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Thyroid hypoplasia as a cause of congenital hypothyroidism in Williams syndrome. In the Williams-Beuren syndrome (WBS), disorders of the thyroid function and morphology have been reported and programs of thyroid screening and surveillance are recommended. However, the frequency of biochemical thyroid assessment, particularly in the first year of life, is being debated. In this report we describe an infant with WBS and congenital hypothyroidism, due to an important thyroid hypoplasia. The patient, a 1-month-old female, negative at primary neonatal thyroid screening, was referred to our hospital for dyspnea. Thyroid function tests showed a raised TSH (42 mIU/l; normal range 0.5-4 mIU/l) with a low FT(4) concentration (10.21 pmol/l; normal range: 10.29-24.45 pmol/l). Ultrasound examination of the neck showed a significant thyroid hypoplasia, whereas (99m)Tc-pertechnetate thyroid scintigraphy evidenced a thyroid gland in normal position, with reduced shape and overall weak fixation. Therefore, treatment with L-thyroxinewas started. Thyroid hypoplasia is a frequent characteristic of WBS and abnormalities of thyroid function are common in patients with this feature. Therefore, the possibility of congenital hypothyroidism should always be taken into consideration too and, even if congenital hypothyroidism neonatal screening is negative, thyroid (morphology and function) evaluation should be regularly assessed when the diagnosis is made and, thereafter, every year in the first years of life.

Which hormone abnormalities are common in Williams syndrome ?

530cefaaad0bf1360c00000d_002

Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor. Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.

Which infection can be prevented with Dapivirine?

5880b812c872c95565000006_019

Familial isolated pituitary adenoma: evidence for genetic heterogeneity. The identification of mutations in the Aryl hydrocarbon receptor interacting protein (AIP) gene in a subset of familial isolated pituitary adenoma (FIPA) cases has recently expanded our understanding of the pathophysiology of inherited pituitary adenoma disorders. However, a genetic cause of has not yet been determined in the majority (85%) of FIPA families and half of the families with isolated familial somatotropinoma. Several studies and reviews have assessed the genetic and clinical features of AIP-mutated FIPA patients, which range from a complete lack of symptoms in adult/elderly individuals to large, aggressive early-onset pituitary tumors. In this study, we aimed to briefly revise the data available for the 11q13 locus and other additional loci that have been implicated in genetic susceptibility to FIPA: 2p16-12; 3q28; 4q32.3-4q33; chr 5, 8q12.1, chr 14, 19q13.4 and 21q22.1. These candidate regions may contain unidentified gene(s) that can be potentially disrupted in AIP-negative FIPA families. A better knowledge of these susceptibility loci may disclose modifier genes that are likely to play exacerbating or protective roles in the phenotypic diversity of AIP-mutated families.

Mutation of which gene is implicated in the familial isolated pituitary adenoma?

551c23bc6b348bb82c00000b_011

Specific antidotes in development for reversal of novel anticoagulants: a review. In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.

Andexanet Alfa is an antidote of which clotting factor inhibitors?

5880b073c872c95565000003_068

Frontal hypometabolism in elderly breast cancer survivors determined by [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET): a pilot study. PURPOSE: The term "chemobrain" is sometimes used to denote deficits in neuropsychological functioning that may occur as a result of cancer treatment. As breast cancer survivors now commonly reach late life, it is not known whether previous exposure to chemotherapy may affect long-term risk for cognitive impairment. To help address this concern, this study tested whether successfully surviving chemotherapy earlier in life was associated with later differences in brain metabolic function as an older adult compared to controls. This question was examined using positron emission tomography measures of brain glucose metabolism in elderly women cancer survivors. METHODS: Breast cancer survivors (N = 10), currently free of recurrent cancer and without a diagnosis of a cognitive disorder, were compared to matched healthy controls (N = 10). All subjects were imaged at rest with [(18)F]fluorodeoxyglucose. Images were analyzed semi-quantitatively using the Alzheimer's Discrimination Tool and a volume of interest-based approach derived from co-registered magnetic resonance imaging. RESULTS: Relative [(18)F]fluorodeoxyglucose uptake (normalized to global) was significantly lower in the survivors compared with control subjects in bilateral orbital frontal regions, consistent with differences between the groups in cognition and executive function (i.e., Trail Making Test, Part B and mini-mental state examination) and despite no significant differences with respect to age, education, intelligence, or working memory. None of the survivors and only one control manifested a global positron emission tomography score consistent with an Alzheimer's disease metabolic pattern. CONCLUSION: Breast cancer survivors treated with chemotherapy may manifest long-term changes in brain glucose metabolism indicative of subtle frontal hypometabolism, a finding consistent with results from neuropsychological testing and other imaging modalities.

What is a "chemobrain"?

58efa1b870f9fc6f0f000003_001

Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.

In which yeast chromosome does the rDNA cluster reside?

5710e131a5ed216440000001_002

Future agents and treatment directions in multiple myeloma. The development of bortezomib and immunomodulatory agents resulted in a revolution in the treatment of multiple myeloma (MM). Moreover, second-generation proteasome inhibitors (carfilzomib) and immunomodulatory agents (pomalidomide) have recently been approved. Nevertheless, the incurability of this disease requires other drugs with different mechanisms of action to either prolong the survival of patients refractory to current therapies, or achieve cure. Active research has been done exploring the pathogenesis of MM and searching for novel, druggable targets. In this regard, some of these novel agents seem promising, such as monoclonal antibodies (anti-CD38 - daratumumab or anti-CS1 - elotuzumab) or the kinesin protein inhibitor Arry-520. Other agents under investigation are kinase inhibitors, signaling pathways inhibitors or deacetylase inhibitors. With so many novel agents under investigation, future therapy in MM will probably involve the combined use of the already approved drugs with some of those newly discovered.

What is the target of daratumumab?

5880aef4c872c95565000001_027

Mowat-Wilson syndrome in a fetus with antenatal diagnosis of short corpus callosum: advocacy for standard autopsy. Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene rarely diagnosed prenatally and with little fetal description reported. It is mainly characterized by moderate-to-severe intellectual disability, epilepsy, facial dysmorphism and various malformations including Hirschsprung disease and corpus callosum anomalies. Here we report a fetal case of MWS well described, suspected at standard autopsy. The association of a corpus callosum hypoplasia with a histological Hirschsprung disease and a typical facial gestalt allowed the guiding of genetic testing. Classical fetopathological examination still keeps indications in cases of syndromic association in the era of virtual autopsy.

Which gene is responsible for the development of the Mowat-Wilson syndrome?

5519113b622b19434500000f_033

1,25-dihydroxyvitamin D3 enhances the apoptotic activity of MDM2 antagonist nutlin-3a in acute myeloid leukemia cells expressing wild-type p53. The tumor suppressor p53 is often referred to as "the guardian of the genome" because of its central role in the cellular response to oncogenic stress and prevention of tumor development. Mutations of p53 in acute myeloid leukemia (AML) are rare but resistance to chemotherapy has been reported because of the deregulation of the p53 signaling and differentiation pathways. It is known that the interaction of the vitamin D metabolite 1,25-dihydroxyvitamin D(3) (1,25D) with its functional vitamin D receptor leads to differentiation, G(1) arrest, and increased cell survival in p53-null AML cells. However, there are no reports on the effect of 1,25D in leukemia cells expressing wild-type p53. Here, we examine vitamin D signaling in AML cells MOLM-13 and OCI-AML3 expressing wild-type p53 in the presence and absence of the MDM2 antagonist nutlin-3. We find that 1,25D alone induces monocytic differentiation in these cell lines similar to that seen in p53-null AML cells, suggesting that the presence of wild-type p53 is compatible with activation of vitamin D signaling. Combination of nutlin-3a with 1,25D accelerated programmed cell death, likely because of enhanced nutlin-induced upregulation of the proapoptotic PIG-6 protein and downregulation of antiapoptotic BCL-2, MDMX, human kinase suppressor of Ras 2, and phosphorylated extracellular signal-regulated kinase 2.

Which tumor suppressor is referred to as "the guardian of the genome"?

55421ee7ccca0ce74b000002_015

The oral spleen tyrosine kinase inhibitor fostamatinib attenuates inflammation and atherogenesis in low-density lipoprotein receptor-deficient mice. OBJECTIVE: Spleen tyrosine kinase (SYK) has come into focus as a potential therapeutic target in chronic inflammatory diseases, such as rheumatoid arthritis and asthma, as well as in B-cell lymphomas. SYK has also been involved in the signaling of immunoreceptors, cytokine receptors, and integrins. We therefore hypothesized that inhibition of SYK attenuates the inflammatory process underlying atherosclerosis and reduces plaque development. METHODS AND RESULTS: Low-density lipoprotein receptor-deficient mice consuming a high-cholesterol diet supplemented with 2 doses of the orally available SYK inhibitor fostamatinib for 16 weeks showed a dose-dependent reduction in atherosclerotic lesion size by up to 59±6% compared with the respective controls. Lesions of fostamatinib-treated animals contained fewer macrophages but more smooth muscle cells and collagen-characteristics associated with more stable plaques in humans. Mechanistically, fostamatinib attenuated adhesion and migration of inflammatory cells and limited macrophage survival. Furthermore, fostamatinib normalized high-cholesterol diet -induced monocytosis and inflammatory gene expression. CONCLUSIONS: We present the novel finding that the SYK inhibitor fostamatinib attenuates atherogenesis in mice. Our data identify SYK inhibition as a potentially fruitful antiinflammatory therapeutic strategy in atherosclerosis.

Which enzyme is inhibited by a drug fostamatinib?

53357ca0d6d3ac6a3400004b_011

Analysis of protein profile of tomato root infected with Fusarium oxysporum f. sp lycopersici. Fusarium wilt caused by Fusarium oxysporum f. sp lycopersici (Fol) is one of the main diseases affecting tomatoes. The BHRS 2,3 genotype of tomato is, however, resistant to this disease. A proteomic approach was used to understand the defense mechanisms of this genotype using the tomato root, the first tissue that interacts with the fungus, as a target. Protein was extracted and separated by two-dimensional electrophoresis followed by staining with Coomassie brilliant blue. The proteins were identified by MALDI-TOF/TOF mass spectrometry. A total of 22 proteins were identified, 21 of which showed differential expression with 12 proteins being upregulated and nine being downregulated. Plants responded to the pathogen with increased expression of pathogenesis-related proteins. We noted the induction of proteins involved in hypersensitivity reaction and other defense mechanisms. The expression of proteins of primary metabolism related to energy production, however, decreased, as did the expression of two proteins related to defense against abiotic stress. These results demonstrate the presence of important mechanisms for defense against Fol in the tomato genotype BHRS 2,3.

Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?

5a8b1264fcd1d6a10c00001d_003

ACS chemical neuroscience molecule spotlight on semagacestat (LY450139). Semagacestat (LY450139) is a novel γ-secretase inhibitor currently in late-stage development by Eli Lilly and Company as a potential treatment for Alzheimer's disease (AD). Semagacestat is currently being studied in two phase III clinical trials.

LY450139 is investigational name of which drug?

54f35ad864850a5854000004_004

A rare G6490-->A substitution at the last nucleotide of exon 10 of the glucocerebrosidase gene in two unrelated Italian Gaucher patients. Mutation screening of the glucocerebrosidase gene by SSCP analysis revealed an abnormal pattern of exon 10 in two unrelated Italian Gaucher patients. Direct sequencing of the mutated samples identified a G6490-->A transition. The same mutation has been described before in a Japanese patient with Gaucher disease type III. The clinical phenotype of our patients was type I in one whose second allele carried the N370S mutation and type II in the other one with a L444P mutation. In this latter the G6490-->A substitution cancels a normal Msp I site, while on the opposite chromosome the T6433-->C mutation (L444P) introduces a new Msp I site. Thus, digestion with Msp I of the amplified exon 10 is a useful method for identifying the two mutations simultaneously.

What is the gene mutated in the Gaucher disease?

532f55fed6d3ac6a34000036_015

Potent antitumor activity of the novel HSP90 inhibitors AUY922 and HSP990 in neuroendocrine carcinoid cells. The heat shock protein (HSP) 90 chaperone machine involved in numerous oncogenic signaling pathways is overexpressed in cancer cells and is currently being evaluated for anticancer therapy. Neuroendocrine tumors (NETs) of the gastroenteropancreatic (GEP) system comprise a heterogeneous group of tumors with increasing incidence and poor prognosis. Here, we report the antiproliferative effects of the HSP90 inhibitors AUY922 and HSP990 in neuroendocrine tumor cells. Treatment of human pancreatic BON1, bronchopulmonary NCI-H727 and midgut carcinoid GOT1 neuroendocrine tumor cells with increasing concentrations of AUY922 and HSP990 dose-dependently suppressed cell viability. Significant effects on neuroendocrine cell viability were observed with inhibitor concentrations as low as 5 nM. Inhibition of cell viability was associated with the induction of apoptosis as demonstrated by an increase in sub-G1 events and PARP cleavage. HSP90 inhibition was associated with decreased neuroendocrine ErbB and IGF-I receptor expression, decreased Erk and Akt phospho-rylation and the induction of HSP70 expression. These findings provide evidence that targeted inhibition of upregulated HSP90 activity could be useful for the treatment of aggressive neuroendocrine tumors resistant to conventional therapy.

Which heat shock protein is found to be upregulated during Hsp90 inhibition?

534abe8aaeec6fbd07000013_001

A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc) + B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high-dose dexamethasone could be added to S/plc. Response and progression-free survival (PFS) were analyzed pre-dexamethasone by European Group for Blood and Marrow Transplantation (EBMT) criteria. For the 281 randomized patients, median PFS for S + B and plc + B was 8.0 and 7.6 months (HR 0.869, P = 0.345), overall response rate was 55 versus 47% (P = 0.213), complete response rate was 11 versus 7%, and median overall survival (OS) was 30.8 versus 36.8 months (HR 1.353, P = 0.103). Sustained suppression of C-reactive protein, a marker reflective of inhibition of interleukin-6 activity, was seen with S + B. Siltuximab did not affect B pharmacokinetics. Siltuximab/placebo discontinuation (75 versus 66%), grade > 3 neutropenia (49 versus 29%), thrombocytopenia (48 versus 34%), and all-grade infections (62 versus 49%) occurred more frequently with S + B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma.

Which interleukin is blocked by Siltuximab?

56c1f02aef6e39474100004b_002

Chediak-Higashi syndrome: description of two novel homozygous missense mutations causing divergent clinical phenotype. Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease resulting from mutations in the LYST/CHS1 gene, which encodes for a 429 kDa protein, CHS1/LYST, that regulates vesicle trafficking and determines the size of lysosomes and other organelles. To date, 60 different mutations have been characterized, and a reasonably straightforward phenotype-genotype correlation has been suggested. We describe two patients on opposite ends of the CHS clinical spectrum with novel missense mutations. We characterized these patients in terms of their mutations, protein localization and expression, mRNA stability, and electrostatic potential. Patient 1 is the first report of a severe early-onset CHS with a homozygous missense mutation (c.11362 G>A, p.G3725R) in the LYST/CHS1 gene. This molecular change results in a reduction at the CHS1 protein level, not due to an mRNA effect, but maybe a consequence of both, a change in the structure of the protein and most likely attributable to the remarkable serious perturbation in the electrostatic potential. Patient 2, who exhibited the adolescence form of the disease, was found to be homozygous for a novel missense mutation c.961 T>C, p.C258R, which seemed to have minor effect on the structure of the CHS1/LYST protein. Reexamining accepted premises of missense mutant alleles being reported among patients with clinically mild forms of the disorder should be carried out, and attempts to link genotype and clinical phenotype require identifying the actual molecular effect of the mutation. Early and accurate diagnosis of the severity of the disease is extremely important to early differentiate patients who would benefit from premature enrollment into a transplantation protocol.

Which syndrome is associated with mutations in the LYST gene?

56f564f909dd18d46b000009_002

Redox regulation of the transcriptional repressor Bach1. Bach1 is a transcriptional repressor of heme oxygenase-1, one of the most inducible phase 2 proteins. Bach1 binds in conjunction with a small Maf protein to tandem repeats of the antioxidant response element (ARE) and quenches the target gene expression. On the other hand, the transactivator Nrf2 binds and up-regulates the ARE-governed gene expression. By using a sulfhydryl oxidizing agent, diamide, here we provide evidence which indicates that the Bach1 function is regulated by the redox state. Diamide showed restricted Nrf2 nuclear translocation and ARE-driven reporter activity but reversed the ARE transcriptional activity suppressed by ectopically expressed Bach1. Substitution of the conserved cysteine residue in the DNA binding domain of Bach1 to serine (C574S mutant) caused a refractory response to the diamide-mediated reactivation of the Bach1-suppressed reporter activity. Moreover, diamide induced cytoplasmic translocation of the GFP-Bach1 fusion protein but failed to translocate the fusion protein consisting of the C574S mutant. These data suggest that redox regulation of Bach1 is an alternative mechanism to induce multiple ARE-governed genes.

Is the transcriptional regulator BACH1 an activator or a repressor?

52fa6ac72059c6d71c000055_014

Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis. BACKGROUND & AIMS: T-cell-mediated biliary injury is a feature of primary sclerosing cholangitis (PSC). We studied the roles of CD28(-) T cells in PSC and their regulation by vitamin D. METHODS: Peripheral and liver-infiltrating mononuclear cells were isolated from blood or fresh liver tissue. We analyzed numbers, phenotypes, functions, and localization patterns of CD28(-) T cells, along with their ability to activate biliary epithelial cells. We measured levels of tumor necrosis factor (TNF)α in liver tissues from patients with PSC and the effects of exposure to active vitamin D (1,25[OH]2D3) on expression of CD28. RESULTS: A significantly greater proportion of CD4(+) and CD8(+) T cells that infiltrated liver tissues of patients with PSC were CD28(-), compared with control liver tissue (CD4(+): 30.3% vs 2.5%, P < .0001; and CD8(+): 68.5% vs 31.9%, P < .05). The mean percentage of CD4(+)CD28(-) T cells in liver tissues from patients with PSC was significantly higher than from patients with primary biliary cirrhosis or nonalcoholic steatohepatitis (P < .05). CD28(-) T cells were activated CD69(+)CD45RA(-) C-C chemokine receptor (CCR)7(-) effector memory and perforin(+) granzyme B(+) cytotoxic cells, which express CD11a, CX3CR1, C-X3-C motif receptor 6 (CXCR6), and CCR10-consistent with their infiltration of liver and localization around bile ducts. Compared with CD28(+) T cells, activated CD28(-) T cells produced significantly higher levels of interferon γ and TNFα (P < .05), and induced up-regulation of intercellular cell adhesion molecule-1, HLA-DR, and CD40 by primary epithelial cells (3.6-fold, 1.5-fold, and 1.2-fold, respectively). Liver tissue from patients with PSC contained high levels of TNFα; TNFα down-regulated the expression of CD28 by T cells in vitro (P < .01); this effect was prevented by administration of 1,25(OH)2D3 (P < .05). CONCLUSIONS: Inflammatory CD28(-) T cells accumulate in livers of patients with PSC and localize around bile ducts. The TNFα-rich microenvironment of this tissue promotes inflammation; these effects are reversed by vitamin D in vitro.

To which disease does the loss of CD28 expression by liver-infiltrating T cells contribute?

58853922e56acf5176000016_002

Positive and negative selection in murine ultraconserved noncoding elements. There are many more selectively constrained noncoding than coding nucleotides in the mammalian genome, but most mammalian noncoding DNA is subject to weak selection, on average. One of the most striking discoveries to have emerged from comparisons among mammalian genomes is the hundreds of noncoding elements of more than 200 bp in length that show absolute conservation among mammalian orders. These elements represent the tip of the iceberg of a much larger class of conserved noncoding elements (CNEs). Much evidence suggests that CNEs are selectively constrained and not mutational cold-spots, and there is evidence that some CNEs play a role in the regulation of development. Here, we quantify negative and positive selection acting in murine CNEs by analyzing within-species nucleotide variation and between-species divergence of CNEs that we identified using a phylogenetically independent comparison. The distribution of fitness effects of new mutations in CNEs, inferred from within-species polymorphism, suggests that CNEs receive a higher number of strongly selected deleterious mutations and many fewer nearly neutral mutations than amino acid sites of protein-coding genes or regulatory elements close to genes. However, we also show that CNEs experience a far higher proportion of adaptive substitutions than any known category of genomic sites in murids. The absolute rate of adaptation of CNEs is similar to that of amino acid sites of proteins. This result suggests that there is widespread adaptation in mammalian conserved noncoding DNA elements, some of which have been implicated in the regulation of crucially important processes, including development.

Which is the process that Conserved noncoding elements mostly regulate?

51387022bee46bd34c000002_001

Effect of opicapone and entacapone upon levodopa pharmacokinetics during three daily levodopa administrations. BACKGROUND AND OBJECTIVES: Opicapone is a novel third generation catechol-O-methyltransferase (COMT) inhibitor. The purpose of this study was to compare the levodopa pharmacokinetic profile throughout a day driven by the COMT inhibition either following repeated doses of opicapone or concomitant administration with entacapone. METHODS: A randomized, double-blind, gender-balanced, parallel-group study was performed in 4 groups of 20 healthy subjects each. Four subjects in each group received placebo during the entire study. Sixteen subjects in one group received placebo once daily for 11 days and on day 12, 200 mg entacapone concomitantly with each levodopa/carbidopa dose (three times separated by a 5-h interval). Sixteen subjects in each of the remaining three groups received respectively 25, 50, and 75 mg opicapone once daily for 11 days and on day 12, placebo concomitantly with each levodopa/carbidopa dose. RESULTS: Levodopa minimum plasma concentration (Cmin) for each levodopa/carbidopa dose and for the mean of all levodopa/carbidopa doses increased substantially with all active treatments (entacapone and opicapone) when compared to the control group (placebo), with values ranging from 1.7-fold (200 mg entacapone) to 3.3-fold (75 mg opicapone). No statistical difference was found for levodopa peak of systemic exposure (as assessed by maximum observed plasma concentration (Cmax)) between all active treatments and placebo. A significant increase in the levodopa extent of systemic exposure (as assessed by concentration-time curve (AUC)) occurred with all opicapone treatments in relation to placebo. No statistical difference was found for levodopa AUC when entacapone was compared to placebo. When compared to entacapone, both 50 and 75 mg opicapone presented a significant increase for the levodopa AUC. All active treatments significantly inhibited both peak (as assessed by Emax) and extent (as assessed by effect-time curve (AUEC)) of the COMT activity in relation to placebo. When compared to entacapone, all opicapone treatments significantly decreased the extent (AUEC) of the COMT activity due to a long-lasting and sustained effect. The tolerability profile was favorable for all active treatments. CONCLUSION: Opicapone, a novel third generation COMT inhibitor, when compared to entacapone, provides a superior response upon the bioavailability of levodopa associated to more pronounced, long-lasting, and sustained COMT inhibition. The tolerability profile was favorable. On the basis of the results presented in this study and along with the earlier pharmacology studies, it is anticipated that opicapone adjunct therapy at the dosages of 25 and 50 mg will provide an enhancement in levodopa availability that will translate into clinical benefit for Parkinson's disease patients.

What enzyme is inhibied by Opicapone?

56c1d857ef6e394741000033_003

[Pharmacologic and clinical characteristics of direct inhibitors of factor Xa: rivaroxaban, apixaban, edoxaban and betrixaban]. Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.

Which clotting factor is inhibited by betrixaban?

55200c606b348bb82c000013_085

Analysis of amino acid 13C abundance from human and faunal bone collagen using liquid chromatography/isotope ratio mass spectrometry. The scope of compound-specific stable isotope analysis has recently been increased with the development of the LC IsoLink which interfaces high-performance liquid chromatography (HPLC) and isotope ratio mass spectrometry (IRMS) to provide online LC/IRMS. This enables isotopic measurement of non-volatile compounds previously not amenable to compound-specific analysis or requiring substantial modification for gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS), which results in reduced precision. Amino acids are an example of such compounds. We present a new chromatographic method for the HPLC separation of underivatized amino acids using an acidic, aqueous mobile phase in conjunction with a mixed-mode stationary phase that can be interfaced with the LC IsoLink for compound-specific delta13C analysis. The method utilizes a reversed-phase Primesep-A column with embedded, ionizable, functional groups providing the capability for ion-exchange and hydrophobic interactions. Baseline separation of 15 amino acids and their carbon isotope values are reported with an average standard deviation of 0.18 per thousand (n = 6). In addition delta13C values of 18 amino acids are determined from modern protein and archaeological bone collagen hydrolysates, demonstrating the potential of this method for compound-specific applications in a number of fields including metabolic, ecological and palaeodietary studies.

Which bone protein is used in archaelogy for dating and species identification?

55054f8af73303d458000002_017

The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. BACKGROUND: In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS: We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS: In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION: The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.

ROSIER scale is used for which disorder?

551fd9c06b348bb82c000012_026

Ecallantide (DX-88) for acute hereditary angioedema attacks: integrated analysis of 2 double-blind, phase 3 studies. BACKGROUND: Hereditary angioedema (HAE) is a rare disorder characterized by recurrent angioedema attacks. Ecallantide, a novel plasma kallikrein inhibitor, inhibits production of bradykinin, the key mediator of these angioedema attacks. OBJECTIVE: We sought to further characterize the safety and efficacy of ecallantide for HAE attacks by performing an integrated analysis of pooled data from 2 phase 3 studies. METHODS: An integrated analysis was conducted with data from 2 randomized, double-blind, placebo-controlled studies in which patients with HAE (age > 10 years) received 30 mg of subcutaneous ecallantide or placebo within 8 hours of onset of a moderate-to-severe attack at any anatomic site. Efficacy was evaluated by using validated patient-reported outcome measures: the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS). RESULTS: Compared with placebo, ecallantide resulted in significantly greater reduction in MSCS scores from baseline to 4 hours after dosing (ecallantide [mean ± SD], -0.97 ± 0.78; placebo, -0.47 ± 0.71; P < .001) and a significantly greater increase in TOSs at 4 hours (ecallantide, 55.5 ± 46.5; placebo, 20.0 ± 58.9; P < .001). Significantly greater symptomatic improvement over placebo occurred through 24 hours after dosing (MSCS score, P = .028; TOS, P = .039). Ecallantide demonstrated efficacy at all attack sites. The incidence of treatment-emergent adverse events was similar between groups. CONCLUSIONS: This integrated analysis supports and expands on the results of the phase 3 studies. Ecallantide appears to be effective and well tolerated for the treatment of HAE attacks.

DX-88 is investigational name of which drug?

54f1e031c409818c32000001_002

NKX2-1 mutations in brain-lung-thyroid syndrome: a case series of four patients. Brain-lung-thyroid syndrome (BLTS) characterized by congenital hypothyroidism, respiratory distress syndrome, and benign hereditary chorea is caused by thyroid transcription factor 1 (NKX2-1/TTF1) mutations. We report the clinical and molecular characteristics of four cases presenting with primary hypothyroidism, respiratory distress, and neurological disorder. Two of the four patients presenting with the triad of BLTS had NKX2-1 mutations, and one of these NKX2-1 [c.890_896del (p.Ala327Glyfs*52)] is a novel variant. The third patient without any identified NKX2-1 mutations was a carrier of mitochondrial mutation; this raises the possibility of mitochondrial mutations contributing to thyroid dysgenesis. Although rare, the triad of congenital hypothyroidism, neurological, and respiratory signs is highly suggestive of NKX2-1 anomalies. Screening for NKX2-1 mutations in patients with thyroid, lung, and neurological abnormalities will enable a unifying diagnosis and genetic counseling for the affected families. In addition, identification of an NKX2-1 defect would be helpful in allaying the concerns about inadequate thyroxine supplementation as the cause of neurological defects observed in some children with congenital hypothyroidism.

Mutation of which gene is implicated in the Brain-lung-thyroid syndrome?

56c1f03bef6e394741000053_006

Menin links estrogen receptor activation to histone H3K4 trimethylation. The product of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene, menin, is an integral component of MLL1/MLL2 histone methyltransferase complexes specific for Lys4 of histone H3 (H3K4). We show that menin is a transcriptional coactivator of the nuclear receptors for estrogen and vitamin D. Activation of the endogenous estrogen-responsive TFF1 (pS2) gene results in promoter recruitment of menin and in elevated trimethylation of H3K4. Knockdown of menin reduces both activated TFF1 (pS2) transcription and H3K4 trimethylation. In addition, menin can directly interact with the estrogen receptor-alpha (ERalpha) in a hormone-dependent manner. The majority of disease-related MEN1 mutations prevent menin-ERalpha interaction. Importantly, ERalpha-interacting mutants are also defective in coactivator function. Our results indicate that menin is a critical link between recruitment of histone methyltransferase complexes and nuclear receptor-mediated transcription.

Which is the histone residue methylated by MLL1?

533be71dfd9a95ea0d000009_017

BDNF Val66Met and DRD2 Taq1A polymorphisms interact to influence PTSD symptom severity: a preliminary investigation in a South African population. BACKGROUND: We evaluated the role that selected variants in serotonin transporter (5-HTT), dopamine receptor 2 (DRD2) and brain-derived neurotrophic factor (BDNF) genes play in PTSD symptom severity in an at-risk population. We also investigated the interaction between the genetic variants to determine whether these variables and the interactions between the variables influenced the severity of PTSD symptoms. METHODS: PTSD symptoms were quantitatively assessed using the Davidson Trauma Scale (DTS) in 150 participants from an at-risk South African population. All participants were genotyped for the 5-HTTLPR, DRD2 Taq1A and BDNF Val66Met polymorphisms. Gene-gene interactions were investigated using various linear models. All analyses were adjusted for age, gender, major depressive disorder diagnosis, level of resilience, level of social support and alcohol dependence. RESULTS: A significant interaction effect between DRD2 Taq1A and BDNF Val66Met variants on DTS score was observed. On the background of the BDNF Val66Val genotype, DTS score increased significantly with the addition of a DRD2 Taq1A A1 allele. However, on the BDNF Met66 allele background, the addition of an A1 allele was found to reduce total DTS score. CONCLUSIONS: This study provides preliminary evidence for an epistatic interaction between BDNF Val66Met and DRD2 Taq1A polymorphisms on the severity of PTSD symptoms, where both too little and too much dopamine can result in increased PTSD symptom severity.

Symptoms of which disorder are evaluated with the Davidson Trauma Scale?

58861d413b87a8a738000002_021

Downregulation of SMARCB1/INI1 expression in pediatric chordomas correlates with upregulation of miR-671-5p and miR-193a-5p expressions. Loss of SMARCB1/INI1 expression is considered to be a hallmark for childhood chordomas (CCs). Although mutation/loss of 22q has strongly established the loss of SMARCB1/INI1 in cancers, the cause in CCs remains elusive. Recent studies suggest role of miRNAs in regulation of SMARCB1/INI1 expressions. We examined 5 reported/target predicted miRNAs to SMARCB1/INI1 in SMARCB1/INI1 immunonegative and immunopositive cases, and found upregulation of miR-671-5p and miR-193a-5p in SMARCB1/INI1-immunonegative cases. Notably, these two miRNAs were significantly predicted to target TGF-β signaling, suggestive of dysregulation of developmental and osteoblast regulation pathway in CCs. Overall, we suggest miR-671-5p- and miR-193a-5p-mediated epigenetic mode of SMARCB1/INI1 loss and downregulated TGF-β pathway in CCs.

With which cancers has the loss of SMARCB1 been associated?

5a86f074faa1ab7d2e00003a_003

The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

What disease is the drug aducanumab targeting?

58a95c711978bbde22000001_001

Treatment-emergent mutations in NAEβ confer resistance to the NEDD8-activating enzyme inhibitor MLN4924. MLN4924 is an investigational small-molecule inhibitor of NEDD8-activating enzyme (NAE) in clinical trials for the treatment of cancer. MLN4924 is a mechanism-based inhibitor, with enzyme inhibition occurring through the formation of a tight-binding NEDD8-MLN4924 adduct. In cell and xenograft models of cancer, we identified treatment-emergent heterozygous mutations in the adenosine triphosphate binding pocket and NEDD8-binding cleft of NAEβ as the primary mechanism of resistance to MLN4924. Biochemical analyses of NAEβ mutants revealed slower rates of adduct formation and reduced adduct affinity for the mutant enzymes. A compound with tighter binding properties was able to potently inhibit mutant enzymes in cells. These data provide rationales for patient selection and the development of next-generation NAE inhibitors designed to overcome treatment-emergent NAEβ mutations.

Which enzyme does MLN4924 inhibit?

56ed03862ac5ed1459000004_005

Mutations in MED12 cause X-linked Ohdo syndrome. Ohdo syndrome comprises a heterogeneous group of disorders characterized by intellectual disability (ID) and typical facial features, including blepharophimosis. Clinically, these blepharophimosis-ID syndromes have been classified in five distinct subgroups, including the Maat-Kievit-Brunner (MKB) type, which, in contrast to the others, is characterized by X-linked inheritance and facial coarsening at older age. We performed exome sequencing in two families, each with two affected males with Ohdo syndrome MKB type. In the two families, MED12 missense mutations (c.3443G>A [p.Arg1148His] or c.3493T>C [p.Ser1165Pro]) segregating with the phenotype were identified. Upon subsequent analysis of an additional cohort of nine simplex male individuals with Ohdo syndrome, one additional de novo missense change (c.5185C>A [p.His1729Asn]) in MED12 was detected. The occurrence of three different hemizygous missense mutations in three unrelated families affected by Ohdo syndrome MKB type shows that mutations in MED12 are the underlying cause of this X-linked form of Ohdo syndrome. Together with the recently described KAT6B mutations resulting in Ohdo syndrome Say/Barber/Biesecker/Young/Simpson type, our findings point to aberrant chromatin modification as being central to the pathogenesis of Ohdo syndrome.

What is the genetic basis of Ohdo syndrome?

58f89eb270f9fc6f0f00001a_001

TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to poor growth conditions. Through its GTPase-activating protein (GAP) activity toward Rheb, this complex inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of cell growth. Here, we identify and biochemically characterize TBC1D7 as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. We demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity. Sequencing analyses of samples from TSC patients suggest that TBC1D7 is unlikely to represent TSC3. TBC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the localization of TSC2 to the lysosome. Like the other TSC-TBC components, TBC1D7 knockdown results in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions.

Which is the third subunit of the TSC1-TSC2 complex upstream of mTORC1?

5319ac99b166e2b806000034_001

Calcium/calmodulin-dependent protein kinase IIalpha mediates activation of mitogen-activated protein kinase and cytosolic phospholipase A2 in norepinephrine-induced arachidonic acid release in rabbit aortic smooth muscle cells. We have investigated the contribution of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) and mitogen-activated protein kinase (MAP kinase) in norepinephrine (NE)-induced arachidonic acid (AA) release in rabbit aortic vascular smooth muscle cells (VSMC). NE enhanced release of AA via activation of cytosolic phospholipase A2 (cPLA2) but not secretory PLA2 in VSMC prelabeled with [3H]AA. NE (10 microM) enhanced CaM kinase II and MAP kinase activity. In cells transiently transfected with antisense oligonucleotides complementary to the translation initiation sites of CaM kinase II and MAP kinase, NE-induced AA release was inhibited by 100 and 35% respectively. Treatment of cells with PD-098059, a MAP kinase kinase inhibitor, or with MAP kinase antisense oligonucleotide reduced NE-induced activation of MAP kinase and cPLA2. NE-induced MAP kinase and cPLA2 activation was also inhibited in cells treated with a CaM kinase II inhibitor, KN-93, or with CaM kinase II antisense oligonucleotide. On the other hand, inhibition of MAP kinase kinase with PD-098059 or of MAP kinase with antisense oligonucleotides did not alter the NE-induced increase in CaM kinase II activity. Phosphorylation of MAP kinase and CaM kinase II by NE, studied by 32P incorporation and immune complex kinase assays, was inhibited by KN-93. Collectively, these data suggest that CaM kinase II can activate MAP kinase, which in turn activates cPLA2 to release AA for prostacyclin synthesis in the rabbit VSMC. This novel pathway for activation of MAP kinase by CaM kinase II appears to be mediated through stimulation of MAP kinase kinase. Activation of adrenergic receptors with NE in VSMC caused translocation of CaM kinase II, MAP kinase, and cPLA2 to the nuclear envelope only in the presence of extracellular Ca2+. Okadaic acid, which increased phosphorylation and activity, did not translocate these enzymes. Therefore, it appears that in rabbit VSMC, NE, by promoting extracellular Ca2+ influx, increases CaM kinase II activity, leading to activation of MAP kinase and cPLA2 and translocation to the nuclear envelope, resulting in release of AA from the nuclear envelope for prostacyclin synthesis.

Which kinase is inhibited by the small molecule KN-93?

54f89e1a06d9727f76000001_001

Erlotinib at a dose of 25 mg daily for non-small cell lung cancers with EGFR mutations. PURPOSE: The tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are effective in non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) gene mutations. The usual clinical dose of gefitinib (250 mg/d) is only one third of its maximum tolerated dose, whereas the dose of erlotinib (150 mg/d) is at its maximum tolerated dose. In NSCLC cell lines, both TKIs have similar micromolar inhibitory concentrations. We explored whether erlotinib at 25 mg/d (trough serum concentration similar to gefitinib 250 mg/d) would be efficacious in EGFR-mutated NSCLC. METHODS: To study the inhibitory concentrations of gefitinib and erlotinib, we exposed EGFR-mutated cell lines (HCC827, H3255, PC-9, and H1975) to increasing concentrations of these TKIs. Further on, we performed a retrospective evaluation of seven patients with advanced EGFR-mutated (exon 19 deletions and L858R) NSCLC that were given erlotinib at 25 mg/d as their first EGFR TKI. RESULTS: Gefitinib and erlotinib generated similar inhibitory curves across our panel of EGFR-mutated NSCLC cell lines with overlapping mean 50% inhibitory concentration 95% confidence intervals for HCC827, PC-9, and H1975. Both drugs also displayed a high degree of correlation in mean 50% inhibitory concentration (Pearson's r = 0.99, p = 0.0417). Of the seven patients, five patients (71.5%) had partial responses to erlotinib 25 mg/d. Median progression-free survival was 17 months (95% confidence interval, 6-35 months). Toxicities were minimal, with only two (28.5%) patients having a rash and none experiencing (0%) diarrhea. CONCLUSIONS: In NSCLC cell lines, gefitinib and erlotinib have similar inhibitory profiles. In patients with NSCLC and EGFR-activating mutations, a dose of erlotinib 25 mg/d (equivalent to gefitinib 250 mg/d) leads to impressive response rates and progression-free survival similar to the growing experience with the approved doses of gefitinib (250 mg/d) and erlotinib (150 mg/d). Identifying prospectively the lowest and clinically active dose ranges of erlotinib and gefitinib will help further to personalize care for patients with tumors harboring EGFR mutations.

Mutations in which gene determine response to both erlotinib and gefitinib?

51542e44d24251bc05000081_006

Two regions within the amino-terminal half of APOBEC3G cooperate to determine cytoplasmic localization. APOBEC3G limits the replication of human immunodeficiency virus type 1, other retroviruses, and retrotransposons. It localizes predominantly to the cytoplasm of cells, which is consistent with a model wherein cytosolic APOBEC3G packages into assembling virions, where it exerts its antiviral effect by deaminating viral cDNA cytosines during reverse transcription. To define the domains of APOBEC3G that determine cytoplasmic localization, comparisons were made with APOBEC3B, which is predominantly nuclear. APOBEC3G/APOBEC3B chimeric proteins mapped a primary subcellular localization determinant to a region within the first 60 residues of each protein. A panel of 25 APOBEC3G mutants, each with a residue replaced by the corresponding amino acid of APOBEC3B, revealed that several positions within this region were particularly important, with Y19D showing the largest effect. The mislocalization phenotype of these mutants was only apparent in the context of the amino-terminal half of APOBEC3G and not the full-length protein, suggesting the existence of an additional localization determinant. Indeed, a panel of five single amino acid substitutions within the region from amino acids 113 to 128 had little effect by themselves but, in combination with Y19D, two substitutions-F126S and W127A-caused full-length APOBEC3G to redistribute throughout the cell. The critical localization-determining residues were predicted to cluster on a common solvent-exposed surface, suggesting a model in which these two regions of APOBEC3G combine to mediate an intermolecular interaction that controls subcellular localization.

Is APOBEC3B protein predominantly cytoplasmic or nuclear?

54e0ace81388e8454a000010_012

Influence of lateral association on forced unfolding of antiparallel spectrin heterodimers. Protein extensibility appears to be based broadly on conformational changes that can in principle be modulated by protein-protein interactions. Spectrin family proteins, with their extensible three-helix folds, enable evaluation of dimerization effects at the single molecule level by atomic force microscopy. Although some spectrin family members function physiologically only as homodimers (e.g. alpha-actinin) or are strictly monomers (e.g. dystrophin), alpha- and beta-spectrins are stable as monomeric forms but occur physiologically as alpha,beta-heterodimers bound laterally lengthwise. For short constructs of alpha- and beta-spectrin, either as monomers or as alpha,beta-dimers, sawtooth patterns in atomic force microscopy-forced extension show that unfolding stochastically extends repeats approximately 4-5-fold greater in length than native conformations. For both dimers and monomers, distributions of unfolding lengths appear bimodal; major unfolding peaks reflect single repeats, and minor unfolding peaks at twice the length reflect tandem repeats. Cooperative unfolding thus propagates through helical linkers between serial repeats (1, 2). With lateral heterodimers, however, the force distribution is broad and shifted to higher forces. The associated chains in a dimer can stay together and unfold simultaneously in addition to unfolding independently. Weak lateral interactions do not inhibit unfolding, but strong lateral interactions facilitate simultaneous unfolding analogous to serial repeat coupling within spectrin family proteins.

Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?

5540b9800083d1bf0e000002_002

The Roles of Arabidopsis CDF2 in Transcriptional and Posttranscriptional Regulation of Primary MicroRNAs. The precise regulation of microRNA (miRNA) transcription and processing is important for eukaryotic development. Plant miRNAs are first transcribed as stem-loop primary miRNAs (pri-miRNAs) by RNA polymerase II,then cleaved in the nucleus into mature miRNAs by Dicer-like 1 (DCL1). We identified a cycling DOF transcription factor, CDF2, which interacts with DCL1 and regulates the accumulation of a population of miRNAs. CDF2 binds directly to the promoters of some miRNAs and works as a transcription activator or repressor for these miRNA genes. CDF2 binds preferentially to the pri-miRNAs regulated by itself and affects DCL1-mediated processing of these pri-miRNAs. Genetically, CDF2 works in the same pathway as miR156 or miR172 to control flowering. We conclude that CDF2 regulates a group of pri-miRNAs at both the transcriptional and posttranscriptional levels to maintain proper levels of their mature miRNAs to control plant development.

Which polymerase transcribes pri-miRNAs?

589d965a78275d0c4a000049_006

The Genetic Cost of Neanderthal Introgression. Approximately 2-4% of genetic material in human populations outside Africa is derived from Neanderthals who interbred with anatomically modern humans. Recent studies have shown that this Neanderthal DNA is depleted around functional genomic regions; this has been suggested to be a consequence of harmful epistatic interactions between human and Neanderthal alleles. However, using published estimates of Neanderthal inbreeding and the distribution of mutational fitness effects, we infer that Neanderthals had at least 40% lower fitness than humans on average; this increased load predicts the reduction in Neanderthal introgression around genes without the need to invoke epistasis. We also predict a residual Neanderthal mutational load in non-Africans, leading to a fitness reduction of at least 0.5%. This effect of Neanderthal admixture has been left out of previous debate on mutation load differences between Africans and non-Africans. We also show that if many deleterious mutations are recessive, the Neanderthal admixture fraction could increase over time due to the protective effect of Neanderthal haplotypes against deleterious alleles that arose recently in the human population. This might partially explain why so many organisms retain gene flow from other species and appear to derive adaptive benefits from introgression.

What percentage of Homo sapiens DNA is of Neanderthal origin?

5ace1a590340b9f05800000b_001

Ataxin-3 protein and RNA toxicity in spinocerebellar ataxia type 3: current insights and emerging therapeutic strategies. Ataxin-3 is a ubiquitously expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription. The C-terminus of the ataxin-3 protein contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the neurodegenerative disease spinocerebellar ataxia 3 (SCA3). In spite of extensive research, the molecular mechanisms underlying the cellular toxicity resulting from mutant ataxin-3 remain elusive and no preventive treatment is currently available. It has become clear over the last decade that the hallmark intracellular ataxin-3 aggregates are likely not the main toxic entity in SCA3. Instead, the soluble PolyQ containing fragments arising from proteolytic cleavage of ataxin-3 by caspases and calpains are now regarded to be of greater influence in pathogenesis. In addition, recent evidence suggests potential involvement of a RNA toxicity component in SCA3 and other PolyQ expansion disorders, increasing the pathogenic complexity. Herein, we review the functioning of ataxin-3 and the involvement of known protein and RNA toxicity mechanisms of mutant ataxin-3 that have been discovered, as well as future opportunities for therapeutic intervention.

Which is the protein implicated in Spinocerebellar ataxia type 3?

57138eb21174fb175500000a_004

Ebola outbreak in Western Africa 2014: what is going on with Ebola virus? The 2014 outbreak of Ebola virus disease (EVD) in West Africa, caused by Ebola virus (Zaire Ebola virus species), is the largest outbreak of EVD in history. It cause hemorrhagic fever in human and nonhuman primates with high mortality rate up to 90% and can be transmitted by direct contact with blood, body fluids, skin of EVD patients or persons who have died of EVD. As of December 17, 2014, 450 healthcare personnel are known to have been infected with Ebola, of whom 244 died. For development of Ebola vaccine and treatment are highly difficult due to its dangerous and accessibility that requires biosafety level 4 (BSL-4) to conduct experiment. Also there is no specific vaccine and treatment for Ebola virus; however, many candidate vaccines and antiviral-drugs such as ZMapp and TKM-Ebola are being developed for Ebola virus disease. In this review, we focus on the epidemiology of 2014 outbreak of Ebola virus and candidate agent for preventing and curing from Ebola virus.

Which disease is treated with ZMapp?

5880e417713cbdfd3d000001_004

A revised six-kingdom system of life. A revised six-kingdom system of life is presented, down to the level of infraphylum. As in my 1983 system Bacteria are treated as a single kingdom, and eukaryotes are divided into only five kingdoms: Protozoa, Animalia, Fungi, Plantae and Chromista. Intermediate high level categories (superkingdom, subkingdom, branch, infrakingdom, superphylum, subphylum and infraphylum) are extensively used to avoid splitting organisms into an excessive number of kingdoms and phyla (60 only being recognized). The two 'zoological' kingdoms, Protozoa and Animalia, are subject to the International Code of Zoological Nomenclature, the kingdom Bacteria to the International Code of Bacteriological Nomenclature, and the three 'botanical' kingdoms (Plantae, Fungi, Chromista) to the International Code of Botanical Nomenclature. Circumscriptions of the kingdoms Bacteria and Plantae remain unchanged since Cavalier-Smith (1981). The kingdom Fungi is expanded by adding Microsporidia, because of protein sequence evidence that these amitochondrial intracellular parasites are related to conventional Fungi, not Protozoa. Fungi are subdivided into four phyla and 20 classes; fungal classification at the rank of subclass and above is comprehensively revised. The kingdoms Protozoa and Animalia are modified in the light of molecular phylogenetic evidence that Myxozoa are actually Animalia, not Protozoa, and that mesozoans are related to bilaterian animals. Animalia are divided into four subkingdoms: Radiata (phyla Porifera, Cnidaria, Placozoa, Ctenophora), Myxozoa, Mesozoa and Bilateria (bilateral animals: all other phyla). Several new higher level groupings are made in the animal kingdom including three new phyla: Acanthognatha (rotifers, acanthocephalans, gastrotrichs, gnathostomulids), Brachiozoa (brachiopods and phoronids) and Lobopoda (onychophorans and tardigrades), so only 23 animal phyla are recognized. Archezoa, here restricted to the phyla Metamonada and Trichozoa, are treated as a subkingdom within Protozoa, as in my 1983 six-kingdom system, not as a separate kingdom. The recently revised phylum Rhizopoda is modified further by adding more flagellates and removing some 'rhizopods' and is therefore renamed Cercozoa. The number of protozoan phyla is reduced by grouping Mycetozoa and Archamoebae (both now infraphyla) as a new subphylum Conosa within the phylum Amoebozoa alongside the subphylum Lobosa, which now includes both the traditional aerobic lobosean amoebae and Multicilia. Haplosporidia and the (formerly microsporidian) metchnikovellids are now both placed within the phylum Sporozoa. These changes make a total of only 13 currently recognized protozoan phyla, which are grouped into two subkingdoms: Archezoa and Neozoa the latter is modified in circumscription by adding the Discicristata, a new infrakingdom comprising the phyla Percolozoa and Euglenozoa). These changes are discussed in relation to the principles of megasystematics, here defined as systematics that concentrates on the higher levels of classes, phyla, and kingdoms. These principles also make it desirable to rank Archaebacteria as an infrakingdom of the kingdom Bacteria, not as a separate kingdom. Archaebacteria are grouped with the infrakingdom Posibacteria to form a new subkingdom, Unibacteria, comprising all bacteria bounded by a single membrane. The bacterial subkingdom Negibacteria, with separate cytoplasmic and outer membranes, is subdivided into two infrakingdoms: Lipobacteria, which lack lipopolysaccharide and have only phospholipids in the outer membrane, and Glycobacteria, with lipopolysaccharides in the outer leaflet of the outer membrane and phospholipids in its inner leaflet. (ABSTRACT TRUNCATED)

In which kingdom do microsporidia belong, according to their current classification scheme?

5547a01cf35db75526000005_019

Reversal of direct oral anticoagulants: a practical approach. Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.

Andexanet Alfa is an antidote of which clotting factor inhibitors?

5880b073c872c95565000003_089

SEA0400, a novel and selective inhibitor of the Na+-Ca2+ exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models. The effect of the newly synthesized compound 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) on the Na+-Ca2+ exchanger (NCX) was investigated and compared against that of 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R7943). In addition, the effects of SEA0400 on reperfusion injury in vitro and in vivo were examined. SEA0400 was extremely more potent than KB-R7943 in inhibiting Na+-dependent Ca2+ uptake in cultured neurons, astrocytes, and microglia: IC50s of SEA0400 and KB-R7943 were 5 to 33 nM and 2 to 4 microM, respectively. SEA0400 at the concentration range that inhibited NCX exhibited negligible affinities for the Ca2+ channels, Na+ channels, K+ channels, norepinephrine transporter, and 14 receptors, and did not affect the activities of the Na+/H+ exchanger, Na+,K+-ATPase, Ca2+-ATPase, and five enzymes. SEA0400, unlike KB-R7943, did not inhibit the store-operated Ca2+ entry in cultured astrocytes. SEA0400 attenuated dose- dependently paradoxical Ca2+ challenge-induced production of reactive oxygen species, DNA ladder formation, and nuclear condensation in cultured astrocytes, whereas it did not affect thapsigargin-induced cell injury. Furthermore, administration of SEA0400 reduced infarct volumes after a transient middle cerebral artery occlusion in rat cerebral cortex and striatum. These results indicate that SEA0400 is the most potent and selective inhibitor of NCX, and suggest that the compound may exert protective effects on postischemic brain damage.

The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?

5506c3e38e1671127b00000a_055

A yeast functional screen predicts new candidate ALS disease genes. Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.

Which domain allowing self-association do exist in TDP-43 and FUS proteins?

56c83f365795f9a73e000011_003

Abnormal distribution of the non-Abeta component of Alzheimer's disease amyloid precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment. The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as alpha-synuclein) is a presynaptic terminal molecule that abnormally accumulates in the plaques of Alzheimer's disease (AD) and in the Lewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and Parkinson's disease. To better understand the distribution of NACP/alpha-synuclein and its fragments in the LB-bearing neurons and neurites, as well as to clarify the patterns of NACP/alpha-synuclein compartmentalization, we studied NACP/alpha-synuclein immunoreactivity using antibodies against the C-terminal, N-terminal, and NAC regions after Proteinase K and formic acid treatment in the cortex of patients with LBs. Furthermore, studies of the subcellular localization of NACP/alpha-synuclein within LB-bearing neurons were performed by immunogold electron microscopy. These studies showed that the N-terminal antibody immunolabeled the LBs and dystrophic neurites with great intensity and, to a lesser extent, the synapses. In contrast, the C-terminal antibody strongly labeled the synapses and, to a lesser extent, the LBs and dystrophic neurites. Whereas Proteinase K treatment enhanced NACP/alpha-synuclein immunoreactivity with the C-terminal antibody, it diminished the N-terminal NACP/alpha-synuclein immunoreactivity. Furthermore, formic acid enhanced LB and dystrophic neurite labeling with both the C- and N-terminal antibodies. In addition, whereas without pretreatment only slight anti-NAC immunoreactivity was found in the LBs, formic acid pretreatment revealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells. Ultrastructural analysis revealed that NACP/alpha-synuclein immunoreactivity was diffusely distributed within the amorphous electrodense material in the LBs and as small clusters in the filaments of LBs and neurites. These results support the view that aggregated NACP/alpha-synuclein might play an important role in the pathogenesis of disorders associated with LBs.

Against which protein is the antibody used for immonostaining of Lewy bodies raised?

53189656b166e2b80600001c_021

Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. The mTORC1 complex supports cell growth and proliferation in response to energy levels, growth factors, and nutrients. The Rag guanosine triphosphatases (GTPases) activate mTORC1 in response to amino acids by promoting its redistribution to lysosomes. In this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression. Interaction of TFEB with active Rag heterodimers promoted recruitment of TFEB to lysosomes, leading to mTORC1-dependent phosphorylation and inhibition of TFEB. The interaction of TFEB with Rags required the first 30 residues of TFEB and the switch regions of the Rags G domain. Depletion or inactivation of Rags prevented recruitment of TFEB to lysosomes, whereas expression of active Rags induced association of TFEB with lysosomal membranes. Finally, Rag GTPases bound and regulated activation of microphthalmia-associated transcription factor, suggesting a broader role for Rags in the control of gene expression. Our work provides new insight into the molecular mechanisms that link nutrient availability and TFEB localization and activation.

Which transcription factor is considered as a master regulator of lysosomal genes?

56cdf40d5795f9a73e00003d_007

Evolutionary conservation of possible functional domains of the human and murine XIST genes. The human XIST gene, a candidate for a role in X chromosome inactivation, has recently been cloned and sequenced, yielding a 17 kb cDNA with no apparent significant, conserved open reading frame. In addition, the XIST transcript has been localized within the nucleus to the Barr body by RNA in situ hybridization. This subnuclear localization and lack of any significant protein-coding potential suggest that XIST may act as a functional RNA within the nucleus. In the absence of a conserved open reading frame, we have turned to evolutionary studies as a first step toward elucidating a function for XIST in the process of X inactivation. While probes for XIST detect homologues in numerous eutherians, sequence comparisons require significant gapping and reveal identity levels intermediate between those seen for coding and non-coding regions in other genes. Further, sequence comparison of the most likely candidate open reading frame among several primate species reveals sequence changes not normally associated with protein-coding regions. Other features of XIST are conserved in different species, however, including the position of a major transcription start site and active X chromosome-specific DNA methylation patterns at the gene's 5' end. Finally, a possible molecular basis for differing propensity toward X inactivation between Xce alleles in mouse is investigated by comparing the sequence of the Xist conserved 5' repeats in mouse strains carrying different Xce alleles.

Which is the transcript responsible for X-chromosome inactivation?

5353aedb288f4dae47000006_037

[Immune regulatory effect of citalopram on microglial cells]. OBJECTIVE: To investigate the effects of antidepressant citalopram on the gene expressions of tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β), and to discuss the impacts of citalopram on p38 and c-jun N-terminal kinase (JNK) of mitogen-activated protein kinase (MAPK) family in microglial cells. METHODS: BV2 cells were induced by lipopolysaccharide (LPS) to produce TNF-α and IL-1β. After pretreatment with citalopram (20 μmol/L) for 4 h, the mRNA levels of TNF-α and IL-1β were measured by quantitative real-time PCR (qRT-PCR); after pretreatment for 24 h, the protein levels of TNF-α and IL-1β were analyzed by ELISA; the effects of citalopram on the phosphorylation of p38MAPK and JNK were observed after pretreatment for 30 min. RESULTS: Citalopram significantly inhibited the mRNA and protein expressions of TNF-α and IL-1β, and the phosphorylation of p38MAPK and JNK. CONCLUSION: Citalopram may play the anti-inflammatory role by inhibiting MAPK pathway in microglial cells.

Which MAP kinase phosphorylates the transcription factor c-jun?

5518e7da622b194345000004_003

Reference ranges and determinants of total hCG levels during pregnancy: the Generation R Study. Human chorionic gonadotropin (hCG) is a pregnancy hormone secreted by the placental synctiotrophoblast cell layer that has been linked to fetal growth and various placental, uterine and fetal functions. In order to investigate the effects of hCG on clinical endpoints, knowledge on reference range (RR) methodology and determinants of gestational hCG levels is crucial. Moreover, a better understanding of gestational hCG physiology can improve current screening programs and future clinical management. Serum total hCG levels were determined in 8195 women participating in the Generation R Study. Gestational age specific RRs using 'ultrasound derived gestational age' (US RRs) were calculated and compared with 'last menstrual period derived gestational age' (LMP RRs) and a model-based RR. We also investigated which pregnancy characteristics were associated with hCG levels. Compared to the US RRs, the LMP RRs were lower, most notably for the median and lower limit levels. No considerable differences were found between RRs calculated in the general population or in uncomplicated pregnancies only. Maternal smoking, BMI, parity, ethnicity, fetal gender, placental weight and hyperemesis gravidarum symptoms were associated with total hCG. We provide gestational RRs for total hCG and show that total hCG values and RR cut-offs during pregnancy vary depending on pregnancy dating methodology. This is likely due to the influence of hCG on embryonic growth, suggesting that ultrasound based pregnancy dating might be less reliable in women with high/low hCG levels. Furthermore, we identify different pregnancy characteristics that influence total hCG levels considerably and should therefore be accounted for in clinical studies.

Which protein is associated with hyperemesis gravidarum during pregrancy?

58da1aa08acda34529000012_001

Genetic associations in type I interferon related pathways with autoimmunity. Type I interferons play an outstanding role in innate and adaptive immunity by enhancing functions of dendritic cells, inducing differentiation of monocytes, promoting immunoglobulin class switching in B cells and stimulating effector functions of T cells. The increased production of IFNα/β by plasmacytoid dendritic cells could be responsible for not only efficient antiviral defence, but it also may be a pathological factor in the development of various autoimmune disorders. The first evidence of a genetic link between type I interferons and autoimmune diseases was the observation that elevated IFNα activity is frequently detected in the sera of patients with systemic lupus erythematosus, and that this trait shows high heritability and familial aggregation in their first-degree healthy relatives. To date, a number of genes involved in interferon signalling have been associated with various autoimmune diseases. Patients with systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, psoriasis, and a fraction of patients with rheumatoid arthritis display a specific expression pattern of interferon-dependent genes in their leukocytes, termed the interferon signature. Here, in an attempt to understand the role of type I interferons in the pathogenesis of autoimmunity, we review the recent advances in the genetics of autoimmune diseases focusing on the association of genes involved in type I interferon pathways.

Which is the most common gene signature in Rheumatoid Arthritis patients?

58e7902b3e8b6dc87c000007_002

Long-term safety and efficacy of taliglucerase alfa in pediatric Gaucher disease patients who were treatment-naïve or previously treated with imiglucerase. Taliglucerase alfa is an enzyme replacement therapy approved for treatment of Gaucher disease (GD) in children and adults in several countries. This multicenter extension study assessed the efficacy and safety of taliglucerase alfa in pediatric patients with GD who were treatment-naïve (n=10) or switched from imiglucerase (n=5). Patients received taliglucerase alfa 30 or 60U/kg (treatment-naïve) or the same dose as previously treated with imiglucerase every other week. In treatment-naïve patients, taliglucerase alfa 30 and 60U/kg, respectively, reduced mean spleen volume (-18.6 multiples of normal [MN] and -26.0MN), liver volume (-0.8MN and -0.9MN), and chitotriosidase activity (-72.7% and -84.4%), and increased mean Hb concentration (+2.0g/dL and +2.3g/dL) and mean platelet count (+38,200/mm and +138,250/mm) from baseline through 36 total months of treatment. In patients previously treated with imiglucerase, these disease parameters remained stable through 33 total months of treatment with taliglucerase alfa. Most adverse events were mild/moderate; treatment was well tolerated. These findings extend the taliglucerase alfa safety and efficacy profile and demonstrate long-term clinical improvement in treatment-naïve children receiving taliglucerase alfa and maintenance of disease stability in children switched to taliglucerase alfa. Treatment was well-tolerated, with no new safety signals. This study is registered at www.clinicaltrials.gov as NCT01411228.

Which disease is treated with taliglucerase alfa?

5891b125621ea6ff7e00000e_007

Clinical perspective on antiretroviral drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor etravirine. Etravirine is an effective and well-tolerated recently approved non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV type-1-infected patients with previous antiretroviral treatment experience. Considering the importance of combining antiretrovirals for their optimal use in treating HIV, a number of drug-drug interactions with etravirine and other antiretrovirals have been evaluated. Etravirine is a weak inducer of cytochrome P450 (CYP)3A and a weak inhibitor of CYP2C9/CYP2C19 and P-glycoprotein, and although etravirine is metabolized by the CYP enzyme system, the extent of clinically relevant interactions with other antiretrovirals is limited. Etravirine can be combined with all currently available nucleoside/nucleotide reverse transcriptase inhibitors without dose adjustments, but not with other NNRTIs. Available data indicate that etravirine can be coadministered with most of the currently available ritonavir-boosted HIV protease inhibitors. Coadministration with tipranavir/ritonavir or unboosted HIV protease inhibitors is not recommended because of clinically relevant changes in exposure to etravirine or the coadministered HIV protease inhibitor, respectively. Etravirine can be coadministered with the integrase inhibitors elvitegravir/ritonavir or raltegravir, and with the fusion inhibitor enfuvirtide, without dose adjustments. Dose adjustment of the C-C chemokine receptor type-5 antagonist maraviroc is required, with the type of adjustment depending on whether a boosted HIV protease inhibitor is included in the regimen. In conclusion, etravirine can be combined with most antiretrovirals, with no clinically meaningful effect on drug exposure or safety/tolerability profiles.

Cytochrome p450 CYP3A is induced by rifampicin and compounds used to treat what virus?

5ab2cc66fcf4565872000015_002

Who, when, and how to reverse non-vitamin K oral anticoagulants. Non-vitamin K oral anticoagulants (NOACs) have been a major addition to our therapeutic armamentarium. They are at least as effective as warfarin in the thromboprophylaxis of non-valvular atrial fibrillation and management of thromboembolic disease, with a more favorable safety profile. Their predictable pharmacokinetics and pharmacodynamics allow for a fixed oral dosing without the need for anticoagulation monitoring. A major concern regarding NOACs is the lack of a readily available antidote to reverse their anticoagulation effect in case of life-threatening bleeding or need for emergent surgery. In this review, we summarize preclinical and clinical data on (a) hemostatic agents used to reverse NOACs, and (b) novel, target-specific NOACs reversal agents under development. The prothrombin complex concentrates, activated prothrombin complex concentrates and recombinant activated factor VII are hemostatic agents that have been assessed in reversing NOACs. Preclinical studies with hemostatic agents report variable results and there is only limited clinical data available to date. Idarucizumab and andexanet alfa are NOAC-specific reversal agents designed to reverse dabigatran and factor Xa inhibitors accordingly. Aripazine is a universal anticoagulation reversal agent. Preclinical studies show promising results and these agents are already in different stages of clinical development. Phase I and II clinical trials demonstrate efficacy in reversing NOACs without major side effects. Until these agents become commercially available, management of patients receiving NOACs who present with major bleeding or require emergent surgery should focus on (a) immediate discontinuation of NOACs, (b) supportive measures or postponing surgery for 12-24 h after the last NOAC dose, and/or

Andexanet Alfa is an antidote of which clotting factor inhibitors?

5880b073c872c95565000003_005

Fanconi anemia: at the crossroads of DNA repair. Fanconi anemia (FA) is an autosomal disorder that causes genome instability. FA patients suffer developmental abnormalities, early-onset bone marrow failure, and a predisposition to cancer. The disease is manifested by defects in DNA repair, hypersensitivity to DNA crosslinking agents, and a high degree of chromosomal aberrations. The FA pathway comprises 13 disease-causing genes involved in maintaining genomic stability. The fast pace of study of the novel DNA damage network has led to the constant discovery of new FA-like genes involved in the pathway that when mutated lead to similar disorders. A majority of the FA proteins act as signal transducers and scaffolding proteins to employ other pathways to repair DNA. This review discusses what is known about the FA proteins and other recently linked FA-like proteins. The goal is to clarify how the proteins work together to carry out interstrand crosslink repair and homologous recombination-mediated repair of damaged DNA.

What is the disease in which patients are sensitive to DNA crosslinking agents, presenting with a high frequency of chromosomal aberrations?

54ede28094afd61504000003_001

Small-molecule antagonists of the orexin receptors. The orexin-1 and orexin-2 receptors are two G protein-coupled receptors that bind the neuropeptides orexin-A and orexin-B. Dual antagonism of the receptors by small molecules is clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has recently been approved. The scope of this article is to review the small molecule orexin receptor antagonist patent literature between January 2012 and January 2014.

What molecule is targeted by suvorexant?

56c1f003ef6e394741000039_018

Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.

In which yeast chromosome does the rDNA cluster reside?

5710e131a5ed216440000001_012

Treatment of benzodiazepine overdose with flumazenil. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. Flumazenil, a specific benzodiazepine antagonist, was evaluated as adjunctive therapy in the management of benzodiazepine overdose. Thirteen emergency departments enrolled 326 patients in this double-blind, placebo-controlled trial; 162 patients were randomly allocated to receive flumazenil (maximum dose, 30 ml, providing 3 mg of flumazenil), and 164 were allocated to receive placebo (maximum dose, 30 ml). A successful response was the attainment of a score of 1 or 2 on the Clinical Global Impression Scale (CGIS), denoting a very much improved or much improved status, 10 minutes after the start of intravenous administration of the test drug. Among those patients whose drug screen revealed the presence of benzodiazepines, 75 (77%) of 97 patients given flumazenil and 13 (16%) of 83 given placebo attained such a response. The mean CGIS score at 10 minutes for benzodiazepine-positive patients treated with flumazenil was 1.95 versus 3.58 for those given placebo. As determined by the Neurobehavioral Assessment Scale, 61% of patients who initially responded became resedated; in these patients, the effect of flumazenil lasted a median of 90 minutes. At the investigator's discretion, patients who did not achieve a criterion response in the double-blind trial could receive open-label flumazenil, titrated as in the double-blind phase. Among the benzodiazepine-positive patients, 9 (53%) of 17 patients from the flumazenil group responded to the additional flumazenil, and 58 (81%) of patients previously given placebo responded. Safety was assessed in all 326 patients given the test drug. The most frequent adverse experiences after the administration of flumazenil were agitation (7%), vomiting (7%), abnormal crying (4%), and nausea (4%); these effects were observed with a lower frequency in the placebo group. Serious adverse experiences were reported in 4 patients; these included seizures and cardiac arrhythmias. Of the 3 patients with seizures, 2 had ingested large doses of cyclic antidepressants in addition to the benzodiazepine. The toxicology screen for 1 of the 2 showed 1900 ng/ml of amoxapine and 900 ng/ml of nortriptyline; the toxicology screen for the other, who also had ventricular tachycardia, showed 1928 ng/ml of loxapine and 301 ng/ml of amoxapine. The results of this study confirm published reports of the efficacy of flumazenil in reversing benzodiazepine-induced sedation in patients with benzodiazepine overdose. This was accomplished irrespective of the presence of coingested drugs. Flumazenil is not recommended for patients with serious cyclic antidepressant poisoning or those who use benzodiazepines therapeutically to control seizure disorders. When used as recommended, however, flumazenil has been shown to have an acceptable safety level.

Which drug should be used as an antidote in benzodiazepine overdose?

514a0a57d24251bc05000051_023

Phosphorylation of Noxo1 at threonine 341 regulates its interaction with Noxa1 and the superoxide-producing activity of Nox1. UNLABELLED: Superoxide production by Nox1, a member of the Nox family NAPDH oxidases, requires expression of its regulatory soluble proteins Noxo1 (Nox organizer 1) and Noxa1 (Nox activator 1) and is markedly enhanced upon cell stimulation with phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC). The mechanism underlying PMA-induced enhancement of Nox1 activity, however, remains to be elucidated. Here we show that, in response to PMA, Noxo1 undergoes phosphorylation at multiple sites, which is inhibited by the PKC inhibitor GF109203X. Among them, Thr341 in Noxo1 is directly phosphorylated by PKC in vitro, and alanine substitution for this residue reduces not only PMA-induced Noxo1 phosphorylation but also PMA-dependent enhancement of Nox1-catalyzed superoxide production. Phosphorylation of Thr341 allows Noxo1 to sufficiently interact with Noxa1, an interaction that participates in Nox1 activation. Thus phosphorylation of Noxo1 at Thr341 appears to play a crucial role in PMA-elicited activation of Nox1, providing a molecular link between PKC-mediated signal transduction and Nox1-catalyzed superoxide production. Furthermore, Ser154 in Noxo1 is phosphorylated in both resting and PMA-stimulated cells, and the phosphorylation probably participates in a PMA-independent constitutive activity of Nox1. Ser154 may also be involved in protein kinase A (PKA) mediated regulation of Nox1; this serine is the major residue that is phosphorylated by PKA in vitro. Thus phosphorylation of Noxo1 at Thr341 and at Ser154 appears to regulate Nox1 activity in different manners. STRUCTURED DIGITAL ABSTRACT: Noxo1 binds to p22phox by pull down (1, 2, 3) Noxo1 binds to Noxo1 by pull down (View interaction) Noxa1 binds to Noxo1 by pull down (1, 2, 3, 4, 5).

Which NADPH oxidase family member requires interaction with NOXO1 for function?

58a5a51060087bc10a000021_009

Lewy body pathology in Alzheimer's disease. Lewy bodies, the characteristic pathological lesion of substantia nigra neurons in Parkinson's disease (PD), are frequently observed to accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer's disease (AD). However the typical anatomic distribution of Lewy bodies in AD is distinct from PD. The most common site of occurrence is the amygdala, where Lewy bodies are observed in approximately 60% of both sporadic and familial AD. Other common sites of occurrence include the periamygdaloid and entorhinal cortex, while neocortical and brainstem areas develop Lewy bodies in a lower percentage of cases. In contrast, dementia with Lewy bodies (DLB), defined by widespread neocortical and brainstem Lewy bodies but frequently accompanied by variable levels of AD-type pathology, represents the other end of a spectrum of pathology associated with dementia. The observation of Lewy bodies in familial AD cases suggests that like neurofibrillary tangles, the formation of Lewy bodies can be induced by the pathological state caused by Abeta-amyloid overproduction. The role of Lewy body formation in the dysfunction and degeneration of neurons remains unclear. The protein alpha-synuclein appears to be an important structural component of Lewy bodies, an observation spurred by the discovery of point mutations in the alpha-synuclein gene linked to rare cases of autosomal dominant PD. Further investigation of alpha-synuclein and its relationship to pathological conditions promoting Lewy body formation in AD, PD, and DLB may yield further insight into pathogenesis of these diseases.

Which is the primary protein component of Lewy bodies?

58a2e5f760087bc10a000007_032

Comprehensive ZEB2 gene analysis for Mowat-Wilson syndrome in a North American cohort: a suggested approach to molecular diagnostics. Mowat-Wilson syndrome is a genetic condition characterized by a recognizable facial phenotype in addition to moderate to severe cognitive disability with severe speech impairment and variable multiple congenital anomalies. The anomalies may include Hirschsprung disease, heart defects, structural eye anomalies including microphthalmia, agenesis of the corpus callosum, and urogenital anomalies. Microcephaly, seizure disorder and constipation are common. All typical cases result from haploinsufficiency of the ZEB2 (also known as ZFHX1B or SIP-1) gene, with over 100 distinct mutations now described. Approximately 80% of patients have a nonsense or frameshift mutation detectable by sequencing, with the rest having gross deletions necessitating a dosage sensitive assay. Here we report on the results of comprehensive molecular testing for 27 patients testing positive for MWS. Twenty-one patients had a nonsense, frameshift, or splice site mutation identified by sequencing; 14 of which localized to exon 8 and 17 of which are novel. Six patients had deletions in the ZEB2 gene, including two novel partial gene deletions. This report, the first such analysis in North American patients, adds to the growing list of both novel pathogenic mutations associated with MWS, as well as other variants in the ZEB2 gene. In addition, we suggest an economical testing strategy.

Which gene is responsible for the development of the Mowat-Wilson syndrome?

5519113b622b19434500000f_004

Interrupting anticoagulation in patients with nonvalvular atrial fibrillation. Three target-specific oral anticoagulants (TSOACs)-dabigatran, rivaroxaban, and apixaban-have been approved by the FDA to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; however, no agents are currently approved to reverse the anticoagulant effects of these TSOACs in cases of active bleeding. This review discusses the benefits and risks of these TSOACs from a clinician's perspective, with a focus on the interruption of treatment for either elective or emergent surgery, monitoring, and reversal of anticoagulation. Available coagulation assays are not ideal for monitoring the effects of TSOACs and do not provide reliable quantitative measurement of their anticoagulant effects. When necessary, activated partial thromboplastin time (aPTT) may provide qualitative information on dabigatran, and prothrombin time (PT) may provide qualitative assessment of the presence of the factor Xa inhibitors, rivaroxaban and apixaban. Current recommendations for reversal of TSOACs are based largely on limited and sometimes conflicting data from in vitro or in vivo animal models, and clinical experience with these recommendations is also limited. Methods that have been investigated for effectiveness for reversal of the pharmacodynamic effects of the TSOACs include dialysis, activated charcoal, prothrombin complex concentrate (PCC), and recombinant activated factor VII. It is important to note that even within a class of anticoagulant drugs, compounds respond differently to reversal agents; therefore, recommendations for one agent should not be extrapolated to another, even if they are from the same therapeutic class. New antidotes are being explored, including a mouse monoclonal antibody to dabigatran; andexanet alfa, a potential universal factor Xa inhibitor reversal agent; and a synthetic small molecule (PER977) that may be effective for the reversal of factor Xa inhibitors and direct thrombin inhibitors. Given the short half-lives of TSOACs, watchful waiting, rather than reversal, may be the best approach in some circumstances.

Andexanet Alfa is an antidote of which clotting factor inhibitors?

5880b073c872c95565000003_082

The role of SERCA2a/PLN complex, Ca(2+) homeostasis, and anti-apoptotic proteins in determining cell fate. Intracellular calcium is a major coordinator of numerous aspects of cellular physiology, including muscle contractility and cell survival. In cardiac muscle, aberrant Ca(2+) cycling has been implicated in a range of pathological conditions including cardiomyopathies and heart failure. The sarco(endo)plasmic reticulum Ca(2+) transport adenosine triphosphatase (SERCA2a) and its regulator phospholamban (PLN) have a central role in modulating Ca(2+) homeostasis and, therefore, cardiac function. Herein, we discuss the mechanisms through which SERCA2a and PLN control cardiomyocyte function in health and disease. Emphasis is placed on our newly identified PLN-binding partner HS-1-associated protein X-1 (HAX-1), which has an anti-apoptotic function and presents with numerous similarities to Bcl-2. Recent evidence indicates that proteins of the Bcl-2 family can influence ER Ca(2+) content, a critical determinant of cellular sensitivity to apoptosis. The discovery of the PLN/HAX-1 interaction therefore unveils an important new link between Ca(2+) homeostasis and cell survival, with significant therapeutic potential.

Which is the main regulatory molecule of SERCA2A function in the cardiac muscle?

54cb9c94f693c3b16b000005_022

McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement. BACKGROUND: The X-linked McLeod neuroacanthocytosis syndrome is a multisystem disorder with hematologic, neuromuscular, and central nervous system (CNS) manifestations. All carriers of the McLeod blood group phenotype examined so far had at least subclinical signs of systemic involvement. STUDY DESIGN AND METHODS: Evaluation of two brothers carrying the McLeod phenotype with neurologic examination, immunohematology, RBC membrane protein Western blotting, analysis of XK DNA sequence and RNA levels, muscle histology including XK/Kell immunohistochemistry, cerebral magnetic resonance imaging (MRI), and quantified positron emission tomography (PET). RESULTS: Immunohematology and Western blotting confirmed presence of the McLeod blood group phenotype. No acanthocytosis or other hematologic anomalies were found. XK gene sequence analysis revealed a missense mutation in exon 3 (E327K). WBC XK RNA levels were not decreased. There were no neuromuscular and CNS signs or symptoms. In addition, no subclinical involvement was discovered on the basis of normal muscle histology with a physiologic pattern of XK and Kell immunohistochemistry, normal cerebral MRI, and quantified PET. CONCLUSION: Known disease-causing XK gene mutations comprised deletions, nonsense, or splice-site mutations predicting absent or truncated XK protein devoid of the Kell-protein binding site. Although the E327K missense mutation was associated with the immunohematologic characteristics of McLeod syndrome, the mutated XK protein seemed to be largely functional. These findings contribute to the understanding of the physiology of XK and Kell proteins, and the pathogenetic mechanisms of acanthocytosis, myopathy, and striatal neurodegeneration in McLeod syndrome.

Mutation of which gene is associated with McLeod syndrome?

531464a6e3eabad021000014_039

Functional analysis of splicing mutations in exon 7 of NF1 gene. BACKGROUND: Neurofibromatosis type 1 is one of the most common autosomal dominant disorders, affecting about 1:3,500 individuals. NF1 exon 7 displays weakly defined exon-intron boundaries, and is particularly prone to missplicing. METHODS: In this study we investigated the expression of exon 7 transcripts using bioinformatic identification of splicing regulatory sequences, and functional minigene analysis of four sequence changes [c.910C>T (R304X), c.945G>A/c.946C>A (Q315Q/L316M), c.1005T>C (N335N)] identified in exon 7 of three different NF1 patients. RESULTS: Our results detected the presence of three exonic splicing enhancers (ESEs) and one putative exonic splicing silencer (ESS) element. The wild type minigene assay resulted in three alternative isoforms, including a transcript lacking NF1 exon 7 (NF1DeltaE7). Both the wild type and the mutated constructs shared NF1DeltaE7 in addition to the complete messenger, but displayed a different ratio between the two transcripts. In the presence of R304X and Q315Q/L316M mutations, the relative proportion between the different isoforms is shifted toward the expression of NF1DeltaE7, while in the presence of N335N variant, the NF1DeltaE7 expression is abolished. CONCLUSION: In conclusion, it appears mandatory to investigate the role of each nucleotide change within the NF1 coding sequence, since a significant proportion of NF1 exon 7 mutations affects pre-mRNA splicing, by disrupting exonic splicing motifs and modifying the delicate balance between aberrantly and correctly spliced transcripts.

Which is the gene mutated in type 1 neurofibromatosis?

5343fc1aaeec6fbd07000003_012

Expression and function of Noxo1gamma, an alternative splicing form of the NADPH oxidase organizer 1. Activation of the superoxide-producing NADPH oxidase Nox1 requires both the organizer protein Noxo1 and the activator protein Noxa1. Here we describe an alternative splicing form of Noxo1, Noxo1gamma, which is expressed in the testis and fetal brain. The Noxo1gamma protein contains an additional five amino acids in the N-terminal PX domain, a phosphoinositide-binding module; the domain plays an essential role in supporting superoxide production by NADPH oxidase (Nox) family oxidases including Nox1, gp91(phox)/Nox2, and Nox3, as shown in this study. The PX domain isolated from Noxo1gamma shows a lower affinity for phosphoinositides than that from the classical splicing form Noxo1beta. Consistent with this, in resting cells, Noxo1gamma is poorly localized to the membrane, and thus less effective in activating Nox1 than Noxo1beta, which is constitutively present at the membrane. On the other hand, cell stimulation with phorbol 12-myristate 13-acetate (PMA), an activator of Nox1-3, facilitates membrane translocation of Noxo1gamma; as a result, Noxo1gamma is equivalent to Noxo1beta in Nox1 activation in PMA-stimulated cells. The effect of the five-amino-acid insertion in the Noxo1 PX domain appears to depend on the type of Nox; in activation of gp91(phox)/Nox2, Noxo1gamma is less active than Noxo1beta even in the presence of PMA, whereas Noxo1gamma and Noxo1beta support the superoxide-producing activity of Nox3 to the same extent in a manner independent of cell stimulation.

Which NADPH oxidase family member requires interaction with NOXO1 for function?

58a5a51060087bc10a000021_015

Novel combinatorial interactions of GATA-1, PU.1, and C/EBPepsilon isoforms regulate transcription of the gene encoding eosinophil granule major basic protein. GATA-1 and the ets factor PU.1 have been reported to functionally antagonize one another in the regulation of erythroid versus myeloid gene transcription and development. The CCAAT enhancer binding protein epsilon (C/EBPepsilon) is expressed as multiple isoforms and has been shown to be essential to myeloid (granulocyte) terminal differentiation. We have defined a novel synergistic, as opposed to antagonistic, combinatorial interaction between GATA-1 and PU.1, and a unique repressor role for certain C/EBPepsilon isoforms in the transcriptional regulation of a model eosinophil granulocyte gene, the major basic protein (MBP). The eosinophil-specific P2 promoter of the MBP gene contains GATA-1, C/EBP, and PU.1 consensus sites that bind these factors in nuclear extracts of the eosinophil myelocyte cell line, AML14.3D10. The promoter is transactivated by GATA-1 alone but is synergistically transactivated by low levels of PU.1 in the context of optimal levels of GATA-1. The C/EBPepsilon(27) isoform strongly represses GATA-1 activity and completely blocks GATA-1/PU.1 synergy. In vitro mutational analyses of the MBP-P2 promoter showed that both the GATA-1/PU.1 synergy, and repressor activity of C/EBPepsilon(27) are mediated via protein-protein interactions through the C/EBP and/or GATA-binding sites but not the PU.1 sites. Co-immunoprecipitations using lysates of AML14.3D10 eosinophils show that both C/EBPepsilon(32/30) and epsilon(27) physically interact in vivo with PU.1 and GATA-1, demonstrating functional interactions among these factors in eosinophil progenitors. Our findings identify novel combinatorial protein-protein interactions for GATA-1, PU.1, and C/EBPepsilon isoforms in eosinophil gene transcription that include GATA-1/PU.1 synergy and repressor activity for C/EBPepsilon(27).

Which gene controls the expression of GATA-1 isoforms?

58e75d483e8b6dc87c000005_003

Acquired cerebral hemiatrophy: Dyke-Davidoff-Masson Syndrome - a case report. A rare syndrome, Dyke-Davidoff-Masson Syndrome (DDMS), with a diagnostic conundrum, and the way it was solved is presented. A 13-year-old boy presented with recurrent seizures for the past 10 years. He had been treated with anticonvulsant medication which was satisfactory at first but later the seizures recurred. Recently, the frequency of the seizures increased with preictal dizziness and postictal drowsiness. Physical examination revealed mild left hemiparesis and left deviated gait irregularity. He was mentally alert but had not achieved all the developmental milestones as compared to normal child of his age. CT and MRI scan of the head showed hemiatrophic cerebral parenchyma with prominent sulci and encephalomalacia. 24-hour intensive video EEG monitoring revealed suppression of alpha rhythm and local slow wave activity on the side of the atrophic hemisphere. PET-CT showed highly functional left cerebral hemisphere and less functional right cerebral hemisphere. The patient underwent functional hemispherectomy under neurophysiological monitoring and the nonfunctional brain tissues were resected while selectively preserving the functional areas detected by fMRI and PET-CT scan. During follow up, the patient was seizure free as well as without difficulties in performing his daily activities and communications. Functional hemispherectomy for DDMS patient has a good prognosis.

What is the characteristic feature of the Dyke-Davidoff-Masson syndrome.

55032e65e9bde69634000034_002

Molecular analysis of the ret and GDNF genes in a family with multiple endocrine neoplasia type 2A and Hirschsprung disease. The clinical association between multiple endocrine neoplasia type 2 (MEN2) and Hirschsprung disease (HSCR) is infrequent. Germline mutations of the ret protooncogene are the underlying cause of the MEN2 syndromes and a proportion of cases of HSCR. In this report, we describe a new kindred in which the MEN2 and HSCR phenotypes are associated with a single C620S point mutation at one of the cysteine codons of the extracellular domain of the ret protooncogene. We also speculate about the role of a silent mutation in exon 2 of this same gene (A45A), present in a homozygous state in the patient with both MEN2A and HSCR. To investigate the contribution of GDNF to the phenotype observed in this kindred, we scanned the coding region of GDNF in the patient with MEN2/HSCR, but no mutation was found.

What is the gene frequently mutated in Multiple endocrine neoplasia 2 (MEN2) and Hisrchsprung disease?

5171438a8ed59a060a000007_015

Neuronal calcium sensor proteins are unable to modulate NFAT activation in mammalian cells. Calcium activated gene transcription through Nuclear Factor of Activated T-cells, (NFAT) proteins, is emerging as a ubiquitous mechanism for the control of important physiological processes. Of the five mammalian NFAT isoforms, transcriptional activities of NFATs 1-4 are stimulated by a calcium driven association between the ubiquitous phosphatase calcineurin and the calcium-sensing protein calmodulin. Published in vitro evidence has suggested that other members of the calmodulin super-family, in particular the neuronal calcium sensor (NCS) proteins, can similarly modulate calcineurin activity. In this study we have assessed the ability of NCS proteins to interact directly with calcineurin in vitro and report a specific if weak association between various NCS proteins and the phosphatase. In an extension to these analyses we have also examined the effects of over-expression of NCS-1 or NCS-1 mutants on calcineurin signalling in HeLa cells in experiments examining the dephosphorylation of an NFAT-GFP reporter construct as a readout of calcineurin activity. Results from these experiments indicate that NCS-1 was not able to detectably modulate calcineurin/NFAT signalling in a live mammalian cell system, findings that are consistent with the idea that calmodulin and not NCS-1 or other NCS family proteins is the physiologically relevant modulator of calcineurin activity.

Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?

54f9c40ddd3fc62544000001_009

LepChorionDB, a database of Lepidopteran chorion proteins and a set of tools useful for the identification of chorion proteins in Lepidopteran proteomes. Chorion proteins of Lepidoptera have a tripartite structure, which consists of a central domain and two, more variable, flanking arms. The central domain is highly conserved and it is used for the classification of chorion proteins into two major classes, A and B. Annotated and unreviewed Lepidopteran chorion protein sequences are available in various databases. A database, named LepChorionDB, was constructed by searching 5 different protein databases using class A and B central domain-specific profile Hidden Markov Models (pHMMs), developed in this work. A total of 413 Lepidopteran chorion proteins from 9 moths and 1 butterfly species were retrieved. These data were enriched and organised in order to populate LepChorionDB, the first relational database, available on the web, containing Lepidopteran chorion proteins grouped in A and B classes. LepChorionDB may provide insights in future functional and evolutionary studies of Lepidopteran chorion proteins and thus, it will be a useful tool for the Lepidopteran scientific community and Lepidopteran genome annotators, since it also provides access to the two pHMMs developed in this work, which may be used to discriminate A and B class chorion proteins. LepChorionDB is freely available at http://bioinformatics.biol.uoa.gr/LepChorionDB.

Which database is available for the identification of chorion proteins in Lepidopteran proteomes?

554148c23f2354b713000001_007

Novel NF1 gene mutation in a Japanese patient with neurofibromatosis type 1 and a gastrointestinal stromal tumor. Many mutations of the NF1 gene have been reported in patients with neurofibromatosis type 1 (NF1); however, there have been no documented NF1 gene mutations in Japanese NF1 patients. In the present study, we used the polymerase chain reaction (PCR) and DNA sequencing analysis to characterize the NF1 gene in a 53-year-old Japanese patient with NF1 who suffered from neurofibroma, pheochromocytoma, and gastrointestinal stromal tumor (GIST). Direct sequence analyses revealed a single base substitution in the splicing donor site of intron 6 (IVS6 888+1, G --> A) in one NF1 allele, resulting in an altered splice site (ss) in the mutated allele. Splicing at the cryptic 5' ss in the mutated allele generated mRNA with an insertion of 60 nucleotides. In addition, we screened for mutations in exons 9, 11, 13, and 17 of the c-kit gene in GIST and the succinate dehydrogenase subunit D (SDHD) gene in the pheochromocytoma, but we did not detect any somatic mutations. We report here the first case of an NF1 patient with four neoplasms: neurofibroma, pheochromocytoma, astrocytoma and GIST. Our results suggest that the molecular pathogenesis of GISTs in NF1 patients is different from that in non-NF1 patients.

Which is the gene mutated in type 1 neurofibromatosis?

5343fc1aaeec6fbd07000003_018

Gender differences in Latin-American patients with rheumatoid arthritis. BACKGROUND: Data on the effect of gender in rheumatoid arthritis (RA) in non-Caucasian populations is scarce. Latin America and the Caribbean (LAC) is a large population with unique characteristics, including high admixture. OBJECTIVE: Our aim was to examine the effect of gender in patients with RA in LAC. METHODS: This was a 2-phase study. First we conducted a cross-sectional and analytical study in which 1128 consecutive Colombian patients with RA were assessed. Second, a systematic review of the literature was done to evaluate the effect of gender in LAC patients with RA. RESULTS: Our results show a high prevalence of RA in LAC women with a ratio of 5.2 women per man. Colombian women with RA are more at risk of having an early age at onset and developing polyautoimmunity and abdominal obesity, and they perform more household duties than their male counterparts. However, male gender was associated with the presence of extra-articular manifestations. Of a total of 641 potentially relevant articles, 38 were considered for final analysis, in which several factors and outcomes related to gender were identified. CONCLUSIONS: RA in LAC women is not only more common but presents with some clinical characteristics that differ from RA presentation in men. Some of those characteristics could explain the high rates of disability and worse prognosis observed in women with RA in LAC.

Is Rheumatoid Arthritis more common in men or women?

5118dd1305c10fae75000001_003

Molecular characterization of the breakpoints of a 12-kb deletion in the NF1 gene in a family showing germ-line mosaicism. Neurofibromatosis type 1 (NF1) is caused by deletions, insertions, translocations, and point mutations in the NF1 gene, which spans 350 kb on the long arm of human chromosome 17. Although several point mutations have been described, large molecular abnormalities have rarely been characterized in detail. We describe here the molecular breakpoints of a 12-kb deletion of the NF1 gene, which is responsible for the NF1 phenotype in a kindred with two children affected because of germline mosaicism in the unaffected father, who has the mutation in 10% of his spermatozoa. The mutation spans introns 31-39, removing 12,021 nt and inserting 30 bp, of which 19 bp are a direct repetition of a sequence located in intron 31, just 4 bp before the 5' breakpoint. The 5' and 3' breakpoints contain the sequence TATTTTA, which could be involved in the generation of the deletion. The most plausible explanation for the mechanism involved in the generation of this 12-kb deletion is homologous/nonhomologous recombination. Since sperm of the father does not contain the corresponding insertion of the 12-kb deleted sequence, this deletion could have occurred within the NF1 chromosome through loop formation. RNA from lymphocytes of one of the NF1 patients showed similar levels of the mutated and normal transcripts, suggesting that the NF1-mRNA from mutations causing frame shifts of the reading frame or stop codons in this gene is not degraded during its processing. The mutation was not detected in fresh lymphocytes from the unaffected father by PCR analysis, supporting the case for true germ-line mosaicism.

Which is the gene mutated in type 1 neurofibromatosis?

5343fc1aaeec6fbd07000003_039

Gevokizumab, an anti-IL-1β mAb for the potential treatment of type 1 and 2 diabetes, rheumatoid arthritis and cardiovascular disease. The inflammatory cytokine IL-1β has an essential role in the innate immune response. High levels of IL-1β have been implicated in the development of many diseases, including type 1 and 2 diabetes (T1D and T2D), rheumatoid arthritis (RA) and cardiovascular disease. XOMA is developing gevokizumab (XOMA-052), an IgG2 humanized mAb against human IL-1β, for the potential treatment of these diseases. Gevokizumab has a high affinity for IL-1β and a long t1/2, which would allow for once-monthly dosing and offer a considerable advantage for patients over agents requiring more frequent dosing. Data from preclinical studies and clinical trials suggest that gevokizumab is a potentially effective and well-tolerated treatment for the indicated diseases. At the time of publication, phase II clinical trials were ongoing in patients with T1D, T2D and RA, with the T2D trials assessing key cardiovascular markers. Following promising data from a recent pilot trial, XOMA was also planning a phase I/II trial of gevokizumab for the potential treatment of uveitis in patients with the vasculitic inflammatory disorder Behçet's disease and the autoinflammatory conditions familial cold autoinflammatory syndrome and Muckle-Wells syndrome.

Which molecule is targeted by the drug Gevokizumab?

550e828c71445a662f000002_014

Disease Development Following Infection of Tomato and Basil Foliage by Airborne Conidia of the Soilborne Pathogens Fusarium oxysporum f. sp. radicis-lycopersici and F. oxysporum f. sp. basilici. ABSTRACT Fusarium oxysporum f. sp. radicis-lycopersici, the causal agent of Fusarium crown and root rot of tomato, and F. oxysporum f. sp. basilici, the causal agent of Fusarium wilt in basil, are soilborne pathogens capable of producing conspicuous masses of macroconidia along the stem. The role of the airborne propagules in the epidemics of the disease in tomato plants was studied. In the field, airborne propagules of F. oxysporum f. sp. radicis-lycopersici were trapped with a selective medium and their prevalence was determined. Plants grown in both covered and uncovered pots, detached from the field soil, and exposed to natural aerial inoculum developed typical symptoms (82 to 87% diseased plants). The distribution of inoculum in the growth medium in the pots also indicated the occurrence of foliage infection. In greenhouse, foliage and root inoculations were carried out with both tomato and basil and their respective pathogens. Temperature and duration of high relative humidity affected rate of colonization of tomato, but not of basil, by the respective pathogens. Disease incidence in foliage-inoculated plants reached 75 to 100%. In these plants, downward movement of the pathogens from the foliage to the crown and roots was observed. Wounding enhanced pathogen invasion and establishment in the foliage-inoculated plants. The sporulation of the two pathogens on stems, aerial dissemination, and foliage infection raise the need for foliage protection in addition to soil disinfestation, in the framework of an integrated disease management program.

Fusarium oxysporum f. sp lycopersici. is a plant pathogen in plants producing what common food?

5a8b1264fcd1d6a10c00001d_013

Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation. Double bromodomain proteins bind to acetylated lysines in histones, bringing associated histone modification and nucleosome remodeling activity to chromatin. The ability of bromodomain regulators to alter chromatin status and control gene expression has long been appreciated to be important in the development of certain human cancers. However, bromodomain proteins have now been found also to be critical, non-redundant players in diverse, non-malignant phenotypes, directing transcriptional programs that control adipogenesis, energy metabolism and inflammation. The fact that such different processes are functionally linked by the same molecular machinery suggests a common epigenetic basis to understand and interpret the origins of several important co-morbidities, such as asthma or cancer that occurs in obesity, and complex inflammatory diseases like cardiovascular disease, systemic lupus erythematosus, rheumatoid arthritis and insulin resistance that may be built on a common pro-inflammatory foundation.

What histone modification is recognized by the bromodomain?

53398855d6d3ac6a3400005b_002

A gatekeeper residue for NEDD8-activating enzyme inhibition by MLN4924. Inhibition of NEDD8-activating enzyme (NAE) has emerged as a highly promising approach to treat cancer through the adenosine sulfamate analog MLN4924. Here, we show that selective pressure results in HCT116 colorectal carcinoma cells with decreased MLN4924 sensitivity and identify a single-nucleotide transition that changes alanine 171 to threonine (A171T) of the NAE subunit UBA3. This reduces the enzyme's affinity for MLN4924 and ATP while increasing NEDD8 activation at physiological ATP concentrations. Expression of UBA3 A171T is sufficient to decrease MLN4924 sensitivity of naive HCT116 cells, indicating that it is a dominant suppressor of MLN4924-mediated cell death. Our data suggest that the on-target potency of MLN4924 selects for a point mutation in NAE that overcomes the molecule's inhibitory effects, allowing cancer cell survival.

Which enzyme does MLN4924 inhibit?

56ed03862ac5ed1459000004_004

Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds. NFAT (nuclear factor of activated T cell) proteins are expressed in most immune system cells and regulate the transcription of cytokine genes critical for the immune response. The activity of NFAT proteins is tightly regulated by the Ca(2+)/calmodulin-dependent protein phosphatase 2B/calcineurin (CaN). Dephosphorylation of NFAT by CaN is required for NFAT nuclear localization. Current immunosuppressive drugs such as cyclosporin A and FK506 block CaN activity thus inhibiting nuclear translocation of NFAT and consequent cytokine gene transcription. The inhibition of CaN in cells outside of the immune system may contribute to the toxicities associated with cyclosporin A therapy. In a search for safer immunosuppressive drugs, we identified a series of 3,5-bistrifluoromethyl pyrazole (BTP) derivatives that block Th1 and Th2 cytokine gene transcription. The BTP compounds block the activation-dependent nuclear localization of NFAT as determined by electrophoretic mobility shift assays. Confocal microscopy of cells expressing fluorescent-tagged NFAT confirmed that the BTP compounds block calcium-induced movement of NFAT from the cytosol to the nucleus. Inhibition of NFAT was selective because the BTP compounds did not affect the activation of NF-kappaB and AP-1 transcription factors. Treatment of intact T cells with the BTP compounds prior to calcium ionophore-induced activation of CaN caused NFAT to remain in a highly phosphorylated state. However, the BTP compounds did not directly inhibit the dephosphorylation of NFAT by CaN in vitro, nor did the drugs block the dephosphorylation of other CaN substrates including the type II regulatory subunit of protein kinase A and the transcription factor Elk-1. The data suggest that the BTP compounds cause NFAT to be maintained in the cytosol in a phosphorylated state and block the nuclear import of NFAT and, hence, NFAT-dependent cytokine gene transcription by a mechanism other than direct inhibition of CaN phosphatase activity. The novel inhibitors described herein will be useful in better defining the cellular regulation of NFAT activation and may lead to identification of new therapeutic targets for the treatment of autoimmune disease and transplant rejection.

Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?

54f9c40ddd3fc62544000001_019

Marfan syndrome patient experiences as ascertained through postings on social media sites. Marfan syndrome (MS) is a connective tissue disorder that affects thousands of adolescents [Population Reference Bureau, 2013]. Some adolescent patients with MS may use social media to express their experiences and emotions, but little is known about what patients choose to share online. To investigate social media content related to Marfan syndrome we used search terms "Marfan syndrome" and "Marfans" on six different social media sites. The top five recent and popular posts for each site were collected and coded weekly for five weeks. Posts were excluded if they were reshared content or not in English. A codebook was developed using an iterative process to categorize posts and comments. Out of 300 posts collected 147 posts (49.0%) were included for evaluation. Categories of displayed content included personal pictures, memes and pictures featuring symptoms of MS (41.5%) and personal MS experiences (27.1% of posts). One quarter of the posts specifically mentioned a positive experience or how thankful the profile owner was for their life. A unique category of posts (13.7%) referenced Austin Carlile, a celebrity singer with MS, as a role model. Physicians and healthcare providers may consider using social media to understand common MS concerns and to place future health education materials.

What tissue is commonly affected in Marfan's syndrome

58dd0dde8acda34529000027_001

Identification of a microdeletion at the 7q33-q35 disrupting the CNTNAP2 gene in a Brazilian stuttering case. Speech and language disorders are some of the most common referral reasons to child development centers accounting for approximately 40% of cases. Stuttering is a disorder in which involuntary repetition, prolongation, or cessation of the sound precludes the flow of speech. About 5% of individuals in the general population have a stuttering problem, and about 80% of the affected children recover naturally. The causal factors of stuttering remain uncertain in most cases; studies suggest that genetic factors are responsible for 70% of the variance in liability for stuttering, whereas the remaining 30% is due to environmental effects supporting a complex cause of the disorder. The use of high-resolution genome wide array comparative genomic hybridization has proven to be a powerful strategy to narrow down candidate regions for complex disorders. We report on a case with a complex set of speech and language difficulties including stuttering who presented with a 10 Mb deletion of chromosome region 7q33-35 causing the deletion of several genes and the disruption of CNTNAP2 by deleting the first three exons of the gene. CNTNAP2 is known to be involved in the cause of language and speech disorders and autism spectrum disorder and is in the same pathway as FOXP2, another important language gene, which makes it a candidate gene for causal studies speech and language disorders such as stuttering.

Which gene is responsible for proper speech development?

5ace12be0340b9f058000007_013

Induction of hemeoxygenase-1 expression after inhibition of hemeoxygenase activity promotes inflammation and worsens ischemic brain damage in mice. Hemeoxygenase (HO) is an enzymatic system that degrades heme. HO-1 is an inducible isoform whereas HO-2 is constitutive. Stroke strongly induces HO-1 expression but the underlying mechanisms are not fully elucidated. Cytokines that are up-regulated after ischemia, like interleukin (IL)-10, can induce HO-1 gene expression, which is positively regulated by the transcriptional activator nuclear factor erythroid 2-related factor 2 (Nrf2) and negatively regulated by the transcriptional repressor breast cancer type 1 susceptibility protein (BRCA1) associated C-terminal helicase 1 (Bach-1). While Nrf2 is activated after ischemia and drugs promoting Nrf2 activation increase HO-1 and are beneficial, the involvement of Bach-1 is unknown. Here we investigated mechanisms involved in HO-1 induction and evaluated the effects of HO activity inhibition in mouse permanent middle cerebral artery occlusion (pMCAO). HO-1 was induced after ischemia in IL-10-deficient mice suggesting that post-ischemic HO-1 induction was IL-10-independent. Attenuation of Bach-1 gene repression after ischemia was associated to enhanced HO-1 induction. Administration of the HO activity inhibitor zinc proto-porphyrin IX (ZnPP) i.p. 24h before pMCAO exacerbated ischemia-induced tumor necrosis factor-α (TNF-α) and IL-1β, nitro-oxidative stress, and the presence of neutrophils at 8h, and increased infarct volume at day 4. However, ZnPP did not worsen ischemic damage when given 30min before pMCAO. ZnPP induced HO-1 expression in the cerebral vasculature at 24h, when it was still detected by high-performance liquid chromatography (HPLC) in plasma. While ZnPP was not found in brain tissue extracts of controls, it could be detected after ischemia, supporting that a small fraction of the injected drug can reach the tissue following blood-brain barrier breakdown. The deleterious effect of inhibiting HO activity in ischemia became apparent in the presence of ZnPP-induced HO-1, which is known to exert effects independent of its enzymatic activity. In conclusion, HO-1 induction after ischemia was associated to down-regulation of transcriptional repressor Bach-1, and induction of HO-1 when HO enzymatic activity was inhibited was related to worst outcome after brain ischemia.

Is the transcriptional regulator BACH1 an activator or a repressor?

52fa6ac72059c6d71c000055_002

Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. OBJECTIVE: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). METHODS: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. RESULTS: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study. CONCLUSIONS: Results from this study support continued development of nusinersen for treatment of SMA. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.

Which disease is treated with Nusinersen?

589185cc621ea6ff7e00000b_020

Genetics of pituitary adenomas. Pituitary adenomas are common tumors of the adenohypophysis which can cause considerable morbidity, due to excessive hormonal secretion or compression and local invasion of surrounding structures. The vast majority of pituitary adenomas occur sporadically. Altered gene expression is commonly detected but somatic mutations, epigenetic changes and abnormal microRNAs have also been described. Occurrence of GNAS mutations at a postzygotic stage lead to McCune-Albright syndrome (MAS), a disease causing endocrine hyperfunction and tumors in several organs, including the pituitary. Familial pituitary adenomas occur as part of a syndrome affecting other organs, such as in MEN1 or Carney complex, or occur with pituitary adenomas only as in familial isolated pituitary adenoma (FIPA). FIPA, an autosomal-dominant disease with variable penetrance, is explained in 20% of patients by germline mutations in the tumor suppressor aryl hydrocarbon receptor interacting protein(AIP), while no gene abnormality has been identified to date in the majority of the FIPA families. AIP mutation-positive patients have a characteristic clinical phenotype with usually young- or childhood-onset growth hormone (GH) and/or prolactin (PRL)-secreting adenomas and can be seen in cases with no apparent family history as well. Understanding the tumorigenic process in AIP-positive and AIP-negative FIPA patients could result in better diagnostic and treatment options for both familial and sporadic cases.

Mutation of which gene is implicated in the familial isolated pituitary adenoma?

551c23bc6b348bb82c00000b_001

[Antileukemic drug--a selective inhibitor of BCR-ABL tyrosine kynase, imatinib(STI571)]. Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by Philadelphia chromosome and resultant production of the constitutively activated BCR-ABL tyrosine kinase. Imatinib (STI571), selective inhibitor of the ABL-tyrosine kinase, inhibits the activity of BCR-ABL tyrosine kinase. A phase I and II study of STI571 showed remarkable cytogenetic effect in patients with interferon-refractory CML, offering new hope for therapy for CML. It will, however, require long-term follow-up data from phase II and III clinical studies to validate the effect of STI571 on survival. As therapy for CML improves, monitoring minimal residual disease will be important.

What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?

5324a8ac9b2d7acc7e000018_095

Treatment of idiopathic parkinsonism with L-dopa in the absence and presence of decarboxylase inhibitors: effects on plasma levels of L-dopa, dopa decarboxylase, catecholamines and 3-O-methyl-dopa. The effect of levodopa (L-dopa), alone or in combination with a peripheral decarboxylase inhibitor (PDI), on plasma levels of aromatic-L-amino acid decarboxylase (ALAAD, = dopa decarboxylase), L-dopa, 3-O-methyl-dopa (3-OMD), dopamine (DA), noradrenaline, adrenaline and dopamine beta-hydroxylase has been studied. In healthy subjects and in patients with parkinsonism plasma ALAAD level fell after administration of L-dopa + benserazide, but returned to previous levels within 90 min. In a cross-sectional study blood was obtained, 2 h after dosing, from 104 patients with idiopathic parkinsonism, divided into four groups: no L-dopa treatment (group 1), L-dopa alone (group 2), L-dopa + benserazide (Madopar) (group 3) and L-dopa + carbidopa (Sinemet) (group 4). Plasma ALAAD, which was normal in groups 1 and 2, was increased 3-fold in groups 3 and 4, indicating that there was induction of ALAAD by the co-administration of PDI. Despite this induction of ALAAD, in groups 3 and 4, with half the daily L-dopa dose compared with group 2, plasma L-dopa and 3-OMD levels were 5 times higher, while plasma DA levels were not different. The DA/L-dopa ratio was decreased 5-fold in group 2 and 16-fold in groups 3 and 4 as compared with group 1. Neither 3-OMD levels nor 3-OMD/L-dopa ratios correlated with the occurrence of on-off fluctuations. In a longitudinal study of three patients started on Madopar treatment the induction of plasma ALAAD was found to occur gradually over 3-4 weeks. Further detailed pharmacokinetic studies in plasma and cerebrospinal fluid are required in order to elucidate whether the ALAAD induction by PDI may be related to the loss of clinical efficacy of combination therapy in some patients and how it is related to end-of-dose deterioration and on-off phenomena.

Which drug is benserazide usually co-administered with?

52bf1f2d03868f1b06000015_025

Panton-Valentine leukocidin-positive Staphylococcus aureus osteomyelitis of the tibia in a 10-year-old child. Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is increasing in prevalence among asymptomatic carriers and in cases of paediatric soft-tissue infections alike. CA-MRSA may express virulence factors such as Panton-Valentine leukocidin, which makes soft-tissue and hard-tissue infections due to such organisms challenging to treat. We report a case of osteomyelitis of the proximal tibia in a 10-year-old boy and discuss its management in what is to the authors' knowledge the first case report of Panton-Valentine leukocidin-positive CA-MRSA osteomyelitis in a child in the UK.

What is MRSA?

58a32efe60087bc10a000013_008

Functional centromeres determine the activation time of pericentric origins of DNA replication in Saccharomyces cerevisiae. The centromeric regions of all Saccharomyces cerevisiae chromosomes are found in early replicating domains, a property conserved among centromeres in fungi and some higher eukaryotes. Surprisingly, little is known about the biological significance or the mechanism of early centromere replication; however, the extensive conservation suggests that it is important for chromosome maintenance. Do centromeres ensure their early replication by promoting early activation of nearby origins, or have they migrated over evolutionary time to reside in early replicating regions? In Candida albicans, a neocentromere contains an early firing origin, supporting the first hypothesis but not addressing whether the new origin is intrinsically early firing or whether the centromere influences replication time. Because the activation time of individual origins is not an intrinsic property of S. cerevisiae origins, but is influenced by surrounding sequences, we sought to test the hypothesis that centromeres influence replication time by moving a centromere to a late replication domain. We used a modified Meselson-Stahl density transfer assay to measure the kinetics of replication for regions of chromosome XIV in which either the functional centromere or a point-mutated version had been moved near origins that reside in a late replication region. We show that a functional centromere acts in cis over a distance as great as 19 kb to advance the initiation time of origins. Our results constitute a direct link between establishment of the kinetochore and the replication initiation machinery, and suggest that the proposed higher-order structure of the pericentric chromatin influences replication initiation.

Do origins of replication close to yeast centromeres fire early or late?

58eb99f3eda5a57672000009_006

Treatment of refractory ulcerative necrobiosis lipoidica diabeticorum with infliximab: report of a case. BACKGROUND: Necrobiosis lipoidica diabeticorum (NLD) is a rare, granulomatous inflammatory skin disease of unknown origin, sometimes associated with diabetes mellitus. Skin lesions usually develop on the lower extremities and can progress toward ulceration and scarring. Many treatments have been proposed, but few have demonstrated consistent efficacy, and no standard regimens have emerged to date. OBSERVATIONS: An 84-year-old woman with type 1 diabetes mellitus presented with a 3-year history of chronic right-lower-extremity erythematous papules and plaques that had developed into confluent ulcers with prominent granulation tissue and an orange-yellow hue. The results of a biopsy of the lesion was consistent with a diagnosis of NLD. The wound did not respond to 4 months of intensive local wound care. After the first intravenous infusion of infliximab (5 mg/kg), there was rapid reduction in wound size, pain, and drainage. There was complete wound healing with excellent cosmesis at 6 weeks (total of 3 infusions). CONCLUSIONS: Infliximab should be considered in the treatment of refractory, ulcerative NLD. Its anti-tumor necrosis factor activity may underlie its efficacy in targeting this granulomatous process, and further investigation should be undertaken to confirm these results.

Which disease the skin condition Necrobiosis lipoidica diabeticorum is associated to?

58bfd8e902b8c60953000018_006

Extensive axonal Lewy neurites in Parkinson's disease: a novel pathological feature revealed by alpha-synuclein immunocytochemistry. Lewy bodies and coarse Lewy neurites are the pathological hallmarks of degenerating neurons in the brains of patients suffering from Parkinson's disease (PD). Recently, the presynaptic protein alpha-synuclein was shown to be a major component of Lewy bodies and Lewy neurites. This study demonstrates for the first time that extensive and thin alpha-synuclein-immunoreactive inclusions are present in the axonal processes of neurons.

Which is the primary protein component of Lewy bodies?

58a2e5f760087bc10a000007_027

[Pharmacologic treatment of sarcoidosis]. Sarcoidosis is still a mysterious disease since we don't know exactly what is the cause. Interestingly some patients get cured without any treatment. There is still a controversy about the indications of treatment in sarcoidosis. This article is an update on pharmacologic treatment in sarcoidosis. Corticosteroids are still the first-line treatment, but alternative therapy with anti-TNF agents, like pentoxifylline, thalidomide and anti-TNF monoclonal antibodies become more interesting, especially in refractory sarcoidosis.

What is the first line treatment for sarcoidosis?

5a7877c0faa1ab7d2e00000c_003

[New therapeutical options for heavy gastrointestinal bleeding]. The number of patients taking new oral anticoagulants is rising, so is the number of serious bleeding events. In severe bleeding, the decision to start a procoagulant therapy is difficult to take. With Idarucizumab and Andexanet Alfa, specific antidotes have been developed against both, direct thrombin inhibitors as well as direct Factor Xa inhibitors. In the endoscopic treatment of severe gastrointestinal bleeding, alternative treatment options are available with Hemospray™, Endoclot™ and new hemostasis clips. Especially in the recurrent ulcer bleeding, the newly developed clips can achieve hemostasis and prevent an operational procedure.

Andexanet Alfa is an antidote of which clotting factor inhibitors?

5880b073c872c95565000003_049

Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer. Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development. In this review, we will focus on clinical data on these 2 new drugs, highlighting their differences compared to palbociclib in terms of single-agent activity, central nervous system penetration, and common adverse events. In addition, we will present the ongoing clinical trials and discuss future directions in the field.

Which enzyme is inhibited by ribociclib?

5880dba9c872c95565000009_006

Active transcription of the human FAS/CD95/TNFRSF6 gene involves the p53 family. p63 and p73 express two main classes of isoforms: isoforms which contain the transactivation domain (TAp73 and TAp63) executing transcriptional activity and dominant-negative isoforms which are truncated at the NH2-terminus acting as operant inhibitors of TAp73, TAp63 and wild-type p53, and thus possessing oncogenic potential. Like wt p53, TAp63 and TAp73 isoforms transactivate target genes that activate apoptosis signaling pathways. In an attempt to understand how the CD95 gene is regulated by the p53 family, we investigated the contributions of a p53-responsive element (RE) within the first intron of the CD95 gene as well as three elements within the promoter. The intronic element conferred transcriptional activation by p53, TAp63 and TAp73 and cooperated with the p53-REs in the promoter of the CD95 gene. Cooperation between the p53-REs in the promoter and the intronic p53-binding site resulted in maximal transcriptional activation of the CD95 gene by the p53 family.

How many TAp73 isoforms have been identified in humans?

5173bdb38ed59a060a000020_053

Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.

In which yeast chromosome does the rDNA cluster reside?

5710e131a5ed216440000001_004

RRAG GTPases link nutrient availability to gene expression, autophagy and lysosomal biogenesis. When the levels of intracellular amino acids are high, RRAG GTPases recruit MTORC1 to lysosomes and promote its activation. We found that RRAGs also recruit specific MTORC1 substrates to the lysosomal surface, thus facilitating MTORC1-mediated phosphorylation and regulation. In particular, active RRAGs interact with the transcription factor EB (TFEB), the master regulator of a gene network that promotes lysosomal biogenesis and autophagy. Redistribution to lysosomes is critical for MTORC1-dependent inactivation of TFEB under nutrient-rich conditions. Therefore, RRAGs play a critical role coordinating nutrient availability and cellular clearance.

Which transcription factor is considered as a master regulator of lysosomal genes?

56cdf40d5795f9a73e00003d_013

The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. The Ewing family of tumors harbors chromosomal translocations that join the N-terminal region of the EWS gene with the C-terminal region of several transcription factors of the ETS family, mainly FLI1, resulting in chimeric transcription factors that play a pivotal role in the pathogenesis of Ewing tumors. To identify downstream targets of the EWS/FLI1 fusion protein, we established 293 cells expressing constitutively either the chimeric EWS/FLI1 or wild type FLI1 proteins and used cDNA arrays to identify genes differentially regulated by EWS/FLI1. DAX1 (NR0B1), an unusual orphan nuclear receptor involved in gonadal development, sex determination and steroidogenesis, showed a consistent up-regulation by EWS/FLI1 oncoprotein, but not by wild type FLI1. Specific induction of DAX1 by EWS/FLI1 was confirmed in two independent cell systems with inducible expression of EWS/FLI1. We also analyzed the expression of DAX1 in Ewing tumors and derived cell lines, as well as in other nonrelated small round cell tumors. DAX1 was expressed in all Ewing tumor specimens analyzed, and in seven out of eight Ewing tumor cell lines, but not in any neuroblastoma or embryonal rhabdomyosarcoma. Furthermore, silencing of EWS/FLI1 by RNA interference in a Ewing tumor cell line markedly reduced the levels of DAX1 mRNA and protein, confirming that DAX1 up-regulation is dependent upon EWS/FLI1 expression. The high levels of DAX1 found in Ewing tumors and its potent transcriptional repressor activity suggest that the oncogenic effect of EWS/FLI1 may be mediated, at least in part, by the up-regulation of DAX1 expression.

Which fusion protein is involved in the development of Ewing sarcoma?

552fac4fbc4f83e828000006_006

Developmental and androgenic regulation of chromatin regulators EZH2 and ANCCA/ATAD2 in the prostate Via MLL histone methylase complex. BACKGROUND: Chromatin regulators ANCCA and EZH2 are overexpressed in prostate cancer and play crucial roles in androgen-stimulated and castration-refractory prostate tumor growth and survival. However, how their expression is regulated in the tumors and whether they play a role in prostate development remains unclear. METHODS: Prostate tissue from different developmental stages of mouse and human were examined by IHC, qRT-PCR and Western for expression of ANCCA, EZH2, and Ki-67. Animals were castrated and T-implanted for the expression response in normal prostate and tumors. siRNA knockdown and ChIP were performed for the mechanism of ANCCA regulation of EZH2. RESULTS: In contrast to their very low level expression in adult prostate, ANCCA and EZH2 are strongly expressed in the epithelium and mesenchyme of mouse and human UGS. Their expression becomes more restricted to epithelial cells during later development and displays a second peak during puberty, which correlates with the proliferative status of the epithelium. Importantly, their expression in normal prostate and tumors is strongly suppressed by castration and markedly induced by testosterone replacement. While androgen suppresses EZH2 in CRPC cells, in LNCaP cells, physiological concentrations of androgen stimulate expression of PRC2 genes (EZH2, SUZ12, and EED), which is mediated by androgen-induced ANCCA and involves E2F and histone H3K4me3 methylase MLL1 complex. CONCLUSION: EZH2 and ANCCA are androgen regulated and strongly expressed in early prostate morphogenesis and during puberty, suggesting their important role in prostate development. Regulation of EZH2 by ANCCA emphasizes bromodomain protein ANCCA as a potential therapeutic target against prostate cancer.

Which is the histone residue methylated by MLL1?

533be71dfd9a95ea0d000009_002

RADAR: a rigorously annotated database of A-to-I RNA editing. We present RADAR--a rigorously annotated database of A-to-I RNA editing (available at http://RNAedit.com). The identification of A-to-I RNA editing sites has been dramatically accelerated in the past few years by high-throughput RNA sequencing studies. RADAR includes a comprehensive collection of A-to-I RNA editing sites identified in humans (Homo sapiens), mice (Mus musculus) and flies (Drosophila melanogaster), together with extensive manually curated annotations for each editing site. RADAR also includes an expandable listing of tissue-specific editing levels for each editing site, which will facilitate the assignment of biological functions to specific editing sites.

Which annotated database of A-to-I RNA editing is available?

587e1a01fc7e8dd84f000001_009

Chromosome XII context is important for rDNA function in yeast. The rDNA cluster in Saccharomyces cerevisiae is located 450 kb from the left end and 610 kb from the right end of chromosome XII and consists of approximately 150 tandemly repeated copies of a 9.1 kb rDNA unit. To explore the biological significance of this specific chromosomal context, chromosome XII was split at both sides of the rDNA cluster and strains harboring deleted variants of chromosome XII consisting of 450 kb, 1500 kb (rDNA cluster only) and 610 kb were created. In the strain harboring the 1500 kb variant of chromosome XII consisting solely of rDNA, the size of the rDNA cluster was found to decrease as a result of a decrease in rDNA copy number. The frequency of silencing of URA3 inserted within the rDNA locus was found to be greater than in a wild-type strain. The localization and morphology of the nucleolus was also affected such that a single and occasionally (6-12% frequency) two foci for Nop1p and a rounded nucleolus were observed, whereas a typical crescent-shaped nucleolar structure was seen in the wild-type strain. Notably, strains harboring the 450 kb chromosome XII variant and/or the 1500 kb variant consisting solely of rDNA had shorter life spans than wild type and also accumulated extrachromosomal rDNA circles. These observations suggest that the context of chromosome XII plays an important role in maintaining a constant rDNA copy number and in physiological processes related to rDNA function in S.cerevisiae.

In which yeast chromosome does the rDNA cluster reside?

5710e131a5ed216440000001_011

Cardiomyocyte ryanodine receptor degradation by chaperone-mediated autophagy. AIMS: Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of soluble cytosolic proteins bearing the sequence KFERQ. These proteins are targeted by chaperones and delivered to lysosomes where they are translocated into the lysosomal lumen and degraded via the lysosome-associated membrane protein type 2A (LAMP-2A). Mutations in LAMP2 that inhibit autophagy result in Danon disease characterized by hypertrophic cardiomyopathy. The ryanodine receptor type 2 (RyR2) plays a key role in cardiomyocyte excitation-contraction and its dysfunction can lead to cardiac failure. Whether RyR2 is degraded by CMA is unknown. METHODS AND RESULTS: To induce CMA, cultured neonatal rat cardiomyocytes were treated with geldanamycin (GA) to promote protein degradation through this pathway. GA increased LAMP-2A levels together with its redistribution and colocalization with Hsc70 in the perinuclear region, changes indicative of CMA activation. The inhibition of lysosomes but not proteasomes prevented the loss of RyR2. The recovery of RyR2 content after incubation with GA by siRNA targeting LAMP-2A suggests that RyR2 is degraded via CMA. In silico analysis also revealed that the RyR2 sequence harbours six KFERQ motifs which are required for the recognition Hsc70 and its degradation via CMA. Our data suggest that presenilins are involved in RyR2 degradation by CMA. CONCLUSION: These findings are consistent with a model in which oxidative damage of the RyR2 targets it for turnover by presenilins and CMA, which could lead to removal of damaged or leaky RyR2 channels.

Which autophagy pathway is trigered by the KFERQ motif of cytosolic proteins?

5540fbce234c5a7c75000001_003