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5314896adae131f847000001

Is corpus callosum involved in the Mowat–Wilson syndrome?

The syndrome is characterized by typical facial features, moderate-to-severe mental retardation, epilepsy and variable congenital malformations, including Hirschsprung disease, genital anomalies, congenital heart disease, agenesis of the corpus callosum, and eye defects. Mowat-Wilson syndrome in a fetus with antenatal diagnosis of short corpus callosum: advocacy for standard autopsy. It is mainly characterized by moderate-to-severe intellectual disability, epilepsy, facial dysmorphism and various malformations including Hirschsprung disease and corpus callosum anomalies. The association of a corpus callosum hypoplasia with a histological Hirschsprung disease and a typical facial gestalt allowed the guiding of genetic testing. Mowat-Wilson syndrome (MWS) is a severe intellectual disability (ID)-distinctive facial gestalt-multiple congenital anomaly syndrome, commonly associating microcephaly, epilepsy, corpus callosum agenesis, conotruncal heart defects, urogenital malformations and Hirschsprung disease (HSCR). Mowat-Wilson syndrome (MWS) is characterized by severe mental retardation with seizures, specific facial dysmorphism, Hirschsprung disease, anomalies of the corpus callosum, and genitourinary and cardiac malformations. Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. The striking facial phenotype in addition to other features such as severely impaired speech, hypotonia, microcephaly, short stature, seizures, corpus callosum agenesis, congenital heart defects, hypospadias, and Hirschsprung disease are particularly important clues for the initial clinical diagnosis. Mowat-Wilson syndrome is a genetic disorder characterized by a distinct facial appearance, moderate-to-severe mental retardation, microcephaly, agenesis of the corpus callosum, Hirschsprung disease, congenital heart disease, and genital anomalies. It is characterized by a distinctive facial appearance in association with intellectual disability (ID) and variable other features including agenesis of the corpus callosum, seizures, congenital heart defects, microcephaly, short stature, hypotonia, and Hirschsprung disease. Mowat-Wilson syndrome (MWS) is an autosomal dominant intellectual disability syndrome characterised by unique facial features and congenital anomalies such as Hirschsprung disease, congenital heart defects, corpus callosum agenesis and urinary tract anomalies. Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation; a multiple congenital anomaly syndrome characterised by a typical facial gestalt, Hirschsprung disease or severe constipation, genitourinary anomaly, congenital heart defects, agenesis of corpus callosum and eye defects. Agenesis or hypogenesis of the corpus callosum. The anomalies may include Hirschsprung disease, heart defects, structural eye anomalies including microphthalmia, agenesis of the corpus callosum, and urogenital anomalies. Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene, and characterized by typical face, moderate-to-severe mental retardation, epilepsy, Hirschsprung disease, and multiple congenital anomalies, including genital anomalies (particularly hypospadias in males), congenital heart defects, agenesis of the corpus callosum, and eye defects. In 11 of the 28 patients with ACC, the following diagnoses could be established: Mowat-Wilson syndrome (n = 2), Walker-Warburg syndrome (n = 1), oro-facial-digital syndrome type 1 (n = 1), and chromosomal rearrangements (n = 7), including a patient with an apparently balanced reciprocal translocation, which led to the disruption and a predicted loss of function in the FOXG1B gene. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype (high forehead, frontal bossing, large eyebrows, medially flaring and sparse in the middle part, hypertelorism, deep set but large eyes, large and uplifted ear lobes, with a central depression, saddle nose with prominent rounded nasal tip, prominent columella, open mouth, with M-shaped upper lip, frequent smiling, and a prominent but narrow and triangular pointed chin), moderate-to-severe intellectual deficiency, epilepsy and variable congenital malformations including Hirschsprung disease (HSCR), genitourinary anomalies (in particular hypospadias in males), congenital heart defects, agenesis of the corpus callosum and eye anomalies. Mowat-Wilson syndrome is a mental retardation-multiple congenital anomaly syndrome characterized by a typical facies, developmental delay, epilepsy, and variable congenital malformations, including Hirschsprung disease, urogenital anomalies, congenital heart disease, and agenesis of the corpus callosum. Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation (MR)-multiple congenital anomaly syndrome, characterized by typical facies, severe MR, epilepsy, and variable congenital malformations, including Hirschsprung disease (HSCR), genital anomalies, congenital heart disease (CHD), and agenesis of the corpus callosum (ACC). Medical issues in our cohort of patients included seizures (75%) with no predeliction for any particular seizure type; agenesis of the corpus callosum (60% of our patients studied); congenital heart defects (75%), particularly involving the pulmonary arteries and/or valves; hypospadias (55% of males); severely impaired or absent speech (100% of individuals over 1 year of age) with relatively spared receptive language; and Hirschsprung disease (50%) or chronic constipation (25%). Mowat-Wilson syndrome (MWS) is a mental retardation syndrome associated with distinctive facial features, microcephaly, epilepsy, and a variable spectrum of congenital anomalies, including Hirschsprung disease (HSCR), agenesis of the corpus callosum, genitourinary abnormalities, and congenital heart disease. ACC is found in 40% of the cases of Mowat-Wilson syndrome (MWS), a polytopic embryonic defect including a distinctive facial gestalt, severe mental retardation, epilepsy and postnatal microcephaly as constant features. However, analysis of MWS should be considered in the differential diagnosis of ACC, especially when the facial features raise the possibility of MWS. Frameshift mutation of the zinc finger homeo box 1 B gene in syndromic corpus callosum agenesis (Mowat-Wilson syndrome). We report a girl who had Hirschsprung disease in association with distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation (Mowat-Wilson syndrome). Congenital anomalies, including Hirschsprung disease (HSCR), congenital heart disease, hypospadias, genitourinary anomalies, agenesis of the corpus callosum, and short stature are common.

yes

54d62faf3706e89528000003

Can NXY-059 be used for treatment of acute ischemic stroke patients?

Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY-059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria This occurred during 1993-2006, when the 2,4-disulfonylphenyl PBN derivative, called NXY-059 in the stroke studies, was shown to be safe in humans and was taken all the way through clinical phase 3 trials and then was deemed to be ineffective. The nitrone-based compound NXY-059, which is the first drug to reach clinical trials for the treatment of acute ischemic stroke, has provided promise for the development of more robust pharmacological agents. OKN-007 is a proprietary compound that has had extensive commercial development (designated as NXY-059) for another indication, acute ischemic stroke, and after extensive clinical studies was shown to lack efficacy for this indication but was shown to be very safe for human use. NXY-059, a polar compound with limited transport across the blood-brain barrier, has demonstrated neuroprotection in several animal models of acute ischemic stroke but failed to confirm clinical benefit in the second phase III trial (SAINT-II). NXY-059 is no longer in development following a lack of efficacy found in a Phase III trial in patients with acute ischemic stroke. We analyzed the quality and adequacy of animal studies supporting the efficacy of NXY-059 and other neuroprotective agents that are currently being investigated in phase II/III trials In the aftermath of the failed stroke clinical trials with the nitrone spin trap/radical scavenger, NXY-059, a number of articles raised the question: are we doing the right thing? In 2006, the first positive trial of neuroprotection was published: the SAINT I (Stroke-Acute Ischemic NXY Treatment) study. In February 2008, the SAINT II study was published, indicating that NXY-059 was not effective for AIS treatment. CONCLUSIONS: NXY-059 is ineffective for treatment of AIS within 6 hours of symptom onset. BACKGROUND AND PURPOSE: The SAINT I trial that showed a significant benefit of the neuroprotectant NXY-059 used a novel outcome for acute ischemic stroke trials: a shift toward good functional outcome on the 7-category modified Rankin scale (mRS). BACKGROUND: The free-radical-trapping agent NXY-059 showed promise as a neuroprotectant in the Stroke-Acute Ischemic NXY Treatment I (SAINT I) trial, reducing disability when given to patients who had acute ischemic stroke. CONCLUSIONS: NXY-059 is ineffective for the treatment of acute ischemic stroke within 6 hours after the onset of symptoms. The continued failure in approving new drugs for treatment of acute stroke has been recently set back by the failure of the NXY-059 (Stroke-Acute Ischemic NXY Treatment (SAINT) II) trial. The SAINT II Trial, a large randomized multicenter clinical trial of the putative neuroprotectant, NXY-059, failed to demonstrate a treatment benefit in acute ischemic stroke. The positive results from the first Stroke-Acute-Ischaemic-NXY-Treatment (SAINT-I) trial of the free-radical spin-trap drug, NXY-059, which followed many of the STAIR guidelines, reinvigorated enthusiasm in neuroprotection, but the SAINT-II trial did not replicate the positive effect on the same primary prespecified outcome measure. NXY-059, a free radical spin trap agent, was felt by many to have followed these criteria and it was recently shown to improve outcome in AIS patients in the SAINT I trial. However, the repeat, SAINT II trial was a neutral study, the results of which cast doubt on neuroprotection as a viable strategy for AIS. NXY-059 is a novel free radical-trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke. It is the first neuroprotectant to demonstrate a reduction in global disability in a phase III clinical trial, as measured by the modified Rankin Scale. BACKGROUND AND PURPOSE: NXY-059 is a free radical-trapping neuroprotectant demonstrated to reduce disability from ischemic stroke. CONCLUSIONS: NXY-059 within 6 hours of acute ischemic stroke significantly reduced disability. CONCLUSIONS: The administration of NXY-059 within six hours after the onset of acute ischemic stroke significantly improved the primary outcome (reduced disability at 90 days), but it did not significantly improve other outcome measures, including neurologic functioning as measured by the NIHSS score. Additional research is needed to confirm whether NXY-059 is beneficial in ischemic stroke. BACKGROUND: The free-radical-trapping agent NXY-059 showed promise as a neuroprotectant in the Stroke-Acute Ischemic NXY Treatment I (SAINT I) trial, reducing disability when given to patients who had acute ischemic stroke. NXY-059 is no longer in development following a lack of efficacy found in a Phase III trial in patients with acute ischemic stroke. The free-radical-trapping agent NXY-059 showed promise as a neuroprotectant in the Stroke-Acute Ischemic NXY Treatment I (SAINT I) trial, reducing disability when given to patients who had acute ischemic stroke The continued failure in approving new drugs for treatment of acute stroke has been recently set back by the failure of the NXY-059 (Stroke-Acute Ischemic NXY Treatment (SAINT) II) trial

no

56bb6b0eac7ad1001900000e

Is flibanserin effetive for Hypoactive Sexual Desire Disorder?

Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder. Flibanserin is a novel multifunctional serotonin agonist and antagonist (MSAA) that improves sexual functioning in premenopausal women who suffer from reduced sexual interest and desire. Flibanserin is a novel, non-hormonal drug for the treatment of HSDD in pre- and postmenopausal women, although the application submitted to the U.S. Food and Drug Administration by Sprout Pharmaceuticals is only for premenopausal women. CONCLUSIONS: In naturally postmenopausal women with HSDD, flibanserin, compared with placebo, has been associated with improvement in sexual desire, improvement in the number of SSEs, and reduced distress associated with low sexual desire, and is well tolerated. INTRODUCTION: Flibanserin is a mixed 5-HT1A agonist/5-HT2A antagonist that has been developed for the treatment of hypoactive sexual desire disorder in women BACKGROUND: Flibanserin, a novel serotonin (5-HT)(1A) agonist and 5-HT(2A) antagonist, has been shown to increase sexual desire and reduce distress in women with Hypoactive Sexual Desire Disorder (HSDD). Hypoactive sexual desire disorder (HSDD) is the most commonly described form of female sexual dysfunction. There is currently no pharmacological therapy approved to treat HSDD, and therefore, there is an unmet medical need for the development of efficacious treatment alternatives. Flibanserin is a novel, non-hormonal drug for the treatment of HSDD in pre- and postmenopausal women, although the application submitted to the U.S. Sexual function adverse events across flibanserin groups were generally comparable to placebo.Although these studies were not designed or powered to compare sexual function outcomes, results suggested a potential benefit of flibanserin on sexual function, particularly on female sexual desire, and provided a rationale to evaluate the efficacy of flibanserin as a treatment for female hypoactive sexual desire disorder.

yes

53267871d6d3ac6a3400000a

Is recommended the use of perioperative treatment with thyroid hormone therapy in patients undergoing coronary artery bypass grafting?

Short duration postoperative iv T(3) therapy increases cardiac index and does not alter mortality. We conclude that although widespread interest has been shown on the use of thyroid hormones in the perioperative period, and the effect of cardiopulmonary bypass on thyroid hormone metabolism widely studied, there is no substantial evidence to justify routine use of thyroid hormones in patients undergoing coronary artery bypass grafting. There is no clear evidence at this point to support thyroid hormone replacement in the latter patients, and it may be potentially harmful. Rather, we hold that T3 treatment of various surgical and other patients with nonthyroidal illness should be deferred until proof of its therapeutic efficacy is demonstrated. Perioperative administration of triiodothyronine increased cardiac output slightly and decreased systemic vascular resistance, but it had no effect on operative outcome. Routine use after coronary surgery is thus not recommended. Although mild effects on myocardial performance may exist, we cannot recommend at this time the routine use of intravenous T(3) as an inotropic agent in patients undergoing coronary artery bypass graft surgery. Raising serum triiodothyronine concentrations in patients undergoing coronary-artery bypass surgery increases cardiac output and lowers systemic vascular resistance, but does not change outcome or alter the need for standard postoperative therapy. Thus, there seems to be no sound justification for a routine use of T3 in patients undergoing open-heart procedures.

no

56e68967edfc094c1f000002

Is protein CXCR4 used as a prognostic marker of cancer?

Aberrant overexpression of CXCR4 is associated with worse overall survival, adenocarcinoma histology, distant metastasis, lymph node involvement in NSCLC. CXCR4 belongs to a family of G protein-coupled cell surface receptors and has been proved to a prognostic marker in a various tumors, including esophageal squamous cell cancer. The chemokine C-X-C motif receptor 4 (CXCR4) has been found to be a prognostic marker in various types of cancer, being involved in chemotaxis, stemness and drug resistance. The chemokine receptor CXCR4 that has been shown to be implicated in PDAC tumorigenicity and aggressiveness could serve as a prognostic marker for survival after a curative-intent surgery and was associated with the pattern of tumour recurrence (distant versus local relapse). XCR4 promotes tumor growth, angiogenesis and metastasis, and is a prognostic marker in a number of different types of tumors. CXCR4 has been identified as a prognostic marker for acute myeloid leukemia (AML) and other malignancies. The chemokine receptor CXCR4 has been found to be a prognostic marker in various types of cancer, including breast cancer. Upregulated expression of C-X-C chemokine receptor 4 is an independent prognostic predictor for patients with gastric cancer. detection of CXCR4 expression will be helpful for predicting prognosis for patients with gastric cancer. The chemokine receptor CXCR4 is a marker of metastatic disease. High CXCR4 level in cancer specimens independently predicts a poor outcome for patients with node-positive breast cancer. Univariate and multivariate analyses demonstrated that the high levels of nuclear CXCR4 and CXCL12 expression in hepatocytes were significantly better prognostic factors for overall and hepatic disease-free survival in patients with CLM. The chemokine receptor CXCR4 has been implicated in sarcoma development and has been found to be a prognostic marker for poor clinical outcome. high CXCR4 expression is correlated to shorter DFS and could be used as a prognostic marker in order to stratify melanoma patients at higher progression risk.

yes

5321b4959b2d7acc7e000007

Is transcapillary albumin escape altered in diabetic patients?

On the contrary, altered TERalb and increased carotid artery intimal thickness are shown by all hypertensive type 2 diabetic patients, both with normal and altered patterns of AER. Altered systemic capillary permeability characterizes insulin-resistant hypertensive patients with Metabolic Syndrome. TERalb is increased in normo-albuminuric type 1 diabetic patients.

yes

553d02c1f321868558000012

Are conserved noncoding elements associated with developmental genes?

Some characteristics of CNEs include their high frequency in mammalian genomes, their potential regulatory role in gene expression, and their enrichment in gene deserts nearby master developmental genes we review recent findings that disruptions of CNEs, within or at long distance from the coding sequences of key genes involved in NCC development, result in neurocristopathies via the alteration of tissue- or stage-specific long-distance regulation of gene expression Genomic regulatory blocks are chromosomal regions spanned by long clusters of highly conserved noncoding elements devoted to long-range regulation of developmental genes Analysis of CNEs, at least some of which are candidate regulatory elements, suggests that ancestral CNEs partitioned between gene duplicates. These results help explain the evolutionary pathways by which the developmentally important family of FgfD molecules arose and the deduced principles that guided FgfD evolution are likely applicable to the evolution of developmental regulation in many vertebrate multigene families Pan-vertebrate developmental cis-regulatory elements are discernible as highly conserved noncoding elements (HCNEs) and are often dispersed over large areas around the pleiotropic genes whose expression they control. On the loci of two developmental transcription factor genes, SOX3 and PAX6, we demonstrate that HCNEs conserved between human and zebrafish can be systematically and reliably tested for their regulatory function in multiple stable transgenes in zebrafish, and their genomic reach estimated with confidence using synteny conservation and HCNE density along these loci. HCNEs of both human and zebrafish function as specific developmental enhancers in zebrafish We show that human HCNEs result in expression patterns in zebrafish equivalent to those in mouse, establishing zebrafish as a suitable model for large-scale testing of human developmental enhancers HCNEs from the same area often drive overlapping patterns, suggesting that multiple regulatory inputs are required to achieve robust and precise complex expression patterns exhibited by developmental genes Organization of conserved elements near key developmental regulators in vertebrate genomes Further positional analysis of these conserved noncoding elements (CNEs) in the genome demonstrates that they cluster around genes involved in developmental regulation Ancora: a web resource for exploring highly conserved noncoding elements and their association with developmental regulatory genes Metazoan genomes contain arrays of highly conserved noncoding elements (HCNEs) that span developmental regulatory genes and define regulatory domains The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development We found the largest mammal-teleost conserved chromosomal segments to be spanned by highly conserved noncoding elements (HCNEs), their developmental regulatory target genes, and phylogenetically and functionally unrelated "bystander" genes. Ancora: a web resource for exploring highly conserved noncoding elements and their association with developmental regulatory genes. Pan-vertebrate developmental cis-regulatory elements are discernible as highly conserved noncoding elements (HCNEs) and are often dispersed over large areas around the pleiotropic genes whose expression they control. Metazoan genomes contain arrays of highly conserved noncoding elements (HCNEs) that span developmental regulatory genes and define regulatory domains. Further positional analysis of these conserved noncoding elements (CNEs) in the genome demonstrates that they cluster around genes involved in developmental regulation. The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). Disruption of long-distance highly conserved noncoding elements in neurocristopathies. Fish-mammal genomic comparisons have proved powerful in identifying conserved noncoding elements likely to be cis-regulatory in nature, and the majority of those tested in vivo have been shown to act as tissue-specific enhancers associated with genes involved in transcriptional regulation of development. Despite this, attempts at unearthing genome-wide regulatory elements conserved throughout the vertebrate lineage using BLAST-like approaches have thus far detected noncoding conservation in only a few hundred genes, mostly associated with regulation of transcription and development. Further positional analysis of these conserved noncoding elements (CNEs) in the genome demonstrates that they cluster around genes involved in developmental regulation. We found the largest mammal-teleost conserved chromosomal segments to be spanned by highly conserved noncoding elements (HCNEs), their developmental regulatory target genes, and phylogenetically and functionally unrelated "bystander" genes. Organization of conserved elements near key developmental regulators in vertebrate genomes. Pan-vertebrate developmental cis-regulatory elements are discernible as highly conserved noncoding elements (HCNEs) and are often dispersed over large areas around the pleiotropic genes whose expression they control

yes

55032d8be9bde69634000033

Is myasthenia gravis associated with osteoporosis?

We performed PVP in 4 patients with generalized MG associated with recent steroid-induced symptomatic VFs. In this case report, we used tacrolimus to successfully treat a 13-year-old boy with ocular MG who had suffered from severe steroid complications, including a failure of thrive and osteoporosis. INTRODUCTION: Myasthenia gravis (MG) is a neuromuscular disease which has been associated with an increased falls risk and glucocorticoid-induced osteoporosis, recognized determinants of increased fracture risk. RESULTS: Compared to the control cohort, there was no statistically significant increased risk observed in patients with MG for any fracture (adjusted hazard ratio [AHR] 1.11; 95 % confidence interval [CI], 0.84-1.47) or osteoporotic fractures (AHR 0.98 [95 % CI 0.67-1.41]). Further, use of oral glucocorticoids up to a cumulative dose exceeding 5 g prednisolone equivalents did not increase risk of osteoporotic fracture (AHR 0.99 [95 % CI, 0.31-3.14]) compared with MG patients without glucocorticoid exposure. The RANKL/OPG ratio and indices of bone metabolisms are also not affected by THX, although THX increases the levels of IL-7 and RANKL. Both disorders had been controlled for around 15 years by oral prednisolone and a cholinesterase inhibitor following surgical removal of invasive thymoma and radiotherapy, but muscular weakness due to myalgia and an increase in serum levels of myogenic enzymes, mainly ascribable to the recurrence of PM, reappeared immediately after cessation of these drugs, which was done because the patient had multiple bone fractures and severe osteoporosis due to the long-term corticosteroid therapy. We measured bone density in 36 patients (26 females and 10 males) who had undergone long-term prednisolone administration, and found a decrease in bone density in 31% of female patients and osteoporosis in only 11.5% (three cases). In conclusion, prednisolone-treated patients with myasthenia gravis have an acceptable risk of bone loss if prophylactic medication is administered. INTRODUCTION: Myasthenia gravis (MG) is a neuromuscular disease which has been associated with an increased falls risk and glucocorticoid-induced osteoporosis, recognized determinants of increased fracture risk. Alendronate should be used with caution in patients with myasthenia gravis who have corticosteroid-induced osteoporosis In this paper we present two cases of young women who developed severe PAO with vertebral fractures: a 42-year-old woman with a family history of osteoporosis, and a 21-year-old woman affected with myasthenia gravis Myasthenia gravis (MG) is a neuromuscular disease which has been associated with an increased falls risk and glucocorticoid-induced osteoporosis, recognized determinants of increased fracture risk

yes

5540a8d20083d1bf0e000001

Does a selective sweep increase genetic variation?

An East African population that gave rise to non-Africans underwent a selective sweep affecting the subcentromeric region where MTMR8 is located. This and similar sweeps in four other regions of the X chromosome, documented in the literature, effectively reduced genetic diversity of non-African chromosomes a selective sweep that has removed genetic variation from much of the drive X chromosome. evidence of reduced diversity and an excess of fixed replacement sites, consistent with a species-wide selective sweep. recent independent selective sweeps in AGO2 have reduced genetic variation episodes of natural selection (likely a selective sweep) predating the coalescent of human lineages, within the last 25 million years, account for the observed reduced diversity reduced variation or deviations from neutrality that might indicate a recent selective sweep Consider a genetic locus carrying a strongly beneficial allele which has recently fixed in a large population. As strongly beneficial alleles fix quickly, sequence diversity at partially linked neutral loci is reduced. This phenomenon is known as a selective sweep. a local selective sweep or demographic process that reduced variability reduced variation (a selective sweep) the mtDNA diversity, but not the nuclear DNA diversity, has been reduced relative to the neutral expectation of molecular evolution, suggesting the action of a selective sweep Furthermore, the amount of genetic variation after a selective sweep is expected to be unequal over demes: a greater reduction in expected heterozygosity occurs in the subpopulation from which the beneficial mutation originates than in its neighboring subpopulations. Our observation of reduction in variation at both intragenic and flanking loci of mutant pfcrt gene confirmed the selective sweep model of natural selection in chloroquine resistant P. A selective sweep describes the reduction of linked genetic variation due to strong positive selection. In these situations, adaptation should commonly produce 'soft' selective sweeps, where multiple adaptive alleles sweep through the population at the same time, either because the alleles were already present as standing genetic variation or arose independently by recurrent de novo mutations. CONCLUSIONS: The severe reduction in nucleotide variation at OsAMT1;1 in rice was caused by a selective sweep around OsAMT1;1, which may reflect the nitrogen uptake system under strong selection by the paddy soil during the domestication of rice. A selective sweep describes the reduction of linked genetic variation due to strong positive selection

no

53329c84d6d3ac6a34000040

Is indicated the use of antioxidant supplements in patients at risk for coronary artery disease?

We and others have published observational epidemiologic studies in support of vitamins in the primary prevention of CVD, but the results from intervention studies are mixed. For vitamin E, observational data suggest benefit at doses of 100 to 400 IU/d. Results from recent large-scale trials are mixed, with some showing modest benefit but others suggesting no benefit, especially for secondary prevention. Results for B vitamins are also mixed and further complicated by the recent folate fortification of the flour supply. If greater B vitamin intake does reduce CVD, the benefits are likely to be greatest for primary prevention and in populations with intake below dietary reference standards. In the dose-response meta-analysis, each 30 mg/day increase in vitamin C, 30 IU/day increase in vitamin E, and 1 mg/day increase in beta-carotene yielded the estimated overall relative risk for CHD of 1.01 (95% CI, 0.99-1.02), 0.96 (95% CI, 0.94-0.99), and 1.00 (95% CI, 0.88-1.14), respectively. CONCLUSIONS: Our findings in this meta-analysis suggest that an increase in dietary intake of antioxidant vitamins has encouraging prospects for possible CHD prevention. High levels of α-tocopherol in serum were associated with 30% lower CAD risk in another study (HR 0.71; 95%CI 0.53-0.94). Among minerals (zinc, selenium, and chromium), an inverse association between zinc and CAD was observed; levels lower than 14.1 µmol/L were associated with an increased risk for CAD (RR 1.70; 95%CI 1.21-2.38). The information available on this issue is scarce. Further prospective studies are needed to elucidate the role of these nutrients in the cardiovascular risk of patients with diabetes. Coenzyme Q10 supplementation at a dosage of 150 mg appears to decrease the inflammatory marker IL-6 in patients with CAD. Coenzyme Q10 supplements at a dose of 150 mg can decrease oxidative stress and increase antioxidant enzyme activity in patients with CAD. A higher dose of coenzyme Q10 supplements (>150 mg/d) might promote rapid and sustainable antioxidation in patients with CAD. Alpha-tocopherol or beta-carotene supplementation has no protective effect on macrovascular outcomes or total mortality of diabetic male smokers. Sodium selenite supplementation increases GPx-1 activity in endothelial cells and in CAD patients. Future studies have to demonstrate whether long-term CAD outcome can be improved. After 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6, and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering. In this population-based study, vitamin E use was unrelated to mortality, but this apparently null finding seems to represent a combination of increased mortality in those with severe cardiovascular disease and a possible protective effect in those without. In this large cohort of apparently healthy US male physicians, self-selected supplementation with vitamin E, vitamin C, or multivitamins was not associated with a significant decrease in total CVD or CHD mortality. The American Heart Association has recommended consumption of a balanced diet with emphasis on antioxidant-rich fruits and vegetables but has made no recommendations regarding vitamin E supplementation for the general population. Although vitamin E supplementation seems to be safe for most people, recommendations from health care professionals should reflect the uncertainty of established benefit as demonstrated in clinical trials Recent studies show that supplementation with antioxidant vitamins E and C have benefits in CHD prevention; however, supplementation with beta-carotene may have deleterious effects and is not recommended. Current evidence suggests that patients with CHD would probably benefit from taking vitamin E in a dosage of 400 IU per day and vitamin C in a dosage of 500 to 1,000 mg per day. Clinicians may also want to consider vitamin supplementation for CHD prevention in high-risk patients. Folate lowers elevated homocysteine levels, but evidence for routine supplemental use does not yet exist. In patients at high risk for cardiovascular events, treatment with vitamin E for a mean of 4.5 years had no apparent effect on cardiovascular outcomes.

no

552010076b348bb82c000015

Is there evidence to suggest that triiodothyronine has neuroprotective properties in traumatic brain injury?

Exogenous T3 administration provides neuroprotection in a murine model of traumatic brain injury. Treatment with T3 (1.2μg/100g body weight, i.p.) 1h after TBI resulted in a significant improvement in motor and cognitive recovery after CCI, as well as in marked reduction of lesion volumes. Western blot analysis revealed the ability of T3 to reduce brain trauma through modulation of cytoplasmic-nuclear shuttling of nuclear factor-κB (NF-κB). Twenty-four hours after brain trauma, T3-treated mice also showed significantly lower number of TUNEL(+) apoptotic neurons and curtailed induction of Bax, compared to vehicle control. In addition, T3 significantly enhanced the post-TBI expression of the neuroprotective neurotrophins (BDNF and GDNF) compared to vehicle. The stimulating effect of T3 on peripheral nerve regeneration may have considerable therapeutic potential. The present study provides evidence that the peripheral nervous system has its own system responsible for the local production of 3,5,3'-triiodothyronine, which may play a key role during the regeneration process. Although it has been hypothesized that T3 may facilitate neuronal regeneration after CNS injury, the 5'-D2 response to brain injury is unknown. The outcome after brain injury is closely correlated with the intensity of these changes, particularly with catecholamine plasma levels and the severity of the low triiodothyronine syndrome. The thyroid hormones triiodothyronine (T3) and L-thyroxine appear to enhance regeneration in the peripheral and central nervous system (CNS). T3 treatment influenced the general levels of incorporation of all treated groups over all days postoperation. T3 effects appear to involve an increased sensitivity of the cells of the injured nervous system to the hormone. T3, when administered over an 8 week period, stimulated axonal regeneration in the dorsal cortex and corpus callosum and promoted healing of the wound in the corpus callosum. The results of this investigation suggest that the use of T3 in the clinical treatment of injury to the central nervous system may be of less value than the work of earlier authors had indicated. In addition, T3 significantly enhanced the post-TBI expression of the neuroprotective neurotrophins (BDNF and GDNF) compared to vehicle

yes

553c011af321868558000009

Is Lysine-specific demethylase 1 (LSD1) a critical regulator of hematopoiesis?

Histone lysine-specific demethylase 1 (LSD1) protein is involved in Sal-like protein 4 (SALL4)-mediated transcriptional repression in hematopoietic stem cells shRNA-mediated knockdown of LSD1 in hematopoietic precursor cells resulted in altered SALL4 downstream gene expression and increased cellular activity our data revealed that histone demethylase LSD1 may negatively regulate SALL4-mediated transcription, and the dynamic regulation of SALL4-associated epigenetic factors cooperatively modulates early hematopoietic precursor proliferation Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation LSD1 represents a central regulator of hematopoietic stem and progenitor cells LSD1-kd led to an extensive expansion of granulomonocytic, erythroid and megakaryocytic progenitors LSD1-kd was associated with the upregulation of key hematopoietic genes our findings distinguish LSD1 as a critical regulator of hematopoiesis A short Gfi-1B isoform controls erythroid differentiation by recruiting the LSD1-CoREST complex through the dimethylation of its SNAG domain Dynamic interaction between TAL1 oncoprotein and LSD1 regulates TAL1 function in hematopoiesis and leukemogenesis Here, we reported that protein kinase A (PKA)-mediated phosphorylation regulates TAL1 interaction with the lysine-specific demethylase (LSD1) that removes methyl group from methylated Lys 4 on histone H3 tails. Phosphorylation of serine 172 in TAL1 specifically destabilizes the TAL1-LSD1 interaction leading to promoter H3K4 hypermethylation and activation of target genes that have been suppressed in normal and malignant hematopoiesis LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis we show that TAL1 is associated with histone demethylase complexes containing lysine-specific demethylase 1 (LSD1), RE1 silencing transcription factor corepressor (CoREST), histone deacetylase 1 (HDAC1), and histone deacetylase 2 in erythroleukemia and T cell leukemia cells we demonstrate that the TAL1-associated LSD1, HDAC1, and their enzymatic activities are coordinately down-regulated during the early phases of erythroid differentiation TAL1 recruits LSD1 to the silenced p4.2 promoter in undifferentiated, but not in differentiated, murine erythroleukemia (MEL) cells the dynamic regulation of TAL1-associated LSD1/HDAC1 complex may determine the onset of erythroid differentiation programs Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1 Inhibition of CoREST and LSD1 perturbs differentiation of erythroid, megakaryocytic, and granulocytic cells as well as primary erythroid progenitors we show that chromatin regulatory proteins CoREST and LSD1 mediate transcriptional repression by Gfi proteins. Lineage-restricted deployment of these cofactors through interaction with Gfi proteins controls hematopoietic differentiation Taken together, our findings distinguish LSD1 as a critical regulator of hematopoiesis and point to severe, but reversible, side effects of a LSD1-targeted therapy. LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis. Dynamic interaction between TAL1 oncoprotein and LSD1 regulates TAL1 function in hematopoiesis and leukemogenesis. Phosphorylation of serine 172 in TAL1 specifically destabilizes the TAL1-LSD1 interaction leading to promoter H3K4 hypermethylation and activation of target genes that have been suppressed in normal and malignant hematopoiesis. Histone lysine-specific demethylase 1 (LSD1) protein is involved in Sal-like protein 4 (SALL4)-mediated transcriptional repression in hematopoietic stem cells. Taken together, our findings distinguish LSD1 as a critical regulator of hematopoiesis and point to severe, but reversible, side effects of a LSD1-targeted therapy.

yes

550899c92e93f0133a000003

Is K-63 linked protein ubiquitination related to proteasomal degradation?

In contrast to K48-linked polyubiquitin chains, K63-linked polyubiquitin chains function in nonproteasomal biological processes. Modification of proteins by the addition of lysine (K)-63-linked polyubiquitin (polyUb) chains is suggested to play important roles in a variety of cellular events, including DNA repair, signal transduction, and receptor endocytosis. Ubiquitination is best known for its role in targeting proteins for degradation by the proteasome, but evidence of the nonproteolytic functions of ubiquitin is also rapidly accumulating. One example of the regulatory, rather than proteolytic, function of ubiquitin is provided by study of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins, which function as ubiquitin ligases to synthesize lysine 63 (K(63))-linked polyubiquitin chains to mediate protein kinase activation through a proteasome-independent mechanism. Some TRAF proteins, such as TRAF2 and TRAF3, have recently been shown to have a positive role in the canonical pathway that activates nuclear factor kappaB (NF-kappaB) through IkappaB kinase beta (IKKbeta), but a negative role in the noncanonical pathway that activates NF-kappaB through IKKalpha. These opposing roles of TRAF proteins may be linked to their ability to synthesize distinct forms of polyubiquitin chains. Indeed, the TRAF2-interacting protein RIP can mediate IKK activation when it is modified by K(63) polyubiquitin chains, but is targeted to degradation by the proteasome when it is K(48)-polyubiquitinted by the NF-kappaB inhibitor A20. Thus, ubiquitin chains are dynamic switches that can influence signaling outputs in dramatically different ways. Importantly, although Lys-48-linked ubiquitin chains appear to trigger proteasomal degradation, the presence of Lys-63-linked ubiquitin chains suggests that ubiquitination of IP(3)Rs may have physiological consequences beyond signaling for degradation. Chains of ubiquitin linked via lysine 48 (K48) are associated with protein degradation while chains linked via lysine 63 (K63) are associated with intracellular signaling. Lys(48)-linked chains target proteins for proteasomal degradation, and Lys(63)-linked chains function in signal transduction, endocytosis and DNA repair Remarkably, the attached Lys-48- and Lys-63-linked ubiquitin chains are homogeneous and are segregated to separate IP(3)R subunits, and Lys-48-linked ubiquitin chains, but not Lys-63-linked chains, are required for IP(3)R degradation Activated inositol 1,4,5-trisphosphate receptors are modified by homogeneous Lys-48- and Lys-63-linked ubiquitin chains, but only Lys-48-linked chains are required for degradation.

no

56a7d32fa17756b72f000001

Could transcription factors act as cell-cell signalling molecules?

Pax6 is a transcription factor essential for the development of tissues including the eyes, central nervous system and endocrine glands of vertebrates and invertebrates. It regulates the expression of a broad range of molecules, including transcription factors, cell adhesion and short-range cell-cell signalling molecules, hormones and structural proteins Recent data support the view that transcription factors - in particular, homeoproteins - can be transferred from cell to cell and have direct non-cell-autonomous (and therefore paracrine) activities

yes

52d7b45e98d0239505000002

is pharmacological treatment of subclinical hypothyroidism effective in reducing cardiovascular events?

The decision to treat elderly people is still an unresolved clinical challenge--first, due to a lack of appropriately powered randomized controlled trials of L-T4 in sHT patients, examining cardiovascular hard endpoints in various classes of age; and second, because of the negative effects of possible overtreatment. The lack of specific randomized trials enrolling either old or very old subjects, aimed at evaluate the efficacy of hormonal replacement on overall survival and cardiovascular risk reduction along with the negative effects of possible over-treatment, makes the decision to treat older people a still unresolved clinical challenge In patients with type 2 DM, the presence of SH serves as an additional risk factor for endothelial dysfunction. Treatment of SCH with levothyroxine was associated with fewer IHD events in younger individuals, but this was not evident in older people. Subclinical hyperthyroidism seems to be a risk factor of developing major cardiovascular events, especially stroke in older adults from the general population with normal left ventricular function. SCH appears to influence the postoperative outcome for patients by increasing the development of postoperative atrial fibrillation. However, it is still unproven whether preoperative thyroxine replacement therapy for patients with SCH might prevent postoperative atrial fibrillation after CABG. In CHF patients TSH levels even slightly above normal range are independently associated with a greater likelihood of heart failure progression. In current RCTs, levothyroxine replacement therapy for subclinical hypothyroidism did not result in improved survival or decreased cardiovascular morbidity. Data on health-related quality of life and symptoms did not demonstrate significant differences between intervention groups. However, the actual effectiveness of thyroid hormone substitution in reducing the risk of cardiovascular events remains to be elucidated. In conclusion, the multiplicity and the possible reversibility of subclinical hypothyroidism-associated cardiovascular abnormalities suggest that the decision to treat a patient should depend on the presence of risk factors, rather than on a TSH threshold. However, whether SH confers a high risk for cardiovascular disease, and whether LT4 therapy has a long-term benefit that clearly outweighs the risks of overzealous treatment in these individuals, remain topics of controversy.

no

52e8e96698d023950500001f

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

Two siblings died suddenly at the ages of 9 and 10 years Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a type of cardiac arrhythmia that occurs in people with a structurally normal heart. Stress or anxiety-induced release of endogenous catecholamines causes a dysfunction in the myocytic calcium-ion channel, leading to ventricular arrhythmias that can cause dizziness, syncope, or sudden cardiac death. During a follow-up of 48±94 months, arrhythmia events (sudden cardiac death and aborted cardiac arrest) associated with noncompliance occurred in 2 patients. 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 ryanodine receptor. 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. catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS), leave no evidence to be found at autopsy a spectrum of sudden cardiac death (SCD)-predisposing heritable cardiac arrhythmia syndromes, including long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT is a familial arrhythmogenic syndrome characterized by abnormal calcium (Ca(2+)) handling, ventricular arrhythmias, and sudden cardiac death Mutations in RyR2 are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT) and sudden cardiac death. Patients with CPVT often present with exercise- or emotion induced syncope, the first presentation can also be sudden cardiac death. Among the five major arrhythmogenic disorders occurring in the absence of a structural heart disease is catecholaminergic polymorphic ventricular tachycardia (CPVT), which is a highly lethal form of inherited arrhythmias. Patients with CPVT are at high risk of developing life-threatening ventricular arrhythmias when untreated. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by VT induced by adrenergic stress in the absence of structural heart disease and high incidence of sudden cardiac death. CPVT is an inherited arrhythmia syndrome caused by gene mutations that destabilize cardiac ryanodine receptor Ca(2+) release channels. Sudden cardiac death is incompletely prevented by conventional drug therapy with β-blockers with or without Ca(2+) channel blockers. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease that can cause sudden cardiac death due to ventricular fibrillation (VF). Important potential causes of sudden cardiac deaths in the absence of heart disease are primary electrical diseases such as Brugada syndrome, long QT syndrome (LQTS), short QT syndrome and catecholaminergic polymorphic ventricular tachyarrhythmias. catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) are primary inherited arrhythmia syndromes that may cause syncope and sudden cardiac death in young individuals. 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. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder that causes syncopal episodes related with stress or emotion and even sudden cardiac deaths. Catecholaminergic polymorphic ventricular tachycardia caused by mutations in the RyR2 gene manifests as severe arrhythmias, and may provide a candidate for sudden cardiac deaths. Patients diagnosed with an electrical cardiomyopathy have an increased risk of syncope and sudden cardiac death (SCD). Patients with CPVT present with exercise-induced syncope and sudden cardiac death but normal resting electrocardiograms. Over 80% of SCD occurs in patients with organic heart disease. However, approximately 10-15% of SCD occurs in the presence of structurally normal heart and the majority of those patients are young. In this group of patients, changes in genes encoding cardiac ion channels produce modification of the function of the channel resulting in an electrophysiological substrate of VA and SCD. Collectively these disorders are referred to as Cardiac Ion Channelopathies. The 4 major syndromes in this group are: The Long QT Syndrome (LQTS), the Brugada Syndrome (BrS), the Short QT Syndrome (SQTS), and the Catecholaminergic Polymorphic VT (CPVT). Important potential causes of sudden cardiac deaths in the absence of heart disease are primary electrical diseases such as Brugada syndrome, long QT syndrome (LQTS), short QT syndrome (SQTS), and catecholaminergic polymorphic ventricular tachyarrhythmias (CPVT). Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial cardiac arrhythmia that is related to RYR2 or CASQ2 gene mutation. It occurs in patients with structurally normal heart and causes exercise-emotion-triggered syncope and sudden cardiac death. Potentially lethal ion channel disorders (channelopathies) such as the long QT syndromes (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT) Aberrant spontaneous, diastolic Ca2+ leak from the SR due to dysfunctional RyR2 contributes to the formation of delayed after-depolarisations, which are thought to underlie the fatal arrhythmia that occurs in both heart failure (HF) and in catecholaminergic polymorphic ventricular tachycardia (CPVT). Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon heritable disease presenting with syncope or sudden cardiac death. Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a heritable arrhythmia unmasked by exertion or stress, characterized by triggered activity and sudden cardiac death in affected patients. families that exhibit CPVT (catecholaminergic polymorphic ventricular tachycardia), a condition in which physical or emotional stress can trigger severe tachyarrhythmias that can lead to sudden cardiac death. that often leads to sudden death in HF and in CPVT. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by adrenergically mediated polymorphic ventricular tachycardia leading to syncope and sudden cardiac death. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an autosomal dominant inherited disorder characterized by adrenergic induced polymorphic ventricular tachycardias and associated with sudden cardiac death. These data suggest that "leaky" RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare arrhythmogenic disorder characterized by syncopal events and sudden cardiac death at a young age during physical stress or emotion, in the absence of structural heart disease. catecholaminergic polymorphic ventricular tachycardia (CPVT), idiopathic ventricular fibrillation (VF), and arrhythmogenic right ventricular cardiomyopathy (ARVC) account for a relevant proportion of sudden cardiac death cases in young patients cohorts. has recently been shown to be involved in at least two forms of sudden cardiac death (SCD): (1) Catecholaminergic polymorphic ventricular tachycardia (CPVT)

yes

517404878ed59a060a000023

Are histone deacetylase (HDAC) inhibitors good candidates to control metastasis of solid tumors?

JNJ-26481585 also fully inhibited the growth of C170HM2 colorectal liver metastases, whereas again 5-fluorouracil/Leucovorin showed modest activity. Although not meeting the RECIST response criteria for adequate single-agent activity, the observed tolerable toxicities and the potential for clinical benefit in terms of stable disease suggest that further assessment of vorinostat as a part of combination therapy with either chemotherapeutic or targeted agents in metastatic breast might be undertaken. Treatments of different structural classes of HDACi simultaneously induced cell death and promoted cell migration and metastasis in multiple cancer cell types. Suppression of HDACi-induced PKCs leads to development of low toxic and long-term therapeutic strategies to potentially treat cancer as a chronic disease. mRNA expression analysis of lung tumor bearing mice suggested that the enhanced chemopreventive activity of the combination is related to atorvastatin modulation of DNA repair, SAHA modulation of angiogenesis, and both drugs modulating invasion and metastasis pathways. Histone deacetylase (HDAC) inhibitors induced morphologic differentiation, cell-cycle exit, and a shift to a differentiated, melanocytic gene expression profile in cultured UM cells. VPA inhibited the growth of UM tumors in vivo. When both drugs were used in concert additive effects were observed on the migratory and invasive behavior but not on tumor-endothelium and tumor-matrix interaction. Separate mTOR or HDAC inhibition slows processes related to tumor metastasis. The RAD001-VPA combination showed advantage over VPA monotreatment with particular respect to migration and invasion. In conclusion, sequential treatments of mice with MS-275 followed by TRAIL may target multiple pathways to reverse EMT and inhibit tumor progression, angiogenesis, and metastasis and represent a novel therapeutic approach to treat cancer. In vivo, AA98 synergized with vorinostat to inhibit tumor growth and metastasis. We report the first preclinical data for the prevention of brain metastasis of triple-negative breast cancer. Vorinostat is brain permeable and can prevent the formation of brain metastases by 62%. Its mechanism of action involves the induction of DNA double-strand breaks, suggesting rational combinations with DNA active drugs or radiation. Combining vorinostat with radiation may be a potential treatment option for patients with breast cancer who develop brain metastases. Although single-agent PCI-24781 had modest effects on STS growth and metastasis, marked inhibition was observed when combined with chemotherapy. In a 4T1 metastatic breast carcinoma model, AN-7 inhibited the formation of lung lesions by 76% and AN-9 by 47%, further demonstrating the greater efficacy of AN-7 compared to AN-9 (P<0.02). Both AN-7 and AN-9 exhibited antimetastatic and antiangiogenic activities by reducing vascularization, bFGF expression and HIF-1alpha. Since prolonged oral administration with 50 mg/kg or a single oral dose of 1.2 g/kg AN-7 did not cause adverse effects and the former exhibited significant anticancer activity, AN-7 is likely to display a high therapeutic index and may be beneficial for prostate cancer patients. We show that apicidin significantly inhibits H-ras-induced invasive phenotype of MCF10A human breast epithelial cells in parallel with a specific downregulation of matrix metalloproteinase (MMP)-2, but not MMP-9. We also show that apicidin induces a morphological reversal and growth inhibition of H-ras MCF10A cells similar to that induced by other HDAC inhibitors. We also found that NaB induced three genes, which are known metastatic suppressors, and downregulated 11 genes, which have been shown to promote metastasis.

yes

54f704b630767eb92e000001

Is muscle lim protein (MLP) involved in cardiomyopathies?

Muscle LIM protein (MLP) has been proposed to be a central player in the pathogenesis of heart muscle disease. In line with this notion, the homozygous loss of MLP results in cardiac hypertrophy and dilated cardiomyopathy. Moreover, MLP is induced in several models of cardiac hypertrophy such as aortic banding and myocardial infarction. Muscle LIM protein (MLP) null mice are often used as a model for human dilated cardiomyopathy. A lack of MLP leads to an age-dependent impairment of excitation-contraction coupling with resulting contractile dysfunction and secondary fibrosis. Loss of murine MLP results in dilated cardiomyopathy, and mutations in human MLP lead to cardiac hypertrophy, indicating a critical role for MLP in maintaining normal cardiac function. Our data indicate that MLP contributes to muscle stiffness and is necessary for maximum work and power generation. Interestingly, MLP was also found to be down-regulated in humans with heart failure (Zolk et al. Circulation 101:2674-2677, 2000) and MLP mutations are able to cause hypertrophic and dilated forms of cardiomyopathy in humans (Bos et al. Mol Genet Metab 88:78-85, 2006; Geier et al. Circulation 107:1390-1395, 2003; Hershberger et al. Clin Transl Sci 1:21-26, 2008; Knöll et al. Cell 111:943-955, 2002; Knöll et al. Circ Res 106:695-704, 2010; Mohapatra et al. Mol Genet Metab 80:207-215, 2003). MLP soon became an important model for experimental cardiology when it was first demonstrated that MLP deficiency leads to myocardial hypertrophy followed by a dilated cardiomyopathy and heart failure phenotype (Arber et al. Cell 88:393-403, 1997). Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations. We used a newly designed monoclonal antibody to show that muscle LIM protein (MLP), the protein encoded by CSRP3, is mainly a cytosolic component of cardiomyocytes and not tightly anchored to sarcomeric structures. Our functional data from both in vitro and in vivo analyses suggest that at least one of MLP's mutated forms seems to be destabilized in the heart of HCM patients harbouring a CSRP3 missense mutation. Muscle LIM protein (MLP) is a cytoskeletal protein located at the Z-disc of sarcomeres. Mutations in the human MLP gene are associated with hypertrophic and dilated cardiomyopathy. Our data demonstrate that Mlp84B is essential for normal cardiac function and establish the Drosophila model for the investigation of the mechanisms connecting defective cardiac Z-disc components to the development of cardiomyopathy. Muscle LIM protein (MLP) is a cytoskeletal LIM-only protein expressed in striated muscle. Mutations in human MLP are associated with cardiomyopathy; TTN-encoded titin, CSRP3-encoded muscle LIM protein, and TCAP-encoded telethonin are Z-disc proteins essential for the structural organization of the cardiac sarcomere and the cardiomyocyte's stretch sensor. All three genes have been established as cardiomyopathy-associated genes for both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Approximately 4.1% of unrelated patients had HCM-associated MLP or TCAP mutations. MLP/TCAP-HCM phenotypically mirrors myofilament-HCM and is more severe than the subset of patients who still remain without a disease-causing mutation. The precise role of W4R-MLP in the pathogenesis of either DCM or HCM warrants further investigation. MLP (muscle-LIM-protein) deficient mice develop DCM and changes in the mechanical coupling of cardiomyocytes result in alterations at the intercalated disks and enhanced accumulation of adherens junction proteins. Targeted deletion of cytoskeletal muscle LIM protein (MLP) in mice consistently leads to dilated cardiomyopathy (DCM) after one or more months. In summary, young MLPKO mice revealed substantial alterations in passive myocardial properties and relaxation time, but not in most systolic characteristics. These results indicate that the progression to heart failure in the MLPKO model may be driven by diastolic myocardial dysfunction and abnormal passive properties rather than systolic dysfunction. Mice lacking the muscle LIM protein (MLP) develop morphological and clinical signs resembling human dilated cardiomyopathy and heart failure. Our results show that the absence of MLP causes a local loss of mitochondria. We hypothesize that this is caused by a disturbed interaction between cytoskeleton and mitochondria, which interferes with energy sensing and energy transfer. Recovery of energy depletion by stimulating mitochondrial biogenesis might be a useful therapeutic strategy for improving the energy imbalance in heart failure. Previous work has shown that mutations in muscle LIM protein (MLP) can cause hypertrophic cardiomyopathy (HCM). In order to gain an insight into the molecular basis of the disease phenotype, we analysed the binding characteristics of wild-type MLP and of the (C58G) mutant MLP that causes hypertrophic cardiomyopathy. The molecular basis for HCM-causing mutations in the MLP gene might therefore be an alteration in the equilibrium of interactions of the ternary complex MLP-N-RAP-alpha-actinin. Muscle LIM protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been implicated in both myogenesis and sarcomere assembly. In the latter role, it binds zyxin and alpha-actinin, both of which are involved in actin organization. An MLP-deficient mouse has been described; these mice develop dilated cardiomyopathy and heart failure. We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R). MLP-knockout mice develop a marked cardiac hypertrophy reaction and dilated cardiomyopathy (DCM). MLP is therefore a candidate gene for heritable forms of hypertrophic cardiomyopathy (HCM) and DCM in humans. Family studies revealed cosegregation of clinically affected individuals with the respective mutations in MLP. CONCLUSION: Here, we present evidence that mutations in the CRP3/MLP gene can cause HCM. The skeletal muscle LIM protein 1 (SLIM1) is highly expressed in skeletal and cardiac muscle, and its expression is downregulated significantly in dilated human cardiomyopathy. Targeted disruption of muscle LIM protein (MLP) has previously been shown to result in dilated cardiomyopathy with many of the clinical signs of heart failure, although the effects of MLP disruption on passive ventricular mechanics and myocyte architecture are not known. These results suggest that the disruption of the cytoskeletal protein MLP results in less compliant passive tissue and concomitant structural alterations in the three-dimensional myocyte architecture that may in part explain the ventricular dysfunction in the dilated heart. Mutations in cysteine and glycine-rich protein 3 (CSRP3), the gene encoding MLP, have been directly associated with human cardiomyopathies, whereas aberrant expression patterns are reported in human cardiac and skeletal muscle diseases. Muscle LIM protein (MLP) has been proposed to be a central player in the pathogenesis of heart muscle disease. Previous work has shown that mutations in muscle LIM protein (MLP) can cause hypertrophic cardiomyopathy (HCM)

yes

571f33f10fd6f91b68000004

Have 5q35 microdeletions been implicated in Sotos syndrome development?

Loss-of-function mutations of NSD1 and 5q35 microdeletions encompassing NSD1 are a major cause of Sotos syndrome (Sos), which is characterized by overgrowth, macrocephaly, characteristic facies, and variable intellectual disability (ID) We observed a novel 3.5 Mb 5q subtelomeric deletion in a 3-year-old girl with developmental delay, hypotonia and multiple minor anomalies. Comparison of her phenotype with the few published patients with terminal 5q35 deletions revealed several overlapping features, but also showed remarkable differences such as shortness of stature versus macrosomia. After the report of 5q35.3 microdeletions in Sotos syndrome we integrated the published BACs into the public draft sequence and exactly mapped the deletion size in our patient by FISH analysis with 15 BAC probes. We demonstrated that the deletion in our patient is immediately adjacent to the reported Sotos syndrome deletion site Switch in FGFR3 and -4 expression profile during human renal development may account for transient hypercalcemia in patients with Sotos syndrome due to 5q35 microdeletions. Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome. After the report of 5q35.3 microdeletions in Sotos syndrome we integrated the published BACs into the public draft sequence and exactly mapped the deletion size in our patient by FISH analysis with 15 BAC probes. Clinical and genetic spectrum of 18 unrelated Korean patients with Sotos syndrome: frequent 5q35 microdeletion and identification of four novel NSD1 mutations. Here we describe a new case of Sotos syndrome with a 5q35 microdeletion, affecting the fibroblast growth factor receptor 4 (FGFR4) gene, presenting with infantile hypercalcemia. Microdeletions at 5q35.3, encompassing NSD1, are responsible for approximately 10% of non-Japanese cases of Sotos. Alu-related 5q35 microdeletions in Sotos syndrome. Most cases of Sotos syndrome are caused by intragenic NSD1 mutations or 5q35 microdeletions. Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome Clinical and genetic spectrum of 18 unrelated Korean patients with Sotos syndrome: frequent 5q35 microdeletion and identification of four novel NSD1 mutations Microdeletions at 5q35.3, encompassing NSD1, are responsible for approximately 10% of non-Japanese cases of Sotos A case of Sotos syndrome with 5q35 microdeletion and novel clinical findings. Here we describe a new case of Sotos syndrome with a 5q35 microdeletion, affecting the fibroblast growth factor receptor 4 (FGFR4) gene, presenting with infantile hypercalcemia. There are two types of mutations that cause NSD1 haploinsufficiency: mutations within the NSD1 gene (mutation type) and a 5q35 submicroscopic deletion encompassing the entire NSD1 gene (deletion type). aCGH and metaphase FISH are useful for rapid diagnosis of 5q35 microdeletion associated with Sotos syndrome. Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome. Switch in FGFR3 and -4 expression profile during human renal development may account for transient hypercalcemia in patients with Sotos syndrome due to 5q35 microdeletions. A case of Sotos syndrome with 5q35 microdeletion and novel clinical findings. Most cases of Sotos syndrome are caused by intragenic NSD1 mutations or 5q35 microdeletions. aCGH and metaphase FISH are useful for rapid diagnosis of 5q35 microdeletion associated with Sotos syndrome. Alu-related 5q35 microdeletions in Sotos syndrome.

yes

5328185dd6d3ac6a3400000e

Is metabolic syndrome related with cardiovascular disease?

The metabolic syndrome (MetS) is characterized by a cluster of risk factors including central obesity, hypertension, dyslipidemia and insulin resistance, The MetS is associated with an increased risk for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). As a molecular link between metabolic signals, inflammation, and vascular dysfunction, resistin can be proposed as playing a significant role in the heightened inflammatory state induced by metabolic stress linked to excessive caloric intake, thus contributing to the risk for metabolic syndrome (MetS), type 2 diabetes (T2DM), and cardiovascular disease (CVD). The metabolic syndrome (MetS) is associated with a higher risk for both, type 2 diabetes mellitus and cardiovascular disease. arotid intima-media thickness (CIMT) has been widely used as a surrogate marker of atherosclerosis and cardiovascular disease (CVD)

yes

52f77f752059c6d71c00002b

Are defects in recombination repair involved in carcinogenesis?

Inherited mutations in genes involved in HR are associated with gene rearrangement and may be a prerequisite for tumor development in some cancer-prone hereditary diseases like Bloom, Werner and Rothmund-Thomson syndromes. Variants in the XRCC3 gene might result in altered protein structure or function which may influence DSBR efficiency and lead to cancer. Although alcohol consumption is related to increased cancer risk, its molecular mechanism remains unclear. Here, we demonstrate that an intake of 10% alcohol for 4 weeks in rats is genotoxic due to induction of micronuclei. Acetaldehyde (AA), the first product of ethanol metabolism, is believed to be responsible for DNA damage induced by alcohol. Although efficiency of these repair processes substantially decrease the efficacy of cancer chemotherapies that target DNA, compromised DNA repair contributes to mutagenesis and genomic instability leading to carcinogenesis. damage response and repair pathways are important barriers to carcinogenesis. olymorphisms in DNA repair genes and differences in repair capacity between individuals have been widely documented. For colorectal cancer, the loss of mismatch repair gene activity is a key genetic determinant. Nucleotide excision repair (NER), recombination repair (RR) and base excision repair (BER) pathways have critical roles in protection against other cancers, and we wished to investigate their role in colorectal cancer.

yes

5721f6f90fd6f91b68000012

Are seizures among the neurological symptoms of incontinentia pigmenti?

High-dose glucocorticoid therapy in the management of seizures in neonatal incontinentia pigmenti Incontinentia pigmenti is an X-linked dominant disorder resulting from a mutation of IKBKG. This disorder has a classic dermatologic presentation, but neurologic involvement, with seizures and cortical infarction, can arise shortly after birth Some children with incontinentia pigmenti exhibit encephalopathic features with severe seizures and disturbed consciousness, from the neonatal through the early infantile period Incontinentia pigmenti (IP) is a rare X-linked dominant neurocutaneous disorder affecting ectodermal tissue: skin, eyes, central nervous system, hair, nails, and teeth. It is usually lethal for males in utero. The involved gene is NEMO, an essential component of the nuclear factor-kappa B (NF-κB) signaling pathway. Skin lesions are highly diagnostic, occurring in neonates, with a particular distribution on Blaschko lines. The severity of the disease is related to ocular and neurological impairment. The hallmark of ocular IP is retinal vasculopathy including peripheral retinal vascular nonperfusion, macular infarction and neovascularization, and preretinal neovascularization. CNS involvement consists of seizures, mental retardation, hemiparesis, spasticity, microcephaly, cerebellar ataxia, and coma Incontinentia Pigmenti is a rare X-linked multisystem disorder with well described and pathognomonic skin manifestations. Neurological manifestations are found in 30% of IP patients, forming one of the major causes of morbidity and mortality of the condition. In this review, clinical and brain imaging data of 45 IP patients with a neurological phenotype are reviewed. Several clinical presentations could be identified, comprising seizures, infantile encephalopathy, acute disseminated encephalomyelitis and ischemic stroke Incontinentia pigmenti presenting as seizures. Neonatal seizures in two sisters with incontinentia pigmenti. High-dose glucocorticoid therapy in the management of seizures in neonatal incontinentia pigmenti: a case report. Incontinentia Pigmenti is an X-linked dominant neurocutaneous disorder with central nervous system manifestations in 30% of cases, including seizures and mental retardation. Neonatal seizures in two sisters with incontinentia pigmenti A rare cause of neonatal seizure: incontinentia pigmenti. Here, we describe the clinical, electrographic, and neuroradiologic effect of systemic glucocorticoid therapy in a neonate with incontinentia pigmenti manifesting an epileptic encephalopathy. Incontinentia pigmenti presenting as seizures. Neonatal seizures in two sisters with incontinentia pigmenti.

yes

56c332a350c68dd41600000d

Is there a genome-wide technique for the detection of R-loop formation?

Genome-wide analysis of fragile sites by chromatin immunoprecipitation (ChIP) and microarray (ChIP-chip) of phosphorylated H2A in these mutants supported a transcription-dependent mechanism of DNA damage characteristic of R loops We have used a bisulfite-sensitivity assay to demonstrate genome-wide increase in the occurrence of RNA-DNA hybrids (R-loops), including from antisense and read-through transcripts, in a nusG missense mutant defective for Rho-dependent termination. The results demonstrate a key function of FACT in the resolution of R-loop-mediated transcription-replication conflicts, likely associated with a specific chromatin organization. Previous work revealed that GC skew and R-loop formation associate with a core set of unmethylated CpG island (CGI) promoters in the human genome

yes

571394141174fb175500000b

Can bioprinting use human cells?

In this study, human adipose-derived stem cells (hASCs) were printed in a free-scalable 3D grid pattern by means of LaBP. Additionally, we provide the proof that even pre-differentiated hASCs could be utilized for the generation of 3D tissue grafts. To explore the three dimensional(3D)bioprinting technology, using human dental pulp cells (hDPCs) mixture as bioink and to lay initial foundations for the application of the 3D bioprinting technology in tooth regeneration. In this study, 3-D printable formulations of hybrid hydrogels are developed, based on methacrylated hyaluronic acid (Me-HA) and methacrylated gelatin (Me-Gel), and used to bioprint heart valve conduits containing encapsulated human aortic valvular interstitial cells (HAVIC). Bioprinting can be used to precisely position cells and cell-laden materials to generate controlled tissue architecture. Bioprinting can be defined as the use of computer-aided transfer processes for patterning and assembling living and non-living materials with a prescribed 2D or 3D organization in order to produce bio-engineered structures serving in regenerative medicine, pharmacokinetic and basic cell biology studies. 3D bioprinting has already been used for the generation and transplantation of several tissues, including multilayered skin, bone, vascular grafts, tracheal splints, heart tissue and cartilaginous structures. [Three dimensional bioprinting technology of human dental pulp cells mixtures]. To explore the three dimensional(3D)bioprinting technology, using human dental pulp cells (hDPCs) mixture as bioink and to lay initial foundations for the application of the 3D bioprinting technology in tooth regeneration Here we report the development of clinically relevant sized tissue analogs by 3-D bioprinting, delivering human nasal inferior turbinate tissue-derived mesenchymal progenitor cells encapsulated in silk fibroin-gelatin (SF-G) bioink Sodium alginate hydrogel, stabilized with gelatin, is a suitable, biologically inert matrix that can be used for encapsulating and 3D bioprinting of bone-related SaOS-2 cells. Bioactive nanoparticles stimulate bone tissue formation in bioprinted three-dimensional scaffold and human mesenchymal stem cells. OBJECTIVE: To explore the three dimensional(3D)bioprinting technology, using human dental pulp cells (hDPCs) mixture as bioink and to lay initial foundations for the application of the 3D bioprinting technology in tooth regeneration. Cellular behavior in micropatterned hydrogels by bioprinting system depended on the cell types and cellular interaction. Engineering a morphogenetically active hydrogel for bioprinting of bioartificial tissue derived from human osteoblast-like SaOS-2 cells. At the same time, the principal feasibility of bioprinting vascularized human organs as well as in vivo bioprinting has been demonstrated. The bioprinting of complex 3D human tissues and constructs in vitro and especially in vivo are exciting, but long-term, applications. Bioprinting can be defined as the use of computer-aided transfer processes for patterning and assembling living and non-living materials with a prescribed 2D or 3D organization in order to produce bio-engineered structures serving in regenerative medicine, pharmacokinetic and basic cell biology studies. In this study, the 3D bioprinting of hDPCs mixtures was realized, thus laying initial foundations for the application of the 3D bioprinting technology in tooth regeneration. To explore the three dimensional(3D)bioprinting technology, using human dental pulp cells (hDPCs) mixture as bioink and to lay initial foundations for the application of the 3D bioprinting technology in tooth regeneration. Furthermore, it is not known how human valve cells respond to these printed environments. In this study, 3-D printable formulations of hybrid hydrogels are developed, based on methacrylated hyaluronic acid (Me-HA) and methacrylated gelatin (Me-Gel), and used to bioprint heart valve conduits containing encapsulated human aortic valvular interstitial cells (HAVIC). To explore the three dimensional(3D)bioprinting technology, using human dental pulp cells (hDPCs) mixture as bioink and to lay initial foundations for the application of the 3D bioprinting technology in tooth regeneration. [Three dimensional bioprinting technology of human dental pulp cells mixtures]. The bioprinting of complex 3D human tissues and constructs in vitro and especially in vivo are exciting, but long-term, applications. Three-dimensional printed trileaflet valve conduits using biological hydrogels and human valve interstitial cells. Furthermore, it is not known how human valve cells respond to these printed environments. Engineering a morphogenetically active hydrogel for bioprinting of bioartificial tissue derived from human osteoblast-like SaOS-2 cells.

yes

5544f3005beec11c10000008

Is transcription-associated mutagenesis (TAM) related to gene expression levels?

These mutations were frequent in plasmid-borne lacS expressed at a high level but not in single-copy lacS in the chromosome or at lower levels of expression in a plasmid. The results suggest that important DNA repair or replication fidelity functions are impaired or overwhelmed in pJlacS, with results analogous to those of the "transcription-associated mutagenesis" seen in bacteria and eukaryotes. the rate of point mutation in a gene increases with the expression level of the gene. Transcription induces mutagenesis on both DNA strands, indicating simultaneous actions of several TAM mechanisms. High-levels of transcription through a gene stimulate spontaneous mutation rate, a phenomenon termed transcription-associated mutation (TAM). High levels of transcription in Saccharomyces cerevisiae are associated with increased genetic instability, which has been linked to DNA damage. Here, we describe a pGAL-CAN1 forward mutation assay for studying transcription-associated mutagenesis (TAM) in yeast. The acquisition of mutations was directly correlated to the level of transcription Our results demonstrate that the level of Leu(+) reversions increased significantly in parallel with the induced increase in transcription levels. Transcription-associated mutagenesis in yeast is directly proportional to the level of gene expression spontaneous mutation rate is directly proportional to the transcription level, suggesting that movement of RNA polymerase through the target initiates a mutagenic process(es) High transcription is associated with genetic instability, notably increased spontaneous mutation rates, which is a phenomenon termed Transcription-Associated-Mutagenesis (TAM). Using this system, we also investigated two hypotheses that have been proposed to explain transcription-associated mutagenesis (TAM): (1) transcription impairs replication fork progression in a directional manner and (2) DNA lesions accumulate under high-transcription conditions. Transcription-associated mutagenesis in yeast is directly proportional to the level of gene expression and influenced by the direction of DNA replication. High levels of transcription in Saccharomyces cerevisiae are associated with increased genetic instability, which has been linked to DNA damage. Using this system, we also investigated two hypotheses that have been proposed to explain transcription-associated mutagenesis (TAM): (1) transcription impairs replication fork progression in a directional manner and (2) DNA lesions accumulate under high-transcription conditions. Using comparative genomics of related species as well as mutation accumulation lines, we show in yeast that the rate of point mutation in a gene increases with the expression level of the gene High transcription is associated with genetic instability, notably increased spontaneous mutation rates, which is a phenomenon termed Transcription-Associated-Mutagenesis (TAM) Using this system, we also investigated two hypotheses that have been proposed to explain transcription-associated mutagenesis (TAM): (1) transcription impairs replication fork progression in a directional manner and (2) DNA lesions accumulate under high-transcription conditions High-levels of transcription through a gene stimulate spontaneous mutation rate, a phenomenon termed transcription-associated mutation (TAM)

yes

514a1469d24251bc05000056

Is there a pharmacogenetic test for trastuzumab?

The clinical need for novel approaches to improve drug therapy derives from the high rate of adverse reactions to drugs and their lack of efficacy in many individuals that may be predicted by pharmacogenetic testing. the assessment of the human epidermal growth factor receptor (HER-2) expression for trastuzumab therapy of breast cancer HER2 positive breast cancer and the use of the drug Herceptin The dependence on gene copy number or expression levels of HER2 and epidermal growth factor receptor (EGFR) for therapeutic efficacy of trastuzumab and cetuximab (Erbitux), respectively, supports the importance of selecting suitable patient populations based on their pharmacogenetic profile. to explore informed consent issues surrounding the use of the drug Herceptin, widely cited as an example of a novel approach to drug development called pharmacogenetics. Drawing on qualitative semi-structured interviews with 25 UK-based breast cancer specialists, this paper explores Herceptin's disputed epistemological status, as an example of pharmacogenetics or as something out of the ordinary in terms of clinical practice. There have been several success stories in the field of pharmacogenetics in recent years, including the analysis of HER2 amplification for trastuzumab selection in breast cancer Trastuzumab is standard of care in the treatment of human epidermal growth factor receptor (HER)-2⁺ early and advanced breast cancer. HER-2 overexpression as a predictor of response to trastuzumab Pharmacogenomic analysis aspires to identify individuals with specific genetic characteristics in order to predict a positive response or reduce a negative response to a therapeutic modality. Assays are available to detect the HER2 protein receptor or copies of the HER2 gene sequence to determine eligibility for Herceptin treatment or adriamycin treatment in node positive patients, respectively. Determining the HER2 status of breast carcinomas is a prerequisite for the use of the monoclonal antibody trastuzumab (Herceptin), which has recently been licensed for the treatment of metastatic disease. Laboratory testing of HER2/neu in breast carcinoma has become vital to patient care following the approval of trastuzumab as the first therapy to target the HER2/neu oncoprotein. Immunohistochemical (IHC) analysis was performed with use of a diagnostic test for the assessment of HER2 overexpression, the HercepTest. To test for HER-2/neu overexpression in patients with non-Hodgkin's lymphoma and the possible role of the recombinant monoclonal anti-HER-2/neu antibody trastuzumab (Herceptin) in the treatment of non-Hodgkin's lymphoma. To evaluate concordance between local and central laboratory HER2 testing results in patients from the North Central Cancer Treatment Group (NCCTG) N9831 adjuvant trial of trastuzumab. These findings support the importance of using high-volume, experienced laboratories for HER2 testing to improve the process of selecting patients likely to benefit from trastuzumab therapy. we measured trastuzumab levels in the serum and in cerebrospinal fluid of metastatic breast cancer patients with brain metastases receiving trastuzumab for HER2-overexpressing metastatic breast cancer. In a pilot study, metastatic breast cancer patients with brain metastases and HER2-overexpressing tumors (HercepTest; Dako, Copenhagen, Denmark) were included. Monitoring of trastuzumab levels in the serum and cerebrospinal fluid may enable individualized therapy strategies in metastatic breast cancer patients with brain metastases, and lead to a better understanding of trastuzumab pharmacokinetics in the cerebrospinal fluid and serum. Biotin-labeled trastuzumab (BiotHER) can be used to test for HER2 by immunohistochemistry. The results support a role for BiotHER testing in better tailoring trastuzumab-based treatments in patients with advanced HER2-amplified breast cancers. response to anti-human epidermal growth factor receptor 2 (HER2) therapy trastuzumab.

yes

54d630283706e89528000004

Do carmustine wafers improve survival of glioblastoma patients?

At recurrence, treatment options include repeat surgery (with or without Gliadel wafer placement), reirradiation or systemic therapy. DISCUSSION: Carmustine wafers for primary HGG surgery in accordance with the NICE TA121 were associated with a median survival of 15.3 months; this is improved compared with previously reported randomised trials. Multimodal treatment with carmustine wafers, radical radiotherapy and concomitant temozolomide was associated with improved survival. Gliadel wafer is a new approach to the treatment of glioblastoma, which involves controlled release delivery of carmustine from biodegradable polymer wafers. It has shown promising results and provides a silver lining for glioblastoma patients. For patient with and without Gliadel, median and 1-year RFS were 12.9 months and 52% vs. 14 months and 42%, respectively (p = 0.89). According to pathology, Gliadel did not influence OS of patients with Grade III or glioblastoma CONCLUSION: In patients with high-grade gliomas, adding Gliadel before performing a Stupp protocol did not improve survival. Randomized phase III trials have shown significant improvement of survival 1, 2, and 3 years after implantation of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers for patients with newly diagnosed malignant glioma. CONCLUSIONS: The combination of aggressive resection, Gliadel wafer implantation, and GKS in addition to standard fractionated RT in selected patients resulted in increased local control and increased survival compared with a historical control group treated with surgery and involved-field RT alone. OBJECT: Gliadel (BCNU) wafer and concomitant temozolomide (TMZ) therapy, when used individually as adjuvant therapies, extend survival from that achieved by resection and radiation therapy (XRT) for glioblastoma multiforme (GBM). BACKGROUND: Gliadel (polifeprosan 20 with carmustine [BCNU] implant) is commonly used for local delivery of BCNU to high-grade gliomas after resection and is associated with increased survival. Temozolomide administered according to this protocol produced a median survival benefit of 2 months in glioblastomas, and carmustine a similar benefit in high-grade gliomas. Analysis of a large trial by Westphal and colleagues (n = 240) showed a 29% risk reduction (P = 0.03) in the BCNU wafer-treated group over the course of the 30-month trial. Median survival of patients treated with BCNU wafers was 13.8 months vs 11.6 months in placebo-treated patients (P = 0.017) with a hazard ratio of 0.73 (P = 0.018), representing a 27% significant risk reduction. This survival advantage was maintained at 1, 2, and 3 years and was statistically significant (P = 0.01) at 3 years. CONCLUSION: Malignant glioma patients treated with BCNU wafers at the time of initial surgery in combination with radiation therapy demonstrated a survival advantage at 2 and 3 years follow-up compared with placebo. OBJECTIVE: Recently a randomized placebo-controlled phase III trial of biodegradable polymers containing carmustine has demonstrated a significant survival benefit for patients treated with local chemotherapy. CONCLUSION: In this subgroup analysis of a phase III trial population both the clinical progression and radiological progression were significantly delayed in patients treated with local chemotherapy, resulting in an increased survival time. A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme. A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers. Median survival in the intent-to-treat group was 13.9 months for the BCNU wafer-treated group and 11.6 months for the placebo-treated group (log-rank P -value stratified by country = 0.03), with a 29% reduction in the risk of death in the treatment group. When adjusted for factors affecting survival, the treatment effect remained positive with a risk reduction of 28% ( P = 0.03). Controlled release delivery of carmustine from biodegradable polymer wafers was approved as an adjunct to surgical resection in the treatment of recurrent glioblastoma multiforme after it was shown in clinical trials to be well tolerated and effective. Clinical trials have demonstrated significant improvements in survival and quality of life for patients after complete tumour resection and BCNU wafer implantation. BCNU wafers are an effective means of increasing survival and quality of life in patients diagnosed with malignant glioma, and are a valuable addition to the overall multimodal treatment strategy for these tumours. CONCLUSIONS: Carmustine wafer with concurrent TMZ and radiation followed by rotational chemotherapy is a well tolerated, effective therapy, and has a survival benefit compared with radiation alone. Median overall survival in 14 studies of newly-diagnosed patients suggested a modest improvement versus resection followed by Stupp protocol or resection with BCNU wafers, with an acceptable and manageable safety profile. The efficacy of carmustine wafers for older patients with glioblastoma multiforme: prolonging survival. DISCUSSION: Older patients with GBM may benefit from carmustine wafers. The survival for older patients who received carmustine wafers is significantly longer than matched patients who did not receive carmustine wafers. For glioblastoma patients who received ≥90% resection in the BCNU wafer study, median survival increased for BCNU wafer versus placebo (14.5 versus 12.4 months, respectively; P = 0.02), but no survival increase was found for <90% resection (11.7 versus 10.6 months, respectively; P = 0.98). A wafer impregnated with carmustine, for use as an implant after surgical removal of recurrent GBM showed a prolongation in the median survival time of only 2 mo, from 20 to 28 wk in a study with a total of 222 patients. No clear survival benefit associated with wafer implantation was identified. In three of the trials, patients with GBM who received carmustine wafers had significantly longer median survival than patients who did not receive wafers. TMZ and carmustine (BCNU) biodegradable wafer (Gliadel) are the only adjuvant chemotherapies that have improved survival in randomised GB clinical trials . The carmustine implant wafer was demonstrated to improve survival in blinded placebo-controlled trials in selected patients with newly diagnosed or recurrent malignant glioma, with little increased risk of adverse events. For patients undergoing repeat resection for malignant glioma, a randomized, blinded, placebo-controlled trial demonstrated a median survival for 110 patients who received carmustine polymers of 31 weeks compared with 23 weeks for 122 patients who only received placebo polymers. Median survival was improved from 11.6 to 13.9 months (P = 0.03), with a 29% reduction in the risk of death. When patients with glioblastoma multiforme alone were analyzed, the median survival improved from 11.4 to 13.5 months, but this improvement was not statistically significant. OBJECT: Locoregional chemotherapy with carmustine wafers, positioned at surgery and followed by radiation therapy, has been shown to prolong survival in patients with newly diagnosed glioblastoma, as has concomitant radiochemotherapy with temozolomide. Following the resection of newly diagnosed or recurrent glioblastomas, local implantation of carmustine-impregnated biodegradable wafers (Gliadel) in the resection cavity constitutes an adjuvant therapy that can improve the possibilities of survival. The carmustine implant wafer was demonstrated to improve survival in blinded placebo-controlled trials in selected patients with newly diagnosed or recurrent malignant glioma, with little increased risk of adverse events. However, patients with carmustine wafers demonstrated prolonged survival as compared to patients without wafers. The median survival for patients with carmustine wafers was 8.7 months, while median survival for patients without wafers was 5.5 months (P=0.007). Likewise, in subgroup analysis, patients older than 70 years (P=0.0003) and 75 years (P=0.04) who had carmustine wafers had significantly longer survival than matched patients without wafers. Implantation of carmustine wafers did not significantly improve progression-free survival In three of the trials, patients with GBM who received carmustine wafers had significantly longer median survival than patients who did not receive wafers A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers Following the resection of newly diagnosed or recurrent glioblastomas, local implantation of carmustine-impregnated biodegradable wafers (Gliadel) in the resection cavity constitutes an adjuvant therapy that can improve the possibilities of survival Multimodal treatment with carmustine wafers, radical radiotherapy and concomitant temozolomide was associated with improved survival The carmustine implant wafer was demonstrated to improve survival in blinded placebo-controlled trials in selected patients with newly diagnosed or recurrent malignant glioma, with little increased risk of adverse events TMZ and carmustine (BCNU) biodegradable wafer (Gliadel) are the only adjuvant chemotherapies that have improved survival in randomised GB clinical trials

yes

5516fc8832767d0305000002

Is Dicer part of the RISC loading complex?

Dicer is a component of the protein machinery (the RNA Induced Silencing Complex [RISC]) which is involved in catalyzing the formation of mature microRNAs from their precursors in the process of microRNA biogenesis. RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators. The cytoplasmic RNA-induced silencing complex (RISC) contains dsRNA binding proteins, including protein kinase RNA activator (PACT), transactivation response RNA binding protein (TRBP), and Dicer, that process pre-microRNAs into mature microRNAs (miRNAs) that target specific mRNA species for regulation. Although the major RNAi pathway proteins are found in most subcellular compartments, the miRNA- and siRNA-loaded Ago2 populations co-sediment almost exclusively with the rER membranes, together with the RISC loading complex (RLC) factors Dicer, TAR RNA binding protein (TRBP) and protein activator of the interferon-induced protein kinase (PACT). RNA interference (RNAi) is mediated by small interfering RNAs (siRNAs), which are liberated from double-stranded (ds)RNA precursors by Dicer and guide the RNA-induced silencing complex (RISC) to targets. . Dicer, an RNase III enzyme, plays a central role in the RNAi pathway by cleaving precursors of both of these classes of RNAs to form mature siRNAs and miRNAs, which are then loaded into the RNA-induced silencing complex (RISC). Canonical siRNAs are 21 nucleotides (nt) in length and are loaded to the RNA Induced Silencing Complex when introduced into the cells, while longer siRNA molecules are first processed by endogenous Dicer and thus termed Dicer-substrate siRNA (DsiRNA).

yes

54ecb66d445c3b5a5f000002

Is hypersensitivity to DNA crosslinking agents a hallmark of Fanconi anemia?

The Fanconi anemia (FA) core complex plays a central role in the DNA damage response network FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability. Fanconi anemia (FA) is a rare genetic disorder characterized by aplastic anemia, cancer/leukemia susceptibility and cellular hypersensitivity to DNA crosslinking agents, such as cisplatin. Fanconi anemia (FA) is an inherited chromosomal recessive syndrome characterized by cellular hypersensitivity to DNA crosslinking agents and bone marrow failure, which cause aplastic anemia, and an increased incidence of malignancy. Features of chromosomal aberrations, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy have suggested a fundamental anomaly of DNA repair in Fanconi anemia. Fanconi anemia (FA) is one of several genetic diseases with characteristic cellular hypersensitivity to DNA crosslinking agents which suggest that FA proteins may function as part of DNA repair processes. Fanconi anemia (FA) is characterized by cellular hypersensitivity to DNA crosslinking agents, but how the Fanconi pathway protects cells from DNA crosslinks and whether FA proteins act directly on crosslinks remain unclear. Fanconi Anemia (FA) is a rare genetic disorder associated with a bone-marrow failure, cancer predisposition and hypersensitivity to DNA crosslinking agents. Fanconi anemia (FA) is a heterogeneous disease associated with a bone marrow failure, cancer predisposition and hypersensitivity to DNA crosslinking agents. Fanconi anemia (FA) is an inherited disorder characterized by defective DNA repair and cellular sensitivity to DNA crosslinking agents. Fanconi anemia (FA) is an inherited disease characterized by bone marrow failure, increased cancer risk and hypersensitivity to DNA cross-linking agents, implying a role for this pathway in the maintenance of genomic stability. Genetic or epigenetic inactivation of the pathway formed by the Fanconi Anemia (FA) proteins occurs in several cancer types, including head and neck squamous cell carcinomas (HNSCC), rendering the affected tumors potentially hypersensitive to DNA crosslinking agents. Fanconi Anemia (FA) is a rare autosomic recessive and X-linked disease with chromosomal instability after exposure to crosslinking agents as the hallmark. Fanconi Anemia (FA) is an autosomal recessive disease characterized by chromosome instability, cellular hypersensitivity to DNA cross-linking agents, and increased predisposition to malignancies. The Bloom protein (BLM) and Topoisomerase IIIalpha are found in association with proteins of the Fanconi anemia (FA) pathway, a disorder manifesting increased cellular sensitivity to DNA crosslinking agents. Using siRNA depletion and gene knockout techniques, we show that FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability. Fanconi anemia (FA) is a recessive human cancer prone syndrome featuring bone marrow failure, developmental abnormalities and hypersensitivity to DNA crosslinking agents exposure. FA is a chromosome instability syndrome characterized by childhood-onset aplastic anemia, cancer or leukemia susceptibility, and cellular hypersensitivity to DNA crosslinking agents. Functional defects in the Fanconi pathway can result in a marked hypersensitivity to interstrand crosslinking agents, such as mitomycin C. At the cellular level, hypersensitivity to DNA interstrand crosslinks is the defining feature in Fanconi anemia. DNA crosslinking agents may led to DNA cross-linking lesion, and Fanconi anemia pathway plays a key role in repairing its cross-linking. Fanconi anemia (FA), an autosomal recessive disorder of children, is characterized by congenital or childhood aplastic anemia, multiple developmental anomalies, increased incidence of myeloid leukemia, increased spontaneous chromosome breakage, and cellular and chromosomal hypersensitivity to DNA bifunctional crosslinking and alkylating agents. elegans provides an excellent model system for the study of the Fanconi Anemia (FA), one of the hallmarks of which is sensitivity to interstrand crosslinking agents Using siRNA depletion and gene knockout techniques, we show that FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability One of the hallmark phenotypes of FA is cellular hypersensitivity to agents that induce DNA interstrand crosslinks (ICLs), such as mitomycin C (MMC) Furthermore, the cytological hallmark of FA, the DNA crosslink-induced radial chromosome formation, exemplifies an innate impairment in the repair of these particularly cytotoxic DNA lesions [A.D Fanconi anemia (FA) is characterized by cellular hypersensitivity to DNA crosslinking agents, but how the Fanconi pathway protects cells from DNA crosslinks and whether FA proteins act directly on crosslinks remain unclear Features of chromosomal aberrations, hypersensitivity to DNA crosslinking agents, and predisposition to malignancy have suggested a fundamental anomaly of DNA repair in Fanconi anemia Fanconi anemia (FA) is an inherited chromosomal recessive syndrome characterized by cellular hypersensitivity to DNA crosslinking agents and bone marrow failure, which cause aplastic anemia, and an increased incidence of malignancy Genetic or epigenetic inactivation of the pathway formed by the Fanconi Anemia (FA) proteins occurs in several cancer types, including head and neck squamous cell carcinomas (HNSCC), rendering the affected tumors potentially hypersensitive to DNA crosslinking agents Fanconi anemia (FA) is a human autosomal disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinking agents such as mitomycin C and diepoxybutane The Fanconi anemia pathway promotes DNA glycosylase-dependent excision of interstrand DNA crosslinks. DNA crosslinking agents may led to DNA cross-linking lesion, and Fanconi anemia pathway plays a key role in repairing its cross-linking FA is a chromosome instability syndrome characterized by childhood-onset aplastic anemia, cancer or leukemia susceptibility, and cellular hypersensitivity to DNA crosslinking agents The disease is manifested by defects in DNA repair, hypersensitivity to DNA crosslinking agents, and a high degree of chromosomal aberrations

yes

5713c7dd1174fb1755000014

Have C12orf65 mutations been associated with axonal neuropathy and optic atrophy?

Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy Charcot-Marie Tooth disease (CMT) forms a clinically and genetically heterogeneous group of disorders. Although a number of disease genes have been identified for CMT, the gene discovery for some complex form of CMT has lagged behind. The association of neuropathy and optic atrophy (also known as CMT type 6) has been described with autosomaldominant, recessive and X-linked modes of inheritance. Mutations in Mitofusin 2 have been found to cause dominant forms of CMT6. Phosphoribosylpyrophosphate synthetase-I mutations cause X-linked CMT6, but until now, mutations in the recessive forms of disease have never been identified.METHODS: We here describe a family with three affected individuals who inherited in an autosomal recessive fashion a childhood onset neuropathy and optic atrophy. Using homozygosity mapping in the family and exome sequencing in two affected individuals we identified a novel protein-truncating mutation in the C12orf65 gene, which encodes for a protein involved in mitochondrial translation Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families. A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55). Optic atrophy and a Leigh-like syndrome due to mutations in the c12orf65 gene: report of a novel mutation and review of the literature. Recently, we identified the causative gene, C12orf65, that was reported the gene for Leigh syndrome, for autosomal recessive spastic paraplegia with optic atrophy and neuropathy (SPG55). We describe 2 siblings with compound heterozygous mutations in the recently identified C12orf65 gene who presented with optic atrophy and mild developmental delays and subsequently developed bilateral, symmetric lesions in the brainstem reminiscent of Leigh syndrome. C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features CONCLUSIONS: This work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy. C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. We described a large consanguineous family with neuropathy and optic atrophy carrying a loss of function mutation in the C12orf65 gene. In these patients, we identified a homozygous splice mutation, g.21043 T>A (c.282+2 T>A) which leads to skipping of exon 2. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. This work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy. This work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy. A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55). C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families.

yes

550bf315c2af5d5b7000000e

Is cystatin C or cystatin 3 used as a biomarker of kidney function?

to explore the effect of ageing on renal function with cystatin C as the marker of glomerular filtration rate (GFR) in the general population without vascular disease or diabetes. Cystatin C, a more specific kidney function biomarker, was also elevated at 24 h after CLP. This study evaluated FGF-23 as well as traditional markers of kidney disease, namely urine albumin-to-creatinine ratio (UACR) and creatinine-cystatin C estimated GFR (eGFRCrCyC), as risk factors for AKI in elderly individuals. he primary predictor was estimated GFR (eGFR) calculated using serum cystatin C (eGFR(cys)). A number of recent reports have suggested that the cystatin C/creatinine (CysC/Cr) ratio might be a useful biomarker of renal function in pediatric patients. The CKD-EPI equation using cystatin C was the most precise method of renal function evaluation in patients with neurogenic bladder. Serum cystatin C (CysC) is an endogenous marker of kidney function. The urinary content of CysC reflects tubular epithelial dysfunction whereas that of NGAL also characterizes tubular atrophy. Estimated kidney function based on serum cystatin C : Several formulas for glomerular filtration rate (GFR) estimation, based on serum creatinine or cystatin C, have been proposed. he highest and lowest eGFR levels corresponded to the cystatin C-based and MDRD-4 equations, respectively. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recently proposed an equation to estimate GFR in subjects without cirrhosis using both serum creatinine and cystatin C levels. Emerging evidence has shown that cystatin C may improve classification of glomerular filtration rate for defining chronic kidney disease in certain clinical populations and assist in understanding the complications of chronic kidney disease Beta-trace protein (BTP) and cystatin C (CysC) are novel biomarkers of renal function. Cystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine. Iohexol clearance and cystatin C formulae identify a greater proportion of patients with a GFR <60 mL/min/1.73 m(2), which also predicts the development of AKI. Cystatin C was recently reported to be an endogenous surrogate of kidney function, and a high level of cystatin C is reported to be a strong predictor of CVD; Studies that have simultaneously compared measured GFR and estimated GFR (using endogenous filtration markers such as creatinine, or newer ones such as cystatin C or β-trace protein)

yes

57136cbf1174fb1755000007

Can fetal aneuploidy be detected with non-invasive prenatal testing?

Non-invasive prenatal testing with cell-free DNA: US physician attitudes toward implementation in clinical practice. The aim of this study was to assess awareness, potential adoption, and current utilization of non-invasive prenatal testing (NIPT) analysis for common fetal aneuploidies among obstetricians Cell-free DNA has been used for fetal rhesus factor and sex determination, fetal aneuploidy screening, cancer diagnostics and monitoring, and other applications. 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 testing (NIPT) for aneuploidy using cell-free DNA in maternal plasma is revolutionizing prenatal screening and diagnosis. SNP-based non-invasive prenatal testing detects sex chromosome aneuploidies with high accuracy. Non-invasive prenatal testing (NIPT) of cell-free fetal DNA in maternal plasma is a novel approach, designed for detecting common aneuploidies in the fetus. This study aimed to develop a single-nucleotide polymorphism-based and informatics-based non-invasive prenatal test that detects sex chromosome aneuploidies early in pregnancy. RAPIDR: an analysis package for non-invasive prenatal testing of aneuploidy. Non-invasive prenatal testing for aneuploidy: current status and future prospects. Non-invasive prenatal testing of fetal whole chromosome aneuploidy by massively parallel sequencing. Attitudes towards non-invasive prenatal testing for aneuploidy among US adults of reproductive age. [Non-invasive prenatal test in the diagnosis of aneuploidy 13, 18 and 21--theoretical and practical aspects]. To track and analyze two false positive cases from non-invasive prenatal testing for potential fetal aneuploidy. Non-invasive prenatal testing (NIPT) of fetal aneuploidy using cell-free fetal DNA is becoming part of routine clinical practice. To report secondary or additional findings arising from introduction of non-invasive prenatal testing (NIPT) for aneuploidy by whole genome sequencing as a clinical service. Israeli Society of Medical Genetics NIPT Committee Opinion 072013: Non-invasive prenatal testing of cell-free DNA in maternal plasma for detection of fetal aneuploidy. 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 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 Non-invasive prenatal testing (NIPT) using cell-free fetal DNA in maternal plasma has been developed for the detection of fetal aneuploidy Israeli Society of Medical Genetics NIPT Committee Opinion 072013: Non-invasive prenatal testing of cell-free DNA in maternal plasma for detection of fetal aneuploidy Non-invasive prenatal testing for fetal aneuploidies in the first trimester of pregnancy To explore the value of next-generation sequencing for the non-invasive prenatal testing of fetal chromosomal aneuploidies Secondary findings from non-invasive prenatal testing for common fetal aneuploidies by whole genome sequencing as a clinical service To report secondary or additional findings arising from introduction of non-invasive prenatal testing (NIPT) for aneuploidy by whole genome sequencing as a clinical service Secondary findings from non-invasive prenatal testing for common fetal aneuploidies by whole genome sequencing as a clinical service. Motivations for undertaking DNA sequencing-based non-invasive prenatal testing for fetal aneuploidy: a qualitative study with early adopter patients in Hong Kong. OBJECTIVE: To determine whether non-invasive prenatal testing by maternal plasma DNA sequencing can uncover all fetal chromosome aneuploidies in one simple sequencing event. Non-invasive prenatal diagnosis of fetal aneuploidies using massively parallel sequencing-by-ligation and evidence that cell-free fetal DNA in the maternal plasma originates from cytotrophoblastic cells. Non-invasive prenatal testing (NIPT) using cell-free fetal DNA in maternal plasma has been developed for the detection of fetal aneuploidy. Non-invasive prenatal testing (NIPT) of cell-free fetal DNA in maternal plasma is a novel approach, designed for detecting common aneuploidies in the fetus. 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 testing (NIPT) of fetal aneuploidy using cell-free fetal DNA is becoming part of routine clinical practice. RAPIDR (Reliable Accurate Prenatal non-Invasive Diagnosis R package) is an easy-to-use open-source R package that implements several published NIPT analysis methods. The clinical data collected thus far indicate that NIPT is highly sensitive in detecting trisomies 21 and 18, and fairly sensitive in detecting trisomy 13 and sex chromosome aneuploidies. Because false-positive results may occur, an abnormal result must be validated by invasive prenatal testing. When non-invasive prenatal screening for aneuploidy is available, maternal age alone should not be an indication for invasive prenatal diagnosis in a twin pregnancy. (II-2A) If non-invasive prenatal screening is not available, invasive prenatal diagnosis in twins should be offered to women aged 35 and over. Therefore, methods with high sensitivity and precision are required to detect and differentiate fetal DNA from the large background of maternal DNA. 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. Non-invasive prenatal testing for fetal aneuploidies in the first trimester of pregnancy. Secondary findings from non-invasive prenatal testing for common fetal aneuploidies by whole genome sequencing as a clinical service. To explore the value of next-generation sequencing for the non-invasive prenatal testing of fetal chromosomal aneuploidies. [Cell-free nucleic acid-based non-invasive prenatal diagnosis of fetal aneuploidies]. Maternal age alone is a poor minimum standard for prenatal screening for aneuploidy, and it should not be used a basis for recommending invasive testing when non-invasive prenatal screening for aneuploidy is available. Israeli Society of Medical Genetics NIPT Committee Opinion 072013: Non-invasive prenatal testing of cell-free DNA in maternal plasma for detection of fetal aneuploidy. Attitudes towards non-invasive prenatal testing for aneuploidy among US adults of reproductive age. 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 testing (NIPT) of fetal aneuploidy using cell-free fetal DNA is becoming part of routine clinical practice. Non-invasive prenatal testing (NIPT) by massively parallel sequencing is a useful clinical test for the detection of common fetal aneuploidies. The clinical data collected thus far indicate that NIPT is highly sensitive in detecting trisomies 21 and 18, and fairly sensitive in detecting trisomy 13 and sex chromosome aneuploidies.

yes

56c1d841ef6e39474100002d

Is dichlorphenamide effective for periodic paralysis?

BACKGROUND AND PURPOSE: Acetazolamide and dichlorphenamide are carbonic anhydrase (CA) inhibitors effective in the clinical condition of hypokalemic periodic paralysis (hypoPP). In one study dichlorphenamide (DCP) vs placebo was tested in two groups of participants: 42 with hypokalemic periodic paralysis (HypoPP) and 31 with hyperkalemic periodic paralysis (HyperPP), based on clinical criteria. Thirty-four of 42 participants with hypokalemic periodic paralysis completed both treatment phases. For the 34 participants having attack rate data for both treatment phases, the mean improvement in attack rate (P = 0.02) and severity-weighted attack rate (P = 0.01) on DCP relative to placebo were statistically significant. AUTHORS' CONCLUSIONS: The largest included study that met our inclusion criteria suggested that DCP was effective in the prevention of episodic weakness in both hypokalemic and hyperkalemic periodic paralyses. For periodic paralysis, dichlorphenamide--a carbonic anhydrase inhibitor--has been shown in a controlled trial to prevent attacks for many patients with both hypokalemic and hypokalemic periodic paralysis. Chronically, acetazolamide, dichlorphenamide, or potassium-sparing diuretics decrease attack frequency and severity but are of little value acutely. In the HypoPP trial, there were 13 subjects who exhibited a preference (in terms of the end point) for either DCP or placebo, and 11 of these preferred DCP. In the PSPP trial, DCP significantly reduced attack rates relative to placebo. DCP also significantly reduced attack rates relative to placebo in the HypoPP subjects. We conclude that DCP is effective in the prevention of episodic weakness in both HypoPP and PSPP. Diclofenamid has now already been administered for 2 years. It is well tolerated and has suppressed further attacks. Three patients with Hypokalemic Periodic Paralysis (HOPP)-associated progressive interattack muscle weakness, who became unresponsive or worsened by acetazolamide, responded favorably to dichlorophenamide, a more potent carbonic anhydrase inhibitor. Dichlorophenamide in single-blind placebo-controlled trials, considerably improved functional strength in two of the patients and had a moderate but definite effect in the third. Dichlorophenamide should be considered as an alternate to acetazolamide in the treatment of patients with HOPP-associated interattack muscle weakness who have become unresponsive or worsened by acetazolamide. Acetazolamide and dichlorphenamide are carbonic anhydrase (CA) inhibitors effective in the clinical condition of hypokalemic periodic paralysis (hypoPP). For periodic paralysis, dichlorphenamide--a carbonic anhydrase inhibitor--has been shown in a controlled trial to prevent attacks for many patients with both hypokalemic and hypokalemic periodic paralysis. BACKGROUND AND PURPOSE: Acetazolamide and dichlorphenamide are carbonic anhydrase (CA) inhibitors effective in the clinical condition of hypokalemic periodic paralysis (hypoPP). Whether these drugs prevent vacuolar myopathy, which is a pathogenic factor in hypoPP, is unknown. Acetazolamide and dichlorphenamide are carbonic anhydrase (CA) inhibitors effective in the clinical condition of hypokalemic periodic paralysis (hypoPP). For periodic paralysis, dichlorphenamide--a carbonic anhydrase inhibitor--has been shown in a controlled trial to prevent attacks for many patients with both hypokalemic and hypokalemic periodic paralysis. A second trial, comparing dichlorphenamide with acetazolamide versus placebo, is currently in progress. Despite our better understanding of the pathogenesis of these disorders, current treatments are largely empirical and the evidence in favor of specific therapy largely anecdotal. For periodic paralysis, dichlorphenamide--a carbonic anhydrase inhibitor--has been shown in a controlled trial to prevent attacks for many patients with both hypokalemic and hypokalemic periodic paralysis.

yes

56bb68a5ac7ad1001900000a

Is nivolumab used for treatment of Non–Small-Cell Lung Cancer?

BACKGROUND: Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. CONCLUSIONS: Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. Agents currently in active clinical development for lung cancer include ipilimumab, which modulates the cytotoxic T-lymphocyte-associated antigen 4 pathway, and multiple agents targeting the programmed death protein 1 (PD-1) pathway, both anti-PD-1 compounds (nivolumab, pembrolizumab [MK-3475]) and those that target programmed death ligand 1 (PD-L1), a key ligand for PD-1 (BMS-936559, MPDL3280A). Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial.PATIENTS AND METHODS: Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. CONCLUSION: Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing. Two PD-1 inhibitors, Bristol-Myers Squibb's nivolumab and Merck's MK-3475, both demonstrated positive results in phase I trials of previously treated patients with non-small cell lung cancer, reported at the World Conference on Lung Cancer in Sydney, Australia. Recently, many trials addressed the role of such therapies for metastatic NSCLC treatment: ipilimumab, tremelimumab, nivolumab and lambrolizumab are immunotherapeutic agents of main interest in this field. Two PD-1 inhibitors, Bristol-Myers Squibb&apos;s nivolumab and Merck&apos;s MK-3475, both demonstrated positive results in phase I trials of previously treated patients with non-small cell lung cancer, reported at the World Conference on Lung Cancer in Sydney, Australia Nivolumab, pembrolizumab (formerly known as MK-3475 and lambrolizumab), and pidilizumab are anti-PD-1 antibodies in clinical development for melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers, lymphoma, and several other cancers Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment.

yes

516c0e08298dcd4e5100006d

Does thyroid hormone receptor beta1 affect insulin secretion?

We demonstrated that thyroid hormone T3 rapidly induces Akt activation in pancreatic beta cells rRINm5F and hCM via thyroid hormone receptor (TR) beta1. The silencing of TRbeta1 expression through RNAi confirmed this receptor to be crucial for the T3-induced activation of Akt. T3 is able to specifically activate Akt in the islet beta cells rRINm5F and hCM through the interaction between TRbeta1 and PI3K p85alpha, demonstrating the involvement of TRbeta1 in this novel T3 non-genomic action in islet beta cells.

no

5710dd61cf1c32585100002e

Does replication timing affect the rate of somatic mutations?

Here we observe that mutation rate, as reflected in recent evolutionary divergence and human nucleotide diversity, is markedly increased in later-replicating regions of the human genome ll classes of substitutions are affected, suggesting a generalized mechanism involving replication time-dependent DNA damage We show that mutation rate varies 6-fold across a single chromosome, that this variation is correlated with replication timing, and we propose a model to explain this variation that relies on the temporal separation of two processes for replicating past damaged DNA: error-free DNA damage tolerance and translesion synthesis. Recent studies revealed a long suspected replication-timing effect on mutation rate, but the mechanisms that regulate the increase in mutation rate as the genome is replicated remain unclear. DNA repair systems, in general, are less efficient in late replicating heterochromatic regions compared to early replicating euchromatic regions of the genome. The mutational profile of the yeast genome is shaped by replication the mutation rate increases with the replication timing by more than 30% between the earliest and the latest replicating regions. Thus, we show that the leading replicating strands present an excess of C over G and of A over T in the genome of S. cerevisiae (reciprocally an excess of G + T over C + A in lagging strands) Late-replicating domains have higher divergence and diversity in Drosophila melanogaster Recent evidence also suggests that late replication is associated with high mutability in yeast. Limited evidence from one chromosome arm in Drosophila melanogaster suggests the opposite pattern, with regions overlapping early-firing origins showing increased levels of diversity and divergence The mutation rate for DNA mismatch repair null strains was approximately 1 mutation per genome per generation, 225-fold greater than the wild-type rate. The mutations were distributed randomly throughout the genome, independent of replication timing. Many single-nucleotide substitutions in cancer genomes arise because of errors in DNA replication, which is spatio-temporally stratified. Here we propose that DNA replication patterns help shape the mutational landscapes of normal and cancer genomes Using data on five fully sequenced cancer types and two personal genomes, we determined that the frequency of intergenic single-nucleotide substitution is significantly higher in late DNA replication timing regions, even after controlling for a number of genomic features we found that genomic regions in close spatial proximity to late-replicating domains display similar mutation spectra as the late-replicating regions themselves In addition, certain chromosome rearrangements found in cancer cells and in cells exposed to ionizing radiation display a significant delay in replication timing of >3 hours that affects the entire chromosome(2,3). Recent work from our lab indicates that disruption of discrete cis-acting autosomal loci result in an extremely late replicating phenotype that affects the entire chromosome(4). A conservative estimate is that at least 1-2% of new deleterious mutations affect some aspect of DNA replication, repair, or chromosome segregation. Since deleterious mutations can have an effect even as heterozygotes, this mutation accumulation can create an inherited background of late-acting mutations that themselves enhance mutation rate. Drake calculates that lytic RNA viruses display spontaneous mutation rates of approximately one per genome while most have mutation rates that are approximately 0.1 per genome (Drake 1993). This constancy of germline mutation rates among microbial species need not necessarily mean constancy of the somatic mutation rates. A recent flurry of reports correlates replication timing (RT) with mutation rates during both evolution and cancer. DNA replication timing, genome stability and cancer: late and/or delayed DNA replication timing is associated with increased genomic instability. Since deleterious mutations can have an effect even as heterozygotes, this mutation accumulation can create an inherited background of late-acting mutations that themselves enhance mutation rate. In addition, this method allows for the unambiguous identification of chromosomal rearrangements that correlate with changes in replication timing that affect the entire chromosome.

yes

57091eefcf1c325851000016

Is NOD1 activated in inflammation?

Nod1 and Nod2 control bacterial infections and inflammation The Nod proteins Nod1 and Nod2 are two NLR family members that trigger immune defense in response to bacterial peptidoglycan Nod proteins fight off bacterial infections by stimulating proinflammatory signaling and cytokine networks and by inducing antimicrobial effectors, such as nitric oxide and antimicrobial peptides. Nod1 is also critically implicated in shaping adaptive immune responses towards bacterial-derived constituents. Together, Nod1 and Nod2 represent central players in the control of immune responses to bacterial infections and inflammation. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. we show that Nod1 deficiency results in the increased development of both colitis-associated and Apc tumor suppressor-related colon tumors. In the absence of Nod1 signaling, there is a greater disruption of the intestinal epithelial cell barrier due to chemically induced injury as manifested by increased surface epithelial apoptosis early on during chemically induced colitis and increased intestinal permeability. The increased intestinal permeability is associated with enhanced inflammatory cytokine production and epithelial cell proliferation in Nod1-deficient mice as compared with wild-type mice. Depletion of the gut microbiota suppressed tumor development in Nod1-deficient mice, thus highlighting a link between the commensal bacteria within the intestine and the host innate immune Nod1 signaling pathway in the regulation inflammation-mediated colon cancer development. NOD1 protein is expressed in the eye and promotes ocular inflammation in a dose- and time-dependent fashion. NOD1 expression in the eye and functional contribution to IL-1beta-dependent ocular inflammation in mice Polymorphisms in NOD1 are associated with autoinflammatory diseases characterized by uveitis such as Crohn's disease and sarcoidosis NOD1 is homologous to NOD2, which is responsible for an autosomal dominant form of uveitis. Nonetheless, the role of NOD1 in intraocular inflammation has not been explored. Nod1 and Nod2 regulation of inflammation in the Salmonella colitis model mice deficient for both Nod1 and Nod2 had attenuated inflammatory pathology, reduced levels of inflammatory cytokines, and increased colonization of the mucosal tissue The present study has demonstrated an unexpected role of Nod1 in the development of site-specific vascular inflammation, especially coronary arteritis. Nod1 ligands induce site-specific vascular inflammation Phenotyping of Nod1/2 double deficient mice and characterization of Nod1/2 in systemic inflammation and associated renal disease The present study analyzed Nod1 and Nod2 double deficient (Nod1/2 DKO) mice under physiological and inflammatory conditions Several inflammatory disorders, such as Crohn's disease and asthma, are linked to genetic changes in either Nod1 or Nod2. Systematic analysis of Nod1/2 DKO mice revealed a possible role of Nod1/2 in the development of renal disease during systemic inflammation. NOD1 and NOD2 Signaling in Infection and Inflammation NOD1 engagement generates an inflammatory response via activation of NFκB and MAPK pathways. In addition we profile novel inhibitors of RIP2 and NOD1 itself, which specifically inhibit NOD1 ligand induced inflammatory signalling in the vasculature. This data supports the potential utility of NOD1 and RIP2 as therapeutic targets in human disease where vascular inflammation is a clinical feature, such as in sepsis and septic shock. NOD1 expression elicited by iE-DAP in first trimester human trophoblast cells and its potential role in infection-associated inflammation This study aimed to investigate the expression and function of NOD1 in first trimester trophoblast cells, and evaluate the potential role of trophoblast cells in infection-associated inflammation NOD1 may have a role in mediating infection-associated inflammation. Once iE-DAP is recognized by NOD1, the inflammatory response may be induced via NOD1-RICK-NF-κB-mediated pathways. NOD1/2(-/-) mice were protected from HFD-induced inflammation, lipid accumulation, and peripheral insulin intolerance. In contrast, Nod1 gene-deficient mice developed enhanced joint inflammation with concomitant elevated levels of proinflammatory cytokines and cartilage damage, consistent with a model in which Nod1 controls the inflammatory reaction. These data indicate that the NLR family members Nod1 and Nod2 have different functions in controlling inflammation, and that intracellular Nod1-Nod2 interactions may determine the severity of arthritis in this experimental model. Whereas the lymphotoxin pathway was critical for the induction of the B cell chemoattractant CXCL13 in response to Nod1 agonists, B cell accumulation within the spleen following Nod1-induced systemic inflammation was independent of the lymphotoxin pathway. The effect of NOD1 and NOD2 activation on inflammation and the insulin signalling pathway was also assessed. Nonetheless, the role of NOD1 in intraocular inflammation has not been explored. A key role for the endothelium in NOD1 mediated vascular inflammation: comparison to TLR4 responses. We previously demonstrated that human first-trimester trophoblasts express Nod1 and Nod2, which trigger inflammation upon stimulation. In addition, recent studies have revealed a role for intracellular NOD1 receptors in the regulation of vascular inflammation and metabolism. In conclusion, the present findings describe an important role for NOD1 in the development of insulin resistance and inflammation in pregnancies complicated by GDM. Phenotyping of Nod1/2 double deficient mice and characterization of Nod1/2 in systemic inflammation and associated renal disease. Nod1 activation by bacterial iE-DAP induces maternal-fetal inflammation and preterm labor. The nucleotide-binding oligomerisation domain (NOD) intracellular molecules recognise a wide range of microbial products, as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor κB (NFκB). Nod1 ligands induce site-specific vascular inflammation. The nucleotide oligomerization domain (NOD) intracellular molecules recognize a wide range of microbial products as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor KB (NFKB), a central regulator of the terminal processes of human labor and delivery. CONCLUSIONS: We identify NOD proteins as innate immune components that are involved in diet-induced inflammation and insulin intolerance. Nod1 and Nod2 regulation of inflammation in the Salmonella colitis model. In particular, muramyl peptides trigger inflammation, contribute to host defense against microbial infections, and modulate the adaptive immune response to antigens. Systemic and tissue-specific inflammation was assessed using enzyme-linked immunosorbent assays in NOD ligand-injected mice. CONCLUSIONS: We identify NOD proteins as innate immune components that are involved in diet-induced inflammation and insulin intolerance. Acute activation of NOD proteins by mimetics of bacterial PGNs causes whole-body insulin resistance, bolstering the concept that innate immune responses to distinctive bacterial cues directly lead to insulin resistance. Interferon-gamma (IFN gamma), which is a potent pro-inflammatory cytokine in intestinal mucosal inflammation, activates CARD4/NOD1 mRNA transcription in a time- and dose-dependent manner and results in augmentation of CARD4/NOD1 protein in SW480 cells. These studies suggest that the Th1 cytokine, IFN gamma, activates CARD4/NOD1 transcription and regulate innate immune mechanisms in the condition of intestinal mucosal inflammation. NOD1 activation triggers inflammation, In contrast to enhanced leptin mRNA by LPS and TNFα, NOD1 activation suppressed leptin mRNA in adipocytes, suggesting the differential effects of NOD1 activation in adipocytes. Overall, our results suggest that NOD1 represents a novel target for adipose inflammation in obesity. NOD1 activation triggers inflammation, antimicrobial mechanisms and autophagy in both epithelial cells and murine macrophages. NOD1 is an intracellular immune receptor that senses peptidoglycan from Gram-negative bacteria and responds by inducing autophagy and activating NF-κB, leading to inflammation-mediated bacterial clearance; however chronic pathogens can evade NOD1-mediated clearance by altering peptidoglycan structure. Bacterial NOD1 activation is positioned as a component of metabolic endotoxemia that can contribute to hyperlipidemia, systemic inflammation and insulin resistance by acting directly on adipocytes. NOD1 ligand also caused inflammation and insulin resistance directly in primary hepatocytes from WT, but not NOD1(-/-), mice. We conclude that NOD1 activation reduced AHR in allergen-induced lung inflammation, which was accompanied by a reduction of allergen-specific T-cell proliferation. The effect of NOD1 and NOD2 activation on inflammation and the insulin signalling pathway was also assessed. Interferon-gamma (IFN gamma), which is a potent pro-inflammatory cytokine in intestinal mucosal inflammation, activates CARD4/NOD1 mRNA transcription in a time- and dose-dependent manner and results in augmentation of CARD4/NOD1 protein in SW480 cells.

yes

54d62ede3706e89528000002

Does magnesium sulfate improve outcomes of subarachnoid hemorrhage patients?

CONCLUSION: Patients assigned a higher serum magnesium concentration had a reduced incidence of vasospasm as seen by angiography, but the difference was not statistically significant. Clinically significant outcomes were not different between groups. 158 patients (26·2%) had poor outcome in the magnesium group compared with 151 (25·3%) in the placebo group (risk ratio [RR] 1·03, 95% CI 0·85-1·25). Our updated meta-analysis of seven randomised trials involving 2047 patients shows that magnesium is not superior to placebo for reduction of poor outcome after aneurysmal subarachnoid haemorrhage (RR 0·96, 95% CI 0·86-1·08). INTERPRETATION: Intravenous magnesium sulphate does not improve clinical outcome after aneurysmal subarachnoid haemorrhage, therefore routine administration of magnesium cannot be recommended. There is a tendency in the magnesium group to have better outcomes. Due to inconsistently reported benefits and the occurrence of side effects, phase II data suggested that intravenous magnesium for SAH provided either no overall net benefit or uncertain trade-offs. Benefit was likewise not supported in the single phase III clinical trial. tatistically significant clinical benefits could not be demonstrated for the other drugs (clazosentan, statins, and magnesium). CONCLUSIONS: Insufficient evidence is available to support the use of the triple-H therapy, clazosentan, statins, or magnesium sulfate for the prevention of cerebral vasospasm following subarachnoid hemorrhage. Magnesium sulfate decreased the rate of cerebral infarction, but not of DCI or poor functional outcome. Regarding outcome, a beneficial effect of magnesium sulfate on outcome can not be ruled out because of sample size limitations. CONCLUSIONS: The present findings do not lend support to a beneficial effect of magnesium sulphate infusion on delayed cerebral infarction. The reduction in DCI and improvement in the clinical outcomes of aneurysmal SAH patients following magnesium sulphate infusion observed in previous pilot studies are not confirmed, although a beneficial effect cannot be ruled out because of sample size limitation. Favorable outcome (Good recovery and moderate disability, as defined by Glasgow Outcome Scale) was achieved in 20 of 30 (67%) patients receiving magnesium sulfate infusion and 16 of 30 (53%) patients receiving placebo treatment, p = 0.292, odds ratio 1.750, 95% CI 0.616-4.974. Similarly, the pooled odds ratio for favorable outcome is 1.598, 95% CI 1.074-2.377, statistically significant. RESULTS: The worst clinical outcomes at 6 months were seen in MgSO(4) group patients, with mean plasma magnesium concentrations in the fourth quartile, and in placebo group patients, with mean such concentrations in the third and fourth quartiles. CONCLUSIONS: No evidence was found to suggest that a higher mean plasma magnesium concentration improves clinical outcomes. On the contrary, we found an association between high plasma magnesium concentration and worse clinical outcomes. The proportions of patients with a favorable outcome at 6 months (Extended Glasgow Outcome Scale 5 to 8) were similar, 64% in the magnesium sulfate group and 63% in the saline group (OR, 1.0; 95% CI, 0.7 to 1.6). Secondary outcome analyses (modified Rankin Scale, Barthel Index, Short Form 36, and clinical vasospasm) also showed no significant differences between the 2 groups. CONCLUSIONS: The results do not support a clinical benefit of intravenous magnesium sulfate infusion over placebo infusion in patients with acute aneurysmal subarachnoid hemorrhage. Magnesium infusion reduced the risk of poor outcome and delayed cerebral ischemia (DCI): the relative risk was 0.62 (95% confidence interval (CI) 0.46-0.83) and 0.73 (95% CI 0.53-1.00), respectively. CONCLUSION: The meta-analysis suggests that intravenous magnesium therapy reduces the risk of DCI and poor outcome after aneurysmal SAH. The incidence of delayed ischemic infarction was significantly lower in magnesium-treated patients (22% vs. 51%; p = .002); 34 of 54 magnesium patients and 27 of 53 control patients reached good outcome (p = .209). BACKGROUND: A meta-analysis of current data suggests that magnesium sulfate infusion improves the outcome after aneurysmal subarachnoid hemorrhage through a reduction in delayed ischemic neurological deficit. These data imply that intravenous magnesium therapy, besides a supposed beneficial effect on outcome, also provides pain relief for SAH patients, for whom it might also improve functional outcome. Preliminary evidence has suggested that magnesium sulfate infusion reduces delayed ischemic neurological deficit and improves clinical outcome after aneurysmal subarachnoid hemorrhage. In a phase II randomized clinical trial of 283 patients, magnesium treatment reduced the risk of DCI by 34% and of poor outcome by 23%. BACKGROUND: Recent studies suggest that high-dose MgSO4 therapy is safe and reduces the incidence of DIND and subsequent poor outcome after SAH. On-treatment analysis showed a significantly better outcome after 3 months (P = .017) and a trend toward better outcome after 1 year (P = .083). CONCLUSIONS: High-dose MgSO4 therapy might be efficient as a prophylactic adjacent therapy after SAH to reduce the risk for poor outcome. There was no significant difference in mortality rate at discharge (p = 0.328). A trend toward improved outcome as measured by the modifed Rankin Scale (p = 0.084), but not the Glasgow Outcome Scale (p = 1.0), was seen in the MgSO4 treated group. CONCLUSIONS: Analysis of the results suggests that MgSO4 infusion may have a role in cerebral vasospasm prophylaxis if therapy is initiated within 48 hours of aneurysm rupture. There was, however, no difference between groups in functional recovery or Glasgow Outcome Scale score. Patients receiving MgSO4 tended to have fewer neurological deficits, better functional recovery and an improved score in GOS. CONCLUSIONS: MgSO4 infusion after aneurysmal SAH is well tolerated and may be useful in producing better outcome. CONCLUSION: Magnesium did not seem to interfere in vasospasm frequency but apparently acted favorably in decreasing morbidity and length of hospital stay. None of the patients died; no CT evidence of ischemic infarction was present; and most had good outcomes (GOS 5 in 10 patients; GOS 4 in 8 patients). At that time, 18 patients in the treatment group and 6 in the placebo group had an excellent outcome (risk ratio, 3.4; 95% CI, 1.3 to 8.9). CONCLUSIONS: This study suggests that magnesium reduces DCI and subsequent poor outcome, but the results are not yet definitive. We observed a trend in which a higher percentage of patients obtained GOS scores of 4 or 5 in the group treated with MgSO4, but the trend did not reach a statistically significant level. Magnesium sulfate treatment improves outcome in patients with subarachnoid hemorrhage: a meta-analysis study. BACKGROUND AND PURPOSE: Pilot clinical trials using magnesium sulfate in patients with acute aneurysmal subarachnoid hemorrhage have reported trends toward improvement in clinical outcomes. Preliminary evidence has suggested that magnesium sulfate infusion reduces delayed ischemic neurological deficit and improves clinical outcome after aneurysmal subarachnoid hemorrhage. Our results indicate that although there was reduced likelihood of a poor outcome for patients treated with magnesium sulfate after SAH, patient mortality was not improved. CONCLUSION: Administration of intra-arterial magnesium sulfate in combination with nicardipine was well tolerated in patients with subarachnoid hemorrhage and cerebral vasospasm without a significant change in MAP and ICP. Current evidence does not support the prophylactic use of magnesium sulfate in aneurysmal subarachnoid hemorrhage Preliminary evidence has suggested that magnesium sulfate infusion reduces delayed ischemic neurological deficit and improves clinical outcome after aneurysmal subarachnoid hemorrhage A meta-analysis of current data suggests that magnesium sulfate infusion improves the outcome after aneurysmal subarachnoid hemorrhage through a reduction in delayed ischemic neurological deficit Despite the publication of several randomized controlled studies, there is still much debate on whether magnesium sulfate improves outcome in patients with aneurysmal subarachnoid hemorrhage Magnesium sulphate is a neuroprotective agent that might improve outcome after aneurysmal subarachnoid haemorrhage by reducing the occurrence or improving the outcome of delayed cerebral ischaemia

no

532c169ed6d3ac6a3400001f

Are there plasma membrane receptors for thyroid hormones?

ntegrins are heterodimeric structural components of the plasma membrane whose ligands include a large number of extracellular matrix (ECM) proteins. Recently, integrin αvβ3 has been shown to have a panel of previously unappreciated small molecule receptor sites for thyroid hormone and hormone analogues, for dihydrotestosterone, and for resveratrol, a polyphenol that has certain estrogen-like features. The integrin receptor activation by T4 may take a role in plasma membrane processes involved in the male reproductive system. Rapid signaling via this plasma membrane binding site appears to be responsible for many nongenomic effects of thyroid hormones, independent of the classic nuclear receptors.

yes

56b9c937ac7ad10019000001

Does Rad9 interact with Aft1 in S.cerevisiae?

Rad9 interacts with Aft1 to facilitate genome surveillance in fragile genomic sites under non-DNA damage-inducing conditions in S. cerevisiae. Here we show that Rad9 checkpoint protein, known to mediate the damage signal from upstream to downstream essential kinases, interacts with Aft1 transcription factor in the budding yeast. Aft1 regulates iron homeostasis and is also involved in genome integrity having additional iron-independent functions. Using genome-wide expression and chromatin immunoprecipitation approaches, we found Rad9 to be recruited to 16% of the yeast genes, often related to cellular growth and metabolism, while affecting the transcription of ∼2% of the coding genome in the absence of exogenously induced DNA damage. Importantly, Rad9 is recruited to fragile genomic regions (transcriptionally active, GC rich, centromeres, meiotic recombination hotspots and retrotransposons) non-randomly and in an Aft1-dependent manner. Further analyses revealed substantial genome-wide parallels between Rad9 binding patterns to the genome and major activating histone marks, such as H3K36me, H3K79me and H3K4me. Thus, our findings suggest that Rad9 functions together with Aft1 on DNA damage-prone chromatin to facilitate genome surveillance, thereby ensuring rapid and effective response to possible DNA damage events. Here we show that Rad9 checkpoint protein, known to mediate the damage signal from upstream to downstream essential kinases, interacts with Aft1 transcription factor in the budding yeast Rad9 interacts with Aft1 to facilitate genome surveillance in fragile genomic sites under non-DNA damage-inducing conditions in S. cerevisiae Here we show that Rad9 checkpoint protein, known to mediate the damage signal from upstream to downstream essential kinases, interacts with Aft1 transcription factor in the budding yeast. Aft1 regulates iron homeostasis and is also involved in genome integrity having additional iron-independent functions. Using genome-wide expression and chromatin immunoprecipitation approaches, we found Rad9 to be recruited to 16% of the yeast genes, often related to cellular growth and metabolism, while affecting the transcription of ?2% of the coding genome in the absence of exogenously induced DNA damage. Importantly, Rad9 is recruited to fragile genomic regions (transcriptionally active, GC rich, centromeres, meiotic recombination hotspots and retrotransposons) non-randomly and in an Aft1-dependent manner. Further analyses revealed substantial genome-wide parallels between Rad9 binding patterns to the genome and major activating histone marks, such as H3K36me, H3K79me and H3K4me. Thus, our findings suggest that Rad9 functions together with Aft1 on DNA damage-prone chromatin to facilitate genome surveillance, thereby ensuring rapid and effective response to possible DNA damage events.

yes

5162e011298dcd4e51000049

Are there any desmins present in plants?

Inherited mutations in the gene coding for the intermediate filament protein desmin have been demonstrated to cause severe skeletal and cardiac myopathies. Mutations in the intermediate filament (IF) protein desmin cause severe forms of myofibrillar myopathy characterized by partial aggregation of the extrasarcomeric desmin cytoskeleton and structural disorganization of myofibrils. The family of 70 intermediate filament genes (including those encoding keratins, desmins, and lamins) is now known to be associated with a wide range of diverse diseases, at least 72 distinct human pathologies, including skin blistering, muscular dystrophy, cardiomyopathy, premature aging syndromes, neurodegenerative disorders, and cataract. Mutations in desmin have been associated with a subset of human myopathies. Characterization of a zebrafish (Danio rerio) desmin cDNA: an early molecular marker of myogenesis. Acute effects of desmin mutations on cytoskeletal and cellular integrity in cardiac myocytes. Desmin is a muscle-specific protein and a constitutive subunit of the intermediate filaments (IF) in skeletal, cardiac and smooth muscles. It is an early marker of skeletal muscle myogenesis. We have characterized a clone of desmin cDNA from an embryonic zebrafish (Danio rerio) cDNA library. Immunohistochemical investigation showed a positive reaction for smooth muscle actin and desmins in the spindle cells proliferated in the lymph nodes; no cytokeratin positivity was detected. We have raised monoclonal antibodies (Mab) to the Mr 55,000 desmin polypeptide, electrophoretically purified from cytoskeletal preparations of isolated bovine heart Purkinje fibers. Mesothelial and ovarian carcinoma cells could not be distinguished by (intermediate) filament typing, using monoclonal antibodies (MAbs) to keratins, vimentins and desmins. A fast and convenient procedure for the purification of polymerization-competent smooth-muscle desmin is described. Desmin from chicken gizzard and hog stomach were compared by fingerprint techniques.

no

513711055274a5fb0700000e

Are viruses involved in the etiology of human subacute thyroiditis?

he etiology of subacute (de Quervain's) thyroiditis (SAT) is uncertain, although it probably represents a nonspecific inflammatory response by the thyroid to a variety of viruses. Subacute thyroiditis is an inflammatory disorder of the thyroid caused probably by viruses. I We believe that the etiologic agent was the Epstein-Barr virus because heterophile and Epstein-Barr virus-specific antibodies were positive. ltogether, these results indicate that the mechanism of inhibition of Spumavirinae infection by interferon differs from that described for the other Retroviridae, and particularly for types B, C and D viruses. Our data is of therapeutic interest since Spumavirinae have been linked to pathological processes such as de Quervain thyroiditis.

yes

51485008d24251bc05000028

Is miR-126 involved in heart failure?

he miRNAs miR-126 and miR-508-5p are associated with the outcome of ICM and NICM patients with CHF. These two miRNAs could be useful in the diagnosis of CHF patients, and might provide novel targets for prevention and treatment of CHF. The plasma concentration of miR-126 was negatively correlated with age and NYHA class, and could be a useful biomarker for heart failure. In 10 patients with heart failure, plasma concentrations of miR-126 were up-regulated with improvement of the NYHA class from IV to III.

yes

52e7bbf698d023950500001d

Does resveratrol reduce cardiac remodeling?

In conclusion, resveratrol attenuated cardiac oxidative damage and left ventricular remodeling and enhanced the decreased expression of SIRT1 in hearts of old rats with emphysema and thus might be a therapeutic modality for cardiac injury complicated in chronic obstructive pulmonary disease (COPD). In conclusion, resveratrol is a beneficial pharmacological tool that augments autophagy to bring about reverse remodeling in the postinfarction heart. Resveratrol administration reduced atrial CSPC loss, succeeded in preserving the functional abilities of CSPCs and mature cardiac cells, improved cardiac environment by reducing inflammatory state and decreased unfavorable ventricular remodeling of the diabetic heart, leading to a marked recovery of ventricular function. These findings indicate that RSV can constitute an adjuvant therapeutic option in DCM prevention.

yes

5545dc7de233d84047000001

Is there a role for transcription factories in genome organization?

The mammalian nucleus is a highly complex structure that carries out a diverse range of functions such as DNA replication, cell division, RNA processing, and nuclear export/import. Many of these activities occur at discrete subcompartments that intersect with specific regions of the genome. Over the past few decades, evidence has accumulated to suggest that RNA transcription also occurs in specialized sites, called transcription factories, that may influence how the genome is organized. There may be certain efficiency benefits to cluster transcriptional activity in this way. However, the clustering of genes at transcription factories may have consequences for genome stability, and increase the susceptibility to recurrent chromosomal translocations that lead to cancer In the eukaryotic nucleus, genes are transcribed in transcription factories Based on this analysis, we propose that transcription factories result from the aggregation of RNA polymerase II-containing pre-initiation complexes assembled next to each other in the nuclear space. Such an aggregation can be triggered by the phosphorylation of the C-terminal domain of RNA polymerase II molecules and their interaction with various transcription factors. Individual transcription factories would thus incorporate tissue-specific, co-regulated as well as housekeeping genes based only on their initial proximity to each other in the nuclear space active polymerases cluster into replication and transcription "factories" in both pro- and eukaryotes. We conclude that the second law of thermodynamics acts through nonspecific entropic forces between engaged polymerases to drive the self-organization of genomes into loops containing several thousands (and sometimes millions) of basepairs Since the advent of FISH (fluorescence in situ hybridization), there have been major advances in our understanding of how the genome is organized in interphase nuclei. Indeed, this organization is found to be non-random and individual chromosomes occupy discrete regions known as territories in proliferating cells, there is evidently a correlation between radial positioning and gene density. Indeed, gene-poor chromosomes tend to be located towards the nuclear edge, while those that are more gene-rich are positioned more internally Recently described active chromatin hubs and transcription factories also involve long-range interactions The transcription factory model has implications for the regulation of transcription initiation and elongation, for the organization of genes in the genome, for the co-regulation of genes and for genome instability.

yes

515ed87c298dcd4e51000032

Do selenoproteins and selenium play a role in prostate cancer prevention?

The selenoprotein-deficient mice exhibited accelerated development of lesions associated with prostate cancer progression, implicating selenoproteins in cancer risk and development and raising the possibility that selenium prevents cancer by modulating the levels of these selenoproteins Notably and in contrast to previous studies, RWPE-1 cells were significantly more sensitive to selenite than either of the prostate cancer cell lines. These results demonstrate that selenoproteins and selenium metabolism are regulated at multiple levels in prostate cells In a low-selenium population, SOD2-Ala16+ men homozygous for SEPP1-Ala234 are at an increased risk of prostate cancer/aggressive prostate cancer especially if ever-smokers, because they are likely to produce more mitochondrial H(2)O(2) that they cannot remove, thereby promoting prostate tumor cell proliferation and migration. Our results support a role of selenium and polymorphisms in selenoenzymes in prostate cancer etiology, which warrants confirmation in future studies. This study provides evidence that SEP15 genetic variation may influence PCa mortality. Additionally, the association of selenium with PCa mortality was modified by a variant, suggesting the possibility that some men with PCa may benefit more from selenium than others, depending on their genotype. We conclude that decreased SEPP concentration in serum might represent an additional valuable marker for prostate cancer diagnostics. The recently completed Selenium and Vitamin E Cancer Prevention Trial (SELECT) was one of the largest human cancer prevention trials ever undertaken. Its purpose was to assess the role of selenium and vitamin E in prostate cancer prevention, but SELECT found no decline in prostate cancer. We studied Se levels in whole blood, plasma and prostate of 32 PC and 40 benign prostate hyperplasia (BPH) patients and in the control group composed of 39 healthy subjects. The selenoenzyme glutathione peroxidase (GSH-Px) was also measured in the patients' red cells, plasma and prostate tissue. Se concentration in whole blood and plasma in both groups of patients was lower as compared with controls, while in prostate gland it was significantly higher in PC than in BPH patients and controls. Red cell GSH-Px activity was the same in PC patients and controls but significantly lower in BPH patients. Of particular interest was the positive correlation between tissue GPx activity and Gleason score, with this relationship achieving statistical significance among African-Americans (r = 0.67, P = 0.02)

no

54d796f93706e8952800001e

Has protein citrullination been implicated in rheumatoid arthritis?

: Citrullination has become a hot topic within recent years due to its involvement in diseases such as rheumatoid arthritis (RA), multiple sclerosis and fibrosis. Current literature suggests that increased levels of citrullinated proteins are found in several if not all inflammatory diseases. Antibodies directed against citrullinated proteins and peptides (ACPAs) are the most specific serological markers available for diagnosing RA. Citrullination of proteins is well described in rheumatoid arthritis (RA), and hypercitrullination of proteins may be related to inflammation in general. Some ACPA are remarkably effective as diagnostics in autoimmune disorders, most notably rheumatoid arthritis (RA). Several ACPA can be observed before other clinical RA manifestations are apparent. Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein/peptide autoantibodies (ACPAs). Anti-citrullinated peptides as autoantigens in rheumatoid arthritis-relevance to treatment. The implications of citrullination affecting integrin binding in disease open up a new area of study and might have implications for the pathogenesis of inflammatory diseases like rheumatoid arthritis and periodontitis. In this paper, we will review the three of the main classes of PTMs already associated with RA: citrullination, carbamylation, and oxidation. Citrullinated collagen II (CII) is a well-known autoantigen in rheumatoid arthritis (RA). Among the RA-associated autoantibodies, especially anti-citrullinated protein antibodies (ACPAs) have been studied intensively in the last decade. Protein citrullination is a posttranslational modification that has attracted increased attention, especially for its involvement in rheumatoid arthritis (RA). Identification of citrullinated cellular fibronectin in synovial fluid from patients with rheumatoid arthritis. Cellular fibronectin (cFn) has been implicated in the pathogenesis of rheumatoid arthritis (RA), and we previously demonstrated the presence of citrullinated cFn in rheumatoid synovial tissues. . In rheumatoid arthritis, PAD4 and protein citrullination are increased in inflamed joints, and anti-citrullinated protein antibodies (ACPAs) form against citrullinated antigens are formed.

yes

56e2985951531f7e33000013

Do R-loops tend to form at sites of DNA replication?

Escherichia coli rnhA mutants devoid of RNase HI exhibit constitutive stable DNA replication, cSDR, which is thought to be initiated from R-loops stabilized in the absence of RNase HI. We propose that the organized structure of the R-loop is critical for primer RNA function in vivo with important implications for the RNA processing and DNA replication machinery. The precursor primer RNA exists as a persistent RNA-DNA hybrid, known as an R-loop, formed during transcription through the replication origin (Xu, B., and Clayton, D. A. (1996) EMBO J. 15, 3135-3143). We found that overproduction of RecG protein drastically decreased copy numbers of ColE1-type plasmids, which require R-loop formation between the template DNA and a primer RNA transcript (RNA II) for the initiation of replication. These results suggest that overproduced RecG inhibits the initiation of replication by prematurely resolving the R-loops formed at the replication origin region of these plasmids with its unique helicase activity. The possibility that RecG regulates the initiation of a unique mode of DNA replication, oriC-independent constitutive stable DNA replication, by its activity in resolving R-loops is discussed. We propose that downstream of a replication block, RNA at R-loops is extended by DNA polymerase I, opening up the DNA duplex and leading to the recruitment of the replisome. This would allow replication to proceed while the original block is repaired or bypassed Furthermore, increased RNaseH expression significantly alleviated genomic instability in deficient fibroblasts suggesting that cotranscriptional R-loops formation contributes to the genesis of replication-dependent DSBs in these cells. Transcription is an important source of replicative stress and consequently, maintenance of genome integrity requires the protection of chromosomes from the deleterious effects arising from the interaction between nascent RNAs and template DNA, leading to stable DNA-RNA hybrids (R-loop) formation. Strikingly, we found that attenuation of replication strongly suppresses R-loop-mediated DNA rearrangements in both E. coli and HeLa cells. More importantly, we then show that R-loop formation causes DNA replication fork stalling, and that this in fact underlies the effects of R loops on genomic stabilit R-loop-mediated genomic instability is caused by impairment of replication fork progression When any of these processes are not properly coordinated, aberrant outcomes such as fork reversal and R-loop formation arise and trigger unscheduled recombinogenic events and genome rearrangements. Many studies show that cells can manage R loop formation with efficiency, and can also process the R-loops already formed in the cell, and by which, the bad effects of R-loops on DNA replication, gene mutation and homologous recombination can be regulated. Here we propose that physiological R-loop formation at CpG island promoters can contribute to DNA replication origin specification at these regions, the most efficient replication initiation sites in mammalian cells. In agreement with this, we found that R-loops co-localize with the ORC within the same CpG island region in a significant fraction of these efficient replication origins, precisely at the position displaying the highest density of G4 motifs. connection between transcription and replication in human cells and suggests that R-loop dysregulation at CpG island promoter-origins might contribute to the phenotype of DNA replication abnormalities and loss of genome integrity detected in cancer cells. We show that RNA:DNA hybrids (R-loops) form at sites of transcription/replication collisions and that RNase H1 functions to suppress CFS instability. R-loops and initiation of DNA replication in human cells: a missing link? Stable RNA-DNA hybrids (R-loops) prime the initiation of replication in Escherichia coli cells. We propose that downstream of a replication block, RNA at R-loops is extended by DNA polymerase I, opening up the DNA duplex and leading to the recruitment of the replisome. Immediately after infection, RNA-DNA hybrids (R-loops) occur on (at least some) replication origins, with the annealed RNA serving as a primer for leading-strand synthesis in one direction. Here we propose that physiological R-loop formation at CpG island promoters can contribute to DNA replication origin specification at these regions, the most efficient replication initiation sites in mammalian cells. ColE1 plasmid origins of replication and oriK sites initiate primosome assembly by an RNA-DNA hybrid structure known as R-loop. This scenario builds on the connection between transcription and replication in human cells and suggests that R-loop dysregulation at CpG island promoter-origins might contribute to the phenotype of DNA replication abnormalities and loss of genome integrity detected in cancer cells. The multiple cleavage sites on the R-loop substrate match the priming sites observed in vivo, suggesting that RNase MRP alone is capable of generating virtually all of the leading-strand replication primers. Mechanisms of primer RNA synthesis and D-loop/R-loop-dependent DNA replication in Escherichia coli. Alternative oriC-independent modes of replication initiation are possible, one of which is constitutive stable DNA replication (cSDR) from transcription-associated RNA-DNA hybrids or R-loops. Our results suggest that Top1 execute this function by suppressing the formation of DNA-RNA hybrids during transcription, these so-called R-loops interfering with the progression of replication forks. Critical role of R-loops in processing replication blocks. The possibility that RecG regulates the initiation of a unique mode of DNA replication, oriC-independent constitutive stable DNA replication, by its activity in resolving R-loops is discussed. Competition between the RNA transcript and the nontemplate DNA strand during R-loop formation in vitro: a nick can serve as a strong R-loop initiation site. More importantly, we then show that R-loop formation causes DNA replication fork stalling, and that this in fact underlies the effects of R loops on genomic stability. Consistent with this hypothesis, the 3' ends of the mitochondrial R-loop formed by in vitro transcription are located close to the initiation sites of the mitochondrial DNA replication. A hybrid G-quadruplex structure formed between RNA and DNA explains the extraordinary stability of the mitochondrial R-loop. Previous studies have shown that the newly synthesized primers form a stable and persistent RNA-DNA hybrid, a R-loop, near the leading-strand origin of DNA replication. Escherichia coli rnhA mutants devoid of RNase HI exhibit constitutive stable DNA replication, cSDR, which is thought to be initiated from R-loops stabilized in the absence of RNase HI.

yes

550c1ca3a103b78016000003

Is selenium deficiency involved in autoimmune thyroid disease?

In areas with severe selenium deficiency higher incidence of thyroiditis has been reported due to a decreased activity of selenium-dependent glutathione peroxidase enzyme within thyroid cells Of 30 patients in the selenium treated group, 6 patients were overtly hypothyroid, 15 were subclinical hypothyroid, 6 were euthyroid, and 3 were subclinical hyperthyroid. The mean TPOAb concentration decreased significantly by 49.5% (P < 0.013) in the selenium treated group versus 10.1% (P < 0.95) in the placebo-treated group Selenium substitution has a significant impact on inflammatory activity in thyroid-specific autoimmune disease Serum selenium is low in newly diagnosed Graves' disease S-Se was lower in patients with GD than in controls (mean (SD), GD: 89·9 μg/l (18·4); controls: 98·8 μg/l (19·7), P < 0·01) Patients with newly diagnosed GD and AIH had significantly lower s-Se compared with random controls. Our observation supports the postulated link between inadequate selenium supply and overt autoimmune thyroid disease, especially GD Selenium deficiency is likely to constitute a risk factor for a feedforward derangement of the immune system-thyroid interaction, while selenium supplementation appears to dampen the self-amplifying nature of this derailed interaction The recent recognition that the essential trace element selenium is incorporated as selenocysteine in all three deiodinases has decisively confirmed the clear-cut link between selenium and thyroid function. It has additionally been established that the thyroid contains more selenium than any other tissue and that selenium deficiency aggravates the manifestation of endemic myxedematous cretinism and autoimmune thyroid disease Maintenance of "selenostasis" via optimal intake not only aids preservation of general health but also contributes substantially to the prevention of thyroid disease Low birth weight, iodine excess and deficiency, selenium deficiency, parity, oral contraceptive use, reproductive span, fetal microchimerism, stress, seasonal variation, allergy, smoking, radiation damage to the thyroid gland, viral and bacterial infections all play a role in the development of autoimmune thyroid disorders It has additionally been established that the thyroid contains more selenium than any other tissue and that selenium deficiency aggravates the manifestation of endemic myxedematous cretinism and autoimmune thyroid disease. Selenium deficiency may play an important role in the initiation and progression of autoimmune thyroid disease. [Selenium deficiency in celiac disease: risk of autoimmune thyroid diseases]. Low birth weight, iodine excess and deficiency, selenium deficiency, parity, oral contraceptive use, reproductive span, fetal microchimerism, stress, seasonal variation, allergy, smoking, radiation damage to the thyroid gland, viral and bacterial infections all play a role in the development of autoimmune thyroid disorders. Some clinical studies have demonstrated that selenium-deficient patients with autoimmune thyroid disease benefit from selenium supplementation, although the data are conflicting and many parameters must still be defined. Our observation supports the postulated link between inadequate selenium supply and overt autoimmune thyroid disease, especially GD. Selenium deficiency in celiac disease: risk of autoimmune thyroid diseases]. Selenoproteins contain the essential trace element selenium whose deficiency leads to major disorders including cancer, male reproductive system failure, or autoimmune thyroid disease. It has additionally been established that the thyroid contains more selenium than any other tissue and that selenium deficiency aggravates the manifestation of endemic myxedematous cretinism and autoimmune thyroid disease. EVIDENCE SYNTHESIS: Evidence in support of selenium supplementation in thyroid autoimmune disease is evaluated, the results herein presented demonstrating the potential effectiveness of selenium in reducing the antithyroid peroxidase titer and improving the echostructure in the ultrasound examination. Some investigators suggest that selenium may be a useful adjunctive treatment for autoimmune thyroid diseases, such as Hashimoto and Graves' disease. Therefore, even mild selenium deficiency may contribute to the development and maintenance of autoimmune thyroid diseases. Some clinical studies have demonstrated that selenium-deficient patients with autoimmune thyroid disease benefit from selenium supplementation, although the data are conflicting and many parameters must still be defined. Some clinical studies have demonstrated that selenium-deficient patients with autoimmune thyroid disease benefit from selenium supplementation, although the data are conflicting and many parameters must still be defined High prevalence of hyperplastic and autoimmune diseases of thyroid in Ukrainian population is determined by endemic deficit of iodine and selenium It has additionally been established that the thyroid contains more selenium than any other tissue and that selenium deficiency aggravates the manifestation of endemic myxedematous cretinism and autoimmune thyroid disease. Therefore, even mild selenium deficiency may contribute to the development and maintenance of autoimmune thyroid diseases Some investigators suggest that selenium may be a useful adjunctive treatment for autoimmune thyroid diseases, such as Hashimoto and Graves' disease

yes

52bf1aa503868f1b06000006

Is it safe to use Abatacept during pregnancy?

These patients were exposed to rituximab (anti-CD20 monoclonal antibody) or abatacept (fusion protein CTLA4Ig) during the first trimester of their pregnancies. No significant adverse effects or complications were observed during the pregnancies, and all three patients delivered healthy newborns. Despite these favorable outcomes, the use of these two biological agents must follow international recommendations. Their use is not currently allowed during pregnancy except in cases where the potential benefit to the mother justifies the potential risk to the fetus PREGNANCY: Azathioprine, chloroquine, cyclosporin A, prednisolone, sulfasalazine, tacrolimus and cyclophosphamide (only after the second trimester) may be administered during pregnancy. Biologics should be avoided unless there is a treatment need in cases of uncontrolled disease activity. As such, it is recommended that abatacept, rituximab and tocilizumab be withheld prior to pregnancy; however, tumour necrosis factor inhibitors and anakinra may be continued until conception. Case reports on abatacept, tocilizumab or anakinra in pregnancy are not conclusive. The very limited experience with abatacept, tocilizumab or anakinra in pregnancy allows no statement as to their compatibility with pregnancy. At present use of biological agents throughout pregnancy cannot be recommended. Drugs recommended to be stopped before pregnancy include methotrexate and leflunomide, plus the biologics: anti-TNF agents, rituximab and abatacept. Whereas methotrexate, leflunomide, abatacept and rituximab must be withdrawn before a planned pregnancy, tumor necrosis factor inhibitors and bisphosphonates can be continued until conception. Pregnancy experience with abatacept and rituximab is still too limited to prove their safety for the developing fetus. They must be withdrawn before a planned pregnancy. Prophylactic withdrawal of drugs before pregnancy is mandatory for abatacept, rituximab, LEF and MMF.

no

56cdf3995795f9a73e00003a

Is STAT3 involved in EIF2AK2-dependent suppression of autophagy?

STAT3 may act as a competitive inhibitor of EIF2AK2. Indeed, pharmacological or genetic inhibition of STAT3 stimulates EIF2AK2-dependent EIF2S1 phosphorylation and autophagy. Conversely, the overexpression of wild-type STAT3 as well as of STAT3 mutants that cannot be phosphorylated by JAK2 or are excluded from the nucleus inhibits autophagy. However, STAT3 mutants that fail to interact with EIF2AK2 are unable to suppress autophagy Both STAT3-targeting agents (i.e., Stattic, JSI-124 and WP1066) and EIF2AK2 activators (such as the double-strand RNA mimetic polyinosinic:polycytidylic acid) are capable of disrupting the inhibitory interaction between STAT3 and EIF2AK2 in cellula A further screen designed to identify EIF2AK2-dependent autophagy inducers revealed that several fatty acids including palmitate trigger autophagy via a pathway that involves the disruption of the STAT3-EIF2AK2 complex These results reveal an unsuspected crosstalk between cellular metabolism (fatty acids), pro-inflammatory signaling (STAT3), innate immunity (EIF2AK2), and translational control (EIF2S1) that regulates autophagy Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity The SH2 domain of STAT3 was found to interact with the catalytic domain of the eIF2α kinase 2 EIF2AK2, best known as protein kinase R (PKR). Pharmacological and genetic inhibition of STAT3 stimulated the activating phosphorylation of PKR and consequent eIF2α hyperphosphorylation. Moreover, PKR depletion inhibited autophagy as initiated by chemical STAT3 inhibitors or free fatty acids like palmitate STAT3-targeting chemicals and palmitate caused the disruption of inhibitory STAT3-PKR interactions, followed by PKR-dependent eIF2α phosphorylation, which facilitates autophagy induction Indeed, pharmacological or genetic inhibition of STAT3 stimulates EIF2AK2-dependent EIF2S1 phosphorylation and autophagy. A further screen designed to identify EIF2AK2-dependent autophagy inducers revealed that several fatty acids including palmitate trigger autophagy via a pathway that involves the disruption of the STAT3-EIF2AK2 complex as well as the phosphorylation of mitogen-activated protein kinase 8/c-Jun N-terminal kinase 1 (MAPK8/JNK1) and EIF2S1. A further screen designed to identify EIF2AK2-dependent autophagy inducers revealed that several fatty acids including palmitate trigger autophagy via a pathway that involves the disruption of the STAT3-EIF2AK2 complex as well as the phosphorylation of mitogen-activated protein kinase 8/c-Jun N-terminal kinase 1 (MAPK8/JNK1) and EIF2S1 Indeed, pharmacological or genetic inhibition of STAT3 stimulates EIF2AK2-dependent EIF2S1 phosphorylation and autophagy However, STAT3 mutants that fail to interact with EIF2AK2 are unable to suppress autophagy Direct interaction between STAT3 and EIF2AK2 controls fatty acid-induced autophagy A further screen designed to identify EIF2AK2-dependent autophagy inducers revealed that several fatty acids including palmitate trigger autophagy via a pathway that involves the disruption of the STAT3-EIF2AK2 complex as well as the phosphorylation of mitogen-activated protein kinase 8/c-Jun N-terminal kinase 1 (MAPK8/JNK1) and EIF2S1. Indeed, pharmacological or genetic inhibition of STAT3 stimulates EIF2AK2-dependent EIF2S1 phosphorylation and autophagy. Direct interaction between STAT3 and EIF2AK2 controls fatty acid-induced autophagy. These results unravel an unsuspected mechanism of autophagy control that involves STAT3 and PKR as interacting partners. Both STAT3-targeting agents (i.e., Stattic, JSI-124 and WP1066) and EIF2AK2 activators (such as the double-strand RNA mimetic polyinosinic:polycytidylic acid) are capable of disrupting the inhibitory interaction between STAT3 and EIF2AK2 in cellula, yet only the latter does so in cell-free systems in vitro. A further screen designed to identify EIF2AK2-dependent autophagy inducers revealed that several fatty acids including palmitate trigger autophagy via a pathway that involves the disruption of the STAT3-EIF2AK2 complex as well as the phosphorylation of mitogen-activated protein kinase 8/c-Jun N-terminal kinase 1 (MAPK8/JNK1) and EIF2S1. A further screen designed to identify EIF2AK2-dependent autophagy inducers revealed that several fatty acids including palmitate trigger autophagy via a pathway that involves the disruption of the STAT3-EIF2AK2 complex as well as the phosphorylation of mitogen-activated protein kinase 8/c-Jun N-terminal kinase 1 (MAPK8/JNK1) and EIF2S1. These results reveal an unsuspected crosstalk between cellular metabolism (fatty acids), pro-inflammatory signaling (STAT3), innate immunity (EIF2AK2), and translational control (EIF2S1) that regulates autophagy. Thus, STAT3 may act as a competitive inhibitor of EIF2AK2. Indeed, pharmacological or genetic inhibition of STAT3 stimulates EIF2AK2-dependent EIF2S1 phosphorylation and autophagy. Indeed, pharmacological or genetic inhibition of STAT3 stimulates EIF2AK2-dependent EIF2S1 phosphorylation and autophagy. Conversely, the overexpression of wild-type STAT3 as well as of STAT3 mutants that cannot be phosphorylated by JAK2 or are excluded from the nucleus inhibits autophagy. , Stattic, JSI-124 and WP1066) and EIF2AK2 activators (such as the double-strand RNA mimetic polyinosinic:polycytidylic acid) are capable of disrupting the inhibitory interaction between STAT3 and EIF2AK2 in cellula, yet only the latter does so in cell-free systems in vitro. A further screen designed to identify EIF2AK2-dependent autophagy inducers revealed that several fatty acids including palmitate trigger autophagy via a pathway that involves the disruption of the STAT3-EIF2AK2 complex as well as the phosphorylation of mitogen-activated protein kinase 8/c-Jun N-terminal kinase 1 (MAPK8/JNK1) and EIF2S1.

yes

56a375f8496b62f23f000002

Are CTCF and BORIS involved in genome regulation and cancer?

CTCF is ubiquitously expressed and plays diverse roles in gene regulation, imprinting, insulation, intra/interchromosomal interactions, nuclear compartmentalisation, and alternative splicing. CTCF has a single paralogue, the testes-specific CTCF-like gene (CTCFL)/BORIS. CTCF and BORIS can be deregulated in cancer. The tumour suppressor gene CTCF can be mutated or deleted in cancer, or CTCF DNA binding can be altered by epigenetic changes. BORIS is aberrantly expressed frequently in cancer, leading some to propose a pro-tumourigenic role for BORIS. However, BORIS can inhibit cell proliferation, and is mutated in cancer similarly to CTCF suggesting BORIS activation in cancer may be due to global genetic or epigenetic changes typical of malignant transformation The investigation of the molecular mechanisms engaged by CTCF to modulate tumor-related genes emphasizes the cell-type dependency of its tumor suppressor role. Indeed, the ability of CTCF to bind their promoters strictly depends by cell-type features as DNA methylation, BORIS-binding and post-translational modifications as PARYlation Moreover, reduction of CTCF in normally BORIS-negative human fibroblasts resulted in derepression of BORIS promoters. These results provide a mechanistic basis for understanding cancer-related associations between haploinsufficiency of CTCF and BORIS derepression, and between the lack of functional p53 and aberrant activation of BORIS CTCF and BORIS in genome regulation and cancer. The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer. Collectively, these data indicate that reciprocal binding of CTCF and BORIS to the NY-ESO-1 promoter mediates epigenetic regulation of this CT gene in lung cancer cells, and suggest that induction of BORIS may be a novel strategy to augment immunogenicity of pulmonary carcinomas. BORIS is the only known paralog of CTCF, a gene intimately involved in genomic imprinting, chromatin insulation, and nuclear regulation. However, BORIS can inhibit cell proliferation, and is mutated in cancer similarly to CTCF suggesting BORIS activation in cancer may be due to global genetic or epigenetic changes typical of malignant transformation. We suggest that BORIS is likely tethering epigenetic machinery to a novel class of CTCF/BORIS 11ZF target sequences that mediate induction of cancer-testis genes. Unlike CTCF, BORIS expression has been reported only in the testis and certain malignancies, leading to its classification as a "cancer-testis" antigen.

yes

5709e947cf1c32585100001d

Are Sidekick proteins members of the immunoglobulin superfamily?

Here we show that four closely related immunoglobulin superfamily (IgSF) adhesion molecules--Dscam (Down's syndrome cell adhesion molecule), DscamL (refs 6-9), Sidekick-1 and Sidekick-2 Sidekick-1, a cell adhesion molecule of the immunoglobulin superfamily, is up-regulated in glomerular podocytes in the collapsing glomerulopathy of HIV-associated nephropathy (HIVAN).

yes

53552ed7f1005d6b58000001

Have mutations in the ZEB2 gene been found in any human syndrome?

Mowat-Wilson syndrome is a genetic disease caused by heterozygous mutations or deletions of the zinc finger E-box-binding homeobox 2 (ZEB2) gene Mowat-Wilson syndrome (MWS; OMIM#235730) have characteristic facial features, a variety of congenital anomalies such as Hirschsprung disease, and intellectual disabilities caused by mutation or deletion of ZEB2 gene. owat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene MWS is caused by de novo heterozygous mutations in the ZEB2 gene The cause of MWS is a de novo mutation in the ZEB2 gene owat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene MWS have a heterozygous loss-of-function mutation in the zinc finger E-box protein 2 (ZEB2) gene, also called SIP1 (Smad-interacting protein 1) and ZFHX1B, human Mowat-Wilson syndrome, we suggest that deletion of ZEB2, is responsible for most of the effects of the mutation Mutations at the hZeb2 locus cause Mowat-Wilson syndrome (MWS) Mowat-Wilson syndrome and a mutation in ZEB2 owat-Wilson syndrome (MWS) is caused by a heterozygous mutation or deletion of the ZEB2 gene The syndrome is caused by mutations or deletions of the ZEB2 gene owat-Wilson syndrome (MWS) is an autosomal dominant intellectual disability syndrome single-copy ZEB2 gene deletion at 2q22.3 consistent with Mowat-Wilson syndrome Mowat-Wilson syndrome, confirmed by molecular analysis as a heterozygous deletion of the ZEB2 gene. deletion encompassing ZEB2, the gene responsible for the Mowat-Wilson syndrome Six patients had deletions in the ZEB2 gene ZEB2 gene analysis for Mowat-Wilson syndrome Mowat-Wilson syndrome (MWS) like appearance was noted. The disease is caused by mutation or deletion of ZEB2 gene owat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene owat-Wilson syndrome (MWS) is an autosomal dominant developmental disorder with mental retardation and variable multiple congenital abnormalities due to mutations of the ZEB2 (ZFHX1B) MWS is caused by heterozygous mutations or deletions in the Zinc finger E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1) owat-Wilson syndrome (MWS) is a multiple congenital anomaly-mental retardation complex caused by mutations in the Zinc Finger Homeobox 1 B gene (ZFHX1B) the ZFHX1B gene, which is known to be involved in the Mowat-Wilson syndrom de novo heterozygous mutations or deletions of the ZFHX1B gene located at 2q22 owat-Wilson syndrome (MWS) is a recently delineated mental retardation (MR)-multiple congenital anomaly syndrome FHX1B mutations in patients with Mowat-Wilson syndrome Mutations leading to haploinsufficiency of the ZFHX1B gene mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype ZFHX1B mutation associated with a mild Mowat-Wilson syndrome Patients with zinc finger homeo box 1B (ZFHX1B) mutations or deletions develop multiple congenital anomalies including Hirschsprung disease, known as Mowat-Wilson syndrome (MWS) Heterozygous mutations or deletions involving the gene ZFHX1B (previously SIP1) [OMIM 605802] have recently been found to cause MWS ZFHX1B deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS Mowat-Wilson syndrome with deletion/mutation in the zinc finger homeo box 1B gene (ZFHX1B) mutations in the zinc finger homeo box 1B gene, ZFHX1B (SIP1) ZFHX1B gene transcripts during mouse and human development supports the various clinical manifestations of the "Mowat-Wilson" syndrome ZFHX1B mutations cause a complex developmental phenotype characterized by severe mental retardation (MR) and multiple congenital defects mutation of the zinc finger homeo box 1 B gene in syndromic corpus callosum agenesis (Mowat-Wilson syndrome syndrome is the result of heterozygous deletions or truncating mutations of the ZFHX1B (SIP1) gene humans with Zfhx1b mutations (Mowat-Wilson syndrome syndrome occurs as a result of heterozygous mutations or deletions in the zinc finger E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1) owat-Wilson syndrome (MWS) is a recently delineated mental retardation; Mowat-Wilson syndrome is a congenital syndrome caused by a defect of the transcriptional repressor ZFHX1B (SIP1) Mowat-Wilson syndrome patients, and all siblings had the same E87X nonsense mutation in ZFHX1B

yes

54f42f2764850a5854000005

Are the Fanconi anemia genes a part of the same signalling pathway?

Mutations in at least 14 different genes have been shown to cause FA The FA genes code for proteins that act in complexes to coordinate the repair of damaged DNA The current review describes the structure and function of the Fanconi anemia genes and describes the role of the encoded Fanconi anemia proteins in a cellular pathway controlling chromosome stability. Fanconi anemia (FA) is a rare human genetic disease caused by mutations in any one of 13 known genes that encode proteins functioning in one common signaling pathway, the FA pathway, or in unknown genes. Fanconi anemia (FA) is a rare inherited recessive disease caused by mutations in one of fifteen genes known to encode FA pathway components. Fanconi anemia (FA) proteins function in a DNA damage response pathway that appears to be part of the network including breast cancer susceptibility gene products, BRCA1 and BRCA2. Fanconi anemia (FA) proteins function in a DNA damage response pathway that appears to be part of the network including breast cancer susceptibility gene products, BRCA1 and BRCA2 Fanconi anemia (FA) is a rare human genetic disease caused by mutations in any one of 13 known genes that encode proteins functioning in one common signaling pathway, the FA pathway, or in unknown genes The Fanconi anemia (FA) gene family comprises at least 12 genes interacting in a common pathway involved in DNA repair These findings show that the newly identified FANCE protein is an integral part of the FA pathway, and support the concept of a functional link between all known proteins encoded by the genes that are mutated in this disorder

yes

56f160a52ac5ed1459000013

Are there clinical trials using stem cells for the treatment of cardiac disease?

Therapy with mesenchymal stem cells is one of the promising tools to improve outcomes after myocardial infarction. Adipose-derived stem cells (ASCs) are an ideal source of mesenchymal stem cells due to their abundance and ease of preparation. Furthermore, several ongoing clinical trials using ASCs are producing promising results for heart diseases. Among the cell types under investigation, adult mesenchymal stem cells are widely studied, and in early stage, clinical studies show promise for repair and regeneration of cardiac tissues. Accumulating data from preclinical and early phase clinical trials document their safety when delivered as either autologous or allogeneic forms in a range of cardiovascular diseases, but also importantly define parameters of clinical efficacy that justify further investigation in larger clinical trials. several ongoing clinical trials using ASCs are producing promising results for heart diseases. Clinical application of adult stem cells for therapy for cardiac disease. Stem cell-based therapies have the potential to fundamentally transform the treatment of ischemic cardiac injury and heart failure by achieving what would have been unthinkable only a few years ago-the Holy Grail of myocardial regeneration. Recent therapeutic approaches involve bone marrow (BM)-derived mononuclear cells and their subsets such as mesenchymal stem/stromal cells (MSCs), endothelial progenitor cells as well as adipose tissue-derived MSCs, cardiac tissue-derived stem cells, and cell combinations. Clinical trials employing these cells have demonstrated that cellular therapy is feasible and safe. Accumulating data from preclinical and early phase clinical trials document their safety when delivered as either autologous or allogeneic forms in a range of cardiovascular diseases, but also importantly define parameters of clinical efficacy that justify further investigation in larger clinical trials. se of stem and precursor cells as a therapeutic agent for chronically injured organs. Among the cell types under investigation, adult mesenchymal stem cells are widely studied, and in early stage, clinical studies show promise for repair and regeneration of cardiac tissues. Over the past 2 decades, there have been numerous stem cell studies focused on cardiac diseases, ranging from proof-of-concept to phase 2 trials. Small uncontrolled clinical trials have demonstrated cardiac stem cells as a treatment option for cardiomyopathy. Stem cell populations are rapidly increasing, and we are still in the search of optimal cell types to use in clinical trials as bone marrow stem cells did not show significant improvement in cardiac function following transplantation. Several clinical trials using adult stem cell have shown improvements in cardiac function, however, the mechanism of their action is unclear and widespread tissue regeneration is not evident. As we await results from larger and more prolonged clinical trials, the science of stem cell therapy in cardiac disease keeps progressing. Stem cell therapy for treatment of cardiac disease has shown therapeutic potential. It should be noted that stem cell therapy is not limited to the treatment of ischemic cardiac disease. Over the past 2 decades, there have been numerous stem cell studies focused on cardiac diseases, ranging from proof-of-concept to phase 2 trials. This series of papers focuses on the legacy of these studies and the outlook for future treatment of cardiac diseases with stem cell therapies. Cell transplantation to repair or regenerate injured myocardium is a new frontier in the treatment of cardiovascular disease. Current therapies only delay progression of the cardiac disease or replace the diseased heart with cardiac transplantation. Stem cells represent a recently discovered novel approach to the treatment of cardiac failure that may facilitate the replacement of diseased cardiac tissue and subsequently lead to improved cardiac function and cardiac regeneration. Over the past 2 decades, there have been numerous stem cell studies focused on cardiac diseases, ranging from proof-of-concept to phase 2 trials. This series of papers focuses on the legacy of these studies and the outlook for future treatment of cardiac diseases with stem cell therapies. Stem cell therapy for treatment of cardiac disease has shown therapeutic potential. Over the past 2 decades, there have been numerous stem cell studies focused on cardiac diseases, ranging from proof-of-concept to phase 2 trials. This series of papers focuses on the legacy of these studies and the outlook for future treatment of cardiac diseases with stem cell therapies. It should be noted that stem cell therapy is not limited to the treatment of ischemic cardiac disease. Non-ischemic cardiomyopathy, peripheral vascular disease, and aging may be treated by stem cells. Recent clinical trials have achieved favorable initial endpoints with improvements in cardiac function and clinical symptoms following cellular therapy. we consider how cardiac stem cell biology has led us into clinical trials, and we suggest that achieving true cardiac regeneration in patients may ultimately require resolution of critical controversies in experimental cardiac regeneration. Cell-based therapies and tissue engineering provide new promising platforms to develop upcoming therapeutic options. Initial clinical trials were able to generate promising results. A variety of different stem cell types have been used for the clinical application. Insights gained from clinical trials of adult stem cells, together with fundamental scientific advances in cardiac stem cell and regenerative biology, are beginning to yield potential new targets and strategies for regenerative therapies. Early animal trials have demonstrated the ability to improve cardiac function by transfer of HSCs into the myocardium, and early human studies have demonstrated the feasibility and safety of this approach.

yes

54d9f7894b1fd0d33c00000a

Is DNA methylation an epigenetic modification of chromatin related to gene expression?

DNA methylation is a chemical modification of DNA involved in the regulation of gene expression by controlling the access to the DNA sequence. Epigenetic marks such as DNA methylation play important biological roles in gene expression regulation and cellular differentiation during development. DNA methylation patterns are characterized by highly conserved developmental programs, but allow for divergent gene expression resulting from stochastic epigenetic drift or divergent environments. DNA methylation plays a critical role in the regulation of gene expression. Epigenetic changes such as DNA methylation and histone methylation and acetylation alter gene expression at the level of transcription by upregulating, downregulating, or silencing genes completely. Dysregulation of epigenetic events can be pathological, leading to cardiovascular disease, neurological disorders, metabolic disorders, and cancer development. DNA methylation is a pervasive epigenetic DNA modification that strongly affects chromatin regulation and gene expression. Epigenetic control, which includes DNA methylation and histone modifications, leads to chromatin remodeling and regulated gene expression. Epigenetic modifications on the DNA sequence (DNA methylation) or on chromatin-associated proteins (i.e., histones) comprise the "cellular epigenome"; together these modifications play an important role in the regulation of gene expression. Epigenetics is a process involved in gene regulation, mediated via DNA methylation, histone modification, chromatin remodeling, and functional noncoding RNAs, which influences the accessibility of the underlying DNA to transcriptional regulatory factors that activate or repress expression. Significant progress has been made in the basic understanding of how various epigenetic changes such as DNA methylation, histone modification, miRNA expression, and higher order chromatin structure affect gene expression.

yes

553bd2f0f321868558000008

Is Growth factor independence 1b (GFI1B) important for hematopoiesis?

Growth Factor Independence (Gfi) transcription factors play essential roles in hematopoiesis, differentially activating and repressing transcriptional programs required for hematopoietic stem/progenitor cell (HSPC) development and lineage specification gfi1aa and gfi1b have distinct roles in regulating primitive and definitive hematopoietic progenitors, gfi1b is required for definitive hematopoiesis LSD1-kd was associated with the upregulation of key hematopoietic genes, including Gfi1b GFI1 and GFI1B control the loss of endothelial identity of hemogenic endothelium during hematopoietic commitment Taken together, our findings demonstrate a critical and specific role of the GFI1 transcription factors in the first steps of the process leading to the generation of hematopoietic progenitors from hemogenic endothelium A short Gfi-1B isoform controls erythroid differentiation Gfi-1B is a transcriptional repressor essential for the regulation of erythropoiesis and megakaryopoiesis Among the few down-regulated genes was Gfi1b, a known repressor of erythroid differentiation This reversible modulation of endothelial-haematopoietic state is accomplished by targeting key haematopoietic transcription factors for downregulation, including Runx1, Gata1, Gfi1B, Ikaros, and PU.1 Gfi1 and Gfi1b: key regulators of hematopoiesis we review how Gfi1 and its paralogue Gfi1b control the development of blood cells, discuss how changes in Gfi1 and Gfi1b function contribute to hematological disease and report on the molecular function of these proteins. Gfi-1B controls human erythroid and megakaryocytic differentiation by regulating TGF-beta signaling at the bipotent erythro-megakaryocytic progenitor stage Growth factor independence-1B (Gfi-1B) is a transcriptional repressor essential for erythropoiesis and megakaryopoiesis Targeted gene disruption of GFI1B in mice leads to embryonic lethality resulting from failure to produce definitive erythrocytes, hindering the study of Gfi-1B function in adult hematopoiesis We here show that, in humans, Gfi-1B controls the development of erythrocytes and megakaryocytes by regulating the proliferation and differentiation of bipotent erythro-megakaryocytic progenitors To date, we have identified two common integration sites involving genes encoding transcription factors that play a critical role in hematopoiesis (Evi1 and Gfi1b loci) Transcription factors play essential roles in both normal and malignant hematopoiesis. This is the case for the growth factor independent 1b (GFI1B) transcription factor, which is required for erythroid and megakaryocytic differentiation and over-expressed in leukemic patients and cell lines We localized several conserved non-coding elements containing multiple erythroid specific transcription factor binding sites at the GFI1B locus. In GFI1B-expressing cells a subset of these conserved non-coding elements and the promoter adopt a close spatial conformation, localize with open chromatin sites, harbor chromatin modifications associated with gene activation and bind multiple transcription factors and co-repressors Our findings indicate that GFI1B regulatory elements behave as activators and repressors To investigate the molecular effects of growth factor independence 1B (Gfi-1B), a transcription factor essential for the development of hematopoietic cells and differentiation of erythroid and megakaryocytic lineages Our data indicate that Gfi-1B signalling is important for commitment and maturation of hematopoietic cell populations Gfi-1 and Gfi-1b are homologous transcriptional repressors involved in diverse developmental contexts, including hematopoiesis and oncogenesis Gfi1b:green fluorescent protein knock-in mice reveal a dynamic expression pattern of Gfi1b during hematopoiesis that is largely complementary to Gfi1 We found highly dynamic expression patterns of Gfi1b in erythroid cells, megakaryocytes, and their progenitor cells (MEPS) where Gfi1 is not detected. Vice versa, Gfi1b could not be found in granulocytes, activated macrophages, or their granulomonocytic precursors (GMPs) or in mature naive or activated lymphocytes where Gfi1 is expressed, suggesting a complementary regulation of both loci during hematopoiesis Gfi1 and Gfi1b act equivalently in haematopoiesis our findings show that an intact SNAG domain is essential for all functions of Gfi1 and that Gfi1b can replace Gfi1 functionally in haematopoiesis Gfi-1 oncoproteins in hematopoiesis Recent gene targeting experiments and mutational screening in humans have revealed an essential role for Gfi-1 and Gfi-1B in hematopoiesis Gfi-1B disruption is embryonic lethal due to a block of erythropoiesis. Gfi-1B is required for both erythroid and megakaryocyte development Erythroid expansion mediated by the Gfi-1B zinc finger protein: role in normal hematopoiesis we identified that the expression of Gfi-1B (growth factor independence-1B) is highly restricted to hematopoietic stem cells, erythroblasts, and megakaryocytes These findings establish Gfi-1B as a novel erythroid regulator and reveal its specific involvement in the regulation of erythroid cell growth through modulating erythroid-specific gene expression The zinc-finger proto-oncogene Gfi-1b is essential for development of the erythroid and megakaryocytic lineages we establish that Gfi-1b is required for the development of two related blood lineages, erythroid and megakaryocytic, in mice Gfi-1b(-/-) embryonic stem cells fail to contribute to red cells of adult chimeras. Gfi-1b(-/-) embryos exhibit delayed maturation of primitive erythrocytes and subsequently die with failure to produce definitive enucleated erythrocytes Gfi-1b is an essential transcriptional regulator of erythroid and megakaryocyte development Growth factor independence 1b (GFI1B) is a DNA binding repressor of transcription with vital functions in hematopoiesis. Conversely, loss of gfi1b silences runx-1, c-myb, ikaros and cd41, indicating that gfi1b is required for definitive hematopoiesis. Gfi1b:green fluorescent protein knock-in mice reveal a dynamic expression pattern of Gfi1b during hematopoiesis that is largely complementary to Gfi1. Gfi1 and Gfi1b: key regulators of hematopoiesis. We show that gfi1aa and gfi1b are expressed in the primitive and definitive sites of hematopoiesis in zebrafish. Targeted gene disruption of GFI1B in mice leads to embryonic lethality resulting from failure to produce definitive erythrocytes, hindering the study of Gfi-1B function in adult hematopoiesis. Growth factor independence 1b (gfi1b) is important for the maturation of erythroid cells and the regulation of embryonic globin expression. Growth factor-independence 1b (Gfi1b) is a zinc finger transcription factor essential for erythroid and megakaryocytic development. Gfi1b (growth factor independence 1b) is a zinc finger transcription factor essential for development of the erythroid and megakaryocytic lineages. In fact, we demonstrate that VPA treatment is able to induce the expression of growth factor-independent protein 1B (GFI1B) and of mixed-lineage leukemia translocated to chromosome 3 protein (MLLT3), which are crucial regulators of erythrocyte and megakaryocyte differentiation, and that the up-regulation of these genes is mediated by the histone hyperacetylation at their promoter sites. Growth factor independence-1B (Gfi-1B) is a transcriptional repressor essential for erythropoiesis and megakaryopoiesis. Gfi-1B (growth factor independence-1B) gene is an erythroid-specific transcription factor, whose expression plays an essential role in erythropoiesis. Evidence that growth factor independence 1b regulates dormancy and peripheral blood mobilization of hematopoietic stem cells. We report here that adult mice conditionally deficient for the transcription Growth factor independence 1b (Gfi1b) show a significant expansion of functional HSCs in the bone marrow and blood. Growth factor-independence 1b (Gfi1b) is a zinc finger transcription factor essential for erythroid and megakaryocytic development Teleost growth factor independence (gfi) genes differentially regulate successive waves of hematopoiesis. Gfi-1B (growth factor independence-1B) gene is an erythroid-specific transcription factor, whose expression plays an essential role in erythropoiesis Our data indicate that Gfi-1B signalling is important for commitment and maturation of hematopoietic cell populations. We report here that adult mice conditionally deficient for the transcription Growth factor independence 1b (Gfi1b) show a significant expansion of functional HSCs in the bone marrow and blood

yes

56ed0ba22ac5ed1459000007

Has Revlimid been approved by the US Food and Drug Administration?

In the past decade, immunomodulatory drugs have been approved by the US Food and Drug Administration for the treatment of multiple myeloma (MM)-and a number of emerging agents that target the cellular pathways or proteins involved in the pathophysiology of MM are currently in development. Lenalidomide (Revlimid) and pomalidomide induce apoptosis and sensitize MM cells while demonstrating superior efficacy and better tolerability than thalidomide (Thalomid). In the past decade we have seen four new agents approved by the US Food and Drug Administration for treatment of multiple myeloma: the proteasome inhibitor (PI) bortezomib (Velcade), the immunomodulatory agents lenalidomide (Revlimid) and thalidomide (Thalomid), and liposomal doxorubicin. In the past decade we have seen four new agents approved by the US Food and Drug Administration for treatment of multiple myeloma: the proteasome inhibitor (PI) bortezomib (Velcade), the immunomodulatory agents lenalidomide (Revlimid) and thalidomide (Thalomid), and liposomal doxorubicin. Thalidomide, lenalidomide (Revlimid), and bortezomib (Velcade) are directed not only at MM cells but also at the BM milieu and have moved rapidly from the bench to the bedside and United States Food and Drug Administration approval to treat MM. Lenalidomide (CC-5013, Revlimid; Celgene Corporation, Summit, NJ), a thalidomide analogue, was granted approval by the U.S. Food and Drug Administration (FDA) on June 29, 2006, for use in combination with dexamethasone in patients with multiple myeloma (MM) who have received at least one prior therapy. Lenalidomide, an IMiD drug (a novel type of immunomodulating drug) was recently approved by the US Food and Drug Administration for the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes (MDS) and interstitial deletions of chromosome 5q [del(5q)] Lenalidomide, a second-generation immunomodulatory drug (IMiD), is approved by the US Food and Drug Administration for treatment of transfusion-dependent anemia in lower-risk MDS patients with deletion 5q chromosomal abnormality In the past decade we have seen four new agents approved by the US Food and Drug Administration for treatment of multiple myeloma: the proteasome inhibitor (PI) bortezomib (Velcade), the immunomodulatory agents lenalidomide (Revlimid) and thalidomide (Thalomid), and liposomal doxorubicin. lenalidomide (CC5103 or revlimid) are recently approved for the treatment of multiple myeloma. In the past decade, immunomodulatory drugs have been approved by the US Food and Drug Administration for the treatment of multiple myeloma (MM)-and a number of emerging agents that target the cellular pathways or proteins involved in the pathophysiology of MM are currently in development. Lenalidomide (Revlimid) and pomalidomide induce apoptosis and sensitize MM cells while demonstrating superior efficacy and better tolerability than thalidomide (Thalomid).

yes

56f1547c2ac5ed1459000010

Has single guide RNA been used on human cells?

We used a library containing 73,000 sgRNAs to generate knockout collections and performed screens in two human cell lines. Here we engineer this system to enable RNA-guided genome regulation in human cells by tethering transcriptional activation domains either directly to a nuclease-null Cas9 protein or to an aptamer-modified single guide RNA (sgRNA). The type II CRISPR/Cas system from Streptococcus pyogenes and its simplified derivative, the Cas9/single guide RNA (sgRNA) system, have emerged as potent new tools for targeted gene knockout in bacteria, yeast, fruit fly, zebrafish and human cells. Here we engineer this system to enable RNA-guided genome regulation in human cells by tethering transcriptional activation domains either directly to a nuclease-null Cas9 protein or to an aptamer-modified single guide RNA (sgRNA). Using synthetic single RNA guides, Cas9 can be reprogrammed to create specific double-stranded DNA breaks in the genomes of a variety of organisms, ranging from human cells to bacteria, and thus constitutes a powerful tool for genetic engineering. Here we engineer this system to enable RNA-guided genome regulation in human cells by tethering transcriptional activation domains either directly to a nuclease-null Cas9 protein or to an aptamer-modified single guide RNA (sgRNA).

yes

570a5c27cf1c325851000023

Is Fibroblast Growth Factor 23 a phosphaturic hormone?

PTH can induce skeletal synthesis of another potent phosphaturic hormone, fibroblast growth factor 23 (FGF23), Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that has recently been identified as a CKD-related factor affecting CRS. circulating phosphaturic hormone fibroblast growth factor-23 levels Fibroblast growth factor (FGF) 23 is one of the most recently discovered FGFs. This phosphaturic hormone produced in bones is a risk factor for cardiovascular diseases and thus mortality. fibroblast growth factor 23 (FGF23), a phosphaturic hormone and regulator of 1,25(OH)2 vitamin D3 (1,25VitD3). fibroblast growth factor-23 (FGF23), a bone-derived phosphaturic hormone. the phosphaturic hormone fibroblast growth factor 23 (FGF23) and soluble Klotho with all-cause mortality. In particular, diseases caused by changes in the expression and proteolytic control of the phosphaturic hormone fibroblast growth factor-23 (FGF23) have come to the forefront in terms of directing new models explaining mineral metabolism serum levels of a phosphaturic hormone, fibroblast growth factor 23 (Fgf23),

yes

56bb69d0ac7ad1001900000c

Is amoxicillin used for treatment of malnutrition in children?

Another RCT did not show superiority of ceftriaxone over amoxicilllin for these same outcomes, but adressed SAM children with and without complications (p = 0.27). Another RCT showed no difference between amoxicillin and cotrimoxazole efficacies for pneumonia in underweight, but not SAM. Our meta-analysis of 12 pooled susceptibility-studies for all types of bacterial isolates, including 2767 stricly SAM children, favoured amoxicillin over cotrimoxazole for susceptibility medians: 42% (IQR 27-55%) vs 22% (IQR 17-23%) and population-weighted-means 52.9% (range 23-57%) vs 35.4% (range 6.7-42%). Susceptibility-studies favour amoxicillin over cotrimoxazole. Oral amoxicillin for 5 days was as effective as intramuscular ceftriaxone for 2 days (1 RCT). For uncomplicated SAM, amoxicillin showed no benefit over placebo (1 retrospective study). Children who took amoxicillin and de-worming had 95% (HR = 1.95, 95%-CI = 1.17, 3.23) and 74% (HR = 1.74, 95%-CI = 1.07, 2.83) more probability to recover from SAM as compared to those who didn't take them. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned Malawian children, 6 to 59 months of age, with severe acute malnutrition to receive amoxicillin, cefdinir, or placebo for 7 days in addition to ready-to-use therapeutic food for the outpatient treatment of uncomplicated severe acute malnutrition. In the amoxicillin, cefdinir, and placebo groups, 88.7%, 90.9%, and 85.1% of the children recovered, respectively (relative risk of treatment failure with placebo vs. amoxicillin, 1.32; 95% confidence interval [CI], 1.04 to 1.68; relative risk with placebo vs. cefdinir, 1.64; 95% CI, 1.27 to 2.11). The mortality rates for the three groups were 4.8%, 4.1%, and 7.4%, respectively (relative risk of death with placebo vs. amoxicillin, 1.55; 95% CI, 1.07 to 2.24; relative risk with placebo vs. cefdinir, 1.80; 95% CI, 1.22 to 2.64). Evaluation of the routine use of amoxicillin as part of the home-based treatment of severe acute malnutrition. OBJECTIVE: To determine whether the inclusion of amoxicillin correlates with better recovery rates in the home-based treatment of severe acute malnutrition with ready-to-use therapeutic food. The standard protocol group received a 7-day course of amoxicillin at the onset of treatment. RESULTS: Four hundred and ninety-eight children were treated according to the standard protocol with amoxicillin, and 1955 were treated under the alternate protocol without antibiotics. The recovery rate for children who received amoxicillin was worse at 4 weeks (40%vs. 71%) but similar after up to 12 weeks of therapy (84%vs. 86%), compared to the children treated without antibiotics. CONCLUSIONS: This review of two therapeutic feeding programmes suggests that children with severe acute malnutrition who were treated without amoxicillin did not have an inferior rate of recovery. Treatment of severe malnutrition with 2-day intramuscular ceftriaxone vs 5-day amoxicillin. To determine whether the inclusion of amoxicillin correlates with better recovery rates in the home-based treatment of severe acute malnutrition with ready-to-use therapeutic food. Evaluation of the routine use of amoxicillin as part of the home-based treatment of severe acute malnutrition OBJECTIVE: To determine whether the inclusion of amoxicillin correlates with better recovery rates in the home-based treatment of severe acute malnutrition with ready-to-use therapeutic food. METHODS: This retrospective cohort study compared data from the treatment of two groups of children in Malawi aged 6-59 months with uncomplicated severe acute malnutrition. The recovery rate for children who received amoxicillin was worse at 4 weeks (40%vs. 71%) but similar after up to 12 weeks of therapy (84%vs. 86%), compared to the children treated without antibiotics. Regression modelling indicated that this difference at 4 weeks was most strongly associated with the receipt of amoxicillin. CONCLUSIONS: This review of two therapeutic feeding programmes suggests that children with severe acute malnutrition who were treated without amoxicillin did not have an inferior rate of recovery. CONCLUSIONS: This review of two therapeutic feeding programmes suggests that children with severe acute malnutrition who were treated without amoxicillin did not have an inferior rate of recovery.

yes

52e01f8f98d023950500000f

Is it possible to purify pseudopodia to be used for proteomic analysis?

we developed an approach to biochemically isolate the pseudopodium from the cell body using 3.0-micrometer porous filters for large-scale quantitative proteomic and phosphoproteomic analysis. Recent work using unique subcellular fractionation methodologies combined with spatial genomic, proteomic, and phosphoproteomic profiling has provided insight into the invadopodiome and pseudopodiome signaling networks ere, we purified the pseudopodial proteomes tumor cells were placed on a fibronectin-coated porous membrane to form pseudopodia. According to the motile potentials of the cells, the cells formed pseudopodial microprocesses in the pores. An excimer laser, which was used for ophthalmic refractive surgeries, horizontally ablated cells at the membrane surface to remove the cell body. we describe methods for the immunoaffinity purification of phosphotyrosine proteins (pY) from pseudopodia that have been isolated from migratory cells. These methods are compatible with current mass spectrometry-based protein identification technologies and can be utilized for the large-scale identification of the pseudopodium pY proteome in various migratory cell lines, including primary and cancer cells.

yes

55263a1898daae017c000001

Is farnesoid X receptor (FXR) a nuclear receptor?

Farnesoid X receptor (FXR) belongs to the ligand-activated nuclear receptor superfamily, and functions as a transcription factor regulating the transcription of numerous genes involved in bile acid homeostasis, lipoprotein and glucose metabolism Farnesoid X receptor (FXR) is an ascending target for metabolic and inflammatory diseases. As a nuclear receptor, FXR exhibits many physiological effects in transcription control of several genes. FXR is a member of the nuclear receptor superfamily which is also highly expressed in the liver. Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas Farnesoid X receptor (FXR, Nr1h4) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. the nuclear receptor farnesoid X receptor farnesoid X receptor (FXR), a nuclear receptor activated by bile acid ligands. T-β-MCA is an farnesoid X receptor (FXR) nuclear receptor antagonist, Farnesoid X receptor (FXR), a nuclear receptor (NR) and originally considered as a bile acid-activated transcriptional factor, The nuclear receptor farnesoid X receptor (FXR) plays a major role in the enterohepatic cycling of bile acids Liver X receptors, LXRs, are ligand-activated transcription factors that belong to the group H nuclear receptor (NR) superfamily. The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. ncluding those of nuclear receptors, primarily farnesoid X receptor (FXR), ile acids and their cognate nuclear receptor, FXR, Farnesoid X receptor (FXR, Nr1h4) and small heterodimer partner (SHP, Nr0b2) are nuclear receptors that are critical to liver homeostasis. he activation of the nuclear receptor farnesoid X receptor (FXRα) bile acid-activated nuclear receptor farnesoid X receptor (FXR) nuclear receptor signaling, notably by the farnesoid X receptor (FXR FXR (farnesoid X receptor, NRIH4), a nuclear receptor, plays a major role in the control of cholesterol metabolism. The role of the nuclear receptor FXR is unclear. nuclear receptor FXR a member of the nuclear receptor superfamily of ligand-activated transcription factors, Farnesoid X receptor (FXR) is a nuclear receptor that functions as a bile acid sensor controlling bile acid homeostasis.

yes

5319a752b166e2b806000027

Are DNA helicases involved in progeroid syndromes?

Among these syndromes, relevant advances have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases, Progeroid syndromes (PSs) constitute a group of disorders characterized by clinical features mimicking physiological aging at an early age. However, all the characterized PSs enter in the field of rare monogenic disorders and several causative genes have been identified. These can be separated in subcategories corresponding to (i) genes encoding DNA repair factors, in particular, DNA helicases, and (ii) genes affecting the structure or post-translational maturation of lamin A, a major nuclear component. None of the known progerias represents true precocious ageing. Some of them, including Werner (WS), Bloom (BS), and Rothmund-Thomson syndromes (RTS) as well as combined xeroderma pigmentosa-Cockayne syndrome (XP-CS) are characterised by features resembling precocious ageing and the increased risk of malignant disease. Such phenotypes result from the mutations of the genes encoding proteins involved in the maintenance of genomic integrity, in most cases DNA helicases. Single-gene mutations can produce human progeroid syndromes--phenotypes that mimic usual or "normative" aging. The prototypic example of the former is the Werner syndrome, a condition caused by mutations of the RecQ family of DNA helicases. Progeria and progeroid syndromes are characterized by the earlier onset of complex senescent phenotypes. WRN was originally identified as a gene responsible for Werner syndrome (WS; "Progeria of Adults"). The WRN gene product has RecQ-type helicase domains in the central region of the protein.

yes

56c1d85eef6e394741000035

Is there association of matrix metalloproteinases with behaviour of pituitary adenomas?

While detailed histological subtyping remains the best independent predictor of aggressive behavior in the majority of cases, evidence suggests that the additional analyses of FGFR4, MMP, PTTG, Ki-67, p53, and deletions in chromosome 11 may contribute to decisions concerning management of aggressive pituitary adenomas. We observed elevation of MMP-2 and -9 expression and consequent 3-D cell invasion in cells under-expressing RECK. Based on the significance of matrix metalloproteinases (MMPs) for tumor growth and angiogenesis, we have studied the effect of batimastat (BB-94), a synthetic MMPs inhibitor (MMPI) on the progression of prolactin-secreting pituitary adenoma in rats. Inhibition of estrogen-induced pituitary tumor growth and angiogenesis in Fischer 344 rats by the matrix metalloproteinase inhibitor batimastat. The results of our study provide evidence for an inhibitory effect of batimastat, a synthetic MMPI, on the growth and angiogenesis in an experimental model of human prolactinoma. In summary, the differential expression of extracellular matrix components, integrins and matrix metalloproteinase contributes to the control of pituitary hormone production and cell proliferation during tumorigenesis. Data on the dural invasiveness of pituitary adenomas have been correlated to the expression of matrix metalloproteinases (e.g. MMP-9). We found no correlation of MMP-9 expression and tumour invasion. The matrix metalloproteinases (MMPs) and their nature inhibitors-the tissue inhibitors of metalloproteinases (TIMPs) may play a central role in these processes. CONCLUSIONS: TIMP-1 and TIMP-2 may play a key role in invasive pituitary adenomas to biological behavior. The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that are able to degrade the extracellular matrix and allow angiogenesis and tumor invasion. MMP-9 expression did not differ between noninvasive tumors and normal pituitary gland, or between different sized prolactinomas. MMP-9 expression was related to aggressive tumor behavior. It was higher in invasive macroprolactinomas (P = 0.003) when compared with noninvasive macroprolactinomas or the normal anterior pituitary gland. In addition, although there was no difference in whether MMP-9 was present or not when nonfunctioning adenomas that recurred were compared with those that did not, samples of recurrent tumor at the second presentation were more likely to express MMP-9 (P = 0.01). Pituitary carcinomas were significantly more likely to be MMP-9 positive compared with normal anterior pituitary gland (P = 0.05), but there was no difference from invasive adenomas. Angiogenesis assessed by vascular density was related to MMP-9 expression (P<0.05). In summary, we have shown the presence of MMP-9 expression in some invasive and recurrent pituitary adenomas, and in the majority of pituitary carcinoma. The mechanisms whereby MMP-9 expression influences tumor recurrence and invasiveness, and its association with angiogenesis, remains to be elucidated. Beside the digestion of the extracellular matrix during tumor invasion and metastasis, more recently, new functions for matrix metalloproteinases (MMPs) have been proposed. CONCLUSION: No correlation could be established between the invasive potential of tumors and MMP-1, -2, and -3 expression levels. Matrix metalloproteinase 2 and 9 expression correlated with cavernous sinus invasion of pituitary adenomas. Data on the dural invasiveness of pituitary adenomas have been correlated to the expression of matrix metalloproteinases (e.g. We found surprisingly high levels of MMP activity and low levels of tissue inhibitor of metalloproteinases, indicating a high level of extracellular matrix-degrading activity in pituitary adenomas. The matrix metalloproteinases (MMPs) and their nature inhibitors-the tissue inhibitors of metalloproteinases (TIMPs) may play a central role in these processes. We found surprisingly high levels of MMP activity and low levels of tissue inhibitor of metalloproteinases, indicating a high level of extracellular matrix-degrading activity in pituitary adenomas. There was an association between the invasion of pituitary adenomas and Ki-67 LI (P = 0.039) or the expression of VEGF (P &lt; 0.001) and MMP-9 (P &lt; 0.001). But c-myc LI and bcl-2 expression have no association with invasiveness of pituitary adenomas (P = 0.061 vs. nm23 and MMP-9 have associations with invasiveness of pituitary adenomas, Matrix metalloproteinase secreted by pituitary cells can release growth factors from the extracellular matrix that, in turn, control pituitary cell proliferation and hormone secretion. In summary, the differential expression of extracellular matrix components, integrins and matrix metalloproteinase contributes to the control of pituitary hormone production and cell proliferation during tumorigenesis. There was an association between the invasion of pituitary adenomas and Ki-67 LI (P = 0.039) or the expression of VEGF (P &lt; 0.001) and MMP-9 (P &lt; 0.001). Although our study has shown that MVD and the expression of VEGF, Ki-67, nm23 and MMP-9 have associations with invasiveness of pituitary adenomas, they are lack of specificity.

yes

515def40298dcd4e51000028

Is Vitamin D deficiency in pregnant women associated with gestational diabetes?

Insufficient serum levels of 25-OHD were associated with gestational diabetes (pooled odds ratio 1.49, 95% confidence interval 1.18 to 1.89 Vitamin D insufficiency is associated with an increased risk of gestational diabetes, p Therefore, it is important to identify potentially modifiable risk factors for GDM. Accumulating evidence links vitamin D deficiency with abnormal glucose metabolism, and epidemiological studies have shown that women who develop GDM are more likely to be vitamin D deficient This review discusses the prevalence, risk factors, and outcomes of GDM and vitamin D deficiency in pregnant women, outlines the possible mechanism of action of vitamin D in glucose homeostasis, and summarizes emerging evidence that associates vitamin D deficiency with the risk of developing GDM Women with circulating 25-hydroxyvitamin D [25(OH)D] level less than 50 nmol/l in pregnancy experienced an increased risk of preeclampsia [OR 2.09 (95%CI 1.50 -2.90)], gestational diabetes mellitus [OR1.38 (1.12-1.70)] Low maternal vitamin D levels in pregnancy may be associated with an increased risk of preeclampsia, gestational diabetes mellitus, Association between vitamin D insufficiency and the risk for gestational diabetes mellitus in pregnant Chinese women 25OHD insufficiency is very common in Chinese women. Low 25OHD status may be associated with insulin resistance and act as a risk factor for GDM. Second-trimester 25(OH)D levels were associated inversely with glucose levels after 1-hour 50-g glucose challenge test; low 25(OH)D levels may be associated with increased risk of GDM. Two hundred sixty-six women were screened. Vitamin D deficiency (25[OH]D <20 ng/mL) was observed in 157 women (59%). We observed an inverse correlation between 25(OH)D levels and hemoglobin A1c, homeostasis model assessment of insulin resistance, serum insulin, and fasting and 1-hour oral glucose tolerance test glucose levels Lower 25(OH)D levels are associated with disorders of glucose homeostasis and adverse obstetric and newborn outcomes. An association between mid-gestational 25-hydroxy vitamin D and fasting glucose was confirmed in a largely normoglycaemic and vitamin D-replete pregnant population. The correlation between 25-hydroxy vitamin D and β-cell function suggests that vitamin D may influence glucose metabolism through this mechanism. Women with gestational diabetes had significantly lower serum 25-hydroxyvitamin D compared with control subjects (56.3 vs. 62.0 nmol/l, P = 0.018). After adjusting for gestational age and maternal weight, serum 25-hydroxyvitamin D below the top quartile (< 73.5 nmol/l) was associated with a twofold greater likelihood of gestational diabetes (adjusted odds ratio 2.21, 95% confidence interval 1.19-4.13). CONCLUSIONS: Lower vitamin D status in early pregnancy was associated with a significantly increased risk of subsequent gestational diabetes that was independent of race, age, season and maternal weight. This study suggests that vitamin D may influence glucose tolerance during pregnancy Vitamin D deficiency among pregnant women is frequent in many populations over the world. It is associated with an increased risk of preeclampsia, gestational diabetes mellitus, and caesarean section Consequences in newborns are low birth weight, neonatal rickets, a risk of neonatal hypocalcemia, asthma and/or type 1 diabetes. A single injection of 300,000 IU of vitamin D3 achieves a 3-month serum 25-hydroxyvitamin D range of 50-80 nmol/l and is an efficient, effective and safe procedure for improving the vitamin status and indices of insulin resistance in mothers with gestational diabetes after delivery. In a cohort of pregnant women with mostly sufficient levels of serum 25(OH)D, vitamin D deficiency was not associated with GDM. The aim of the study is evaluating the associations of FokI vitamin D receptor (VDR) gene polymorphisms with gestational diabetes mellitus (GDM), and its relations with postpartum metabolic syndrome. Our results indicate a meaningful association between FokI VDR genotypes and an increase risk of GDM in Iranian population as well as its effects on postpartum metabolic syndrome. The first-trimester maternal serum level of 25(OH)D is not altered in women with type 2 diabetes, those who develop GDM or those who deliver LGA neonates. Lower 25(OH)D levels are independently associated with poorer glycaemic control. Future randomised trials are needed to determine whether vitamin D plays a role in glycaemic control in GDM. These results suggested that rates of vitamin D deficiency are higher among women with IGT/GDM, and the relationship between vitamin D status and glucose tolerance in pregnancy needs further study. It appears that vitamin D insufficiency during pregnancy is potentially associated with increased risk of preeclampsia, insulin resistance and gestational diabetes mellitus Mean serum 25OHD concentration was 53.8 +/- 23.9 nmol/l (sd). Ln-25OHD was negatively correlated with serum parathyroid hormone as expected (r -0.24, confidence intervals -0.35 to -0.12). Ln-25OHD was also negatively correlated with fasting plasma glucose (r-0.20, -0.31 to -0.08), fasting insulin (r -0.20, -0.31 to -0.08) and insulin resistance as calculated by homeostasis model assessment (r -0.21, -0.32 to -0.09). The association between fasting glucose and log-transformed 25OHD concentration was of borderline significance after accounting for ethnicity, age and body mass index in multivariate analyses (-0.13, -0.26 to 0.01). The odds ratio of gestational diabetes in women with 25OHD < 50 nmol/l did not reach statistical significance (1.92, 95% confidence interval 0.89-4.17). CONCLUSIONS: Maternal 25OHD concentrations are inversely related to fasting glucose, although further studies are required to establish whether this is independent of the effects of ethnic background. Vitamin D insufficiency is common in Indian mothers but is not associated with gestational diabetes or variation in newborn size. There was no association between maternal 25(OH)D and gestational diabetes (incidence 7% in women with and without hypovitaminosis D) In mothers with hypovitaminosis D, higher 25(OH)D concentrations were associated with lower 30-min glucose concentrations (P=0.03) and higher fasting proinsulin concentrations (P=0.04) Hypovitaminosis D at 30 weeks gestation is common in Mysore mothers. It is not associated with an increased risk of gestational diabetes, Total prevalence of vitamin D deficiency (<25 nmol/L) was found in 70.6% of pregnant women. Prevalence of severe vitamin D deficiency (<12.5) in GDM patients was higher than in normoglycaemic pregnancies. These results show that a positive correlation of 25(OH) vitamin D concentrations with insulin sensitivity and vitamin D deficiency could be a confirmative sign of insulin resistance. was to examine whether maternal dietary intake of vitamin D, omega-3 fatty acids, and omega-6 fatty acids during pregnancy is associated with the appearance of islet autoimmunity (IA) in offspring Maternal intake of vitamin D via food was significantly associated with a decreased risk of IA appearance in offspring, independent of HLA genotype, family history of type 1 diabetes, presence of gestational diabetes mellitus, and ethnicity (adjusted HR = 0.37; 95% CI 0.17-0.78). Vitamin D intake via supplements, omega-3 fatty acids, and omega-6 fatty acids intake during pregnancy were not associated with appearance of IA in offspring. CONCLUSIONS: Our findings suggest that maternal intake of vitamin D through food during pregnancy may have a protective effect on the appearance of IA in offspring.

yes

52ef6da1c8da898910000011

Does Chromatin Immunoprecipitation (ChIP) show a bias for highly expressed loci?

However, several issues in the processing and analysis of ChIP-chip data have not been resolved fully, including the effect of background (mock control) subtraction and normalization within and across arrays Proper normalization is essential for ChIP-chip experiments. The proposed normalization technique can correct systematic errors and compensate for the lack of mock control data, thus reducing the experimental cost and producing more accurate results. Subtraction of the mock (non-specific antibody or no antibody) control data is generally needed to eliminate the bias, but appropriate normalization obviates the need for mock experiments and increases the correlation among replicates The proposed method can handle several control samples allowing for correction of multiple sources of bias simultaneously However, the data generated will always contain noise due to e.g. repetitive regions or non-specific antibody interactions The generation of high copy numbers of DNA fragments as an artifact of the PCR step in ChIP-seq is an important source of bias of this methodology Here we describe several technical aspects of the ChIP-Seq assay that diminish bias and background noise and allow the consistent generation of high-quality data This theoretical paper systematically characterizes the biases and properties of ChIP-seq data by comparing 62 separate publicly available datasets, using rigorous statistical models and signal processing techniques We detected a chromatin-state bias: open chromatin regions yielded higher coverage, which led to false positives if not corrected This bias had a greater effect on detection specificity than any base-composition bias This problem turns out to be surprisingly difficult, even in simple pairwise comparisons, because of the significant level of noise in ChIP-seq data We show that the ChIPnorm method removes most of the noise and bias in the data and outperforms other normalization methods We investigated the impact of library amplification bias on the identification of allele-specific (AS) molecular events from high-throughput sequencing data derived from chromatin immunoprecipitation assays (ChIP-seq) The 238 loci, termed "hyper-ChIPable", were in highly expressed regions with strong polymerase II and polymerase III enrichment signals, and the correlation between transcription level and ChIP enrichment was not limited to these 238 loci but extended genome-wide The localization of unrelated proteins, including the entire silencing complex, to the most highly transcribed genes was highly suggestive of a technical issue with the immunoprecipitations

yes

5319ac18b166e2b806000030

Is clathrin involved in E-cadherin endocytosis?

We demonstrated that GnT-III induced a stabilizing effect on E-cadherin at the cell membrane by inducing a delay in the turnover rate of the protein, contributing for the formation of stable and functional adherens-junctions, and further preventing clathrin-dependent E-cadherin endocytosis. Conversely, GnT-V promotes the destabilization of E-cadherin, leading to its mislocalization and unstable adherens-junctions with impairment of cell-cell adhesion. Here we show that E-cadherin polarity is controlled by the polarized regulation of clathrin- and dynamin-mediated endocytosis. We delineate a pathway that controls the initiation of E-cadherin endocytosis through the regulation of AP2 and clathrin coat recruitment by E-cadherin. Clathrin dependent endocytosis of E-cadherin is regulated by the Arf6GAP isoform SMAP1 E-cadherin is a central component of the adherens junction in epithelial cells and continuously undergoes endocytosis via clathrin-coated vesicles and/or caveolae depending on the cell type. Collectively, SMAP1 likely represents a key Arf6GAP in clathrin dependent endocytosis of E-cadherin in MDCK cells. Consistent with these observations, we found that selective uncoupling of p120 from E-cadherin by introduction of amino acid substitutions in the p120-binding site increased the level of E-cadherin endocytosis. The increased endocytosis was clathrin-dependent, because it was blocked by expression of a dominant-negative form of dynamin or by hypertonic shock. We found that in this experimental system E-cadherin entered a transferrin-negative compartment before transport to the early endosomal compartment, where it merged with classical clathrin-mediated uptake pathways.

yes

533c3871c45e133714000007

Does splicing occur co-transcriptionally?

Researchers working in multiple model organisms - notably yeast, insects and mammalian cells - have shown that pre-mRNA can be spliced during the process of transcription (i.e. co-transcriptionally), as well as after transcription termination (i.e. post-transcriptionally) The consensus view, based on four organisms, is that the majority of splicing events take place co-transcriptionally in most cells and tissues. Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional We show that in the human genome, splicing occurs predominantly during transcription. Consistent with co-transcriptional spliceosome assembly and splicing, we have found significant enrichment of spliceosomal snRNAs in chromatin-associated RNA compared with other cellular RNA fractions and other nonspliceosomal snRNAs. The majority of introns in higher eukaryotes are excised prior to transcript release in a manner that is dependent on transcription through pol II s a result of co-transcriptional splicing, variations in pol II elongation influence alternative splicing patterns, wherein a slower elongation rate is associated with increased inclusion of alternative exons within mature mRNA. We show that the pattern of intronic sequence read coverage is explained by nascent transcription in combination with co-transcriptional splicing Modelling reveals co-transcriptional splicing to be the most probable and most efficient splicing pathway for the reporter transcripts, due in part to a positive feedback mechanism for co-transcriptional second step splicing RNA processing events that take place on the transcribed pre-mRNA include capping, splicing, editing, 3' processing, and polyadenylation. Most of these processes occur co-transcriptionally while the RNA polymerase II (Pol II) enzyme is engaged in transcriptional elongation Abundant evidence indicates that splicing to excise introns occurs co-transcriptionally, prior to release of the nascent transcript from RNAP II Together, our work establishes a system for co-transcriptional splicing in vitro, in which the spliceosome containing the 5' and 3' exons are tethered to RNAP II for splicing. Co-transcriptional splicing of constitutive and alternative exons Current evidence supports co-transcriptional spliceosomal assembly, but there is little quantitative information on how much splicing is completed during RNA synthesis Thus, we demonstrate that the decision to include or skip an alternative exon is made during transcription and not post-transcriptionally Here, we demonstrated that the co-transcriptional splicing of the intron in vitro was blocked by antisense oligonucleotides (AONs) targeting the P3-P7 core of the intron RNA editing and alternative splicing: the importance of co-transcriptional coordination Co-transcriptional splicing of pre-messenger RNAs: considerations for the mechanism of alternative splicing The realization that splicing occurs co-transcriptionally requires two important considerations

yes

515df5b2298dcd4e5100002c

Are there clinical trials on stem cells in multiple sclerosis

Cells are generally given intravenously. Multiple sclerosis, rheumatoid arthritis and lupus have been successfully treated in human clinical trials Human multipotent mesenchymal stem cell (MSC) therapies are currently being tested in clinical trials for Crohn's disease, multiple sclerosis, graft-versus-host disease, type 1 diabetes, bone fractures, cartilage damage, and cardiac diseases. Based on these results, several small pilot clinical trials in subjects with advanced MS have demonstrated that MSC administration is safe and provided an early signal of clinical effectiveness. The current aim of clinicians and scientists interested in the development of MSC-based strategies for the treatment of MS is to have the ultimate demonstration in large clinical trials that MSC can inhibit CNS inflammation and foster tissue repair Mesenchymal stem cells (MSC) promote functional recovery in experimental models of central nervous system (CNS) pathology and are currently being tested in clinical trials for stroke, multiple sclerosis and CNS injury. Autologous bone marrow stromal cells (BMSCs) offer significant practical advantages for potential clinical applications in multiple sclerosis (MS). Based on recent experimental data, a number of clinical trials have been designed for the intravenous (IV) and/or intrathecal (ITH) administration of BMSCs in MS patients. Fingolimod is a S1P receptor modulator in MS clinical trials due to systemic anti-inflammatory properties, yet may impact cells within the CNS by crossing the blood-brain barrier. Their development in vitro and their use in vivo in animal models of degenerative neurological disease and recent first efforts in human clinical trials were the topics of a recent international meeting sponsored by the Multiple Sclerosis International Federation and the National Multiple Sclerosis Society on "Stem Cells & MS: Prospects and Strategies" Here we discuss key observations and questions emerging from clinical trials of hematopoietic stem cell transplantation for MS Another possibility to achieve remyelination is the transplantation of myelinating cells into the central nervous system. Proof of principle and demonstration of the functionality were shown in numerous experiments, and a first clinical trial in patients with MS has started This first trial will show if cell transplantation is a feasible concept in MS and whether the transplanted cells will survive and form new myelin.

yes

56c6f6005795f9a73e000009

Are piRNAs involved in gene silencing?

In Drosophila ovaries, the nuclear Piwi protein is required for transcriptional silencing of transposons, though the precise mechanisms by which this occurs are unknown. Here we show that the CG9754 protein is a component of Piwi complexes that functions downstream of Piwi and its binding partner, Asterix, in transcriptional silencing. Enforced tethering of CG9754 to nascent messenger RNA transcripts causes cotranscriptional silencing of the source locus and the deposition of repressive chromatin marks. We have named CG9754 "Panoramix," and we propose that this protein could act as an adaptor, scaffolding interactions between the piRNA pathway and the general silencing machinery that it recruits to enforce transcriptional repression. piRNA-guided slicing of transposon transcripts enforces their transcriptional silencing via specifying the nuclear piRNA repertoire Caenorhabditis elegans piRNAs interact with both transposon and nontransposon mRNAs to initiate sustained silencing via the RNAi pathway. To assess the dysregulation of gene silencing caused by lack of piRNAs, we restored RNA silencing in RNAi-defective animals in the presence or absence of piRNAs. Thus, by reanimating RNAi, we uncovered a role for piRNAs in protecting essential genes from RNA silencing. In different organisms, small RNAs were shown to be implicated in the posttranscriptional degradation of mRNA and/or transcriptional repression of the homologous locus. In Drosophila, the mechanism of piRNA-mediated silencing is still far from being understood Analyses of piRNA-mediated transcriptional transposon silencing in Drosophila Transcriptional silencing implies a piRNA-mediated formation of repressive chromatin which diminishes the transcriptional capacity of the target locus. In mice, piRNA-guided transposon repression correlates with establishment of CpG DNA methylation on their sequences, yet the mechanism and the spectrum of genomic targets of piRNA silencing are unknown Using a candidate gene KD-approach, we identified differences in the spatio-temporal requirements of the piRNA pathway components for piRNA-mediated silencing. Spatio-temporal requirements for transposable element piRNA-mediated silencing during Drosophila oogenesis In contrast, piRNA-mediated silencing is strong in germline stem cells in which TE mobilization is tightly repressed ensuring the continued production of viable germline cysts. Piwi induces piRNA-guided transcriptional silencing and establishment of a repressive chromatin state. In germ cells, early embryos, and stem cells of animals, PIWI-interacting RNAs (piRNAs) have an important role in silencing retrotransposons, which are vicious genomic parasites, through transcriptional and post-transcriptional mechanisms. Our results show that the piRNA pathway can be used as a tool for sequence-specific gene silencing in germ cells and support the idea that the piRNA generating regions serve as traps for retrotransposons, enabling the host cell to generate piRNAs against active retrotransposons. Our observations confirm the pivotal role of piRNA-mediated silencing in defending the genome against selfish transposition, yet also suggest limits to the optimization of host genome defense. Analysis of piRNA-mediated silencing of active TEs in Drosophila melanogaster suggests limits on the evolution of host genome defense The Piwi-interacting RNA (piRNA) pathway defends animal genomes against the harmful consequences of transposable element (TE) infection by imposing small-RNA-mediated silencing. A novel organelle, the piNG-body, in the nuage of Drosophila male germ cells is associated with piRNA-mediated gene silencing. Proteins of the PIWI subfamily Aub and AGO3 associated with the germline-specific perinuclear granules (nuage) are involved in the silencing of retrotransposons and other selfish repetitive elements in the Drosophila genome. Telomeric retroelements HeT-A, TART and TAHRE, which are involved in telomere maintenance in Drosophila, are also the targets of piRNA-mediated silencing Mechanism of the piRNA-mediated silencing of Drosophila telomeric retrotransposons. Gene silencing mechanisms mediated by Aubergine piRNA complexes in Drosophila male gonad. The epigenetic trans-silencing effect in Drosophila involves maternally-transmitted small RNAs whose production depends on the piRNA pathway and HP1. Here, we show that mutations in squash and zucchini, which are involved in the piwi-interacting RNA (piRNA) silencing pathway, strongly affect TSE MVH in piRNA processing and gene silencing of retrotransposons piRNA-mediated silencing in Drosophila germlines. These have shed light not only on the molecular mechanisms of gene silencing mediated by piRNAs and PIWI proteins, but also on their intriguing relationship with cellular genes that have been shown to be important for gametogenesis and fertility. The most abundant piRNAs were those corresponding to antisense transcripts of Suppressor of Stellate [Su(Ste)] genes known to be involved in Stellate gene silencing To determine the capacity of piRNA-mediated silencing, we introduced reporter genes into Drosophila OSS cells, which express microRNAs (miRNAs) and piRNAs, and compared the Piwi pathway to the Argonaute pathway in gene regulation PIWI-interacting small non-coding RNAs (piRNAs) are genetic and epigenetic regulatory factors in germline cells, where they maintain genome stability, are involved in RNA silencing and regulate gene expression The piNG-body contains ribonucleoprotein complexes involved in piRNA-silencing of genome repeats including transposons in premeiotic spermatocytes with aid of short piRNAs Our results show that the piRNA pathway can be used as a tool for sequence-specific gene silencing in germ cells and support the idea that the piRNA generating regions serve as traps for retrotransposons, enabling the host cell to generate piRNAs against active retrotransposons Recent studies have revealed not only the biogenesis of piRNAs and their roles in transposon silencing, but also the function of the Piwi-piRNA pathway in epigenetic and post-transcriptional regulation of gene expression A growing number of studies on piRNAs have investigated piRNA-mediated gene silencing, including piRNA biogenesis These have shed light not only on the molecular mechanisms of gene silencing mediated by piRNAs and PIWI proteins, but also on their intriguing relationship with cellular genes that have been shown to be important for gametogenesis and fertility Telomeric retroelements HeT-A, TART and TAHRE, which are involved in telomere maintenance in Drosophila, are also the targets of piRNA-mediated silencing. MVH in piRNA processing and gene silencing of retrotransposons. To determine the capacity of piRNA-mediated silencing, we introduced reporter genes into Drosophila OSS cells, which express microRNAs (miRNAs) and piRNAs, and compared the Piwi pathway to the Argonaute pathway in gene regulation. Therefore piRNA-mediated transcriptional mode of silencing is involved in the control of retrotransposon expression in the Drosophila germline. Panoramix enforces piRNA-dependent cotranscriptional silencing. The most abundant piRNAs were those corresponding to antisense transcripts of Suppressor of Stellate [Su(Ste)] genes known to be involved in Stellate gene silencing. Our results indicate that piRNAs are involved in a posttranscriptional gene-silencing mechanism resulting in RNA nuclear accumulation.

yes

56ed08062ac5ed1459000005

Can RG7112 inhibit MDM2?

To assess the influence of the p53 regulatory pathway further, we studied the effect of RG7112, a small molecule MDM2 antagonist that activates p53 by preventing its interaction with MDM2, on normal megakaryocytopoiesis and platelet production. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. We report a proof-of-mechanism study of RG7112, a small-molecule MDM2 antagonist, in patients with chemotherapy-naive primary or relapsed well-differentiated or dedifferentiated MDM2-amplified liposarcoma who were eligible for resection. To assess the influence of the p53 regulatory pathway further, we studied the effect of RG7112, a small molecule MDM2 antagonist that activates p53 by preventing its interaction with MDM2, on normal megakaryocytopoiesis and platelet production. Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. RG7112 binds MDM2 with high affinity (K(D) ~ 11 nmol/L), blocking its interactions with p53 in vitro. RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. The effects of RG7112 and Peg-IFNα 2a on MPN progenitor cells were dependent on blocking p53-MDM2 interactions and activating the p53 pathway, thereby increasing MPN CD34(+) cell apoptosis The orally bioavailable MDM2 antagonist RG7112 and pegylated interferon α 2a target JAK2V617F-positive progenitor and stem cells Initial testing of the MDM2 inhibitor RG7112 by the Pediatric Preclinical Testing Program In this issue of Blood, Lu et al describe the cooperation between an orally bioavailable mouse double minute 2 (MDM2) antagonist (RG7112) and the pegylated interferon α (Peg-IFNα 2a) to target JAK2V617F hematopoietic progenitors and stem cells MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. The orally bioavailable MDM2 antagonist RG7112 and pegylated interferon α 2a target JAK2V617F-positive progenitor and stem cells. Initial testing of the MDM2 inhibitor RG7112 by the Pediatric Preclinical Testing Program. The primary endpoint was to assess markers of RG7112-dependent MDM2 inhibition and P53 pathway activation (P53, P21, MDM2, Ki-67, macrophage inhibitory cytokine-1 [MIC-1], and apoptosis). RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Treatment with low doses of RG7112, an orally available small-molecule inhibitor of p53-MDM2, both alone and combined with pegylated interferon α 2a (Peg-IFNα 2a), significantly decreased MPN colony-forming unit-granulocyte macrophage and burst-forming unit-erythroid numbers and preferentially eliminated the total number of JAKV617F(+) MPN hematopoietic progenitor cells. The effects of RG7112 and Peg-IFNα 2a on MPN progenitor cells were dependent on blocking p53-MDM2 interactions and activating the p53 pathway, thereby increasing MPN CD34(+) cell apoptosis. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts.

yes

532f08dcd6d3ac6a3400002a

Are there any specific antidotes for dabigatran?

Novel oral anticoagulants (NOACs)--apixaban, dabigatran, and rivaroxaban--have a significantly smaller risk of intracerebral hemorrhage (ICH). However, two facts make this situation complicated: First, the risk of hematoma expansion is unknown for NOACs. Second, there is no specific antidote for neither of the NOACs. However, many physicians are wary of these drugs, since there is limited evidence on how to manage bleeding in patients taking them, and since no specific antidote is known to reverse their anticoagulant effect. Given the absence of a specific antidote, the action to be taken in these situations must be defined. The fact that there is no specific antidote to reverse the anticoagulant action of the new anticoagulants can impair management of hemorrhagic complications; Unlike the vitamin K antagonist, i.e. warfarin, there is no specific antidote for these medications. The lack of guidelines, protocols, and an established specific antidote to reverse the anticoagulation effect of dabigatran potentially increases the rates of morbidity and mortality in patients with closed head injury (CHI). The novel oral anticoagulants (NOAC) dabigatran etexilat (Pradaxa®), rivaroxaban (Xarelto®) and apixaban (Eliquis®), also known as "direct" anticoagulants, act independently from antithrombin by inhibiting thrombin, as in the case of dabigatran, or by inhibiting factor Xa, as in the case of rivaroxaban and apixaban. It is assumed that they are suitable for long-term use and do not require laboratory monitoring. Nevertheless, clinical experience is very limited and caution rather than quick conclusions is necessary. Two major drawbacks are on the one hand the risk of drug accumulation in kidney and/or liver disease and, on the other hand, the lack of specific antidotes. NOA also have other unresolved problems: drug interactions are still possible, specific coagulation test to assess them must be developed, and no specific antidote is currently available in case of hemorrhagic complication. It is critical to identify and subsequently manage dabigatran etexilate toxicity because there is no specific antidote to reverse the drug's anticoagulant effects. In the absence of a specific antidote for this novel oral anticoagulant medication, even in an emergency situation, successful surgical treatment was possible with an aggressive use of available prohaemostatic agents. While these trial data are extremely encouraging, several practical issues (e.g., lack of specific antidote, safety of long-term treatment or cost-effectiveness in "real-life" clinical practice) still need to be elucidated. In case of massive bleeding, management is unclear and none of these newer agents has a specific antidote that completely reverses its anticoagulant effect. The short half-life of these new agents compensates for the lack of any specific antidote in many instances. As there is no specific antidote, the only treatment option is discontinuation of the drug and supportive management. Currently, none of these new agents has a specific antidote, and little advise can be given on how to manage a major bleeding event. Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity.

no

54fefbbc6ad7dcbc1200000a

Are there any Decision support systems for chronic pain management ?

a project to operationalize the 2003 VA/DOD Clinical Practice Guideline for Opioid Therapy for Chronic Non-Cancer Pain into a computerized decision support system (DSS) We based the DSS on the existing ATHENA-DSS Use of this iterative process led to development of a multifunctional DSS interactive decision dashboard format We created a computerized, interactive clinical decision dashboard Interactive decision dashboards can be adapted for clinical use and have the potential to foster informed decision making. Clinical decision support systems are promising tools for improving behavioral medicine care for chronic pain. Improving Patient Safety Using ATHENA-Decision Support System Technology: ATHENA-DSS is an automated decision support system developed in a collaboration between Stanford University and the U.S. Department of Veterans Affairs (VA) to increase guideline-adherent prescribing and to change physician behavior. The use of a computer-based decision support system facilitates primary care physicians' management of chronic pain. The use of a CBDS system may improve the ability of PCPs to manage chronic pain and may also facilitate screening of consults to optimize specialist utilization.

yes

516d5baa298dcd4e51000078

Does amiodarone affect thyroid hormone receptors in the myocardium?

AM and Dron affected TR expression in the RA similarly by decreasing TRalpha 1 and beta 1 expression by about 50% In the LVW, AM and Dron decreased TRbeta 1 and, interestingly, AM increased TRalpha 1. n the apex, AM also increased TRalpha 2. Both in treated and untreated mice, TRalpha2 mRNA had the highest density in mouse heart, whereas TRbeta2 mRNA had the lowest density. Amiodarone dose-dependently downregulated the levels of TRalpha1 and beta1 mRNA in comparison to the control. amiodarone subtype selectively downregulates the TR mRNA levels in mouse myocardium in a dose-dependent manner. Western blot analysis revealed no change in the expression of the ThR protein. Amiodarone and T3, respectively, downregulated T3R alpha 1, T3R beta 1, T3R beta 2 (p < 0.05), but did not affect the levels of T3R alpha 2. Amiodarone and T3, added together, upregulated T3R alpha 2 and T3R beta 1 (p < 0.05) as compared to amiodarone or T3 alone.

yes

52efc041c8da89891000001b

Does thyroid hormone affect cardiac remodeling?

The aim of this brief paper is to highlight new developments in understanding the cardioprotective role of thyroid hormone in reverting regulatory networks involved in adverse cardiac remodeling. Thyroid hormone receptor α1 (TRα1) is shown to be critical for the maturation of cardiomyocytes and for the cellular response to stress. TRα1 is altered during post ischemic cardiac remodeling but the physiological significance of this response is not fully understood. AMI induces downregulation of thyroid hormone signaling and pharmacological inhibition of TRα1 further depresses post-ischemic cardiac function. These findings reveal crucial roles for Dio3 in heart function and remodeling, which may have pathophysiologic implications for human restrictive cardiomyopathy. TH administration after AMI prevented tissue hypothyroidism and resulted in decreased beta-MHC expression, increased wall thickening and normalized wallstress, while stretch-induced p38 MAPK activation was increased. We conclude that diabetes exacerbates post-ischemic cardiac remodeling and that tissue hypothyroidism may be involved in this response. Thyroid hormone can favorably remodel the diabetic myocardium after acute myocardial infarction. It has been previously shown that regulators of physiological growth such as thyroid hormone (TH) can favorably remodel the post ischaemic myocardium. Acute myocardial infarction in diabetic rats results in TH receptor down-regulation with important physiological consequences. TH treatment prevents this response and improves cardiac hemodynamics. TH affects cardiac remodeling by limiting reperfusion injury, and, at later states, by inducing distinct changes in cardiac chamber geometry in a time-dependent manner. Furthermore, administration of TH can convert pathologic to physiologic hypertrophy. These effects are the result of favorable cellular remodeling. Thyroid hormone (TH) is critical in cardiac cell differentiation (regulating contractile proteins and cell geometry) and this effect could be potentially exploited therapeutically in reversing the process of de-differentiation which underlies postischemic cardiac remodeling. TH treatment partially reverses cardiac dysfunction in rats with old myocardial infarction by favorably changing cardiac chamber geometry and expression of myosin isoforms. Thyroid hormone, unlike current treatments, appears to be a paradigm of therapeutic intervention which aims at restoring cardiac geometry and may prove new effective treatment for heart failure. Changes in thyroid hormone (TH)-TH receptors (TRs) axis occur in the course of post-infarction cardiac remodeling and seem to contribute to cardiac fetal phenotype. TH can "rebuild" the post-infarcted heart by preventing the fetal-like pattern of contractile proteins expression, normalizing wall tension, and optimizing cardiac chamber geometry. TH, apart from its "classical" actions on cardiac contractility and heart rhythm, appears to regulate various intracellular signaling pathways related to stress responses and cardiac remodelling. More importantly, experimental and clinical studies demonstrate that TH can limit ischaemic injury, attenuate cardiac remodeling and improve cardiac hemodynamics. Thyroid hormone attenuates cardiac remodeling and improves hemodynamics early after acute myocardial infarction in rats. Thyroid hormone administration early after infarction attenuates cardiac remodeling and significantly improves myocardial performance. It has previously been shown that thyroid hormone can reverse cardiac remodeling in failing hearts by reducing myocardial wall stress due to the unique changes induced in cardiac myocyte shape.

yes

53353927d6d3ac6a34000043

Are there any HCV replication inhibitors available?

We report here the discovery of the first small-molecule HCV infectivity inhibitor, GS-563253, also called HCV infectivity inhibitor 1 (HCV II-1). Resistance to mericitabine (prodrug of HCV NS5B polymerase inhibitor PSI-6130) is rare and conferred by the NS5B S282T mutation. We tested the ability of NA808 to inhibit SPT's enzymatic activity in FLR3-1 replicon cells The SPT inhibitor NA808 prevents replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in cultured hepatocytes and in mice with humanized livers. Vaniprevir (phase III clinical trials) and MK-5172 (phase II clinical trials) are two potent antiviral compounds that target NS3/4A protease treatment for hepatitis C virus (HCV) infection has been significantly improved with the approval of the first two HCV NS3/4A protease inhibitors, telaprevir (Incivek) and boceprevir (Victrelis). Combination therapy with telaprevir and BMS-788329 (NS5A inhibitor) reduced serum HCV RNA to undetectable levels. The presence of an NS3-V36A telaprevir resistance mutation resulted in poor response to telaprevir monotherapy but showed significant HCV reduction when telaprevir was combined with BMS-788329. However, a BMS-788329-resistant strain emerged at low frequency. Infection with a BMS-788329-resistant NS5A-L31V mutation rapidly resulted in gain of an additional NS5A-Y93A mutation that conferred telaprevir resistance during combination therapy HCV NS5A replication complex inhibitors, exemplified by Daclatasvir (BMS-790052), represent a new class of DAA ACH-806 (or GS-9132) is a novel, small-molecule inhibitor specific for hepatitis C virus (HCV). Telaprevir and boceprevir are the first two protease inhibitor (PI) DAAs to be approved for combination therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV). symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed In vitro, boceprevir is more active than telaprevir against the HCV G3 NS3/4A enzyme in cell-based and biochemical assays and against G3 isolates in replicon assays Alisporivir is the most advanced host-targeting antiviral in clinical development. Alisporivir blocks HCV replication by neutralizing the peptidyl-prolyl isomerase activity of the abundant host cytosolic protein, cyclophilin A Interestingly, the NS5A inhibitor daclatasvir (BMS-790052) caused a decrease in serum HCV RNA levels by about two orders of magnitude within 6 h of administration

yes

511a4ec01159fa8212000004

Is miR-21 related to carcinogenesis?

miR-21* and miR-203 were significantly dysregulated (P < 0.05) in PTC tissues with BRAFV600E. Expressions of miRNAs in papillary thyroid carcinoma and their associations with the BRAFV600E mutation. Levels of miRNA-21 (miR-21) and miR-106a in gastric cancer tissues were significantly higher compared with the levels in adjacent tissues (P = .006 and P = .001, respectively). Patients who had gastric cancer had significantly different levels of gastric juice miR-21 and miR-106a compared with patients who had benign gastric diseases (both P < .001). miR-21 levels in intestinal type gastric cancer specimens were higher than that in diffuse (P = .003) or mixed (P < .001) gastric cancer types. MiR-155 and miR-21 appeared significantly over-expressed in the colonic mucosa of IBD subjects without CRC, but also in neoplastic tissues of IBD patients compared to non-IBD controls (p<0.001). Importantly, in patients with IBD-CRCs, miR-155 and miR-21 over-expression extended to the distant non-neoplastic mucosa (p<0.001). Here we hypothesize that over-expression of miR-155 and miR-21, two inflammation-related miRNAs that target core MMR proteins, may constitute a pre-neoplastic event for the development of MSI IBD-CRCs. After administration, we determined the expressions of miR-21, miR-27a, miR-34a, miR-93, miR-143, miR-146a, miR-148a, miR-155, miR-196a, miR-203, miR-205, miR-221 and nuclear factor kappa-light-chain enhancer of activated B-cells-1 (Nfκb1), mitogen-activated protein kinase-8 (Mapk8) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-ras) genes in the liver of mice. Programmed cell death 4 (PDCD4) is a tumor suppressor gene whose expression is controlled by miR-21. Consistently with PDCD4 downregulation, miR-21 was upregulated in neoplastic by comparison with nonneoplastic tissue samples. Expression of miR-21 (p=0.027), miR-181b (p=0.002), and miR-146b (p=0.021) in tumor tissue and miR-21 (p=0.003) in noncancerous tissue were associated with patients' overall survival. We analyzed the expression of nine miRNAs (miR-21, miR-127, miR-154, miR-224, miR-323, miR-370, miR-9*, miR-183, and miR-375) by quantitative real-time-polymerase chain reaction in 34 cases of sMTC, 6 cases of hMTC, and 2 cases of C-cell hyperplasia (CCH). MTC and CCH were both characterized by a significant overexpression of the whole set of miRNAs (the increase being 4.2-fold for miR-21, 6.7-fold for miR-127, 8.8-fold for miR-154, 6.6-fold for miR-224, 5.8-fold for miR-323, 6.1-fold for miR-370, 13-fold for miR-9*, 6.7-fold for miR-183, and 10.1 for miR-375, p<0.0001). The most frequent changes in miRNAs in CLL cells included downregulation of miR-126, miR-572, miR-494, miR-923, miR-638, miR-130a, miR-181a and miR-181b and up-regulation of miR-29a, miR-660, miR-20a, miR-106b, miR-142-5p, miR-101, miR-30b, miR-34a, miR-let-7f, miR-21 and miR-155. Results: MTC and CCH were both characterized by a significant overexpression of the whole set of miRNAs (the increase being 4.2-fold for miR-21, 6.7-fold for miR-127, 8.8-fold for miR-154, 6.6-fold for miR-224, 5.8-fold for miR-323 and 6.1-fold for miR-370, 13-fold for miR-9*, 6.7-fold for miR-183 and 10.1 for miR-375, p<0.0001). We found that the onco-miRNAs miR-21 and miR-221 displayed upregulated expression while the liver-specific miR-122 was downregulated. The aim of the present review was to describe the mechanisms of several known miR, summarize recent studies on oncogenic miR (e.g. miR-21, miR-106a and miR-17), tumor suppressor miR (e.g. miR-101, miR-181, miR-449, miR-486, let-7a) and controversial roles of miR (e.g. miR-107, miR-126) for gastric cancer. MiR-15b and miR-21 were differentially expressed in CSF samples from patients with gliomas, compared to control subjects with various neurologic disorders, including patients with primary CNS lymphoma and carcinomatous brain metastases. Moreover, inclusion of miR-15b and miR-21 in combined expression analyses resulted in an increased diagnostic accuracy with 90% sensitivity and 100% specificity to distinguish patients with glioma from control subjects and patients with primary CNS lymphoma. Many aberrantly expressed miRNAs were related to various cancers (e.g., miR-125b, hepatocellular carcinoma; miR-21, leukemia; miR-16, chronic lymphocytic leukemia; miR-192, pituitary adenomas; miR-199a-3p, ovarian cancer; miR-34a, pancreatic cancer). Several miRNAs (e.g., miR-34a, miR-21) and proteins (e.g., TGM2, NDRG2) that play crucial roles in liver tumorigenesis were first found to be affected by MC-LR in mouse liver. Except for miR-21 and miR-206, the expression levels of all miRNAs significantly changed during the progression of CaP. In addition, diet and carcinogen exposure modulated a number of microRNAs (miR-16, miR-19b, miR-21, miR26b, miR27b, miR-93, and miR-203) linked to canonical oncogenic signaling pathways. RESULTS: Elevated miR-21 (HR 2.06, 1.13-3.75), miR-17 (HR 2.00, 1.10-3.61), and miR-155 (HR 2.37, 1.27-4.42) was associated with worse cancer-specific mortality in the Maryland cohort. NF-κB targets miR-16 and miR-21 in gastric cancer: involvement of prostaglandin E receptors. Expression of miR-21, miR-29b, miR-34a/b/c, miR-155, and let-7a was determined by quantitative real-time PCR in formalin-fixed paraffin-embedded tumor specimens from 639 IALT patients. hese two miRNAs have previously been identified as being overexpressed in MCF-7 breast cancer cells, with miR-21 specifically implicated in down-regulating the tumor suppressor gene, tropomyosin-1. MicroRNA-21 is involved in ionizing radiation-promoted liver carcinogenesis. We showed here that among several hundred miRNAs, miR-21 was the only one that increased 6 folds in high-LET IR-promoted mouse liver tumors when compared with that in the non-irradiated liver tissues. We also showed that miR-21 was up-regulated in human or mouse hepatocytes after exposure to IR, as well as in liver tissues derived from whole body irradiated mice. After the non-irradiated, low-LET or high-LET irradiated human hepatocytes were over-expressed with miR-21, these cells became tumorigenesis in nude mice. METHODS: We used this combined ISH/IHC assay to study a subset of cancer-associated miRNAs, including miRNAs frequently detected at low (miR-34a and miR-126) and high (miR-21 and miR-155) levels, in a panel of breast, colorectal, lung, pancreas, and prostate carcinomas. The miR-15a, miR-16, miR-143, miR-155, and miR-21 were upregulated in M059K, and the modulation of these miRNAs fluctuated in M059J cells in a time-dependent manner. Aberrantly increased expression of miR-21 plays a significant role in lung carcinogenesis and is a potential therapeutic target in both epidermal growth factor receptor-mutant and wild-type cases. Additionally, high miR-21 expression was associated with significantly decreased 5 year survival in patients (hazard ratio, 1.68; 95% CI: 1.04-2.77) in a model controlled for patient age, gender and tumor stage. ESULTS: In adenocarcinoma patients, miR-21, miR-223, miR-192, and miR-194 expression was elevated, whereas miR-203 expression was reduced in cancerous compared with noncancerous tissue. Significantly, elevated miR-21 expression in noncancerous tissue of SCC patients and reduced levels of miR-375 in cancerous tissue of adenocarcinoma patients with Barrett's were strongly associated with worse prognosis. miR-21, mir-31, miR-130a, miR-146b and miR-377 were consistently upregulated, whereas miR-1 and miR-143 were downregulated in lung tumors relative to normal lungs. In mice treated with VC and given I3C in the diet, levels of miR-21, mir-31, miR-130a, miR-146b and miR-377 were reduced relative to the level in mice treated with the carcinogen only. Further studies with miR-21 indicated that phosphatase and tensin homolog, programmed cell death 4 and rich protein with Kazal motifs are potential targets for the oncogenic effect of miR-21 and the chemopreventive activity of I3C. This study examines the potential clinical utility of an inflammatory gene expression signature as a prognostic biomarker for colon cancer in addition to previously examined miR-21 expression. CONCLUSIONS: IRS and miR-21 expression are independent predictors of colon cancer prognosis and may provide a clinically useful tool to identify high-risk patients. The most highly expressed miRNAs in gastric cancer tissues were miR-20b, miR-20a, miR-17, miR-106a, miR-18a, miR-21, miR-106b, miR-18b, miR-421, miR-340*, miR-19a and miR-658. Recent findings report their involvement in hair follicle morphogenesis (ablation of miRNAs from keratinocytes causes several defects, such as evagination instead of invagination), in psoriasis (skin-specific expression of miR-203 and psoriasisspecific expression of miR-146a, miR-21 and miR-125b in the skin), in autoimmune diseases affecting the skin, such as SLE and ITP, in wound healing (changes in the expression of specific miRNA at specific phases of the regeneration process), and in skin carcinogenesis (a novel miRNA signature that includes induction of miR-21, a candidate oncogenic miRNA). RESULTS: Several microRNAs were differentially expressed in serous ovarian carcinoma compared with normal ovarian tissues, including miR-21, miR-125a, miR-125b, miR-100, miR-145, miR-16, and miR-99a, which were each differentially expressed in >16 patients. Selected for validation were miR-20a, miR-21, miR-106a, miR-181b, and miR-203, and all 5 were enriched in tumors from the validation cohort (P < .001). Higher miR-21 expression was present in adenomas (P = .006) and in tumors with more advanced TNM staging (P < .001). In situ hybridization demonstrated miR-21 to be expressed at high levels in colonic carcinoma cells. To test this hypothesis, we studied the pharmacologic roles of three microRNAs previously implicated in cancer biology (let-7i, mir-16, and mir-21) and also used in silico methods to test pharmacologic microRNA effects more broadly. Changing the cellular levels of let-7i, mir-16, and mir-21 affected the potencies of a number of the anticancer agents by up to 4-fold. The effect was most prominent with mir-21, with 10 of 28 cell-compound pairs showing significant shifts in growth-inhibitory activity. Varying mir-21 levels changed potencies in opposite directions depending on compound class; indicating that different mechanisms determine toxic and protective effects. In silico comparison of drug potencies with microRNA expression profiles across the entire NCI-60 panel revealed that approximately 30 microRNAs, including mir-21, show highly significant correlations with numerous anticancer agents. Conversely, expression of other miRNAs was detected at varying levels predominantly within luminal epithelial cells in normal tissue; expression of miR-21 was frequently increased, whereas that of let-7a was decreased in malignant cells. We describe a novel EMT-specific microRNA signature that includes induction of miR-21, a candidate oncogenic microRNA associated with carcinogenesis. Notable was the high expression of miR-21 and miR-205. Recently, microRNAs (miRNAs) have emerged as key actors in carcinogenesis and we demonstrated that microRNA-21 (miR-21), oncomiR is expressed early during PDA. These results indicated that miR-21 plays a role in the carcinogenesis and metastasis of O. viverrini-associated CCA by suppressing the function of PDCD4. Importantly, in patients with IBD CRCs, miR-155 and miR-21 overexpression extended to the distant non-neoplastic mucosa (P < 0.001). Ectopic overexpression of miR-21 promoted Akt activation and phosphorylation of EZH2, whereas inhibiting miR-21 by transfecting the cells with anti-miR-21 inhibited Akt activation and EZH2 phosphorylation. PDCD4 nuclear down-regulation (which parallels miR-21 up-regulation) is involved in the molecular pathway of IBD-associated carcinogenesis. The expression levels of miR-21 (p = 0.027), miR-181b (p = 0.002) and miR-146b (p = 0.021) in tumor tissue and miR-21 (p = 0.003) in noncancerous tissue were associated with overall survival of patients. OBJECTIVE: As an important oncogenic miRNA, miR-21 has been reported to play crucial roles in glioblastoma (GBM) carcinogenesis. We further analyzed the expression of microRNA-21 (miR-21), an oncogenic noncoding RNA involved in oncogenic Ras signaling, by quantitative reverse-transcription polymerase chain reaction and in situ hybridization. MicroRNA-21 (miR-21) plays crucial roles in carcinogenesis and is considered as one of the most studied oncomiRNAs. Although microRNA-21 (miR-21) has been implicated in various aspects of carcinogenesis, its functions and molecular mechanisms in carcinogen-induced tumorigenesis are unclear. Substantial evidence indicates that microRNA-21 (miR-21) is a key oncomiR in carcinogenesis and is significantly elevated in multiple myeloma (MM). MicroRNA 21 (miR-21) has been implicated in various aspects of carcinogenesis. Conversely, pAkt and miR-21 expression was significantly up-regulated in the whole spectrum of preneoplastic/neoplastic lesions considered. Several miRNAs (e.g., miR-34a, miR-21) and proteins (e.g., TGM2, NDRG2) that play crucial roles in liver tumorigenesis were first found to be affected by MC-LR in mouse liver. RESULTS: Except for miR-21 and miR-206, the expression levels of all miRNAs significantly changed during the progression of CaP. MicroRNA 21 (miR-21) is overexpressed in virtually all types of carcinomas and various types of hematological malignancies. As expected, miR-21 expression was significantly upregulated in preneoplastic/neoplastic samples, consistent with PDCD4 downregulation. Furthermore, miR-21 levels in the primary tumours correlated with disease stage (P < 0.0001). We found that miR-16 and miR-21 were upregulated upon nicotine stimulation, transfection with anti-miR-16 or anti-miR-21 significantly abrogated cell proliferation. MicroRNA-21 (miR-21) is a unique miRNA in that it is overexpressed in most tumour types analysed so far. Although altered expressions of miR-21 and miR-34a were manifested within cancer cells, those of miR-126 and miR-155 were predominantly confined to endothelial cells and immune cells, respectively. However, the function of miR-21 in osteosarcoma is still unclear. In SCC patients, we found elevated miR-21 and reduced miR-375 expression levels in cancerous compared with noncancerous tissue. miR-21, mir-31, miR-130a, miR-146b and miR-377 were consistently upregulated, whereas miR-1 and miR-143 were downregulated in lung tumors relative to normal lungs. Precancerous adenomas also frequently showed miR-21 up-regulation. Higher miR-21 expression was present in adenomas (P = .006) Importantly, the inflammatory ZD esophagus had a distinct microRNA signature resembling human ESCC or tongue SCC miRNAomes with miR-31 and miR-21 as the top-up-regulated species. Several miRNAs have been recently reported to be involved in modulation of glioma development, especially some upregulated miRNAs, such as microRNA-21 (miR-21), which has been found to function as an oncogene in cultured glioblastoma multiforme cells. OBJECTIVE: MicroRNA-21 (miR-21) is one of the miRNAs that are frequently and highly overexpressed in tumor tissue of colorectal cancer (CRC) patients; however, only a little is known about its functional role in CRC. Inhibition of microRNA-21 (mir‑21) induced upregulation of Spry2 and PTEN which underscores the importance of mir-21 in Spry2-associated tumorigenesis of the colon. The microRNA miR-21, a known oncogenic miRNA, was found to be upregulated in papillary and clear cell carcinomas. Since microRNA-21 (miR-21) may contribute to tumorigenesis and chemoresistance in many cancer types, we aimed to investigate its efficacy in TCCs. Several miRNAs have been recently reported to be involved in modulation of glioma development, especially some up-regulated miRNAs, such as microRNA-21 (miR-21), which has been found to function as an oncogene in cultured glioblastoma multiforme cells. In this study, by using high-throughput microRNA profiling, we identified that two miRNAs (miR-21 and miR-148a) overexpressed in CD4+ T cells from both patients with lupus and lupus-prone MRL/lpr mice, which promote cell hypomethylation by repressing DNA methyltransferase 1 (DNMT1) expression. The microRNA-21 (miR-21) has been identified as the only miRNA overexpressed in a variety of cancers, including leukemia. OBJECTIVE: The contribution of overexpressed microRNA-21 and -221 (miR-21 and miR-221) to the malignant phenotype was determined by inhibiting these miRNAs using antisense oligonucleotides. The microRNA-21(miR-21) has been identified as the only miRNA over-expressed in a wide variety of cancers, including cervical cancer. To determine the functions of these microRNAs in lymphomagenesis, we examined the effects of antisense oligonucleotides (ASOs) targeting miR-21 (ASO-21) and/or miR-155 (ASO-155) in NK-cell lymphoma lines overexpressing one or both of these miRNAs. In this study, microRNA (miRNA) expression profiling of 28 cases of never-smoker lung cancer identified aberrantly expressed miRNAs, which were much fewer than in lung cancers of smokers and included miRNAs previously identified (e.g., up-regulated miR-21) and unidentified (e.g., down-regulated miR-138) in those smoker cases. The oncogenic miRNA, microRNA-21 (miR-21), was found to be upregulated in laryngeal carcinoma tissues. OBJECTIVE: To better understand microRNA miR-21 function in carcinogenesis, we analyzed miR-21 expression patterns in different stages of colorectal cancer development using in situ hybridization (ISH). Of these miRNAs, miR-21 appears to be important in tumorigenesis given its up-regulation in almost all types of human cancer examined. The microRNA-21 gene (mir-21) has been identified as the only miRNA commonly overexpressed in solid tumors of the lung, breast, stomach, prostate, colon, brain, head and neck, esophagus and pancreas. RESULTS: Our data showed that a common pattern of microRNA expression distinguishes any tumor type from normal pancreas, suggesting that this set of microRNAs might be involved in pancreatic tumorigenesis; the expression of miR-103 and miR-107, associated with lack of expression of miR-155, discriminates tumors from normal; a set of 10 microRNAs distinguishes endocrine from acinar tumors and is possibly associated with either normal endocrine differentiation or endocrine tumorigenesis; miR-204 is primarily expressed in insulinomas and correlates with immunohistochemical expression of insulin; and the overexpression of miR-21 is strongly associated with both a high Ki67 proliferation index and presence of liver metastasis. To search for tumor-associated mutations that could affect processing and expression of mature miRNAs, a panel of 91 cancer-derived cell lines was analyzed for sequence variations in 15 miRNAs implicated in tumorigenesis by virtue of their known target transcripts (let-7 family targeting oncogenic Ras) or their localization to sites of frequent chromosomal instability (miR-143, miR-145, miR-26a-1, and miR-21).

yes

52ecd56198d023950500002b

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

Mutations in human TRα1 mediate RTH with features of hypothyroidism in particular tissues (e.g. skeleton, gastrointestinal tract), but are not associated with a markedly dysregulated pituitary-thyroid axis. Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRα1 receptor

yes

551910fa622b19434500000b

Is PLK2 involved in alpha-synuclein phosphorylation in Parkinson disease?

An increase in α-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease Here, we report that Polo-like kinase 2 (PLK2), an enzyme up-regulated in synucleinopathy-diseased brains, interacts with, phosphorylates and enhances α-synuclein autophagic degradation in a kinase activity-dependent manner. Polo-like kinase 2 regulates selective autophagic α-synuclein clearance and suppresses its toxicity in vivo Collectively, our findings demonstrate that PLK2 is a previously undescribed regulator of α-synuclein turnover and that modulating its kinase activity could be a viable target for the treatment of synucleinopathies. α-Synuclein increased PLK2 levels and GSK-3β activity and increased the levels of phosphorylated α-Synuclein and Tau Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system Several neurological diseases, including Parkinson disease and dementia with Lewy bodies, are characterized by the accumulation of alpha-synuclein phosphorylated at Ser-129 (p-Ser-129) Here we submit evidence that polo-like kinase 2 (PLK2, also known as serum-inducible kinase or SNK) is a principle contributor to alpha-synuclein phosphorylation at Ser-129 in neurons. PLK2 directly phosphorylates alpha-synuclein at Ser-129 in an in vitro biochemical assay These results indicate that PLK2 plays a critical role in alpha-synuclein phosphorylation in central nervous system.

yes

53177803b166e2b80600000e

Is there evidence for somatic mosaicism in Tuberous Sclerosis?

There are several case reports of solitary SEGA without any other manifestations of TSC. Usually these cases are thought to be forme fruste of TSC due to somatic mosaicism. Female germline mosaicism in tuberous sclerosis confirmed by molecular genetic analysis This is the first case of germline mosaicism in tuberous sclerosis proven by molecular genetic analysis and also the first example of female germline mosaicism for a characterized autosomal dominant gene mutation apparently not associated with somatic mosaicism. Mutation screening by RT-PCR and direct sequencing of the TSC2 gene identified a 4 bp insertion TACT following nucleotide 2077 in exon 18 which was present in the three affected children but not in five unaffected siblings or the parents. This mutation would cause a frameshift and premature termination at codon 703. Absence of the mutation in lymphocyte DNA from the parents was consistent with germline mosaicism and this was confirmed by our finding of identical chromosome 16 haplotypes in affected and unaffected siblings, providing unequivocal evidence of two different cell lines in the gametes. Molecular analysis of the TSC2 alleles present in the affected subjects showed that the mutation had been inherited from the mother.

yes

550e7d6aa103b7801600000e

Does smoking increase risk for glioblastoma?

Glioma risk has consistently been inversely associated with allergy history but not with smoking history despite putative biologic plausibility. No relation was observed between glioma risk and smoking (odds ratio = 0.92, 95% confidence interval: 0.77, 1.10; P = 0.37), and there were no interactions for glioma risk of smoking history with any of the risk alleles. Non-smokers with G/A and A/A genotype showed increased glioma risk compared with G/G genotype (adjusted OR = 1.72, 95%CI: 1.29-2.30, p = 0.0002 and adjusted OR = 1.81, 95%CI: 1.10-2.99, p = 0.020, respectively). This association was not found in ever- or current-smokers. There was no significant association between glioma and alcohol consumption, smoking and mobile phone use. RESULTS: We found no associations between the GSTM3, GSTP1, NQO1, CYP1A1, GSTM1, or GSTT1 polymorphisms and adult brain tumor risk with the possible exception of a weak association between the G-C (Val-Ala) GSTP1 105/114 haplotype and glioma [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.54, 0.99], nor was there an interaction between the effects of the GSTM3 or GSTP1 polymorphisms and cigarette smoking. We did not find any evidence for an association with life-style characteristics such as cigarette smoking, alcohol consumption, use of drugs of any kind, or dietary intake of cured or smoked meat or fish. No relation was observed between glioma risk and smoking (odds ratio = 0 Glioma risk has consistently been inversely associated with allergy history but not with smoking history despite putative biologic plausibility Compared with nonsmokers, duration of cigarette smoking, number of cigarettes smoked per day and pack-years of smoking were associated with increased glioma risk, although the increases in risk were relatively modest Among ever smokers, women who reported having quit smoking had a 51% increase in risk of glioma compared with never smokers (HR = 1.51, 95% CI = 0.97-2.34), while current smokers did not appear to have an increase in risk

no

56e6f027a12c1fc13b000001

Is Wnt16b secreted in response to chemotherapy?

In this study, we found WNT16B could be expressed and secreted into the microenvironment by human ovarian fibroblasts after DNA damage-associated treatment, including chemotherapy drugs and radiation. In a recent article in Nature Medicine, Sun et al. show that increased expression of Wnt family member wingless-type MMTV integration site family member 16B (WNT16B) by the tumor microenvironment in response to cytotoxic damage and signals through the canonical Wnt pathway to promote tumor growth and chemotherapy resistance. Using a genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics, we identified a spectrum of secreted proteins derived from the tumor microenvironment that includes the Wnt family member wingless-type MMTV integration site family member 16B (WNT16B).

yes

5162f5b6298dcd4e5100004c

Do DNA double-strand breaks play a causal role in carcinogenesis?

The DNA non-homologous end-joining repair gene XRCC6/Ku70 plays an important role in the repair of DNA double-strand breaks (DSBs) induced by both exogenous and endogenous DNA-damaging agents. Defects in overall DSB repair capacity can lead to genomic instability and carcinogenesis. The tumor suppressor breast cancer susceptibility protein 1 (BRCA1) protects our cells from genomic instability in part by facilitating the efficient repair of DNA double-strand breaks (DSBs). BRCA1 promotes the error-free repair of DSBs through homologous recombination and is also implicated in the regulation of nonhomologous end joining (NHEJ) repair fidelity. The increased frequency of DSB mutagenesis and MMEJ repair in the absence of BRCA1 suggests a potential mechanism for carcinogenesis. Comet assay under neutral conditions allows detection of DNA double-strand breaks (DSBs), which has consequence to genome instability and carcinogenesis. Loss of p15/Ink4b accompanies tumorigenesis triggered by complex DNA double-strand breaks. Although DSBs are potentially carcinogenic, it is not clear whether complex DSBs that are refractory to repair are more potently tumorigenic compared with simple breaks that can be rapidly repaired, correctly or incorrectly, by mammalian cells. Zinc chromate induces chromosome instability and DNA double strand breaks in human lung cells. Our study shows that zinc chromate induced concentration-dependent increases in cytotoxicity, chromosome damage and DNA double strand breaks in human lung cells. Foci formation of P53-binding protein 1 in thyroid tumors: activation of genomic instability during thyroid carcinogenesis. Nitric oxide and acid induce double-strand DNA breaks in Barrett's esophagus carcinogenesis via distinct mechanisms. DNA double-strand break repair capacity and risk of breast cancer. A tumorigenic role of the non-homologous end-joining (NHEJ) pathway for the repair of DNA double-strand breaks (DSBs) has been suggested by our finding of a significant association between increased breast cancer risk and a cooperative effect of single-nucleotide polymorphisms in NHEJ genes. Carcinogen-induced DNA double strand break repair in sporadic breast cancer. Induction of DNA double strand breaks and alterations in the repair of these breaks is implicated in breast carcinogenesis. Prior studies have demonstrated that peripheral blood mononuclear cells (PBMC) from breast cancer patients exhibit increased numbers of DNA strand breaks after exposure to ionizing radiation, but these studies did not specifically measure DNA double strand breaks and it is not known whether chemical carcinogens produce similar effects. Abnormal DNA end-joining activity in human head and neck cancer. In human cells, DNA double-strand breaks (DSBs) are repaired primarily by the DNA end-joining (EJ) process and thus, abnormal DNA EJ activities lead to an accumulation of mutations and/or aneuploidy, resulting in genetic instability of cells. Since genetic instability is the hallmark of cancer cells, we studied the DNA EJ activities of normal, non-malignant immortalized and malignant human epithelial cells to investigate the association between DNA EJ and carcinogenesis. Homologous recombination repair plays an important role in DSB repair and impairment of this repair mechanism may lead to loss of genomic integrity, which is one of the hallmarks of cancer. Recent research has shown that the tumor suppressor genes p53 and BRCA1 and -2 are involved in the proper control of homologous recombination, suggesting a role of this type of repair in human cancer. In order to study the role of DNA damage processing in the development of cutaneous squamous cell carcinoma (SCC), we assessed the ability of six keratinocyte cell lines from a multistage-tumor progression model to repair three types of DNA damage: pyrimidine dimers, oxidative DNA lesions and DNA double strand breaks (DSB). However, an acquired deficiency in repairing DNA double strand breaks can be one mechanism promoting progression towards malignancy, possibly through impairing chromosomal stability. Recent findings demonstrate that accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks in cells, which escaped apoptosis due to proliferative stress. Although DNA double-strand breaks and apoptosis may relate to arsenite-induced damage and carcinogenesis, the mechanism of action remains obscure.

yes

5544df2a5beec11c10000006

Do conserved noncoding elements co-occur with matrix-attachment regions?

We hypothesized that some of these regions might be matrix-scaffold attachment regions, MARs (or S/MARs). MARs comprise one of the few classes of eukaryotic noncoding DNA with an experimentally characterized function, being involved in the attachment of chromatin to the nuclear matrix, chromatin remodeling and transcription regulation. To test our hypothesis, we analyzed the co-occurrence of predicted MARs with highly conserved noncoding DNA regions in human-mouse genomic alignments. We found that 11% of the conserved noncoding DNA consists of predicted MARs. Conversely, more than half of the predicted MARs co-occur with one or more independently identified conserved sequence blocks. An excess of conserved predicted MARs is seen in intergenic regions preceding 5' ends of genes, suggesting that these MARs are primarily involved in transcriptional control A significant fraction of conserved noncoding DNA in human and mouse consists of predicted matrix attachment regions. To test our hypothesis, we analyzed the co-occurrence of predicted MARs with highly conserved noncoding DNA regions in human-mouse genomic alignments. To test our hypothesis, we analyzed the co-occurrence of predicted MARs with highly conserved noncoding DNA regions in human-mouse genomic alignments

yes

56d1accb67f0cb3d66000001

Are Drosophila ultraconserved elements candidate ncRNAs?

Highly constrained intergenic Drosophila ultraconserved elements are candidate ncRNAs. Here, we report the discovery and characterization of UCEs from 12 sequenced Drosophila species. We identified 98 elements ≥80 bp long with very high conservation across the Drosophila phylogeny. Population genetic analyses reveal that these UCEs are not present in mutational cold spots. Instead we infer that they experience a level of selective constraint almost 10-fold higher compared with missense mutations in protein-coding sequences, which is substantially higher than that observed previously for human UCEs. About one-half of these Drosophila UCEs overlap the transcribed portion of genes, with many of those that are within coding sequences likely to correspond to sites of ADAR-dependent RNA editing. For the remaining UCEs that are in nongenic regions, we find that many are potentially capable of forming RNA secondary structures. Among ten chosen for further analysis, we discovered that the majority are transcribed in multiple tissues of Drosophila melanogaster. We conclude that Drosophila species are rich with UCEs and that many of them may correspond to novel noncoding RNAs. Highly Constrained Intergenic Drosophila Ultraconserved Elements Are Candidate ncRNAs

yes

54f088ee94afd61504000015

Does surgery for ovarian endometriomas improve fertility?

CONCLUSION: Endometriomas per se appear to be the main cause of the reduced long-term reproductive performance of the affected patients, with little or no contribution from surgery. Furthermore, endometrioma surgery seems to improve the success rates of fertility treatment. Amongst the 38 women desiring pregnancy after endometrioma surgery, 19 (50%) achieved a spontaneous pregnancy during the follow-up period. Of 33 women who wished to conceive, 67% became pregnant, spontaneously in 59% CONCLUSIONS: Recurrence and pregnancy rates are encouraging in that they seem comparable to the best reported results after endometrioma cystectomy. While laparoscopic excision is known to improve fertility, recurrence can cause significant ovarian damage and adverse affects on fertility. Surgery is considered to play a role within the framework of the therapeutic options to cure infertile women with the disease even though its effectiveness is generally modest. Randomized controlled trials showed that the excision technique is associated with a higher pregnancy rate and a lower rate of recurrence although it may determine severe injury to the ovarian reserve. Surgical treatment is associated with a high recurrence rate and its employment for women undergoing assisted conception has recently been challenged. Laparoscopic excision of ovarian endometrioma prior to IVF does not offer any additional benefit over expectant management. For those women subsequently attempting to conceive it was also associated with a subsequent increased spontaneous pregnancy rate in women who had documented prior sub-fertility (OR 5.21 CI 2.04-13.29). here is insufficient evidence to favour excisional surgery over ablative surgery with respect to the chance of pregnancy after controlled ovarian stimulation and intra-uterine insemination (OR 1.40 CI 0.47-4.15) . CONCLUSIONS: These findings suggest that in a context of more than one year infertility only related to endometriosis, it is reasonable to offer these patients a complete operative laparoscopic treatment of their lesions, which enables 65% of them to be pregnant within a 8.5 months post-surgical median time to pregnancy and spontaneously in 60%. It was also associated with a subsequent increased rate of spontaneous pregnancy women who had documented prior sub-fertility (OR 5.21 CI 2.04-13.29). AUTHORS' CONCLUSIONS: There is some evidence that excisional surgery for endometriomata provides for a more favourable outcome than drainage and ablation, with regard to the recurrence of the endometrioma, recurrence of symptoms and subsequent spontaneous pregnancy in women who were previously subfertile. Surgery is an option for treatment, but there is no convincing evidence that it promotes a significant improvement in fertility. In conclusion, ovarian surgery for the treatment of endometriosis reduces the ovarian outcome in IVF/ICSI cycles in women >35 years old, and might also decrease pregnancy rates. Improvement of pain symptoms occurred in 87% of the patients and fertility rate was 45%. The long-term results, especially the fertility outcome, have been promising: 12 of 20 women (60%) achieved a term pregnancy following a laparoscopic endometrioma procedure alone. Among this group, 115 patients (54%) conceived following surgery; of these conceptions, 109 resulted in a living child. WIDER IMPLICATIONS OF THE FINDINGS: Despite the available evidence that surgery for endometriomas does not improve the outcome of ART and may damage ovarian reserve, it seems that the majority of gynaecologists in the UK offer ovarian cystectomy to their patients. Ovarian endometriomas does not exclude fertility. Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched, case-control study. Conclusion(s): Laparoscopic cystectomy for endometriomas before commencing an IVF cycle does not improve fertility outcomes. Despite the available evidence that surgery for endometriomas does not improve the outcome of ART and may damage ovarian reserve, it seems that the majority of gynaecologists in the UK offer ovarian cystectomy to their patients. Furthermore, laparoscopic removal of endometriomas does not improve IVF results, but may cause a decrease of ovarian responsiveness to gonadotropins. Furthermore, endometrioma surgery seems to improve the success rates of fertility treatment. Laparoscopic cystectomy for endometriomas before commencing an IVF cycle does not improve fertility outcomes

yes

552440452c8b63434a00000b

Are ACTA1 (alpha actin) and NEB (nebulin) genes related to nemaline myopathy?

Nemaline myopathy (NM) is a group of congenital myopathies, characterized by the presence of distinct rod-like inclusions "nemaline bodies" in the sarcoplasm of skeletal muscle fibers. To date, ACTA1, NEB, TPM3, TPM2, TNNT1, and CFL2 have been found to cause NM. Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). 20-25% of NM cases carry ACTA1 defects and these particular mutations usually induce substitutions of single residues in the actin protein. Nemaline myopathy (NM) is a genetically and clinically heterogenous muscle disorder, which is myopathologically characterized by nemaline bodies. Mutations in six genes have been reported to cause NM: Nebulin (NEB Pelin 1999), alpha-skeletal muscle actin (ACTA1 Nowak 1999), alpha-slow tropomyosin (TPM3 Laing 1995), beta-tropomyosin (TPM2 Donner 2002), slow troponin T (TNNT1 Johnston 2000) and cofilin 2 (CFL2 Agrawal 2007). The majority of cases are due to mutation in NEB and ACTA1. Nemaline myopathy is a heterogenous form of congenital myopathy characterised by a variable spectrum of clinical features, predominated in the severe form by profound muscle hypotonia and weakness accompanied by respiratory insufficiency. The clinical variability, with differing age of onset and severity of symptoms makes the diagnosis of nemaline myopathy difficult in some cases. Severe forms of nemaline myopathy may be caused by mutation of a number of different genes: skeletal muscle actin (ACTA1), nebulin (NEB) and alpha-tropomyosin (TPM3), all of which encode components of the sarcomeric thin filaments of skeletal muscle. Most nemaline myopathy patients have mutations in the nebulin (NEB) or skeletal muscle alpha-actin (ACTA1) genes. We report muscle MRI findings of 10 patients from 8 families with nemaline myopathy. Patients with involvement of the nebulin (NEB) gene showed a consistent pattern of selective muscle involvement corresponding to clinical severity. Patients with nemaline myopathy secondary to mutations in the skeletal muscle alpha-actin (ACTA1) gene showed diffuse involvement of thigh and leg muscles with relative sparing of the gastrocnemii. Congenital myopathies are clinical and genetic heterogeneous disorders characterized by skeletal muscle weakness ranging in severity. Three major forms have been identified: actin myopathy, intranuclear rod myopathy, and nemaline myopathy. Nemaline myopathy is the most common of these myopathies and is further subdivided into seven groups according to severity, progressiveness, and age of onset. At present, five genes have been linked to congenital myopathies. These include alpha-actin (ACTA1), alpha- and beta-tropomyosin (TPM3 and TPM2), troponin T (TNNT1), and nebulin (NEB). Nemaline myopathy is a structural congenital myopathy which may show both autosomal dominant and autosomal recessive inheritance patterns. Mutations in three different genes have been identified as the cause of nemaline myopathy: the gene for slow alpha-tropomyosin 3 (TPM3) at 1q22-23, the nebulin gene (NEB) at 2q21.1-q22, and the actin gene (ACTA1) at 1q42. Nemaline myopathy is a clinically and genetically heterogeneous condition. The clinical spectrum ranges from severe cases with antenatal or neonatal onset and early death to late onset cases with only slow progression. Three genes are known to cause nemaline myopathy: the genes for nebulin (NEB) on chromosome 2q22, slow alpha-tropomyosin (TPM3) on chromosome 1q21 and skeletal muscle alpha-actin (ACTA1) on chromosome 1q42. Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). Three genes are known to cause nemaline myopathy: the genes for nebulin (NEB) on chromosome 2q22, slow alpha-tropomyosin (TPM3) on chromosome 1q21 and skeletal muscle alpha-actin (ACTA1) on chromosome 1q42. Five genes have now been associated with nemaline myopathy: alpha-tropomyosin-3 (TPM3), alpha-actin (ACTA1), nebulin (NEB), beta-tropomysin (TPM2) and troponin T (TNNT1). Most nemaline myopathy patients have mutations in the nebulin (NEB) or skeletal muscle alpha-actin (ACTA1) genes. Severe forms of nemaline myopathy may be caused by mutation of a number of different genes: skeletal muscle actin (ACTA1), nebulin (NEB) and alpha-tropomyosin (TPM3), all of which encode components of the sarcomeric thin filaments of skeletal muscle. Five genes have now been associated with nemaline myopathy: alpha-tropomyosin-3 (TPM3), alpha-actin (ACTA1), nebulin (NEB), beta-tropomysin (TPM2) and troponin T (TNNT1). Three genes are known to cause nemaline myopathy: the genes for nebulin (NEB) on chromosome 2q22, slow alpha-tropomyosin (TPM3) on chromosome 1q21 and skeletal muscle alpha-actin (ACTA1) on chromosome 1q42. Mutations in three different genes have been identified as the cause of nemaline myopathy: the gene for slow alpha-tropomyosin 3 (TPM3) at 1q22-23, the nebulin gene (NEB) at 2q21.1-q22, and the actin gene (ACTA1) at 1q42. Most nemaline myopathy patients have mutations in the nebulin (NEB) or skeletal muscle alpha-actin (ACTA1) genes Five genes have now been associated with nemaline myopathy: alpha-tropomyosin-3 (TPM3), alpha-actin (ACTA1), nebulin (NEB), beta-tropomysin (TPM2) and troponin T (TNNT1) Three genes are known to cause nemaline myopathy: the genes for nebulin (NEB) on chromosome 2q22, slow alpha-tropomyosin (TPM3) on chromosome 1q21 and skeletal muscle alpha-actin (ACTA1) on chromosome 1q42 Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin) Five genes have now been associated with nemaline myopathy: alpha-tropomyosin-3 (TPM3), alpha-actin (ACTA1), nebulin (NEB), beta-tropomysin (TPM2) and troponin T (TNNT1) Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin) Mutations in three different genes have been identified as the cause of nemaline myopathy: the gene for slow alpha-tropomyosin 3 (TPM3) at 1q22-23, the nebulin gene (NEB) at 2q21.1-q22, and the actin gene (ACTA1) at 1q42 Three genes are known to cause nemaline myopathy: the genes for nebulin (NEB) on chromosome 2q22, slow alpha-tropomyosin (TPM3) on chromosome 1q21 and skeletal muscle alpha-actin (ACTA1) on chromosome 1q42 Most nemaline myopathy patients have mutations in the nebulin (NEB) or skeletal muscle alpha-actin (ACTA1) genes Severe forms of nemaline myopathy may be caused by mutation of a number of different genes: skeletal muscle actin (ACTA1), nebulin (NEB) and alpha-tropomyosin (TPM3), all of which encode components of the sarcomeric thin filaments of skeletal muscle

yes

56ed0a372ac5ed1459000006

Could RG7112 be used as cancer therapy?

RG7112 is a potent and selective member of the nutlin family of MDM2 antagonists currently in phase I clinical studies. Our findings offer a preclinical proof-of-concept that RG7112 is effective in treatment of solid tumors expressing wild-type p53. On the other hand, JNJ-26854165, a novel tryptamine derivative and RG7112, a cis-imidazoline representative have shown promising results in early phases of trials in cancer patients. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. On the other hand, JNJ-26854165, a novel tryptamine derivative and RG7112, a cis-imidazoline representative have shown promising results in early phases of trials in cancer patients. RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts. Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis On the other hand, JNJ-26854165, a novel tryptamine derivative and RG7112, a cis-imidazoline representative have shown promising results in early phases of trials in cancer patients RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies We report a proof-of-mechanism study of RG7112, a small-molecule MDM2 antagonist, in patients with chemotherapy-naive primary or relapsed well-differentiated or dedifferentiated MDM2-amplified liposarcoma who were eligible for resection BACKGROUND: RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. Thus, inhibitors of p53-MDM2 binding that can reactivate p53 in cancer cells may offer an effective approach for cancer therapy. Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis. RG7112 showed potent antitumor activity against a panel of solid tumor cell lines. A crystal structure of the RG7112-MDM2 complex revealed that the small molecule binds in the p53 pocket of MDM2, mimicking the interactions of critical p53 amino acid residues. Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96 hours exposure (1 nM to 10 µM). Thus, inhibitors of p53-MDM2 binding that can reactivate p53 in cancer cells may offer an effective approach for cancer therapy. RG7112 is a potent and selective member of the nutlin family of MDM2 antagonists currently in phase I clinical studies. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts. . Restoration of p53 activity by inhibiting the p53-MDM2 interaction may represent a novel approach to cancer treatment. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies.RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96 hours exposure (1 nM to 10 µM). Notably, RG7112 was highly synergistic with androgen deprivation in LNCaP xenograft tumors. Our findings offer a preclinical proof-of-concept that RG7112 is effective in treatment of solid tumors expressing wild-type p53. RG7112 induced tumor regressions in solid tumors from different histotype panels, and exhibited consistent high-level activity against ALL xenografts. This high level of activity supports prioritization of RG7112 for further evaluation. RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies.

yes

52e7b4a198d023950500001b

Does thyroid hormone affect cardiac remodeling ?

Thyroid hormones exert important effects on heart remodeling through mir-208. RV and RA function and mechanics are significantly affected by SHT. l-T4 therapy and 1-year maintenance of euthyroid status improved but did not completely recover RV and RA function and deformation in the SHT patients, which implies that right heart remodeling caused by SHT is not reversible in a 1-year period. These results suggest that long-term T4 treatment after MI has beneficial effects on myocyte, arteriolar, and collagen matrix remodeling in the non-infarcted area. Most importantly, results suggest improved survival of myocytes in the peri-infarct area.

yes

54f1e781c409818c32000003

Is armodafinil used for treatment of insomnia?

Other therapies, such as sedative hypnotics, target daytime insomnia, while pharmacologic agents such as modafinil, armodafinil, and caffeine and non-pharmacologic approaches such as napping promote nighttime alertness. Other treatment options may include pharmacologic interventions such as modafinil and armodafinil, which have shown efficacy in this population. BACKGROUND: Armodafinil (Nuvigil(®), Cephalon, Inc., Frazer, PA, USA), the longer-lasting isomer of racemic modafinil, is a nonamphetamine, wakefulness-promoting medication. In patients with excessive sleepiness associated with shift work disorder, treated obstructive sleep apnoea, or narcolepsy, armodafinil has been found to improve wakefulness throughout the shift or day. In addition, while not approved for this indication, armodafinil has been found to improve excessive sleepiness associated with jet-lag disorder. STUDY OBJECTIVES: Armodafinil is a wakefulness-promoting medication. Its efficacy and tolerability have been established in 12-week studies of patients with excessive sleepiness (ES) associated with treated obstructive sleep apnea (OSA), shift work disorder (SWD), or narcolepsy. Armodafinil represents an option for long-term treatment of patients with ES associated with treated OSA, SWD, or narcolepsy. The wakefulness-promoting agents armodafinil and modafinil are FDA approved for the treatment of ES in patients with SWD. CONCLUSIONS: Armodafinil significantly improved overall clinical condition related to excessive sleepiness as rated by the CGI-C and was well tolerated in patients with treated OSA and comorbid depression. CONCLUSION: In patients with excessive sleepiness associated with chronic SWD of moderate or greater severity, armodafinil significantly improved wakefulness during scheduled night work, raising mean nighttime sleep latency above the level considered to indicate severe sleepiness during the daytime. Armodafinil also significantly improved measures of overall clinical condition, long-term memory, and attention. Adjunct treatment with armodafinil significantly improved wakefulness, long-term memory, and patients' ability to engage in activities of daily living in nCPAP-adherent individuals with ES associated with OSA. A number of studies have evaluated countermeasures or interventions in shift workers; proposed treatments include chronobiotic interventions, such as light exposure, melatonin, hypnotic agents, caffeine and CNS stimulants (amphetamine), and the wake-promoting agents modafinil and armodafinil. These studies showed that modafinil and armodafinil significantly improve the ability to sustain wakefulness during waking activities (e.g. working, driving), overall clinical condition, and sustained attention or memory in patients with SWSD. CONCLUSIONS: In this selected population of patients with OSA/HS and residual ES despite effective treatment with nCPAP, armodafinil QD used as an adjunct to nCPAP treatment was associated with improved wakefulness and overall clinical condition. Other therapies, such as sedative hypnotics, target daytime insomnia, while pharmacologic agents such as modafinil, armodafinil, and caffeine and non-pharmacologic approaches such as napping promote nighttime alertness. Armodafinil represents an option for long-term treatment of patients with ES associated with treated OSA, SWD, or narcolepsy. Other therapies, such as sedative hypnotics, target daytime insomnia, while pharmacologic agents such as modafinil, armodafinil, and caffeine and non-pharmacologic approaches such as napping promote nighttime alertness. In this selected population of patients with OSA/HS and residual ES despite effective treatment with nCPAP, armodafinil QD used as an adjunct to nCPAP treatment was associated with improved wakefulness and overall clinical condition

no

56b481348525abca1e000008

Are there currently applications of deep learning in genomics?

Deep learning of the tissue-regulated splicing code. Using a deep neural network, we developed a model inferred from mouse RNA-Seq data that can predict splicing patterns in individual tissues and differences in splicing patterns across tissues. Our architecture uses hidden variables that jointly represent features in genomic sequences and tissue types when making predictions. A graphics processing unit was used to greatly reduce the training time of our models with millions of parameters. We show that the deep architecture surpasses the performance of the previous Bayesian method for predicting AS patterns. With the proper optimization procedure and selection of hyperparameters, we demonstrate that deep architectures can be beneficial, even with a moderately sparse dataset. An analysis of what the model has learned in terms of the genomic features is presented. Machine learning applications in genetics and genomics

yes

5133b15e5274a5fb0700000b

Are CpG islands located close to housekeeping genes?

our analysis indicates that the association of CGIs with housekeeping genes is not as strong as previously estimated CpG islands are preferentially located at the start of transcription of housekeeping genes and are associated with tissue-specific genes It has been envisaged that CpG islands are often observed near the transcriptional start sites (TSS) of housekeeping genes. These regions represent about 1% of genomic DNA and are generally found in the promoter region of housekeeping genes. CpG islands are stretches of DNA sequence that are enriched in the (CpG)n repeat and are present in close association with all housekeeping genes as well as some tissue-specific genes in the mammalian genome. CpG islands, which are found almost exclusively at the 5'-end of housekeeping genes In housekeeping and many tissue-specific genes, the promoter is embedded in a so-called CpG island. All housekeeping and widely expressed genes have a CpG island covering the transcription start, whereas 40% of the genes with a tissue-specific or limited expression are associated with islands Methylation-free CpG clusters, so-called HTF islands, are most often associated with the promoter regions of housekeeping genes, whereas genes expressed in a single-cell type are usually deficient in these sequences. Unmethylated CpG rich islands are a feature of vertebrate DNA: they are associated with housekeeping and many tissue specific genes. CpG islands were associated with the 5' ends of all housekeeping genes and many tissue-specific genes, and with the 3' ends of some tissue-specific genes.

yes

5162a089298dcd4e51000043

Have microRNAs been implicated in pharmacogenomics?

A major discovery is the ability of miRNAs to determine the efficacy of drugs, which has given rise to the field of 'miRNA pharmacogenomics' through 'Pharmaco-miRs'. miRNAs play a significant role in pharmacogenomics by down-regulating genes that are important for drug function. The potential modulation of toxicology-related changes in miRNA expression, the role of miRNA in immune-mediated drug-induced liver injuries, the use of circulating miRNAs in body fluids as potential toxicological biomarkers, and the link between miRNA-related pharmacogenomics and adverse drug reactions are highlighted. Single nucleotide polymorphisms (SNPs) in the miRNA target sequences may affect or impair the binding of miRNAs. Studies have shown that SNPs in miRNA target sites (miR-TS-SNPs) have a great influence on diverse biological functions, including pharmacogenomics and disease susceptibilities in human. Pharmacogenomics genes can be divided into drug target genes termed as pharmacodynamics genes (PD) and genes involved in drug transport and metabolism termed as pharmacokinetics genes (PK). To clarify the regulatory potential of miRNAs in pharmacogenomics, we have examined the potential regulation by miRNAs of PK and PD genes. Our analysis identify a striking difference in the level of miRNA regulation between PK and PD genes, with the former having less than half predicted conserved miRNA binding sites compared with the latter. Importantly, this finding is reflected in a highly significant difference in the shift in expression levels of PD versus PK genes after depletion of miRNAs. CONCLUSIONS: Our study emphasizes an intrinsic difference between PK and PD genes and helps clarify the role of miRNAs in pharmacogenomics. Pharmacogenomics, toxicogenomics, and small RNA expression analysis are three of the most active research topics in the biological, biomedical, pharmaceutical, and toxicological fields. All of these studies are based on gene expression analysis, which requires reference genes to reduce the variations derived from different amounts of starting materials and different efficiencies of RNA extraction and cDNA synthesis. In contrast, hTBCA and small RNAs are more stable during drug treatment, and they are better reference genes for pharmacogenomics and toxicogenomics studies. Polymorphisms of genes involved in the pharmacokinetic and pharmacodynamic processes underlie the divergent drug responses among individuals. A panel of drug-response genes was constructed, which contains 923 pharmacokinetic genes, 703 pharmacodynamic genes and 720 miRNAs. miRNA variations can affect drug resistance, efficacy, and metabolism, opening new avenues of pharmacogenomics research. we studied the pharmacologic roles of three microRNAs previously implicated in cancer biology (let-7i, mir-16, and mir-21) and also used in silico methods to test pharmacologic microRNA effects more broadly. n silico comparison of drug potencies with microRNA expression profiles across the entire NCI-60 panel revealed that approximately 30 microRNAs, including mir-21, show highly significant correlations with numerous anticancer agents. Ten of those microRNAs have already been implicated in cancer biology. Our results support a substantial role for microRNAs in anticancer drug response, suggesting novel potential approaches to the improvement of chemotherapy. The NCI-60 has also been profiled for mRNA and protein expression, mutational status, chromosomal aberrations, and DNA copy number, generating an unparalleled public resource for integrated chemogenomic studies. To complement the existing NCI-60 data sets, we have measured expression levels of microRNAs in the NCI-60 and incorporated the resulting data into the CellMiner program package for integrative analysis. . Comparison of microRNA expression patterns and compound potency patterns showed significant correlations, suggesting that microRNAs may play a role in chemoresistance. Combined with gene expression and other biological data using multivariate analysis, microRNA expression profiles may provide a critical link for understanding mechanisms involved in chemosensitivity and chemoresistance. This study reports on miRNAs implicated in SSRI sensitivity of LCLs. these miRNAs as tentative SSRI response biomarkers awaits validation with lymphocyte samples of major depression patients.

yes

56c03d1fef6e39474100001a

Is nicotinamide effective for skin cancer prevention?

Nicotinamide (vitamin B3) has been shown to have protective effects against damage caused by UV radiation and to reduce the rate of new premalignant actinic keratoses. ESULTS: At 12 months, the rate of new nonmelanoma skin cancers was lower by 23% (95% confidence interval [CI], 4 to 38) in the nicotinamide group than in the placebo group (P=0.02). Similar differences were found between the nicotinamide group and the placebo group with respect to new basal-cell carcinomas (20% [95% CI, -6 to 39]lower rate with nicotinamide, P=0.12) and new squamous-cell carcinomas (30% [95% CI, 0 to 51] lower rate, P=0.05). The number of actinic keratoses was 11% lower in the nicotinamide group than in the placebo group at 3 months (P=0.01), 14% lower at 6 months (P<0.001), 20% lower at 9 months (P<0.001), and 13% lower at 12 months (P=0.001). CONCLUSIONS: Oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients. Nicotinamide is a safe, widely available vitamin that reduces the immune suppressive effects of UV, enhances DNA repair in keratinocytes and has shown promise in the chemoprevention of non-melanoma skin cancer. In summary, nicotinamide, by enhancing DNA repair in melanocytes, is a potential agent for the chemoprevention of cutaneous melanoma. Recent double-blinded randomized controlled Phase 2 studies in heavily sun-damaged individuals have shown that oral nicotinamide significantly reduces premalignant actinic keratoses, and may reduce new non-melanoma skin cancers. Nicotinamide (vitamin B3) prevents UV-induced immunosuppression and carcinogenesis in mice, and solar-simulated (ss) UV-induced immunosuppression in humans. These results show that nicotinamide enhances two different pathways for repair of UV-induced photolesions, supporting nicotinamide's potential as an inexpensive, convenient and non-toxic agent for skin cancer chemoprevention. Recent double-blinded randomized controlled Phase 2 studies in heavily sun-damaged individuals have shown that oral nicotinamide significantly reduces premalignant actinic keratoses, and may reduce new non-melanoma skin cancers. No noteworthy between-group differences were found with respect to the number or types of adverse events during the 12-month intervention period, and there was no evidence of benefit after nicotinamide was discontinued.CONCLUSIONS: Oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients. Nicotinamide (vitamin B3) has been shown to have protective effects against damage caused by UV radiation and to reduce the rate of new premalignant actinic keratoses.METHODS: In this phase 3, double-blind, randomized, controlled trial, we randomly assigned, in a 1:1 ratio, 386 participants who had had at least two nonmelanoma skin cancers in the previous 5 years to receive 500 mg of nicotinamide twice daily or placebo for 12 months. Similar differences were found between the nicotinamide group and the placebo group with respect to new basal-cell carcinomas (20% [95% CI, -6 to 39]lower rate with nicotinamide, P=0.12) and new squamous-cell carcinomas (30% [95% CI, 0 to 51] lower rate, P=0.05). Oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients. Nicotinamide has shown potential as a safe and effective intervention for the prevention of malignant and premalignant skin lesions. Nicotinamide, which protected against both UVB and UVA, is a promising agent for skin cancer prevention.

yes

54d8d4d1014675820d000006

Do Parkinson's disease patients experience stridor?

The authors describe a patient experiencing stridor and dysphagia with confirmed pulmonary restriction and aspiration following subthalamic nucleus deep brain stimulator adjustment, with a resolution of symptoms and signs when the stimulator was switched off. Stridor was not noted during sleep at night. Endoscopic examination of the larynx revealed insufficient abduction of the bilateral vocal cords, although the glottis was not so small as to cause stridor during inspiration. The stridor was specific to MSA. Patients with MSA can present other clinical features, such as inspiratory stridor and rapid eye movement (REM) sleep behaviour disorder (RBD). We report a patient with pathologically confirmed MSA who presented with a longstanding history of stridor, RBD and autonomic disturbances but did not develop overt parkinsonism or cerebellar signs. This case illustrates that MSA may present clinically without its cardinal motor symptoms, and that stridor and RBD may be clues to recognise the disease in a patient with autonomic failure. Patients with PD did not display sleep hypoventilation, stridor and abnormal central sleep apnea. DEVELOPMENT: Autonomic disorders such as seborrhoeic dermatitis and disorders involving sweating, fatigue, weight loss or respiratory problems (dyspnea, inspiratory stridor) are highly prevalent and very disabling symptoms. In addition, they may be the main problem in a particular phase of PD (fatigue, stridor) and condition the quality of life of patients with Parkinson. . Her dyspneic attacks consisting of inspiratory stridor and cyanosis occurred mainly during the wearing-off time and continued for less than 30 min The most commonly reported sleep disorders were sleep fragmentation (52.5%), vocalisation (60%), REM sleep behaviour disorder (47.5%), and nocturnal stridor (19%). Except for sleep fragmentation, the incidence of these disorders was significantly higher than in PD Six days after admission, dyspnea and inspiratory stridor were noted, and the respiratory distress worsened. A patient is described with idiopathic Parkinson's disease and severe laryngeal stridor. The laryngeal stridor responded to levodopa therapy, and we are not aware that this has been reported previously. The subsequent clinical course of the former eight patients has been typical of idiopathic Parkinson's disease, whilst the ninth patient has developed postural hypotension, urinary incontinence and respiratory stridor typical of multiple system atrophy. Although each of five autonomic domains was affected in variable numbers of IPD patients, AD in MSA generally involved more autonomic domains than in IPD, and to a more severe degree, in particular with regard to inspiratory stridor. However, the presence of severe AD, of AD preceding parkinsonism, or of inspiratory stridor, are all individually suggestive of MSA. Apart from dysautonomia, the principal discriminant clinical features that distinguished SND from PD were the early appearance of the following symptoms and signs: (a) severe and atypical progressive parkinsonism characterized by bilateral bradykinesia and rigidity, slowness of gait, postural instability, and falls, and poor or absent response to adequate levodopa treatment; (b) increased tendon reflexes associated or not with frank pyramidal signs, severe dysarthria, and less consistently, dysphagia, stridor, antecollis, and stimulus-sensitive myoclonus, which, when present, are highly suggestive of the disease. OBJECTIVES: (1) To present a rare case of stridor secondary to prolonged laryngospasm in a patient with Parkinson's disease, and (2) to review the literature on stridor in Parkinson's disease. METHODS: We report a 73-year-old Parkinson's disease patient who developed acute stridor due to prolonged laryngospasm triggered by overspill of excessive secretions. RESULT: Only 12 previously reported cases of stridor in Parkinson's disease patients were identified. This case emphasises the importance of recognising different causes of stridor in Parkinson's disease patients, as this affects management. RESULT: Only 12 previously reported cases of stridor in Parkinsons disease patients were identified. This case emphasises the importance of recognising different causes of stridor in Parkinsons disease patients, as this affects management. OBJECTIVES: (1) To present a rare case of stridor secondary to prolonged laryngospasm in a patient with Parkinsons disease, and (2) to review the literature on stridor in Parkinsons disease. METHODS: We report a 73-year-old Parkinsons disease patient who developed acute stridor due to prolonged laryngospasm triggered by overspill of excessive secretions. (1) To present a rare case of stridor secondary to prolonged laryngospasm in a patient with Parkinson's disease, and (2) to review the literature on stridor in Parkinson's disease.

yes

54cf4bc3f693c3b16b00000d

Is there an association between serum interleukin-6 concentrations and outcomes of stroke patients?

In addition, IL-6 concentrations affect clinical outcomes in ischemic stroke. After appropriate adjustment, the odds ratios for the association of markers and poor outcome (comparing the upper and the lower third) were interleukin-6, 3.1 (95% CI: 1.9-5.0); C-reactive protein, 1.9 (95% CI: 1.2-3.1); fibrinogen, 1.5 (95% CI: 1.0-2.36); white cell count, 2.1 (95% CI: 1.3-3.4); and glucose 1.3 (95% CI: 0.8-2.1). The results for interleukin-6 were similar to other studies. -6 and IL-10 levels were higher in patients with poor outcome. On logistic regression analysis, higher values of IL-6 were significantly associated with clinical outcome at 1 month (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.02-1.54). In hemorrhagic stroke, high levels of IL-6 in the early phase indicated a poor neurological outcome. Initially elevated levels of hs-IL-6 at presentation further correlated with unfavorable clinical outcomes (by NIHSS and mRs) at both time points. Analysis of variance in the different quartiles identified an hs-IL-6 gradient-dependent correlation at both time points, such that the higher the initial hs-IL-6 concentration, the higher the elevation in inflammatory biomarkers and the poorer the neurological state at both time points (p<0.001 for NIHSS and p=0.001 for mRs, for trend across quartiles). CONCLUSIONS: This study demonstrates the potential of employing hs-IL-6 as an early stage biomarker for the prognosis of acute ischemic stroke. Another negative correlation was found between IL-6 and CNS scores (r = -0.451, p = 0.000). In addition, increased levels of IL-6 and reduced levels of protein C and protein S may play a role in acute ischemic stroke severity. Variables that are predictors of adverse stroke outcome include erythrocyte sedimentation rate, and levels of C-reactive protein (CRP), interleukin-6, tumour necrosis factor-alpha and intercellular adhesion molecule-1.

yes

5713968e1174fb175500000d

Could bioprinting be used in regenerative medicine against bone disease?

Before 3D Printing can be used routinely for the regeneration of complex tissues (e.g. bone, cartilage, muscles, vessels, nerves in the craniomaxillofacial complex), and complex organs with intricate 3D microarchitecture (e.g. liver, lymphoid organs), several technological limitations must be addressed. It is expected that these new findings will give an innovation boost for the development of scaffolds for bone repair and reconstruction, which began with the use of bioinert materials, followed by bioactive materials and now leading to functional regenerative tissue units. These new developments have become possible with the discovery of the morphogenic activity of bioinorganic polymers, biocalcit, bio-polyphosphate and biosilica that are formed by a biogenic, enzymatic mechanism, a driving force along with the development of novel rapid-prototyping three-dimensional (3D) printing methods and bioprinting (3D cell printing) techniques that may allow a fabrication of customized implants for patients suffering in bone diseases in the future. These new developments have become possible with the discovery of the morphogenic activity of bioinorganic polymers, biocalcit, bio-polyphosphate and biosilica that are formed by a biogenic, enzymatic mechanism, a driving force along with the development of novel rapid-prototyping three-dimensional (3D) printing methods and bioprinting (3D cell printing) techniques that may allow a fabrication of customized implants for patients suffering in bone diseases in the future. 3D bioprinting has already been used for the generation and transplantation of several tissues, including multilayered skin, bone, vascular grafts, tracheal splints, heart tissue and cartilaginous structures. a driving force along with the development of novel rapid-prototyping three-dimensional (3D) printing methods and bioprinting (3D cell printing) techniques that may allow a fabrication of customized implants for patients suffering in bone diseases in the future. These new developments have become possible with the discovery of the morphogenic activity of bioinorganic polymers, biocalcit, bio-polyphosphate and biosilica that are formed by a biogenic, enzymatic mechanism, a driving force along with the development of novel rapid-prototyping three-dimensional (3D) printing methods and bioprinting (3D cell printing) techniques that may allow a fabrication of customized implants for patients suffering in bone diseases in the future.

yes

51bedaac3148fdcc22da7188

Is macroautophagy a selective degradation process?

Selective autophagy Macroautophagy (autophagy) is a bulk degradation system for cytoplasmic components and is ubiquitously found in eukaryotic cells Here we show that selective autophagy downregulates Ty1 transposition We propose that selective autophagy safeguards genome integrity against excessive insertional mutagenesis caused during nutrient starvation by transposable elements in eukaryotic cells. Moreover, it is becoming apparent that proteins, organelles, and pathogens can be targeted for autophagic clearance by selective mechanisms Cell spreading required ref(2)P, the Drosophila p62 multiadaptor, implicating selective autophagy as a novel mechanism for modulating cortical dynamics The selective macroautophagic degradation There is growing evidence that macroautophagic cargo is not limited to bulk cytosol in response to starvation and can occur selectively for substrates, including aggregated proteins. It remains unclear, however, whether starvation-induced and selective macroautophagy share identical adaptor molecules to capture their cargo. Here, we report that Alfy, a phosphatidylinositol 3-phosphate-binding protein, is central to the selective elimination of aggregated proteins. We propose that Alfy plays a key role in selective macroautophagy by bridging cargo to the molecular machinery that builds autophagosomes. Thus, cytoplasmic NBR1 might be important to maintain basal levels of selective macroautophagy in these neurons. we could show that Smatg8 and Smatg4 are not only required for nonselective macroautophagy, but for selective macropexophagy as well. The latter is performed by proteasome-mediated degradation, chaperone-mediated autophagy (CMA), and selective macroautophagy, Here we demonstrate a role for PtdIns 4-kinases and PtdIns4P 5-kinases in selective and nonselective types of autophagy in yeast. Macroautophagy (hereafter autophagy) is a degradative cellular pathway that protects eukaryotic cells from stress, starvation, and microbial infection. Previously, we showed that macroautophagy is necessary for conidiation in the rice-blast fungus Magnaporthe oryzae. Here, we analyzed the physiological function(s) of selective autophagy in Magnaporthe Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Selective macroautophagy (autophagy) of ubiquitinated protein is implicated as a compensatory mechanism of the ubiquitin-proteasome system. p62/SQSTM1 is a key molecule managing autophagic clearance of polyubiquitinated proteins. Whole organelle turnover is mediated through macroautophagy, a process by which autophagosomes deliver mitochondria to the lysosome for hydrolytic degradation. While mitochondrial autophagy can occur as part of a nonselective upregulation of autophagy, selective degradation of damaged or unneeded mitochondria (mitophagy) is a rapidly growing area in development, cancer, and neurodegeneration, particularly with regard to Parkinson's disease BAG3 was recently described as a mediator of a novel macroautophagy pathway that uses the specificity of heat shock protein 70 (HSP70) to misfolded proteins and also involves other protein partners, such as HSPB8. two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy) Here we show that whole mitochondria are turned over via macroautophagy. Does Huntingtin play a role in selective macroautophagy? In the discussion here I suggest that Htt may have a normal function in the lysosomal mechanism of selective macroautophagy involved in its own degradation Macroautophagy induced by ethanol seemed to be selective for damaged mitochondria and accumulated lipid droplets, but not long-lived proteins, which could account for its protective effects Although macroautophagy can be nonspecific, there are many examples of selective sequestration including pexophagy, mitophagy and the cytoplasm to vacuole targeting (Cvt) pathway. Mitochondria autophagy (mitophagy) is the process of selective degradation of mitochondria that has an important role in mitochondrial quality control. One of the genes identified, YLR356W, is required for mitophagy, but not for macroautophagy or other types of selective autophagy. A genomic screen for yeast mutants defective in selective mitochondria autophagy. Mitophagy is the process of selective mitochondrial degradation via autophagy, which has an important role in mitochondrial quality control. Analysis of this set of targeted deletion mutants demonstrated that loss of any of the 16 genes necessary for nonselective macroautophagy renders the fungus unable to cause rice blast disease, due to impairment of both conidial programmed cell death and appressorium maturation. In contrast, genes necessary only for selective forms of autophagy, such as pexophagy and mitophagy, are dispensable for appressorium-mediated plant infection. This gene is not required for other types of selective autophagy or for nonspecific macroautophagy. However, in contrast to the core autophagy genes such as atg5 and atg7, expression of ulk1 is not essential for induction of macroautophagy in response to nutrient deprivation or for survival of newborn mice. Together, these data suggest that the ATG1 homologue, Ulk1, is a component of the selective autophagy machinery that leads to the elimination of organelles in erythroid cells rather that an essential mechanistic component of autophagy. Growing evidence supports an active role for dysregulated macroautophagy (autophagic stress) in neuronal cell death and neurodegeneration. Alterations in mitochondrial function and dynamics are also strongly implicated in neurodegenerative diseases. Interestingly, whereas the core autophagy machinery is evolutionarily conserved and shared among constitutive and induced or selective autophagy, recent studies implicate distinct mechanisms regulating mitochondrial autophagy (mitophagy) in response to general autophagic stimuli. We discovered that activation of the UPR in yeast also induces a new branch of macroautophagy that selectively targets the ER. We term this process "ER-phagy", in analogy to pexophagy and mitophagy, the two other known forms of organelle-specific marcoautophagy. ER-phagy involves the generation of autophagosomes that selectively include ER membranes and whose delimiting double membranes also derive, at least in part, from the ER. This suggests that in fungi an organism-specific form of selective autophagy may occur, for which specialized Atg proteins have evolved. ransfer of Y. lipolytica cells from oleate/ethylamine to glucose/ammonium chloride medium leads to selective macroautophagy of peroxisomes. Insulin-dependent signaling regulates azurophil granule-selective macroautophagy in human myeloblastic cells. We show that insulin-dependent signals regulate azurophil granule-selective macroautophagy in human myeloid cells. By contrast, other organelles, including the mitochondria, endoplasmic reticulum, and Golgi apparatus remained intact, indicating that the macroautophagy selectively targeted azurophil granules. Thus, insulin-dependent signals are responsible for the control of azurophil granule-selective macroautophagy via Akt-dependent pathways Eukaryotic cells have the ability to degrade proteins and organelles by selective and nonselective modes of micro- and macroautophagy. For example, pexophagy is a selective process for the regulated degradation of peroxisomes by autophagy. We have characterized biochemically, morphologically, and genetically two distinct pathways for the selective degradation of peroxisomes in Pichia pastoris. These pathways are independently regulated and analogous to microautophagy and macroautophagy that have been defined in mammalian cells. If we are willing to slightly modify our definition of autophagy, with a focus on "degradation of a cell's own components through the lysosomal/vacuolar machinery," we can include a newly documented process, programmed nuclear destruction (PND). Autophagy is a lysosomal degradation pathway that can sequester cytosolic material, including organelles, nonspecifically in a process called nonselective macroautophagy, or target specific protein aggregates designated for destruction in a process called selective autophagy. Selective macroautophagy uses double-membrane vesicles, termed autophagosomes, to transport cytoplasmic pathogens, organelles and protein complexes to the vacuole for degradation. Autophagy (macroautophagy), a highly conserved eukaryotic mechanism, is a non-selective degradation process, helping to maintain a balance between the synthesis, degradation and subsequent recycling of macromolecules to overcome various stress conditions. Whole organelle turnover is mediated through macroautophagy, a process by which autophagosomes deliver mitochondria to the lysosome for hydrolytic degradation. Macroautophagy is a catabolic process by which the cell degrades cytoplasmic components through the lysosomal machinery. Macroautophagy maintains cellular homeostasis through targeting cytoplasmic contents and organelles into autophagosomes for degradation. Macroautophagy is a catabolic process by which cytosolic components are sequestered by double membrane vesicles called autophagosomes and sorted to the lysosomes/vacuoles to be degraded. Macroautophagy (hereafter autophagy) is a cellular degradation process, which in yeast is induced in response to nutrient deprivation. Macroautophagy was thought to be an unspecific bulk degradation process. Autophagy is a highly regulated intracellular degradation process by which cells remove cytosolic long-lived proteins and damaged organelles, and can be monitored by imaging the incorporation of microtubule-associated light chain 3 (LC3) fused to a fluorescent protein (GFP or mCherry) into nascent autophagosomes. Beside macroautophagy, there are several forms of selective autophagy, including chaperone-mediated autophagy (CMA), cytoplasm to vacuole targeting (Cvt), pexophagy and mitophagy. Macroautophagy (commonly referred to as autophagy) is the process by which intact organelles and/or large portions of the cytoplasm are engulfed within double-membraned autophagic vacuoles for degradation. This analysis demonstrated that Atg proteins required for non-selective macroautophagy are conserved from yeast to man, stressing the importance of this process in cell survival and viability. Part of the degradation of intracellular proteins occurs in the lysosomes and is mediated by macroautophagy.

yes