclear organization during differentiation We observe that although self-associating chromatin domains are stable during differentiation, chromatin interactions both within and between domains change in a striking manner, altering 36% of active and inactive chromosomal compartments throughout the genome

no

516d4b27298dcd4e51000077

Does dronedarone affect T3 and T4 levels?

Amiodarone resulted in increased T4, T4/T3 and rT3, whereas dronedarone did not alter the thyroid hormone profile in normal animals. Fifty-five Wistar rats were randomly allocated to a 2-week oral treatment with either vehicle (n=18), amiodarone (30 mg/kg, n=20), or dronedarone (30 mg/kg, n=17). Thyroid function was similar in the 3 groups. Plasma levels of T3, T4, and rT3 were changed after SR 33589 treatment except a decrease in T4 level at the highest dose whilst the T4 T3 ratio and the level of rT3 were dose-dependently increased by amiodarone treatment.

no

513f4892bee46bd34c000014

Does triiodothyronine (T3) has cardiac angiogenic effects?

T3-induced cardiac sprouting angiogenesis in adult hypothyroid mice was associated with PDGF-BB, PDGFR-β and downstream activation of Akt. L-T3 significantly increased angiogenesis and cell survival and enhanced the expression of nuclear-encoded transcription factors involved in these processes. T(3) administration restored TRbeta mRNA expression level in AAC hearts to the control level. Rbeta knockout and TRalpha/TRbeta double-knockout mice both exhibited significantly less capillary density in LV compared with wild-type mice. TRbeta in the coronary ECs regulates capillary density during cardiac development, and down-regulation of TRbeta results in coronary microvascular rarefaction during pathological hypertrophy.

yes

54d8f37b4b1fd0d33c000004

Is the HRC Ser96Ala variant associated with sudden cardiac death in patients with dilated cardiomyopathy?

The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias in idiopathic DCM and may serve as an independent predictor of susceptibility to arrhythmogenesis in the setting of DCM. The Ser96Ala (S96A) mutation within the histidine rich Ca(2+) binding protein (HRC) has recently been linked to cardiac arrhythmias in idiopathic dilated cardiomyopathy patients, potentially attributable to an increase in spontaneous Ca(2+) release events. A human genetic variant (Ser96Ala) in the sarcoplasmic reticulum (SR) histidine-rich Ca(2+)-binding (HRC) protein has been linked to ventricular arrhythmia and sudden death in dilated cardiomyopathy. The histidine-rich calcium binding protein (HRC) Ser96Ala polymorphism was shown to correlate with ventricular arrhythmias and sudden death only in dilated cardiomyopathy patients but not in healthy human carriers. HRC has been linked with familiar cardiac conduction disease and an HRC polymorphism was shown to associate with malignant ventricular arrhythmias in the background of idiopathic dilated cardiomyopathy. A human genetic variant (Ser96Ala) in the sarcoplasmic reticulum (SR) histidine-rich Ca(2+)-binding (HRC) protein has been linked to ventricular arrhythmia and sudden death in dilated cardiomyopathy The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias in idiopathic DCM and may serve as an independent predictor of susceptibility to arrhythmogenesis in the setting of DCM. The histidine-rich calcium binding protein (HRC) Ser96Ala polymorphism was shown to correlate with ventricular arrhythmias and sudden death only in dilated cardiomyopathy patients but not in healthy human carriers The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy. These findings indicate that the HRC Ser96Ala variant increases the propensity of arrhythmogenic Ca(2+) waves in the stressed failing heart, suggesting a link between this genetic variant and life-threatening ventricular arrhythmias in human carriers.

yes

5512c91b6a8cde6b7200000b

Are BRAF mutations common in melanoma?

patients with BRAF-mutant melanoma. BRAF-mutated melanoma The RAS/RAF/MEK/ERK pathway has been reported to be activated in over 80% of all cutaneous melanomas, making it the focus of many scientific studies in the melanoma field. Discoveries of mutations and aberrant expression of components in this cascade, in particular, BRAF and NRAS render a deeper understanding of the mechanisms responsible for oncogenesis and provide new therapeutic strategies for this deadly disease. BRAF-targeted therapies (e.g., vemurafenib, dabrafenib) have showed impressive results in systemic therapy for melanoma harboring activating BRAF V600E mutations. An independent cohort of 91 archival MUPs was also screened for 46 hot spot mutations highly prevalent in melanoma including BRAF, NRAS, KIT, GNAQ, and GNA11. a high rate of BRAF (45 of 101, 45%) and NRAS (32 of 101, 32%) mutations, collectively indicating a mutation profile consistent with cutaneous sun-exposed melanomas. Treatment of advanced melanoma has been improved with the advent of the BRAF inhibitors. BRAF is the most prevalent oncogene and an important therapeutic target in melanoma. Activating BRAF mutations, leading to constitutive activation of the MAPK signaling pathway, are common in a variety of human cancers. Several small molecule BRAF inhibitors have been developed during the last years and shown promising results in clinical trials, especially for metastatic melanoma, while they have been less effective in colon cancer. BRAF mutations have emerged as an important predictive biomarker for metastasized melanoma. BRAF V600 selective inhibitors have been approved for the treatment of V600 mutation positive metastatic melanoma, BRAF(V600) mutation-positive melanoma Melanoma is the most aggressive form of skin cancer. The treatment of patients with advanced melanoma is rapidly evolving due to an improved understanding of molecular drivers of this disease. Somatic mutations in BRAF are the most common genetic alteration found in these tumors. genetically activated BRAF, is now commonly prescribed for metastatic melanoma harboring a BRAF mutation. BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAF(V600)-mutant melanoma, but acquired drug resistance is almost universal. Most patients with BRAF(V600)-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. BRAF(V600E) mutation confers constitutive BRAK kinase activation in melanoma cells, promoting tumor growth. This discovery led to the development of BRAF kinase inhibitors like vemurafenib and dabrafenib. (V600)BRAF mutation was identified as an ideal target for clinical therapy due to its indispensable roles in supporting melanoma initiation and progression. The Braf(V600E) mutation has been detected in patients with metastatic melanoma, colon, thyroid, and other cancers. Since the identification of activating BRAF mutations and subsequent development of drugs targeting the mutant BRAF protein, oncologists now need to incorporate prognostic and predictive biomarkers into treatment decisions for their melanoma patient BRAF mutations occur in approximately 8% of all human cancers and approach 50% in melanoma and papillary carcinoma of thyroid. Vemurafenib is a selective and potent small molecule inhibitor of the V600 mutant form of the BRAF protein used in the treatment of melanoma and colorectal cancer. Molecular studies demonstrated that the melanoma was positive for the 1799T>A (V600E) mutation in the BRAF gene. RAF kinase inhibitors have substantial therapeutic effects in patients with BRAF-mutant melanoma. An activating BRAF (V600E) kinase mutation occurs in approximately half of melanomas. Activating mutations in the BRAF gene occur in approximately 50% of melanomas. More than 70% of BRAF mutations are V600E and 10-30% are V600K. Activating BRAF mutations, leading to constitutive activation of the MAPK signaling pathway, are common in a variety of human cancers. Several small molecule BRAF inhibitors have been developed during the last years and shown promising results in clinical trials, especially for metastatic melanoma, while they have been less effective in colon cancer. Personalized melanoma medicine has progressed from histopathologic features to serum markers to molecular profiles. Since the identification of activating BRAF mutations and subsequent development of drugs targeting the mutant BRAF protein, oncologists now need to incorporate prognostic and predictive biomarkers into treatment decisions for their melanoma patients. The clinical activity of BRAF inhibitor (BRAF-I) therapy is a major breakthrough in the treatment of metastatic melanoma carrying BRAF mutations. The discovery of BRAF mutations in melanoma led to the development of BRAF inhibitors for the treatment of advanced melanoma. BRAF represents one of the most frequently mutated protein kinase genes in human tumours. The mutation is commonly tested in pathology practice. BRAF mutation is seen in melanoma, papillary thyroid carcinoma (including papillary thyroid carcinoma arising from ovarian teratoma), ovarian serous tumours, colorectal carcinoma, gliomas, hepatobiliary carcinomas and hairy cell leukaemia. Indeed, recent clinical trials involving BRAF selective inhibitors exhibited promising response rates in metastatic melanoma patients. A majority of cutaneous melanomas show activating mutations in the NRAS or BRAF proto-oncogenes, components of the Ras-Raf-Mek-Erk (MAPK) signal transduction pathway. The discovery of activating BRAF mutations in ∼50% of all melanomas has proved to be a turning point in the therapeutic management of the disseminated disease. This review summarizes the critical role of BRAF in melanoma pathophysiology, the clinical and pathological determinants of BRAF mutation status and finally addresses the current state of the art of BRAF inhibitors. To better understand the BRAF mutation profile in melanomas, we retrospectively analyzed data from 1112 primary and metastatic melanomas at our institution. The cohort included nonacral cutaneous (n = 774), acral (n = 111), mucosal (n = 26), uveal (n = 23), leptomeningeal (n = 1), and metastatic melanomas of unknown primary site (n = 177). BRAF mutation hotspot regions in exons 11 and 15 were analyzed by pyrosequencing or with the primer extension MassARRAY system. A total of 499 (44.9%) specimens exhibited BRAF mutations, involving exon 15 [497 (99.6%)] or exon 11 [2 (0.4%)]. p.V600E was detected in 376 (75.4%) cases; the remaining 123 (24.6%) cases exhibited non-p.V600E mutations, of which p.V600K was most frequent [86 (17.2%)]. BRAF mutations were more frequent in nonacral cutaneous (51.4%) than acral melanomas [18 (16.2%)] (P < 0.001); however, there was no significant difference among cutaneous histological subtypes. All mucosal, uveal, and leptomeningeal melanomas were BRAF wild type (WT). Recently, it was reported that BRAF mutations are frequent in melanoma. Activating mutations in BRAF are the most common genetic alterations in melanoma. Oncogenic BRAF and NRAS mutations are frequent in malignant melanoma. Mutation of BRAF is now known to be common in cutaneous melanomas, and raises possible new therapeutic options of anti-RAF treatment for these patients BRAF mutations are common events in a variety of melanocytic nevi and primary cutaneous melanomas Approximately 40-60% of melanomas from Caucasian populations carry activating mutations in the BRAF oncogene, with the most common being the p.Val600Glu (V600E) hotspot mutation in exon 15 Using a cohort of 115 patients with primary invasive melanomas, we show that BRAF mutations are statistically significantly more common in melanomas occurring on skin subject to intermittent sun exposure than elsewhere (23 of 43 patients; P<.001, two-sided Fisher's exact test) BRAF mutations have been identified as the most common oncogene mutation in melanomas, especially important in those originating on nonchronically sun-damaged skin.

yes

511a1e12df1ebcce7d000009

Is it possible to determine the proteome of a formalin fixed and paraffin embedded (FFPE) tissue?

ver the last few years, advances in methodology have made it possible to recover peptides from FFPE tissues that yield a reasonable representation of the proteins recovered from identical fresh or frozen specimens. Thus, laser capture microdissection of FFPE tissue coupled with downstream proteomic analysis is a valid approach Qualitative proteome profiling of formalin-fixed, paraffin-embedded (FFPE) tissue is advancing the field of clinical proteomics. Recent improvements in proteomics technologies, from the 2D gel analysis of intact proteins to the "shotgun" quantification of peptides and the use of isobaric tags for absolute and relative quantification (iTRAQ) method, have made the analysis of FFPE tissues possible. The ability to investigate the proteome of formalin-fixed, paraffin-embedded (FFPE) tissues can be considered a major recent achievement in the field of clinical proteomics. The label-free approach enables the quantitative measurement of radiation-induced alterations in FFPE tissue and facilitates retrospective biomarker identification using clinical archives. Proteomic analysis of formalin-fixed paraffin-embedded pancreatic tissue using liquid chromatography tandem mass spectrometry. We report that differentially expressed proteins can be identified among FFPE tissue specimens originating from individuals with different pancreatic histologic findings. Formalin-fixed paraffin-embedded (FFPE) proteome analysis using gel-free and gel-based proteomics. This study will facilitate the development of future proteomic analysis of FFPE tissue and provide a tool for the validation in archival samples of biomarkers of exposure, prognosis and disease. The CAAR method presented here complements previously described antigen-retrieval protocols and is an important step in being able to fully analyze the proteome of archived FFPE tissue. Proteome, phosphoproteome, and N-glycoproteome are quantitatively preserved in formalin-fixed paraffin-embedded tissue and analyzable by high-resolution mass spectrometry. It has only recently been shown that proteins in FFPE tissues can be identified by mass spectrometry-based proteomics but analysis of post-translational modifications is thought to be difficult or impossible Results from the FFPE-FASP procedure do not indicate any discernible changes due to storage time, hematoxylin staining or laser capture microdissection. Thus, FFPE biobank material can be analyzed by quantitative proteomics at the level of proteins and post-translational modifications. A novel tissue microdissection technique has been developed and combined with a method to extract soluble peptides directly from FFPE tissue for mass spectral analysis of prostate cancer (PCa) and benign prostate hyperplasia (BPH). Hundreds of proteins from PCa and BPH tissue were identified, espite using tissue blocks stored for as many as 28 years, high confidence and comparative proteome analysis between the leiomyomas and the sarcoma is achieved. These findings demonstrate that formalin fixation, paraffin processing, and LCM do not negatively impact protein quality and quantity as determined by MS and that FFPE samples are amenable to global proteomic analysis. Protein extraction of formalin-fixed, paraffin-embedded tissue enables robust proteomic profiles by mass spectrometry.

yes

550311dae9bde69634000018

Is aganglionic megacolon a feature of Down syndrome?

Down syndrome (DS) is recognized by characteristic facial features, intellectual disability, and an increased risk for cardiac malformations and duodenal atresia. Recently, Hirschsprung disease (HSCR), or congenital aganglionic megacolon, has been seen more often among patients with DS Of the 17 patients with HD who were studied, 10 were isolated (58.8%) and seven (41.1%) were associated to other structural abnormalities and psychomotor retardation. Three of the cases in this latter group were due to chromosome pathology (trisomy 21, Down syndrome) The authors report the case of a female infant with Down syndrome, aganglionic megacolon, severe diarrhea, and jejunal biopsy with ultrastructural changes consistent with microvillous atrophy. The patient condition improved after a colostomy performed in the setting of the treatment of Hirschprung disease Hirschsprung disease, or congenital aganglionic megacolon, is commonly assumed to be a sex-modified multifactorial trait. To test this hypothesis, complex segregation analysis was performed on data on 487 probands and their families. Demographic information on probands and the recurrence risk to relatives of probands are presented. An increased sex ratio (3.9 male:female) and an elevated risk to sibs (4%), as compared with the population incidence (0.02%), are observed, with the sex ratio decreasing and the recurrence risk to sibs increasing as the aganglionosis becomes more extensive. Down syndrome was found at an increased frequency among affected individuals but not among their unaffected sibs, and the increase was not associated with maternal age Intestinal microvillous atrophy in a patient with Down syndrome and aganglionic megacolon. The authors report the case of a female infant with Down syndrome, aganglionic megacolon, severe diarrhea, and jejunal biopsy with ultrastructural changes consistent with microvillous atrophy. The authors report the case of a female infant with Down syndrome, aganglionic megacolon, severe diarrhea, and jejunal biopsy with ultrastructural changes consistent with microvillous atrophy. The authors report the case of a female infant with Down syndrome, aganglionic megacolon, severe diarrhea, and jejunal biopsy with ultrastructural changes consistent with microvillous atrophy

yes

56c5a7605795f9a73e000002

Does HuR protein regulate the splicing process?

HuR and TIA1/TIAL1 are involved in regulation of alternative splicing of SIRT1 pre-mRNA Here we describe experiments showing that HuR and TIA1/TIAL1, two kinds of RNA-binding proteins, were involved in the regulation of alternative splicing of SIRT1 pre-mRNA under normal and stress circumstances HuR increased SIRT1-∆Exon8 by promoting SIRT1 exon 8 exclusion, whereas TIA1/TIAL1 inhibition of the exon 8 exclusion led to a decrease in SIRT1-∆Exon8 mRNA levels. HuR regulates alternative splicing of the TRA2β gene in human colon cancer cells under oxidative stress Hu antigen R (HuR) regulates stress responses through stabilizing and/or facilitating the translation of target mRNAs We show here that the RBP embryonic lethal abnormal vision like 1 (ELAVL1, also know as HuR) regulates the alternative splicing of eukaryotic translation initiation factor 4E nuclear import factor 1 (Eif4enif1), which encodes an eukaryotic translation initiation factor 4E transporter (4E-T) protein and suppresses the expression of capped mRNAs Further, endothelial-specific Elavl1 knockout mice exhibited reduced revascularization after hind limb ischemia and tumor angiogenesis in oncogene-induced mammary cancer, resulting in attenuated blood flow and tumor growth, respectively. Changes in cellular mRNA stability, splicing, and polyadenylation through HuR protein sequestration by a cytoplasmic RNA virus Furthermore, significant changes can be observed in nuclear alternative polyadenylation and splicing events on cellular pre-mRNAs as a result of sequestration of HuR protein by the 3' UTR of transcripts of this cytoplasmic RNA virus. Here we demonstrate that expression of 2A(pro) induces a selective nucleo-cytoplasm translocation of several important RNA binding proteins and splicing factors. Subcellular fractionation studies, together with immunofluorescence microscopy revealed an asymmetric distribution of HuR and TIA1/TIAR in 2A(pro) expressing cells, which modulates splicing of the human Fas exon 6 knockdown of HuR or overexpression of TIA1/TIAR, leads to Fas exon 6 inclusion in 2A(pro)-expressing cells The differential expression levels of T-cell intracellular antigens (TIA) and Hu antigen R (HuR) are concomitant with a splicing switch in apoptosis receptor Fas in HCT-116 cells overexpression and knockdown of HuR led to Fas exon 6 skipping and inclusion, respectively. These results suggest that the TIA and HuR cellular ratio influences cell-type specific Fas exon 6 splicing pattern. Hu antigen R (HuR) functions as an alternative pre-mRNA splicing regulator of Fas apoptosis-promoting receptor on exon definition antiapoptotic regulator Hu antigen R (HuR, ELAVL1), a member of the embryonic lethal, abnormal vision, Drosophila-like (ELAVL) family, promotes Fas exon 6 skipping by binding to an exonic splicing silencer ELAV/Hu proteins bind to AU-rich elements (ARE) in mRNAs and regulate their stability from splicing to translation, and the ubiquitous HuR protein has been implicated in cancerous cell growth. The HuR protein regulates the expression of thousands of cellular transcripts by modulating mRNA splicing, trafficking, translation, and stability. Hu antigen R (HuR) functions as an alternative pre-mRNA splicing regulator of Fas apoptosis-promoting receptor on exon definition. I report that antiapoptotic regulator Hu antigen R (HuR, ELAVL1), a member of the embryonic lethal, abnormal vision, Drosophila-like (ELAVL) family, promotes Fas exon 6 skipping by binding to an exonic splicing silencer. Changes in cellular mRNA stability, splicing, and polyadenylation through HuR protein sequestration by a cytoplasmic RNA virus. Further, the silencing capacity of HuR as splicing regulator resides in the RRM1 and hinge-RRM3 domains. HuR and TIA1/TIAL1 are involved in regulation of alternative splicing of SIRT1 pre-mRNA. HuR regulates alternative splicing of the TRA2β gene in human colon cancer cells under oxidative stress. The HuR protein regulates the expression of thousands of cellular transcripts by modulating mRNA splicing, trafficking, translation, and stability. Further, the silencing capacity of HuR as splicing regulator resides in the RRM1 and hinge-RRM3 domains. Taken together, these results support a functional link between HuR as repressor of alternative Fas splicing and the molecular mechanisms modulating programmed cell death. We are interested in interactions involving hnRNP proteins participating in several steps of mRNA processing (mainly pre-mRNA splicing) and HuR with an established role in stability/translation of associated mRNAs. hnRNP and HuR proteins have a major nucleoplasmic localization and ability to shuttle between nucleus and cytoplasm. We report here on interactions between hnRNP and HuR proteins that were identified in the context of isolated hnRNP and mRNP complexes. Despite the fact that HuR sites are observed in intronic regions, our data do not support a role for HuR in regulating splicing.

yes

55030a6ce9bde6963400000f

Is Titin the largest single protein molecule found in Nature?

Titin, the largest protein in the human body, is well known as a molecular spring in muscle cells and scaffold protein aiding myofibrillar assembly. Titin is the largest protein in mammals; it forms an elastic filament along the myofibril of cardiac and skeletal muscles. Titin is recently known as the largest protein which exists in the striated muscle sarcomere and is dynamic both in biomechanics properties and biochemical functions. Titin, the largest protein known to date, has been linked to sarcomere assembly and function through its elastic adaptor and signaling domains. The giant sarcomere protein titin/connectin is the largest protein known to date. Titin is the largest protein known to date and acts as a mechanosensor that regulates muscle protein expression in a sarcomere strain-dependent fashion. Titin is the largest protein known, and is essential for organising muscle sarcomeres. It has many domains with a variety of functions, and stretches from the Z-line to the M-line in the muscle sarcomere. Titin, is definitely the largest protein in the body, with a molecular weight of 3 million Dalton and composed of 27,000 amino acids. Titin, the largest protein identified to date (over 1 micron long, almost 3 million daltons in mass) is the third most abundant component of the sarcomere. Titin is the largest polypeptide yet described (relative molecular mass approximately 3 x 10(6); refs 1, 2) and an abundant protein of striated muscle. Titin is at present the largest known protein (M(r) 3000 kDa) and its expression is restricted to vertebrate striated muscle. Titin is the largest protein known, and is essential for organising muscle sarcomeres Titin is at present the largest known protein (M(r) 3000 kDa) and its expression is restricted to vertebrate striated muscle Titin is the largest polypeptide yet described (relative molecular mass approximately 3 x 10(6); refs 1, 2) and an abundant protein of striated muscle Titin is recently known as the largest protein which exists in the striated muscle sarcomere and is dynamic both in biomechanics properties and biochemical functions Titin, the biggest single (poly) peptide found in humans, and throughout nature so far, was long considered as a good candidate for inherited muscle diseases

yes

532627d0d6d3ac6a34000001

Does ventriculoperitoneal shunt improve normal pressure hydrocephalus?

Clinical improvement depends not only on the capability to restore the cerebrospinal fluid dynamic, but also on the ability of cerebral parenchyma to recover the metabolic function. After shunting, the global CMRglu significantly increased (2.95 ± 0.44 vs 4.38 ± 0.68, p = 10(-7)) in all INPH patients with a mean percentage value of 48.7%. Our preliminary data show that changes in the CMRglu are promptly reversible after surgery and that there is a relationship between the early metabolic changes and clinical symptoms, independently from the simultaneous changes in the ventricular size. The remarkable and prompt improvement in the global CMRglu and in symptoms may also have important implications for the current concept of "neuronal plasticity" and for the cells' reactivity in order to recover their metabolic function. Outcome of shunting in INPH is most often successful when patients are accurately diagnosed, suitably evaluated for surgical candidacy, and managed carefully throughout the preoperative, surgical, and postoperative periods. The decision to perform the only efficient procedure, i.e., a ventricular shunt operation, depends upon a number of established arguments in favor of that procedure. Clinical improvement, which is often spectacular, can then confirm the diagnosis. During the 1st postoperative year, there was improvement in the condition of 22 patients (96%) who had received a ventricular shunt; 21 of these patients (91%) remained improved until death or for at least 5 years. Shunt treatment showed an effect on cognitive functions of distractibility of attention and motor speed, but not on intelligence of memory. Three patients deteriorated, eleven remained stable and sixteen showed significant improvement on psychological tests, mainly those for attention, motor speed and memory, but rarely did any improvement of intelligence occur.

yes

51680b05298dcd4e51000064

Does Serca2a bind PLN in the heart?

The human phospholamban Arg14-deletion mutant localizes to plasma membrane and interacts with the Na/K-ATPase. Moreover, PLN-R14Del did not co-immunoprecipitate with SERCA2a (as did WT-PLN), n this review, we attempted to highlight the functional significance of PLN in vertebrate cardiac physiology. We will refer to the huge literature on mammals in order to describe the molecular characteristics of this protein, its interaction with SERCA2a There is clear evidence for direct regulatory protein-protein interactions between phospholamban (PLN) and the Ca2+-ATPase of cardiac sarcoplasmic reticulum (SERCA2a) in cytoplasmic domains These results suggest that PLN modulates the apparent Ca2+ affinity of SERCA2a through intramembrane interactions, which are disrupted at long range and in concert with disruption of the well characterized cytoplasmic interactions. Phospholamban (PLN), a homopentameric, integral membrane protein, reversibly inhibits cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity through intramembrane interactions. The concentration of this inhibited complex is determined by the dissociation constant for the PLN pentamer (which is mutation-sensitive) and by the dissociation constant for the PLN/SERCA2a heterodimer (which is likely to be mutation-sensitive). These results support the proposal that PLN inhibition of SERCA2a involves, first, depolymerization of PLN and, second, the formation of inhibitory interactions between monomeric PLN and SERCA2a. SLN and PLN appear to bind to the same regulatory site in SERCA. However, in a ternary complex, PLN occupies the regulatory site and SLN binds to the exposed side of PLN and to SERCA. Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit SERCA2a. . Conversely, using anti-SERCA2a antibody, both PLN and acylphosphatase were co-immunoprecipitated with SERCA2a, and the PLN amount in the precipitate decreased with increasing acylphosphatase concentrations. Reconstitution of the cytoplasmic interaction between phospholamban and Ca(2+)-ATPase of cardiac sarcoplasmic reticulum. Phospholamban (PLN) reversibly inhibits the Ca(2+)-ATPase of cardiac sarcoplasmic reticulum (SERCA2a) through a direct protein-protein interaction, playing a pivotal role in the regulation of intracellular Ca(2+) in heart muscle cells. Phospholamban (PLN) is a key regulator of Ca(2+) homeostasis and contractility in the heart. Its regulatory effects are mediated through its interaction with the sarcoplasmic reticulum Ca(2+)-ATPase, (SERCA2a), resulting in alterations of its Ca(2+)-affinity In a co-immunoprecipitation of PLN with SERCA2a, the physical interaction between the two proteins was increased in PUGNAc-treated cardiomyocytes.

yes

56d1d56b67f0cb3d66000004

Is there any role for long noncoding RNAs in adipogenesis?

Long noncoding RNAs regulate adipogenesis. Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). RNAi-mediated loss of function screens identified functional lncRNAs with varying impact on adipogenesis. Collectively, we have identified numerous lncRNAs that are functionally required for proper adipogenesis. Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα).

yes

532bf6f2d6d3ac6a34000015

Is there any research that relates the function of Notch Signaling with Alzheimer Disease?

RIP regulates signaling pathways by abrogating or releasing signaling molecules. Since the discovery, already >15 years ago, of its catalytic component, presenilin, and even much earlier with the identification of amyloid precursor protein as its first substrate, γ-secretase has been commonly associated with Alzheimer's disease. However, starting with Notch and thereafter a continuously increasing number of novel substrates, γ-secretase is becoming linked to an equally broader range of biological processes. In the last decade, increasing evidence has pointed out an important role of this pathway beyond embryonic development, indicating that Notch also displays a critical function in the mature brain of vertebrates and invertebrates. This pathway appears to be involved in neural progenitor regulation, neuronal connectivity, synaptic plasticity and learning/memory. In addition, Notch appears to be aberrantly regulated in neurodegenerative diseases, including Alzheimer's disease and ischemic injury Along with β-secretase, this enzyme produces the amyloid β-protein of Alzheimer's disease (AD) from the amyloid β-protein precursor. Because of its key role in the pathogenesis of AD, γ-secretase has been a prime target for drug discovery, and many inhibitors of this protease have been developed. The therapeutic potential of these inhibitors is virtually negated by the fact that γ-secretase is an essential part of the Notch signaling pathway, rendering the compounds unacceptably toxic upon chronic exposure High physiological concentrations of Aβ monomer induced angiogenesis by a conserved mechanism that blocks γ-secretase processing of a Notch intermediate, NEXT, and reduces the expression of downstream Notch target genes. Our findings allude to an integration of signaling pathways that utilize γ-secretase activity, which may have significant implications for our understanding of Alzheimer's pathogenesis vis-à-vis vascular changes that set the stage for ensuing neurodegeneration. Aggregated forms of Aβ have a pathogenic role in Alzheimer disease and, thus, reducing the Aβ levels by inhibiting γ-secretase is a possible treatment strategy for Alzheimer disease. Regrettably, clinical trials have shown that inhibition of γ-secretase results in Notch-related side effects. Therefore, it is of great importance to find ways to inhibit amyloid precursor protein (APP) processing without disturbing vital signaling pathways such as Notch. Nicastrin (Nct) is part of the γ-secretase complex and has been proposed to be involved in substrate recognition and selection

yes

54fc845e6ea36a810c000005

Was modafinil tested for schizophrenia treatment?

Modafinil improves antipsychotic-induced parkinsonism but not excessive daytime sleepiness, psychiatric symptoms or cognition in schizophrenia and schizoaffective disorder: a randomized, double-blind, placebo-controlled study. CONCLUSION: The data suggest that modafinil was a safe adjunctive treatment which improved parkinsonian symptoms and signs in patients with schizophrenia or schizoaffective disorder. A review of its effects in schizophrenia suggests that modafinil facilitates cognitive functions, with pro-mnemonic effects and problem solving improvements. Emotional processing also appears to be enhanced by the drug, although to date there are only a limited number of studies. BACKGROUND: Modafinil, a putative cognitive enhancing drug, has previously been shown to improve performance of healthy volunteers as well as patients with attention deficit disorder and schizophrenia, mainly in tests of executive functions. A review of modafinil and armodafinil as add-on therapy in antipsychotic-treated patients with schizophrenia. It has been suggested that modafinil and its isomer armodafinil as an add-on strategy to antipsychotic treatment in patients with schizophrenia may improve cognitive functioning, attenuate fatigue, inactiveness and other negative functions as well as weight gain. Evidence for the use of modafinil or armodafinil as add-on therapy to antipsychotic drugs to alleviate fatigue, sleepiness and inactivity is inconclusive. One cohort study and one out of two single-dose crossover RCTs in which modafinil addition was studied could demonstrate a positive effect. All five RCTs of modafinil (three RCTs) and armodafinil (two RCTs) addition with a longer study duration could not demonstrate a positive effect. In RCTs with a treatment duration of 4 weeks or more, however, no positive effect could be demonstrated on cognitive functioning with modafinil and armodafinil addition. Yet, four single-dose crossover RCTs of modafinil addition show significant positive effects on executive functioning, verbal memory span, visual memory, working memory, spatial planning, slowing in latency, impulse control and recognition of faces expressing sadness and sadness misattribution in the context of disgust recognition. The addition of modafinil or armodafinil to an antipsychotic regime, despite theoretical and preclinical considerations, has not been proved to enhance cognitive function, attenuate fatigue, enhance activity, improve negative symptoms and reduce weight in patients with schizophrenia. RATIONAL: In recent years, evidence suggests that modafinil may be useful for certain symptom domains of schizophrenia, especially for the negative and cognitive symptoms. CONCLUSION: The present study indicates modafinil as a potential adjunctive treatment strategy for treatment of schizophrenia particularly the negative symptoms. Modafinil is a wake-promoting drug that has been shown to improve attention, memory and executive function in the healthy population and in patients with schizophrenia. CONCLUSIONS: Results of this pilot trial do not support routine use of modafinil to counteract increased weight and metabolic diseases in patients taking clozapine. Modafinil (2-((diphenylmethyl)sulfinyl)acetamide) is described as an atypical stimulant and is a putative cognition enhancer for schizophrenia, but the precise mechanisms of action remain unclear. Modafinil is a wake-promoting drug that has been shown to improve emotion discrimination in healthy individuals and attention and executive function in schizophrenia. CONCLUSIONS: These data support clinical evidence that modafinil may alleviate cognitive deficits in schizophrenia and also demonstrate the benefit of applying PLSR modeling to characterize functional brain networks in translational models relevant to central nervous system dysfunction. Modafinil improves working memory in healthy subjects and individuals diagnosed with schizophrenia and Attention Deficit/Hyperactivity Disorder, though the effects of modafinil have not been evaluated on working memory in methamphetamine-dependent subjects. Modafinil is a psychostimulant approved for treating excessive sleepiness in adults; off-label uses (e.g., treatment of cognitive impairment in schizophrenia, ADHD and age-related dementias) are currently being explored. CONCLUSIONS: Results of this pilot trial do not support routine use of modafinil to treat negative symptoms, cognitive deficits, or wakefulness/fatigue in patients on clozapine. We have previously shown that the amount of movement exhibited by patients with schizophrenia is positively correlated with the volume of left anterior cingulate cortex and that this quantity of movement can be increased by modafinil. OBJECTIVE: Given recent reports about the off-label use of modafinil as an adjuvant for the treatment of antipsychotic-associated sedation in schizophrenia patients and the recent interest in its putative cognitive-enhancing effects in this population, we present a systematic review of available data on trials of modafinil as an adjuvant in the treatment of cognitive deficits, negative symptoms, and antipsychotic-induced fatigue, and its tolerability. RESULTS: One of 4 reviewed studies found a significant effect of modafinil as an alerting agent for antipsychotic-induced fatigue and sedation. Neither of 2 reviewed studies found modafinil to improve negative symptoms of schizophrenia. Three of 6 reviewed studies showed that modafinil may improve short-term memory, attention, and the ability to shift mental sets. CONCLUSIONS: While the available data suggest that modafinil is generally well tolerated and may have some efficacy in the treatment of antipsychotic-induced sedation and cognitive domains, the small sample sizes, contradictory results, and methodological differences between trials, especially with respect to cognitive testing, make it difficult to draw firm conclusions about the overall effectiveness of modafinil as an adjunct in the treatment of schizophrenia. Hence, before prescribing modafinil to a schizophrenia patient, the possible risks and benefits of each particular case should be evaluated. Modafinil had a substantial placebo effect on outcomes such as fatigue, excessive sleepiness and depression in patients with traumatic brain injury, major depressive disorder, schizophrenia, post-polio fatigue and multiple sclerosis; however, it did not provide any benefit greater than placebo. RATIONALE: The wake-promoting agent modafinil selectively improves neuropsychological task performance in healthy volunteers, in adults with attention deficit hyperactivity disorder (ADHD) and in schizophrenia. Recently, however, modafinil has been shown to improve attentional set-shifting performance in patients with schizophrenia. In addition, modafinil shows initial promise for a variety of off-label indications in psychiatry, including treatment-resistant depression, attention-deficit/hyperactivity disorder, and schizophrenia. There is increasing interest in the use of modafinil to improve cognition in schizophrenia as well as in other disorders such as attention-deficit/hyperactivity disorder. Initial findings indicate that modafinil may lead to better executive functioning and attentional performance in patients with schizophrenia. CONCLUSIONS: Although no effect on negative symptoms was found, adjunctive therapy with modafinil may result in global improvements in patients with schizophrenia who have prominent negative symptoms. CONCLUSIONS: Modafinil did not improve cognitive control in all schizophrenia patients. . These data suggest that modafinil increases quantifiable motor behaviour in schizophrenia and may have an impact on avolition. One patient was on treatment with both modafinil and trazodone and reported no change after tapering each in separate discontinuation trials, while another 3 patients were taking sleeping medications and also noted no change after discontinuation. Neuroprotective agents as add-on therapies (e.g., modafinil, erythropoietin, glycine, D-serine, memantine and celecoxib) are currently being evaluated in schizophrenia and related disorders. In the modafinil (N = 10) and placebo (N = 10) groups, fatigue improved significantly over time (p < .01), but there were no differences between groups on changes in fatigue, positive and negative symptoms, or cognition. CONCLUSIONS: Modafinil modulates anterior cingulate cortex function in chronic schizophrenia but its beneficial cognitive effects may be restricted to a subset of patients requiring further characterisation. Modafinil significantly improved overall clinical condition, with 64% and 82% of patients rated as clinically improved at week 4 by a blinded clinician and the investigator respectively. Modafinil significantly improved fatigue (P = 0.025, week 3) and tended to improve cognitive functioning scores. Although preliminary, these results suggest modafinil may be an effective and well-tolerated adjunct treatment that improves global functioning and clinical condition, and reduces fatigue in patients with schizophrenia or schizoaffective disorder. Modafinil had some cognitive enhancing properties in schizophrenia similar to those observed in healthy adults and adult patients with ADHD. Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia, particularly because of its beneficial effects on attentional set shifting. While the available data suggest that modafinil is generally well tolerated and may have some efficacy in the treatment of antipsychotic-induced sedation and cognitive domains, the small sample sizes, contradictory results, and methodological differences between trials, especially with respect to cognitive testing, make it difficult to draw firm conclusions about the overall effectiveness of modafinil as an adjunct in the treatment of schizophrenia. Given recent reports about the off-label use of modafinil as an adjuvant for the treatment of antipsychotic-associated sedation in schizophrenia patients and the recent interest in its putative cognitive-enhancing effects in this population, we present a systematic review of available data on trials of modafinil as an adjuvant in the treatment of cognitive deficits, negative symptoms, and antipsychotic-induced fatigue, and its tolerability. The present study indicates modafinil as a potential adjunctive treatment strategy for treatment of schizophrenia particularly the negative symptoms. It has been suggested that modafinil and its isomer armodafinil as an add-on strategy to antipsychotic treatment in patients with schizophrenia may improve cognitive functioning, attenuate fatigue, inactiveness and other negative functions as well as weight gain. CONCLUSION: The present study indicates modafinil as a potential adjunctive treatment strategy for treatment of schizophrenia particularly the negative symptoms. OBJECTIVE: Given recent reports about the off-label use of modafinil as an adjuvant for the treatment of antipsychotic-associated sedation in schizophrenia patients and the recent interest in its putative cognitive-enhancing effects in this population, we present a systematic review of available data on trials of modafinil as an adjuvant in the treatment of cognitive deficits, negative symptoms, and antipsychotic-induced fatigue, and its tolerability. CONCLUSIONS: While the available data suggest that modafinil is generally well tolerated and may have some efficacy in the treatment of antipsychotic-induced sedation and cognitive domains, the small sample sizes, contradictory results, and methodological differences between trials, especially with respect to cognitive testing, make it difficult to draw firm conclusions about the overall effectiveness of modafinil as an adjunct in the treatment of schizophrenia. The present study indicates modafinil as a potential adjunctive treatment strategy for treatment of schizophrenia particularly the negative symptoms. Although preliminary, these results suggest modafinil may be an effective and well-tolerated adjunct treatment that improves global functioning and clinical condition, and reduces fatigue in patients with schizophrenia or schizoaffective disorder. While the available data suggest that modafinil is generally well tolerated and may have some efficacy in the treatment of antipsychotic-induced sedation and cognitive domains, the small sample sizes, contradictory results, and methodological differences between trials, especially with respect to cognitive testing, make it difficult to draw firm conclusions about the overall effectiveness of modafinil as an adjunct in the treatment of schizophrenia The present study indicates modafinil as a potential adjunctive treatment strategy for treatment of schizophrenia particularly the negative symptoms Modafinil, a putative cognitive enhancing drug, has previously been shown to improve performance of healthy volunteers as well as patients with attention deficit disorder and schizophrenia, mainly in tests of executive functions

yes

514cc8dcd24251bc05000066

Is depression associated with poor prognosis of brain tumor patients?

Before surgery 27 patients (35%) had BDI scores indicating the presence of depression. These scores were significantly higher in patients with a history of depression (p = 0.017) and in those with a lower functional outcome (p = 0.015). A lower functional status (KPS score < or = 70) in patients was significantly associated with high depression scores at the 3-month (p = 0.000) and 1-year (p = 0.005) assessments. At all follow-ups, depressed low-grade glioma patients had a significantly shorter survival time, 3.3-5.8 years, compared to non-depressed low-grade glioma patients, 10.0-11.7 years. The results suggest that depression and decreased QOL among low-grade glioma patients is related to shorter survival at long-term follow-up. The adverse impact of depression in relation to survival among cancer patients is currently a subject of great interest in research. In the subgroup of patients with low-grade gliomas, depressive patients had a significantly shorter survival time compared with nondepressive subjects (P = 0.031, Kaplan-Meier survival analysis). Preoperative depression seemed to be a significant prognostic factor for worse survival in low-grade glioma patients. Major depressive disorder was marginally associated with outcomes, while surgical interventions and radiotherapy did not show strong associations with test performances.

yes

5161cfa3298dcd4e5100003d

Have germline variants been associated to colorectal cancer?

Overall, we identified aberrant transcripts in 8% of the patients (familial cases 30%; early-onset manifestation 21%). In eight of them, two different out-of-frame pseudoexons were found consisting of a 167-bp insertion from intron 4 in five families with a shared founder haplotype and a 83-bp insertion from intron 10 in three patients. The pseudoexon formation was caused by three different heterozygous germline mutations, which are supposed to activate cryptic splice sites We apply OS-Seq to resequence the exons of either 10 or 344 cancer genes from human DNA samples. In our assessment of capture performance, >87% of the captured sequence originated from the intended target region with sequencing coverage falling within a tenfold range for a majority of all targets. Single nucleotide variants (SNVs) called from OS-Seq data agreed with >95% of variants obtained from whole-genome sequencing of the same individual. The minor alleles of CD44 rs8193 C>T, ALCAM rs1157 G>A, and LGR5 rs17109924 T>C were significantly associated with increased TTR (9.4 vs. 5.4 years; HR, 0.51; 95% CI: 0.35-0.93; P = 0.022; 11.3 vs. 5.7 years; HR, 0.56; 95% CI: 0.33-0.94; P = 0.024, and 10.7 vs. 5.7 years; HR, 0.33; 95% CI: 0.12-0.90; P = 0.023, respectively) and remained significant in the multivariate analysis stratified by ethnicity. In recursive partitioning, a specific gene variant profile including LGR5 rs17109924, CD44 rs8193, and ALDH1A1 rs1342024 represented a high-risk subgroup with a median TTR of 1.7 years (HR, 6.71, 95% CI: 2.71-16.63, P < 0.001). In this study, we identified common germline variants in VEGF-dependent and -independent angiogenesis genes predicting clinical outcome and tumor response in patients with mCRC receiving first-line bevacizumab and oxaliplatin-based chemotherapy. We identified 22 nonsynonymous somatic mutations of which the majority was of missense type. In germline, three novel nonsynonymous variants were identified in the following genes: CSMD3, EPHB6 and C10orf137, and none of the variants were present in 890 population-matched healthy controls. It is possible that the identified germline variants modulate predisposition to CRC. One patient proved to carry an APC whole-gene deletion; 4 of 25 (16%) patients showed biallelic and 3 of 25 (12%) monoallelic MUTYH mutations. In the three heterozygous subjects no pathogenetic variants were found in OGG1, MTH1, APE1, MSH2, and MSH6 genes. Frequency assessment of MUTYH mutations in healthy subjects showed that only Y165C and G382D reach a subpolymorphic frequency. Scrutinizing the molecular genetic results and family data of 242 index patients with pathogenic APC mutations led to the identification of 10 mosaic cases (4%). C>T transitions were observed in CGA sites in four of the 10 cases with somatic mosaicism, which is significantly more than 26 of the 232 non-mosaic cases (p = 0.02). Phenotypes of patients with somatic mosaicism ranged from an attenuated form of polyposis coli to florid polyposis with major extracolonic manifestations. Altogether 12 previously reported changes and four novel genetic alterations, mostly in intronic sequences, were identified. The results revealed the presence of biallelic germline MYH mutations in two patients. These patients were compound heterozygotes for two of the most common germline mutations c.494 A>G (p.Y165C); c.1,145 G>A (p.G382D). These variants are established to be associated with adenomatous polyposis and colorectal cancer.

yes

5156beb4d24251bc05000089

Can Alzheimer's disease related miRNAs be detected in patients' blood?

miRNAs are aberrantly expressed in AD, and these have been implicated in the regulation of amyloid-β (Aβ) peptide, tau, inflammation, cell death, and other aspects which are the main pathomechanisms of AD. In addition, regulation of miRNAs varies in blood, and cerebral spinal fluid may indicate alterations in AD. miRNA microarray analysis was carried out on blood of rats at 1 week and 2 months after injection. RESULTS: Many up- and downregulated miRNAs were detected. Blood miRNAs could be useful as biomarkers for exposure to nanoparticles. miR-298 regulates β-amyloid (Aβ) precursor protein-converting enzyme-1 (BACE1) in Alzheimer's disease. We previously studied microRNAs (miRNAs) in AD autopsy brain samples and reported a connection between miR-137, -181c, -9, -29a/b and AD, through the regulation of ceramides. In this study, the potential role of these miRNAs as diagnostic markers for AD was investigated. We identified that these miRNAs were down-regulated in the blood serum of probable AD patients. 287 with Alzheimer disease (AD) as compared with 344 age- and gender-matched controls. In addition, we evaluated expression levels of hnRNP-A1 and its regulatory microRNA (miR)-590-3p in blood cells from patients and controls. Decreased relative expression levels of hsa-miR-590-3p was observed in patients with AD versus controls (0.685 ± 0.080 versus 0.931 ± 0.111, p = 0.079), and correlated negatively with hnRNP-A1 mRNA levels (r = -0.615, p = 0.0237). expression analysis of Sp1 and its regulatory microRNAs (hsa-miR-29b and hsa-miR-375) has been performed in peripheral blood mononuclear cells (PBMCs), together with Sp1 protein analysis. Significantly decreased relative expression levels of hsa-miR-29b, but not of hsa-miR-375, were observed in AD patients Sp1 and its regulatory hsa-miR-29b are deregulated in AD patients, possibly leading to aberrant production of downstream target genes involved in the pathogenesis. We previously observed that miR-137, -181c, -9, and 29a/b post-transcriptionally regulate SPT levels, and the corresponding miRNA levels in the blood sera are potential diagnostic biomarkers for AD. Here, we observe a negative correlation between cortical Aβ42 and sera Aβ42, and a positive correlation between cortical miRNA levels and sera miRNA levels suggesting their potential as noninvasive diagnostic biomarkers.

yes

54cf449cf693c3b16b000009

Is it possible to visualize subtahalamic nucleus by using transcranial ultrasound?

After measuring thermal effects of TCS and imaging artefact sizes of DBS lead using a skull phantom, we prospectively enrolled 34 patients with DBS of globus pallidus internus, ventro-intermediate thalamic or subthalamic nucleus. TCS had no influence on lead temperature, electrical parameters of DBS device or clinical state of patients. TCS measures of lead coordinates agreed with MRI measures in anterior-posterior and medial-lateral axis. Lead dislocation requiring reinsertion was reliably detected. TCS may therefore become a first-choice modality to monitor lead location. Two pilot studies have demonstrated that the intraoperative visualization with TCS and the TCS-assisted insertion of deep-brain stimulation (DBS) electrodes into the subthalamic nucleus and the globus pallidus interna are feasible and safe provided there is exact knowledge on the extent of electrode TCS imaging artifacts. Peroperative transcranial sonography for electrode placement into the targeted subthalamic nucleus of patients with Parkinson disease: technical note The correct anatomic position of the electrode tip could be indirectly assessed thanks to the topographic relationship of the STN with the hyperechogenic substantia nigra and the nucleus ruber. CONCLUSIONS: Transcranial sonography is easily feasible during stereotactic surgery. In combination with the clinical effects of electrostimulation on the symptoms of Parkinson's disease and with stereotactic x-ray images, it enables the assessment and the documentation of the correct position of implanted STN electrodes in real time. After measuring thermal effects of TCS and imaging artefact sizes of DBS lead using a skull phantom, we prospectively enrolled 34 patients with DBS of globus pallidus internus, ventro-intermediate thalamic or subthalamic nucleus Two pilot studies have demonstrated that the intraoperative visualization with TCS and the TCS-assisted insertion of deep-brain stimulation (DBS) electrodes into the subthalamic nucleus and the globus pallidus interna are feasible and safe provided there is exact knowledge on the extent of electrode TCS imaging artifacts

yes

533e50fdc45e13371400000f

Do thyroid hormone receptors change after brain injury?

For example, the T3 receptor alpha was predominantly expressed in stroke-tissue, indicating that regeneration of nerves in stroke tissue may be facilitated by increased T3 receptor alpha expression. TRα expression was also increased in human infants with IVH. Thus, in infants with IVH the combined elevation in deiodinase-3 and reduction in deiodinase-2 decreases TH signaling that can be worsened by an increase in unliganded TRα. A rapid increase of the total number of binding sites for T3 appeared within 30 min of ischemia and reached over 40% by 3 h. During the same 3-h period, the relative binding affinity was reduced by 25%. Upon recirculation after 30 min or 3 h of ischemia, a rapid reversal of measured T3 binding sites occurred, which progressed to 20-30% below the control value by the recirculation period of 3 h.

yes

5321ae889b2d7acc7e000006

Is gastro esophageal reflux related to burning mouth syndrome?

Our results suggest that there is no causal connection between LPR episodes and the occurrence of intraoral burning sensations in the examined patients. As reported below, although this symptom may well be diagnostically misleading, careful diagnosis based on clinical signs may distinguish patients with BMS from those with reflux disease, and successful management of burning mouth is often enables.

no

513cdc38bee46bd34c000007

Is thrombophilia related to increased risk of miscarriage?

Thrombophilia does hardly increase the risk of IUGR/PMPC or if so, it can be prevented by LMWH for illustrative purposes, a patient presenting with combined thrombophilia--both genetic and acquired--will be discussed. This patient had suffered severe gestational complications that led to devastating obstetrical outcome Thrombophilias have been implicated in complications related to ischemic placental disease including recurrent pregnancy loss, intrauterine fetal demise, preeclampsia, fetal growth restriction, placental abruption, and preterm delivery Further information about the combined risk of aPC resistance and pregnancy is needed before guidance on the management of affected women can be formulated. Thrombotic risk during pregnancy and the puerperium is higher in asymptomatic women with than without thrombophilia Further studies are required to assess the thrombotic risk in women with preeclampsia as well as early or late recurrent pregnancy loss. Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia In conclusion, homozygous carriers of factor V Leiden and, to a lesser extent, double heterozygous carriers of factor V Leiden and of the prothrombin mutation have an increased risk of venous thrombosis during pregnancy, particularly high during the postpartum period Careful diagnosis, observation and monitoring can add significant benefit to LMWH therapy during pregnancy Pregnancy in healthy women is accompanied by hypercoagulable changes that may interact with thrombophilia risk factors and threaten pregnancy. Fifty-three (13 %) women had antiphospholipid antibodies (lupus anticoagulant and/or anti-beta2-glycoprotein 1 antibodies) mainly associated with the risk of spontaneous abortion during the first trimester thrombophilia was found to be considerably more common in women with pregnancy-associated complications in comparison with the general population, and most frequently in conjunction with venous thromboembolism during pregnancy and the postpartum period When counseling white women with a history of preeclampsia, screening for thrombophilia can be useful for preconceptional counseling and pregnancy management. knowledge combined with the appropriate use of thromboprophylaxis and treatment in women who have objectively confirmed VTE continue to improve maternal and perinatal outcomes The risk of having thrombophilia is doubled in men who have fathered pregnancies which ended in perinatal death as well as in the mothers of such pregnancies. The prevalence of thrombophilic variants is of possible public health significance for other morbidity; but perhaps not in relation to preeclampsia This study suggests that thrombophilia "mediates" in lowering of cardiovascular risk factors in women with a history of preeclampsia

yes

56c313d150c68dd416000002

Does nifedipine inhibit L-type calcium channels?

Nifedipine, an L-type calcium channel blocker, reduced the expression of synaptogamin and syntaxin and blocked the suppressive effect of vecuronium, suggesting that both agents inhibit presynaptic L-type calcium channels. Treatment with nifedipine to inhibit calcium influx via the L-type channel Cav1.2 (alpha(1C)) inhibited the TGFbeta stimulated increase in ANK expression at all phases of chondrogenesis. Finally, we found that PKCepsilon-induced stellation was significantly reduced by the specific L-type channel blocker nifedipine, indicating that calcium influx through VGCC mediates the change in astrocyte morphology induced by PKCepsilon. However, APV and nifedipine, an inhibitor of L-type calcium channels, failed to inhibit LTP when administered following the slow increase in ethanol. Both the metallic ions Cd2+ and Ni2+, known to inhibit voltage-gated calcium channels and T-type channels, respectively, and verapamil and nifedipine, typical blocker of L-type calcium channels completely prevented the hypoxic neuronal NO generation. Further, the L-type calcium channel blocker, nifedipine, was able to inhibit the initial increase in [Ca2+]i, suggesting that at least this phase of the TMT effect was mediated by calcium channels, although nifedipine had no significant effect on the time to reach the maximal [Ca2+]i level Treatment with omega-conotoxin GVIA (3 microM) or nifedipine (10 microM) to inhibit Ca(2+) influx through N- or L-type voltage-dependent calcium channels (VDCCs), respectively, also decreased the rate of AP repolarization and increased AP duration Concentrations of nifedipine (10 microM) and nimodipine (3 microM) that maximally inhibit L-type calcium channels reduced the sI(AHP) by 30 and 50%, respectively Consequently, it was demonstrated in the present study that nimodipine and nitrendipine inhibit both L- and N-type calcium channels and thus seem to be unique among the dihydropyridines examined in their effects on calcium channels in dibutyryl cAMP-differentiated neuroblastoma x glioma hybrid NG 108-15 cells, whereas nifedipine and niguldipine appear to block mainly L-type calcium channels However, APV and nifedipine, an inhibitor of L-type calcium channels, failed to inhibit LTP when administered following the slow increase in ethanol Calcium-channel antagonists, omega-conotoxin GVIA (omega-CgTx GVIA; N-type), nifedipine (L-type), and omega-conotoxin MVIIC (omega-CmTx MVIIC; P/Q type), were used to characterize the voltage-operated Ca(2+) channels (VOCCs) involved in this release The T- and L-type calcium channel blocker (CCB) mibefradil attenuates leg edema induced by the L-type CCB nifedipine in the spontaneously hypertensive rat: a novel differentiating assay. L-type calcium channel antagonist nifedipine reduces neurofilament restitution following traumatic optic nerve injury. Nifedipine, an L-type calcium channel blocker, restores the hypnotic response in rats made tolerant to the alpha-2 adrenergic agonist dexmedetomidine. Comparison of L-type calcium channel blockade by nifedipine and/or cadmium in guinea pig ventricular myocytes. Nifedipine inhibits picrotoxin-induced seizure activity: further evidence on the involvement of L-type calcium channel blockers in epilepsy.

yes

54d76ac63706e89528000016

Is there any data to suggest that TRH (thyrotropin releasing hormone) administration can improve symptom severity of amyotrophic lateral sclerosis patients?

These central nervous system (CNS)-mediated effects provide the rationale for use of TRH and its analogs in the treatment of brain and spinal injury, and CNS disorders like schizophrenia, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, Parkinson's disease, depression, shock and ischemia. The Effect of TRH to correct the abnormal F responses in SSP might be consistent with effects of TRH to reduce spasticity in amyotrophic lateral sclerosis described previously Agents undergoing therapeutic trials at present include CNTF, IGF1 glutamate antagonists, branched-chain amino acids and TRH analogue. Evidence that thyrotropin-releasing hormone (TRH) has prominent trophic effects on the motor system led to several negative therapeutic trials in amyotrophic lateral sclerosis, a disease of the motor system. The results of the clinical evaluation at the beginning and end of the treatment as well as after patient follow up demonstrated that beneficial effects do not occur equally in all patients but rather are transitory and do not improve the natural evolution of the disease. The neurological evaluation after acute TRH-T treatment showed an objective improvement in 3 of the 8. The outcome of the study, in agreement with some and at variance with other studies, was that TRH induced a statistically significant neurological improvement in 17 of the 23 ALS patients but little or none in the other ALS patients and in patients with other neurological diseases. [A case of amyotrophic lateral sclerosis with disturbance of vertical ocular movement responding to thyrotropin releasing hormone (TRH)]. TRH injections resulted in improvement of disturbance of vertical ocular movement, but no effect was seen on the weakness of the limb. 13 patients with amyotrophic lateral sclerosis (ALS) were treated with intravenous infusion of thyrotropin-releasing hormone (TRH). Similar improvements in speech, swallowing and in tongue and jaw movements were seen after iv and oral administration in nine, five and eight patients respectively. No clinical improvement was detected. A trial of Thyrotropin Releasing Hormone (TRH) 5.0 mg/kg body weight subcutaneously every other day for two weeks produced transient increased tone in muscles, along with other (side-) effects in patients with Amyotrophic Lateral Sclerosis (ALS). Although the mechanism is not known, several reports of the effectiveness of thyrotropin releasing hormone (TRH) in ALS were recently published. Protirelin (thyrotropin-releasing hormone) appears to be a neuromodulator in the extrahypothalamic nervous system and has been suggested as an adjunct in the treatment of amyotrophic lateral sclerosis (ALS). Clinical studies have shown that response to TRH is state dependent, that is, it depends on whether the patient has bulbar or nonbulbar signs and is male or female. Future studies must take into consideration this state dependence as a specific feature of the pharmacological action of TRH and its analogues. Three of the studies showed a transient, statistically significant effect in at least some muscles. The two studies that demonstrated no such effect both used TRH in very small doses. It therefore seems reasonable to conclude that the effect of TRH in ALS is a definite, acute, and transient response. It was found that in only 3 out of 14 patients with moderately progressed disease no improvement was achieved, while in 11 cases the improvement was from 10 to 20%. However, the improvement was transient, and TRH treatment failed to stop the progression of the disease. Only 3 patients noted subjective improvement of strength. In 6 of the 9, TRH induced a significant increase in vibratory inhibition. This suggests that the TRH-induced reduction of spasticity might be due to an increase in presynaptic inhibition acting on Ia fibres. However, 2 mg DN-1417, IM twice a day for 1 month in an open-label trial, produced no objective improvement of strength in nine patients with ALS. Our experience suggests that this approach is safe, has high patient acceptance, and is worthy of more careful evaluation. Focal, small-to-moderate and transient improvement occurred in the muscle strength and function of patients with ALS who received TRH in dose-response and screening studies. In a small pilot study of 12 patients, 3 months administration of TRH at 10 mg per kg on alternate days resulted in localized increased strength of jaw muscles as well as significant improvement in lower extremity function. Aerobic exercise capacity was particularly improved in patients with ALS following administration of TRH. Mild to moderate improvement was found in 9 (56%) of 16 patients. We thought such action of TRH to be useful to the therapy of ALS. With daily TRH, 10 patients noted subjective improvement without objective evidence, and 10 patients complained of worsening of the disease with objective decline after TRH was stopped. Statistical analysis, however, showed no beneficial effects from either acute or chronic TRH trials. A temporary increase in the strength of some muscles was detected following the administration of TRH, but no change in functional performance was noted. Neither the patients nor the investigators believed the effects were of any marked clinical significance. Nevertheless, statistically significant improvement was seen only in dynametric strength 1 hour after subcutaneous injection (p less than 0.05). Significant improvement occurred, in one patient only, on subjective speech testing during IV infusion of TRH. In none of six other ratings was there a significant difference between TRH and placebo. Subjective improvement was noted by 11 of 12 patients. Significant improvement, as shown by statistical analysis, was noted in muscle strength in the 9 patients by 5 infusions over a 4-week period and a sub-group of 5 patients treated by 8 infusions over 10 weeks. The progressive course of this disease, manifested by increasing atrophy, paralysis and disability score, was not altered. Very high intravenous doses (2-19 mg/min) of thyrotropin-releasing hormone (TRH, L-pyroglutamyl-L-histidyl-L-prolinamide) given to 12 patients with amyotrophic lateral sclerosis (ALS) produced a moderate to marked improvement of functions caused by deficiency of lower motor neurons (weakness) and upper motor neurons (spasticity). The improvement was sustained throughout the infusion and for about 1 h thereafter; sometimes a slight improvement was evident 20 h after infusion. Aerobic exercise capacity was particularly improved in patients with ALS following administration of TRH

yes

54297ed2289fd6cb07000001

Can siRNA affect response to afatinib treatment?

On the other hand, miR-146a enhanced the inhibition of cell proliferation by drugs targeting EGFR, including both TKIs (gefitinib, erlotinib, and afatinib) and a monoclonal antibody (cetuximab) These effects were independent of the EGFR mutation status (wild type, sensitizing mutation or resistance mutation), but were less potent compared to the effects of siRNA targeting of EGFR Among the anti-EGFR agents tested, the strongest biological effect was observed when afatinib was combined with T790M-specific-siRNAs The combination of a potent, irreversible kinase inhibitor such as afatinib, with T790M-specific-siRNAs should be further investigated as a new strategy in the treatment of lung cancer containing the resistant T790M mutation. The strongest biological effect was observed when afatinib was combined with an EGFR-specific siRNA The addition of EGFR siRNA to either TKIs or cetuximab additively enhanced growth inhibition and induction of apoptosis in all five cell lines, independent of the EGFR mutation status (wild-type or sensitizing mutation or resistant mutation). The combination of a potent, irreversible kinase inhibitor such as afatinib, with EGFR-specific siRNAs should be further investigated as a new strategy in the treatment of lung cancer and other EGFR dependent cancers, including those with downstream resistance mutations.

yes

517a8a718ed59a060a00003e

Does triiodothyronine stimulate red blood cell sodium potassium pump?

reduction in Na+,K+ATPase activity has been demonstrated in red blood cells (RBCs), as well as an inverse correlation between this enzymatic action and free triiodothyronine (FT3) levels. The restoration of normal FT3 values also brings about a normalization of Na+,K+ATPase activity in erythrocytes. at hyperthyroid patients have decreased red cell Na/K-ATPase activity and provide direct evidence that erythrocyte ATPase activity is increased in hypothyroid patients. The change in enzyme activity in patients with nonthyroidal illness and decreased circulating T3 levels was comparable to that in hypothyroidism. The effect of triiodothyronine (T3) on Na+,K(+)-ATPase activity of K562 human erythroleukemic cell was studied to understand why the erythrocyte sodium pump activity is decreased in hyperthyroidism. We conclude that T3 stimulates Na+,K(+)-ATPase activity of K562 cells and in the presence of T3 during differentiation, the enzyme activity remains high.

no

56c1f00aef6e39474100003d

Is selumetinib effective in thyroid cancer?

A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours. BACKGROUND: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor). Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of>6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. CONCLUSIONS: Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition. MHC class I loss is a frequent mechanism of immune escape in papillary thyroid cancer that is reversed by interferon and selumetinib treatment in vitro. Increased antigenicity following selumetinib and IFN treatment warrants further study for immunotherapy of progressive PTC. The role of KIs in differentiated TC may be revolutionised by the finding that selumetinib may restore a clinical response to radioactive iodine (RAI). BACKGROUND AND AIM: Selumetinib is a promising and interesting targeted therapy agent as it may reverse radioiodine uptake in patients with radioiodine-refractory differentiated thyroid cancer. CONCLUSIONS: Compared with current chemotherapy, selumetinib has modest clinical activity as monotherapy in patients with advanced cancer, but combinations of selumetinib with cytotoxic agents in patients with BRAF or KRAS mutations hold great promise for cancer treatment. Selumetinib may be an effective redifferentiating agent and could be used within several years. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. METHODS: We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). CONCLUSIONS: Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. ECENT FINDINGS: For patients with advanced differentiated thyroid cancers, sorafenib, selumetinib, pazopanib and sunitinib have been investigated with promising results. Selumetinib is a promising and interesting targeted therapy agent as it may reverse radioiodine uptake in patients with radioiodine-refractory differentiated thyroid cancer. Selumetinib may be an effective redifferentiating agent and could be used within several years. Here, selumetinib targets the mitogen-activated protein kinase pathway in papillary thyroid carcinoma and shows limited single-agent activity in the patients with tumors that harbor the (V600E)BRAF mutation. CONCLUSIONS: Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease.

yes

56cae51f5795f9a73e000025

Are immune cells affected in Amyotrophic Lateral Sclerosis?

Therapeutic immunization of mSOD1 mice with a myelin-derived peptide led to CP activation, and was followed by the accumulation of immunoregulatory cells, including IL-10-producing monocyte-derived macrophages and Foxp3(+) regulatory T cells, and elevation of the neurotrophic factors IGF-1 and GDNF in the diseased spinal cord parenchyma Immunization with a Myelin-Derived Antigen Activates the Brain's Choroid Plexus for Recruitment of Immunoregulatory Cells to the CNS and Attenuates Disease Progression in a Mouse Model of ALS. Amyotrophic lateral sclerosis (ALS) is a rapidly progressing fatal neurodegenerative disorder characterized by the selective death of motor neurons (MN) in the spinal cord, and is associated with local neuroinflammation. T-cell deficiency increases neuronal loss, while boosting T cell levels reduces it. As disease accelerates, a shift occurs from beneficial immune responses (involving M2 microglia and regulatory T-cells) to deleterious immune responses (involving M1 microglia and Th1 cells). In this review, we underscore the importance of immune-mediated mechanisms in the pathogenesis of ALS and discuss the alterations and distinct phenotypes of immune cells at the different stages of disease. Immunological disturbances have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Chemokines are involved in the recruitment of immune cells. The immune system has been found to be involved with positive and negative effects in the nervous system of amyotrophic lateral sclerosis (ALS) patients. In general, T cells, B cells, NK cells, mast cells, macrophages, dendritic cells, microglia, antibodies, complement and cytokines participate in limiting damage. Immunological disturbances have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Chemokines are involved in the recruitment of immune cells. We propose the following mechanism for the effect of mesenchymal stem cells (MSCs) administered intrathecally in amyotrophic lateral sclerosis (ALS): MSCs increase infiltration of peripheral immune cells into CNS and skew the infiltrated immune cells toward regulatory T lymphocytes (Treg ) and Th2 lymphocytes. Immune cell infiltration to the brain&apos;s territory was considered for decades to reflect a pathological process in which immune cells attack the central nervous system (CNS); such a process is observed in the inflammatory autoimmune disease, multiple sclerosis (MS).

yes

531b4269b166e2b80600003e

Is thyroid hormone therapy indicated in patients with heart failure?

Patients with chronic heart failure and subclinical hypothyroidism significantly improved their physical performance when normal TSH levels were reached. Early and sustained physiological restoration of circulating L-T3 levels after MI halves infarct scar size and prevents the progression towards heart failure. This beneficial effect is likely due to enhanced capillary formation and mitochondrial protection. These data indicate that T(3) replacement to euthyroid levels improves systolic function and tends to improve diastolic function, potentially through changes in myocardial gene expression. In these patients, the administration of synthetic triiodothyronine (T(3)) was well tolerated and induced significant improvement in cardiac function without increased heart rate and metabolic demand. In DC patients, short-term synthetic L-T(3) replacement therapy significantly improved neuroendocrine profile and ventricular performance. Triiodothyronine was well tolerated without episodes of ischemia or clinical arrhythmia. There was no significant change in heart rate or metabolic rate and there was minimal increase in core temperature. Cardiac output increased with a reduction in systemic vascular resistance in patients receiving the largest dose, consistent with a peripheral vasodilatory effect.

no

54edf05494afd6150400000e

Is there a mouse model for Fanconi anemia?

Cyclophosphamide promotes engraftment of gene-modified cells in a mouse model of Fanconi anemia without causing cytogenetic abnormalities We compared Cy preconditioning with fludarabine (Flu) or cytarabine (AraC) or no conditioning as a control in fanca ( -/- ) mutant mice receiving gene-modified bone marrow cells We conclude that Cy is an effective and superior preparative regimen with respect to engraftment of lentivirus-transduced cells and functional correction in fanca ( -/- ) mice To study whether there is a causal relationship between FA pathway defects and tumour development, we have generated a mouse model with a targeted disruption of the FA core complex gene Fancf Fancf-deficient mouse embryonic fibroblasts displayed a phenotype typical for FA cells: they showed an aberrant response to DNA cross-linking agents as manifested by G(2) arrest, chromosomal aberrations, reduced survival, and an inability to monoubiquitinate FANCD2 Fancf homozygous mice were viable, born following a normal Mendelian distribution, and showed no growth retardation or developmental abnormalities. The gonads of Fancf mutant mice functioned abnormally, showing compromised follicle development and spermatogenesis as has been observed in other FA mouse models and in FA patients In a cohort of Fancf-deficient mice, we observed decreased overall survival and increased tumour incidence To provide further experimental access to the FA-M complementation group we have generated Fancm-deficient mice by deleting exon 2 FANCM deficiency caused hypogonadism in mice and hypersensitivity to cross-linking agents in mouse embryonic fibroblasts (MEFs), thus phenocopying other FA mouse models Fancm(Delta2/Delta2) mice also showed unique features atypical for FA mice, including underrepresentation of female Fancm(Delta2/Delta2) mice and decreased overall and tumor-free survival Fancm-deficient mice reveal unique features of Fanconi anemia complementation group M Fancf-deficient mice are prone to develop ovarian tumours In vivo proliferation advantage of genetically corrected hematopoietic stem cells in a mouse model of Fanconi anemia FA-D1 Using an FA mouse model with a marked hematopoietic phenotype, the FA-D1 (Brca2(Delta27/Delta27)) mice, we demonstrate that the lentivirus-mediated gene therapy of FA HSCs results in the progressive expansion of genetically corrected clones in mild-conditioned FA-D1 recipients Consistent with these data, hematopoietic progenitors from FA recipients progressively became mitomycin C resistant and their chromosomal instability was reverted Hematopoietic dysfunction in a mouse model for Fanconi anemia group D1 We have investigated the hematopoietic phenotype of mice with a hypomorphic mutation in the Brca2/Fancd1 gene (Brca2(Delta27/Delta27) mutation) Conventional BM competition experiments showed a marked repopulation defect in Brca2(Delta27/Delta27) hematopoietic stem cells (HSCs), compared to wild-type HSCs Moreover, we have observed for the first time in a DNA repair disease model a very significant proliferation defect in Brca2(Delta27/Delta27) HSCs maintained in their natural physiological environment The hematopoietic phenotype associated with the Brca2(Delta27/Delta27) mutation suggests that this FA-D1 mouse model will constitute an important tool for the development of new therapies for FA, including gene therapy In vitro phenotypic correction of hematopoietic progenitors from Fanconi anemia group A knockout mice In this study we characterized the hematopoietic phenotype of a Fanca knockout mouse model and corrected the main phenotypic characteristics of the bone marrow (BM) progenitors using retroviral vectors The hematopoiesis of these animals was characterized by a modest though significant thrombocytopenia, consistent with reduced numbers of BM megakaryocyte progenitors As observed in other FA models, the hematopoietic progenitors from Fanca(-/-) mice were highly sensitive to mitomycin C (MMC) Aiming to correct the phenotype of Fanca(-/-) progenitors, purified Lin(-)Sca-1(+) cells were transduced with retroviral vectors encoding the enhanced green fluorescent protein (EGFP) gene and human FANCA genes. Lin(-)Sca-1(+) cells from Fanca(-/-) mice were transduced with an efficiency similar to that of samples from wild-type mice. More significantly, transductions with FANCA vectors corrected both the MMC hypersensitivity as well as the impaired ex vivo expansion ability that characterized the BM progenitors of Fanca(-/-) mice The Btbd12 knockout mouse therefore establishes a disease model for Fanconi anemia and genetically links a regulator of nuclease incision complexes to the Fanconi anemia DNA crosslink repair pathway. Hematopoietic dysfunction in a mouse model for Fanconi anemia group D1. Bone marrow failure in the Fanconi anemia group C mouse model after DNA damage. In vivo proliferation advantage of genetically corrected hematopoietic stem cells in a mouse model of Fanconi anemia FA-D1. Assessment of the flexed-tail mouse as a possible model for Fanconi anemia: analysis of mitomycin C-induced micronuclei. The Btbd12 knockout mouse therefore establishes a disease model for Fanconi anemia and genetically links a regulator of nuclease incision complexes to the Fanconi anemia DNA crosslink repair pathway. Cyclophosphamide promotes engraftment of gene-modified cells in a mouse model of Fanconi anemia without causing cytogenetic abnormalities. Mouse models of Fanconi anemia. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability. To study FA complementation group A using the mouse as a model system, we cloned and characterized the mouse homolog of the human FANCA cDNA. Here we describe the phenotype of the Btbd12 knockout mouse, the mouse ortholog of SLX4, which recapitulates many key features of the human genetic illness Fanconi anemia. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia In contrast to observations made in other Fanconi anemia (FA) mouse models, low numbers of hematopoietic colony-forming cells (CFCs) were noted in Brca2(Delta27/Delta27) mice, either young or adult Fanconi anemia group A and C double-mutant mice: functional evidence for a multi-protein Fanconi anemia complex. In addition, mouse models are also useful for testing treatments for FA. Development and characterization of immortalized fibroblastoid cell lines from an FA(C) mouse model. These mouse models display the characteristic FA feature of cellular hypersensitivity to DNA cross-linking agents

yes

553fb11fc6a5098552000003

Could Hyperthermic intraperitoneal chemotherapy (HIPEC) be effective for the treatment of recurrent ovarian cancer?

The use of HIPEC after aggressive cytoreductive surgery in patients with ovarian cancer with peritoneal dissemination can be performed with acceptable postoperative morbidity rates. Knowledge of the factors associated with the onset of these postoperative adverse events allows better management of the same and offers the patient a safe procedure These results showed that the association of HIPEC with a complete cytoreduction for recurrent ovarian cancer presents acceptable morbidity and survival There is level-one evidence suggesting the benefit of postoperative adjuvant intraperitoneal chemotherapy for patients with advanced ovarian cancer after cytoreductive surgery, albeit catheter-related complications resulted after treatment discontinuation. Studies report the use of HIPEC predominantly in the setting of recurrent disease and have demonstrated encouraging results, which merits further investigation in future clinical trials The combination of SCR and HIPEC seems to improve survival rate in patients suffering from platinum-sensitive EOC recurrence with respect to no-HIPEC treatments. This result further supports the need of a randomized trial Cautious extrapolation of data from standard normothermic, nonintraoperative, intraperitoneal chemotherapy and data from Phase II and nonrandomized comparative studies suggest that HIPEC delivered at the time of surgery for ovarian cancer has definite potential The available evidence suggests that a potential survival benefit of adding HIPEC may be largest in the settings of secondary CRS for stage III ovarian cancer and salvage CRS for recurrent ovarian cancer, two time-points representing failure of initial standard therapy. There is much less evidence for a potential benefit of HIPEC for less advanced stages (I-II) and for earlier time-points in the treatment of ovarian cancer (upfront, interval and consolidation) Survival benefit of adding Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) at the different time-points of treatment of ovarian cancer Patients suffering from peritoneal recurrence of ovarian cancer should be considered for radical reoperation with HIPEC in a center with expertise in multimodal therapeutic options. Organ-preserving cytoreductive surgery allows complete cytoreduction with the goal of decreasing morbidity In recurrent platinum-sensitive ovarian cancer patients, the use of CRS plus HIPEC represents a safe treatment, able to significantly influence the survival rates compared to chemotherapy alone or surgery plus standard chemotherapy The results of our study indicate the feasibility and the potential benefit of a protocol including systemic chemotherapy, surgical cytoreduction and HIPEC in patients with peritoneal carcinomatosis from ovarian cancer. A phase III trial to compare this approach with conventional treatment is needed In selected patients with heavily pretreated recurrent ovarian cancer, cytoreduction combined with HIPEC may provide a meaningful OS with acceptable morbidity. Optimal results are achieved in patients with a macroscopically complete resection and biologically favorable disease HIPEC is a complement to radical surgery/ peritonectomy, which has been shown to be a surgical procedure with high tolerability, low morbimortality, enhanced survival and prolonged disease-free interval in patients with peritoneal carcinomatosis for recurrent ovarian cancer Despite the heterogeneity of the studies reviewed, current evidence suggest that complete CRS and HIPEC may be a feasible option with potential benefits that are comparable with the current standard of care. A randomized trial is required to establish the role of HIPEC in ovarian cancer in the majority of patients with primary and recurrent advanced ovarian cancer, cytoreductive surgery combined with HIPEC can lead to a substantial increase in subsequent rates of disease-free and overall survival Peritonectomy procedures combined with HIPEC offer promising long-term survival in patients with diffuse peritoneal ovarian carcinomatosis. They achieve high adequate primary and secondary surgical cytoreduction rates with acceptable morbidity and mortality Cytoreduction surgery with hyperthermic intraperitoneal chemotherapy in recurrent ovarian cancer improves progression-free survival, especially in BRCA-positive patients- a case-control study. Survival benefit of adding Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) at the different time-points of treatment of ovarian cancer: review of evidence. Some encouraging results have been reported by the treatment of peritoneal carcinomatosis (PC) from ovarian cancer by complete surgical cytoreduction, peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC). Although standard treatment for advanced epithelial ovarian cancer (EOC) consists of surgical debulking and intravenous platinum- and taxane-based chemotherapy, favorable oncological outcomes have been recently reported with the use of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Trabectedin, Hyperthermic intraperitoneal chemotherapy (HIPEC) and chemo-immunotherapy may be become a promising therapy for the treatment of ovarian cancer. Hyperthermic intraperitoneal chemotherapy (HIPEC) represents a new treatment strategy aimed to improve outcome of patients with advanced ovarian cancer. Favorable oncological outcomes have been reported in several trials with the introduction of Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in the treatment of Advanced Epithelial Ovarian Cancer (EOC). Based on theoretical and experimental basis, HIPEC should stand as an effective treatment for ovarian cancer. Some encouraging results have been reported by the treatment of peritoneal carcinomatosis (PC) from ovarian cancer by complete surgical cytoreduction, peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC) Based on theoretical and experimental basis, HIPEC should stand as an effective treatment for ovarian cancer Hyperthermic intraperitoneal chemotherapy (HIPEC) represents a new treatment strategy aimed to improve outcome of patients with advanced ovarian cancer [Importance of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer].

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5319abc9b166e2b80600002d

Is Rac1 involved in cancer cell invasion?

In the Matrigel invasion assay, knockdown of CCR1 and inhibition of the ERK and Rac signaling pathways significantly decreased the number of invading cells. These results demonstrated for the first time that the interaction of CCR1 with CCL5 caused by increased expression of CCR1 promotes invasion of PC3PR cells by increasing secretion of MMPs 2 and 9 and by activating ERK and Rac signaling. These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes. Activated PAR1 induced RhoA and Rac1 phosphorylation, and subsequent overexpression of myosin IIA and filamin B which are stress fiber components that were identified by PMF analysis of peptide mass data obtained by MALDI-TOF/MS measurement. These results demonstrate that PAR1 activation induces cell morphological change associated with cell motility via Rho family activation and cytoskeletal protein overexpression, and has a critical role in gastric cancer cell invasion and metastasis. Rac1 was found to be required for actopaxin-induced matrix degradation whereas inhibition of myosin contractility promoted degradation in the phosphomutant-expressing Quint cells, indicating that a balance of Rho GTPase signaling and regulation of cellular tension are important for the process. Taken together, this study demonstrates a new role for actopaxin phosphorylation in matrix degradation and cell invasion via regulation of Rho GTPase signaling. BART inhibits pancreatic cancer cell invasion by Rac1 inactivation through direct binding to active Rac1 We report that Binder of Arl Two (BART) plays a role in inhibiting cell invasion by regulating the activity of the Rho small guanosine triphosphatase protein Rac1 in pancreatic cancer cells. BART interacts with active forms of Rac1, and the BART-Rac1 complex localizes at the leading edges of migrating cancer cells. Suppression of BART increases active Rac1, thereby increasing cell invasion. Treatment of pancreatic cancer cells in which BART is stably knocked down with a Rac1 inhibitor decreases invasiveness. Thus, BART-dependent inhibition of cell invasion is likely associated with decreased active Rac1. The Rac1 inhibitor inhibits the lamellipodia formation that is stimulated by suppression of BART. Our results imply that BART regulates actin-cytoskeleton rearrangements at membrane ruffles through modulation of the activity of Rac1, which, in turn, inhibits pancreatic cancer cell invasion. It has been reported as an important inducer of cancer cell migration and invasion, with underlying molecular mechanisms involving the signalling mediated by its juxtamembrane domain, the secretion of matrix metalloproteases to the extracellular media, and the cleavage of a P-cadherin soluble form with pro-invasive activity. Intracellularly, this protein interferes with the endogenous cadherin/catenin complex, inducing p120-catenin delocalization to the cytoplasm, and the consequent activation of Rac1/Cdc42 and associated alterations in the actin cytoskeleton. Targeted down-regulation of RhoC led to sustained activation of Rac1 GTPase and morphological, molecular and phenotypic changes reminiscent of epithelial to mesenchymal transition. We also find that Rac1 GTPase mediates tight binding of prostate cancer cells to bone marrow endothelial cells and promotes retraction of endothelial cells required for tumor cell diapedesis. Finally, Rac1 leads to β1 integrin activation, suggesting a mechanism that Rac1 can mediate tight binding with endothelial cells. Together, our data suggest that Rac1 GTPase is key mediator of prostate cancer cell-bone marrow endothelial cell interactions. Furthermore, expression of dominant-negative Rac1 (T17N) could largely block EGF-induced PI3K/Akt-PAK1 activation and cell migration. Our study demonstrated that EGF-induced cell migration involves a cascade of signalling events, including activation of Rac1, generation of ROS and subsequent activation of PI3K/Akt and PAK1. Small GTPase proteins, including RhoA, RhoB, RhoC, Rac1, and cdc42, are important molecules for linking cell shape and cell-cycle progression because of their role in both cytoskeletal arrangements and mitogenic signaling. The suppression of MMP-2 expression by CTXG led to an inhibition of SW620 cells invasion and migration by inactivating Rac1 and Cdc42 but not RhoA GTPase. In conclusion, our data demonstrate that CTXG exerted anti-invasion action in SW620 cells by targeting MMP-2 though regulating the activities of Rac1, Cdc42 and their downstream transcriptional factor AP-1. ctivation of H-Ras and Rac1 correlates with epidermal growth factor-induced invasion in Hs578T and MDA-MB-231 breast carcinoma cells We have previously shown that H-Ras, but not N-Ras, induces an invasive phenotype mediated by small GTPase Rac1 in MCF10A human breast epithelial cells. Moreover, siRNA-knockdown of Rac1 significantly inhibited the EGF-induced invasiveness in these cells. Our data demonstrate that the activation of H-Ras and the downstream molecule Rac1 correlates with EGF-induced breast cancer cell invasion, providing important information on the regulation of malignant progression in mammary carcinoma cells. At 50% growth-inhibiting concentration, icariin significantly suppressed tumor cells migration and invasion, which were traceable to down-regulation of Rac1 and VASP. These results indicate that icariin exerts negative effects on tumor cell invasion and migration via the Rac1-dependent VASP pathway and may be a potential anti-cancer drug. RhoGDI2 modulates the invasiveness and metastatic ability of cancer cells through regulation of Rac1 activity. We also showed that GBM cells secrete Sema3A endogenously, and RNA interference-mediated downregulation of Sema3A inhibits migration and alters cell morphology that is dependent on Rac1 activity. LMO1 and Dock180, a bipartite Rac1 guanine nucleotide exchange factor, promote human glioma cell invasion Here, we report for the first time that engulfment and cell motility 1 (ELMO1) and dedicator of cytokinesis 1 (Dock180), a bipartite Rac1 guanine nucleotide exchange factor (GEF), are evidently linked to the invasive phenotype of glioma cells. Inhibition of endogenous ELMO1 and Dock180 expression significantly impeded glioma cell invasion in vitro and in brain tissue slices with a concomitant reduction in Rac1 activation. Members of the Rac family of small GTPases are known to act as regulators of actin cytoskeletal structures and strongly influence the cellular processes of integrin-mediated adhesion and migration. Even though hyperactivated Rac proteins have been shown to influence metastatic processes, these proteins have never been directly linked to metastatic progression. We show that increased activation of Rac proteins directly correlates with increasing metastatic potential in a panel of cell variants derived from a single metastatic breast cancer cell line (MDA-MB-435). Expression of a dominant active Rac1 or a dominant active Rac3 resulted in a more invasive and motile phenotype. Moreover, expression of either dominant negative Rac1 or dominant negative Rac3 into the most metastatic cell variant resulted in decreased invasive and motile properties. This study correlates endogenous Rac activity with high metastatic potential and implicates Rac in the regulation of cell migration and invasion in metastatic breast cancer cells. Taken together, these results suggest a role for both the Rac1 and Rac3 GTPases in human breast cancer progression.

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56d8ba1851531f7e33000005

Is the gene SLC6A2 associated with orthostatic intolerance?

Orthostatic intolerance is a debilitating syndrome characterized by tachycardia on assumption of upright posture. The norepinephrine (NE) transporter (NET) has been implicated in a genetic form of the disorder. Thus attenuated baroreflex function and reduced sympathetic outflow may contribute to the orthostatic intolerance of severe NET deficiency. A mutation in the human norepinephrine transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface expression of mutant and wild-type transporters. Recently, our laboratory reported a polymorphism in the human NET (hNET) gene A457P in an individual with the autonomic disorder orthostatic intolerance (OI). Nonsynonymous single nucleotide polymorphisms (SNPs) in the human NET (hNET) gene that influence transporter function can contribute to disease, such as the nonfunctional transporter, A457P, identified in orthostatic intolerance. Orthostatic intolerance is not necessarily related to a specific mutation (Ala457Pro) in the human norepinephrine transporter gene. We propose that chromatin-modifying events associated with SLC6A2 gene suppression may constitute a mechanism of POTS. The goal of the present study was to further characterize the role and regulation of the SLC6A2 gene in POTS. In the absence of altered SLC6A2 gene sequence or promoter methylation, this reduced expression was directly correlated with chromatin modifications. We propose that chromatin-modifying events associated with SLC6A2 gene suppression may constitute a mechanism of POTS. A coding mutation in the norepinephrine transporter gene (SLC6A2) sequence has been reported in 1 family kindred only. The goal of the present study was to further characterize the role and regulation of the SLC6A2 gene in POTS.

yes