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The role of the humoral immune system in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). The pathogenic events in multiple sclerosis (MS) that result in immune cell infiltration, multifocal demyelination and axonal loss have been focused by the strong impact of the classical MS model experimental autoimmune encephalomyelitis (EAE) towards the hypothesis that MS is an entirely T cell-mediated disease. Although conspicuous humoral immune responses have been known since Kabal's seminal finding of elevated immunoglobulins (Igs) in the cerebrospinal fluid (CSF), only in the past few years evidence derived from recent studies of the MS lesion of anti-myelin antibodies (Abs) in patients with early MS and of MS animal models has led to a renewed interest in the role for B cells, plasma cells and their products in the pathogenesis of MS. This review surveys the actual data concerning the role of the humoral immune system in MS and EAE and explains potential modes of action and long-time persistence in the inflamed brain tissue as a B cell-supportive microenvironment in MS. These mechanisms include the modulation of antigen presentation and costimulation to T cells, increased myelin opsonisation und recruitment of inflammatory cells to the CNS, but also immunoregulatory influences on the remyelination by anti-myelin B cells and Abs. So, affecting the humoral immune system in MS would be a reasonable therapeutic option.

Which is the most widely used model for the study of multiple sclerosis (MS)?

5139b31dbee46bd34c000004_009

Comparison of MRSASelect Agar, CHROMagar Methicillin-Resistant Staphylococcus aureus (MRSA) Medium, and Xpert MRSA PCR for detection of MRSA in Nares: diagnostic accuracy for surveillance samples with various bacterial densities. Rapid laboratory methods provide optimal support for active surveillance efforts to screen for methicillin-resistant Staphylococcus aureus (MRSA). Most laboratories struggle to determine the optimal use of resources, considering options to balance cost, speed, and diagnostic accuracy. To assess the performance of common methods, the first comparison of MRSASelect agar (MS) and CHROMagar MRSA (CA), with and without broth enrichment followed by a 24-h subculture to MS, was performed. Results were compared to those of the Xpert MRSA assay. For direct culture methods, the agreement between MS and CA was 98.8%. At 18 h, direct MS identified 93% of all positive samples from direct culture and 84% of those identified by the Xpert MRSA. For Trypticase soy broth-enriched MS culture, incubated overnight and then subcultured for an additional 24 h, the agreement with Xpert MRSA was 96%. The agreement between direct MS and Xpert MRSA was 100% when semiquantitative culture revealed a bacterial density of 2+ or greater; however, discrepancies between culture and Xpert MRSA arose for MRSA bacterial densities of 1+ or less, indicating low density as a common cause of false-negative culture results. Since 1+ or less was established as the most common MRSA carrier state, broth enrichment or PCR may be critical for the identification of all MRSA carriers who may be reservoirs for transmission. In this active-surveillance convenience sample, the use of broth enrichment followed by subculture to MS offered a low-cost but sensitive method for MRSA screening, with performance similar to that of Xpert MRSA PCR.

What is MRSA?

58a32efe60087bc10a000013_033

Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. Heme oxygenase-1 (HO-1) protects cells from various insults including oxidative stress. Transcriptional activators, including the Nrf2/Maf heterodimer, have been the focus of studies on the inducible expression of ho-1. Here we show that a heme-binding factor, Bach1, is a critical physiological repressor of ho-1. Bach1 bound to the multiple Maf recognition elements (MAREs) of ho-1 enhancers with MafK in vitro and repressed their activity in vivo, while heme abrogated this repressor function of Bach1 by inhibiting its binding to the ho-1 enhancers. Gene targeting experiments in mice revealed that, in the absence of Bach1, ho-1 became expressed constitutively at high levels in various tissues under normal physiological conditions. By analyzing bach1/nrf2 compound-deficient mice, we documented antagonistic activities of Bach1 and Nrf2 in several tissues. Chromatin immunoprecipitation revealed that small Maf proteins participate in both repression and activation of ho-1. Thus, regulation of ho-1 involves a direct sensing of heme levels by Bach1 (by analogy to lac repressor sensitivity to lactose), generating a simple feedback loop whereby the substrate effects repressor-activator antagonism.

Is the transcriptional regulator BACH1 an activator or a repressor?

52fa6ac72059c6d71c000055_021

Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.

Which clotting factor is inhibited by betrixaban?

55200c606b348bb82c000013_118

Transcriptional regulator PRDM12 is essential for human pain perception. Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.

What is the phenotype of people carrying mutations in the gene PRDM12?

58ea7248eda5a57672000002_001

Efficacy and safety of a phyto-SERM as an alternative to hormone therapy. In this review, we analyze the efficacy and safety of DT56a in the treatment of postmenopausal symptoms. Similar to all selective estrogen receptor modulators (SERMs), DT56a demonstrates dual agonistic and antagonistic effects due to the synergy between its components. DT56a is referred to as a plant-origin SERM (phyto-SERM) and, for this reason, its therapeutic capacity in postmenopausal women differs from other phytoestrogens used independently. Although interesting data on relief of vasomotor symptoms have been reported for DT56a, further clinical studies with a greater number of cases and a longer period of study are required to correctly identify its indications for use as an alternative to hormone therapy, especially in preventing osteoporosis.

What is a SERM?

5a74e9ad0384be955100000a_028

psygenet2r: a R/Bioconductor package for the analysis of psychiatric disease genes. Motivation: Psychiatric disorders have a great impact on morbidity and mortality. Genotype-phenotype resources for psychiatric diseases are key to enable the translation of research findings to a better care of patients. PsyGeNET is a knowledge resource on psychiatric diseases and their genes, developed by text mining and curated by domain experts. Results: We present psygenet2r, an R package that contains a variety of functions for leveraging PsyGeNET database and facilitating its analysis and interpretation. The package offers different types of queries to the database along with variety of analysis and visualization tools, including the study of the anatomical structures in which the genes are expressed and gaining insight of gene's molecular function. Psygenet2r is especially suited for network medicine analysis of psychiatric disorders. Availability and implementation: The package is implemented in R and is available under MIT license from Bioconductor (http://bioconductor.org/packages/release/bioc/html/psygenet2r.html). Contact: [email protected] or [email protected]. Supplementary information: Supplementary data are available at Bioinformatics online.

Which R/Bioconductor package has been developed for the analysis of psychiatric disease genes?

5a6e2b1bb750ff445500003e_001

Regional cerebral glucose metabolism after pridopidine (ACR16) treatment in patients with Huntington disease. OBJECTIVES: Huntington disease is a hereditary neurodegenerative disorder resulting in loss of motor, cognitive, and behavioral functions and is characterized by a distinctive pattern of cerebral metabolic abnormalities. Pridopidine (ACR16) belongs to a novel class of central nervous system compounds in development for the treatment of Huntington disease. The objective of the study was to investigate the metabolic changes in patients with Huntington disease before and after pridopidine treatment. METHODS: [(18)F]Fluorodeoxyglucose positron emission tomographic imaging was used to measure the regional cerebral metabolic rate of glucose at baseline and after 14 days of open-label pridopidine treatment in 8 patients with Huntington disease. Clinical assessments were performed using the Unified Huntington's Disease Rating Scale. RESULTS: Statistical parametric mapping analysis showed increased metabolic activity in several brain regions such as the precuneus and the mediodorsal thalamic nucleus after treatment. In addition, after pridopidine treatment, the correlation between the clinical status and the cerebral metabolic activity was strengthened. CONCLUSIONS: Our findings suggest that pridopidine induces metabolic changes in brain regions implicated as important for mediating compensatory mechanisms in Huntington disease. In addition, the finding of a strong relationship between clinical severity and metabolic activity after treatment also suggests that pridopidine treatment targets a Huntington disease-related metabolic activity pattern.

Pridopidine has been tested for treatment of which disorder?

550ea8f1b305b40c5c000005_012

High specific detection and near-infrared photothermal therapy of lung cancer cells with high SERS active aptamer-silver-gold shell-core nanostructures. Lung cancer is the leading cause of cancer death worldwide. Its early detection is of paramount importance for diagnosis, classification, treatment, and improvement of survivorship. However, current methods are not sensitive enough to detect lung cancer in its nascent stage. We reported an aptamer-Ag-Au shell-core nanostructure-based surface-enhanced Raman scattering (SERS) assay for sensitive and specific detection, and near-infrared (NIR) photothermal therapy of lung adenocarcinoma cells (A549 cells). The nanostructures target the cells with high affinity and specificity via the specific interaction between the aptamer (a 45-base oligonucleotide) and the cell, and distinguish A549 cells from other types of cancer cells (HeLa and MCF-7 cells) and subtypes of lung cancer cells (NCI-H157, NCI-H520, NCI-H1299, and NCI-H446 cells). The nanostructures have a high capability to absorb NIR irradiation and are able to perform photothermal therapy of the cells at a very low irradiation power density (0.20 W cm(-2)) without destroying the healthy cells and the surrounding normal tissues. In addition, the nanostructures exhibit a high SERS activity. Based on the SERS signal of the labeled Raman reporter (Rh6G molecules), we can specifically detect A549 cells at a very low abundance (~10 cells per mL) and monitor the therapy process of the cancer cells. Therefore, this nanostructure-based SERS assay has great potential in specific recognition, sensitive detection, and effective photothermal therapy of lung cancer.

From which tissue was the NCI-H520 cell-line derived?

52f89fc62059c6d71c000050_001

Parallel overexpression of seven kallikrein genes in ovarian cancer. Recent evidence suggests that many members of the human kallikrein (KLK) gene family are differentially regulated in ovarian cancer and have potential as diagnostic and/or prognostic markers. We used the serial analysis of gene expression and expressed sequence tag databases of the Cancer Genome Anatomy Project to perform in silico analyses of the expression pattern of the 15 human KLK genes in normal and cancerous ovarian tissues and cell lines. We found that seven KLK genes (KLK5, KLK6, KLK7, KLK8, KLK10, KLK11, and KLK14) are up-regulated in ovarian cancer. Probing 2 normal and 10 ovarian cancer serial analysis of gene expression libraries with gene-specific tags for each KLK indicated that whereas no expression was detected in any normal libraries (with the exception of KLK10 and KLK11), these KLKs were found to be expressed with moderate densities (103-408 tags per million) in 40-60% of the ovarian cancer libraries analyzed. These data were verified by screening the expressed sequence tag databases, where 78 of 79 mRNA clones isolated for these genes were from ovarian cancer libraries. X-profiler comparison of the pools of normal and cancerous ovaries identified a significant difference in expression levels for six of the seven KLKs. We experimentally verified the overexpression of six KLK proteins in cancer versus normal or benign tissues with highly sensitive and specific immunofluorometric assays. A statistically significant stepwise increase in protein levels was found among normal, benign, and cancerous ovarian tissues. The expression of five KLKs showed a strong degree of correlation at the protein level, suggesting the existence of a common mechanism or pathway that controls the expression of this group of adjacent genes during ovarian cancer progression.

How many tissue kallikrein genes are present in the human genome?

511a3573df1ebcce7d000018_010

Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast cancer is the most common tumor in women with Li-Fraumeni Syndrome (LFS), an inherited cancer syndrome associated with germline mutations in the TP53 tumor suppressor gene. Their lifetime breast cancer risk is 49% by age 60. Breast cancers in TP53 mutation carriers recently have more often been reported to be hormone receptor and HER-2 positive by immunohistochemistry and FISH in small series. We seek to complement the existing small literature with this report of a histopathologic analysis of breast cancers from women with documented LFS. Unstained slides and paraffin-embedded tumor blocks from breast cancers from 39 germline TP53 mutation carriers were assembled from investigators in the LFS consortium. Central histology review was performed on 93% of the specimens by a single breast pathologist from a major university hospital. Histology, grade, and hormone receptor status were assessed by immunohistochemistry; HER-2 status was defined by immunohistochemistry and/or FISH. The 43 tumors from 39 women comprise 32 invasive ductal carcinomas and 11 ductal carcinomas in situ (DCIS). No other histologies were observed. The median age at diagnosis was 32 years (range 22-46). Of the invasive cancers, 84% were positive for ER and/or PR; and 81% were high grade. Sixty three percent of invasive and 73% of in situ carcinomas were positive for Her2/neu (IHC 3+ or FISH amplified). Of the invasive tumors, 53% were positive for both ER and HER2+; other ER/PR/HER2 combinations were observed. The DCIS were positive for ER and HER2 in 27% of the cases. This report of the phenotype of breast cancers from women with LFS nearly doubles the literature on this topic. Most DCIS and invasive ductal carcinomas in LFS are hormone receptor positive and/or HER-2 positive. These findings suggest that modern treatments may result in improved outcomes for women with LFS-associated breast cancer.

What is the usual HER-2 status in breast cancer associated with Li-Fraumeni syndrome?

52f21b722059c6d71c00000b_002

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_006

SERCA in genesis of arrhythmias: what we already know and what is new? This review mainly focuses on the structure, function of the sarco(endo)plasmic reticulum calcium pump (SERCA) and its role in genesis of arrhythmias. SERCA is a membrane protein that belongs to the family of P-type ion translocating ATPases and pumps free cytosolic calcium into intracellular stores. Active transport of Ca2+ is achieved, according to the E1-E2 model, changing of SERCA structure by Ca2+. The affinity of Ca2+ -binding sites varies from high (E1) to low (E2). Three different SERCA genes were identified-SERCA1, SERCA2, and SERCA3. SERCA is mainly represented by the SERCA2a isoform in the heart. In heart muscle, during systole, depolarization triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) and starts contraction. During diastole, muscle relaxation occurs as Ca2+ is again removed from cytosol, predominantly by accumulation into SR via the action of SERCA2a. The main regulator of SERCA2a is phospholamban and another regulator proteolipid of SERCA is sarcolipin. There are a lot of studies on the effect of decreased and/or increased SERCA activity in genesis of arrhythmia. Actually both decrease and increase of SERCA activity in the heart result in some pathological mechanisms such as heart failure and arrhythmia.

Which is the main calcium pump of the sarcoplasmic reticulum?

54db62a3034aea571d000001_020

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_002

[Reported use of thalidomide in multiple myeloma: presentation of problems in the Thaled® outpatient department]. BACKGROUND: Thalidomide was approved in Japan for multiple myeloma treatment in October 2008. A program called the Thalidomide Education and Risk Management System (TERMS®) was established to help ensure that every effort is made to use the drug safely. PURPOSE: We report the use of thalidomide to treat multiple myeloma, and describe problems arising in the Thaled® outpatient department. PATIENTS AND METHODS: Multiple myeloma patients treated with thalidomide at Hitachi General Hospital. INTERVENTION: Monitoring of the efficacy and safety of thalidomide, and a questionnaire survey conducted at the Thaled® outpatient department. RESULTS: The thalidomide response rate was 41. 7%. In 5 cases, all patients received steroids along with thalidomide. After auto-PBSCT, 1 of 2 cases demonstrated a good response (PR 1). After treatment with bortezomib, 1 of 2 cases demonstrated a good response (MR 1). After auto-PBSCT and treatment with bortezomib, 1 of 4 cases demonstrated a good response (PR 1). In a case demonstrating hematotoxicity Grade 3 (in addition to neutropenia), administration was discontinued. Regarding problems in the Thaled® outpatient department, the medical staff indicated that TERMS® is a very complicated program, while the patients requested prolongation of the prescription days and reduction of the economic burden of medication costs. CONCLUSION: Thalidomide showed some success in treating multiple myeloma either after auto-PBSCT or following treatment with bortezomib. In the case demonstrating hematotoxicity Grade 3 (in addition to neutropenia), grave complications could have very easily developed, thus underscoring the importance of careful monitoring. Based on a questionnaire survey conducted in the Thaled® outpatient department, the medical staff made comments and patients raised issues that should be examined in the future.

What disease is Velcade (bortezomib) mainly used for?

51631154298dcd4e5100004e_004

Giant axonal neuropathy caused by compound heterozygosity for a maternally inherited microdeletion and a paternal mutation within the GAN gene. Different missense, nonsense and frameshift mutations in the GAN gene encoding gigaxonin have been described to cause giant axonal neuropathy, a severe early-onset progressive neurological disease with autosomal recessive inheritance. By oligonucleotide array CGH analysis, we identified a 57-131 kb microdeletion affecting this gene in a patient with developmental delay, ataxia, areflexia, macrocephaly, and strikingly frizzy hair. The microdeletion was inherited from the mother and mutation analysis revealed a paternally inherited missense mutation c.1456G>A in exon 9 on the other allele. Our findings illustrate the power of higher resolution array CGH studies and highlight the importance of considering copy number variations in autosomal recessive diseases.

Which gene is involved in Giant Axonal Neuropathy?

572096c90fd6f91b6800000e_008

Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.

Which clotting factor is inhibited by betrixaban?

55200c606b348bb82c000013_001

Antinociceptive mechanism of L-DOPA. The mechanism of L-DOPA for antinociception was investigated. Nociceptive behaviors in mice after an intrathecal (i.t.) administration of substance P were evaluated. L-DOPA (i.t.) dose-dependently attenuated the substance P-induced nociceptive behaviors. Co-administration of benserazide (i.t.), a DOPA decarboxylase inhibitor, abolished the antinociceptive effect of L-DOPA. The L-DOPA-induced antinociception was antagonized by sulpiride, a D2 blocker, but not by SCH 23390, a D1 blocker. These results suggest that L-DOPA relieves pain after conversion to dopamine, with the dopamine sedating pain transmission by way of the dopamine D2 receptor.

Which drug is benserazide usually co-administered with?

52bf1f2d03868f1b06000015_010

MARS: improving multiple circular sequence alignment using refined sequences. BACKGROUND: A fundamental assumption of all widely-used multiple sequence alignment techniques is that the left- and right-most positions of the input sequences are relevant to the alignment. However, the position where a sequence starts or ends can be totally arbitrary due to a number of reasons: arbitrariness in the linearisation (sequencing) of a circular molecular structure; or inconsistencies introduced into sequence databases due to different linearisation standards. These scenarios are relevant, for instance, in the process of multiple sequence alignment of mitochondrial DNA, viroid, viral or other genomes, which have a circular molecular structure. A solution for these inconsistencies would be to identify a suitable rotation (cyclic shift) for each sequence; these refined sequences may in turn lead to improved multiple sequence alignments using the preferred multiple sequence alignment program. RESULTS: We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences. MARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences. Experimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency. Our results show, among others, that the average pairwise distance in the multiple sequence alignment of a dataset of widely-studied mitochondrial DNA sequences is reduced by around 5% when MARS is applied before a multiple sequence alignment is performed. CONCLUSIONS: Analysing multiple sequences simultaneously is fundamental in biological research and multiple sequence alignment has been found to be a popular method for this task. Conventional alignment techniques cannot be used effectively when the position where sequences start is arbitrary. We present here a method, which can be used in conjunction with any multiple sequence alignment program, to address this problem effectively and efficiently.

Which algorithm has been developed in order to improve multiple circular sequence alignment using refined sequences?

5a6a3464b750ff4455000026_007

Long-term control of endemic hospital-wide methicillin-resistant Staphylococcus aureus (MRSA): the impact of targeted active surveillance for MRSA in patients and healthcare workers. OBJECTIVE: To evaluate the long-term impact of successive interventions on rates of methicillin-resistant Staphylococcus aureus (MRSA) colonization or infection and MRSA bacteremia in an endemic hospital-wide situation. DESIGN: Quasi-experimental, interrupted time-series analysis. The impact of the interventions was analyzed by use of segmented regression. Representative MRSA isolates were typed by use of pulsed-field gel electrophoresis. SETTING: A 950-bed teaching hospital in Seville, Spain. PATIENTS: All patients admitted to the hospital during the period from 1995 through 2008. METHODS: Three successive interventions were studied: (1) contact precautions, with no active surveillance for MRSA; (2) targeted active surveillance for MRSA in patients and healthcare workers in specific wards, prioritized according to clinical epidemiology data; and (3) targeted active surveillance for MRSA in patients admitted from other medical centers. RESULTS: Neither the preintervention rate of MRSA colonization or infection (0.56 cases per 1,000 patient-days [95% confidence interval {CI}, 0.49-0.62 cases per 1,000 patient-days]) nor the slope for the rate of MRSA colonization or infection changed significantly after the first intervention. The rate decreased significantly to 0.28 cases per 1,000 patient-days (95% CI, 0.17-0.40 cases per 1,000 patient-days) after the second intervention and to 0.07 cases per 1,000 patient-days (95% CI, 0.06-0.08 cases per 1,000 patient-days) after the third intervention, and the rate remained at a similar level for 8 years. The MRSA bacteremia rate decreased by 80%, whereas the rate of bacteremia due to methicillin-susceptible S. aureus did not change. Eighty-three percent of the MRSA isolates identified were clonally related. All MRSA isolates obtained from healthcare workers were clonally related to those recovered from patients who were in their care. CONCLUSION: Our data indicate that long-term control of endemic MRSA is feasible in tertiary care centers. The use of targeted active surveillance for MRSA in patients and healthcare workers in specific wards (identified by means of analysis of clinical epidemiology data) and the use of decolonization were key to the success of the program.

What is MRSA?

58a32efe60087bc10a000013_044

Disruption of SMIM1 causes the Vel- blood type. Here, we report the biochemical and genetic basis of the Vel blood group antigen, which has been a vexing mystery for decades, especially as anti-Vel regularly causes severe haemolytic transfusion reactions. The protein carrying the Vel blood group antigen was biochemically purified from red blood cell membranes. Mass spectrometry-based de novo peptide sequencing identified this protein to be small integral membrane protein 1 (SMIM1), a previously uncharacterized single-pass membrane protein. Expression of SMIM1 cDNA in Vel- cultured cells generated anti-Vel cell surface reactivity, confirming that SMIM1 encoded the Vel blood group antigen. A cohort of 70 Vel- individuals was found to be uniformly homozygous for a 17 nucleotide deletion in the coding sequence of SMIM1. The genetic homogeneity of the Vel- blood type, likely having a common origin, facilitated the development of two highly specific DNA-based tests for rapid Vel genotyping, which can be easily integrated into blood group genotyping platforms. These results answer a 60-year-old riddle and provide tools of immediate assistance to all clinicians involved in the care of Vel- patients.

Which gene-defect causes the Vel-blood type?

58a872bd38c171fb5b000002_001

OCA1 in different ethnic groups of india is primarily due to founder mutations in the tyrosinase gene. Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders characterized by an abnormally low amount of melanin in the eyes, skin and hair, and associated with common developmental abnormalities of the eye. Defects in the tyrosinase gene (TYR) cause a common type of OCA, known as oculocutaneous albinism type 1 (OCA1). The molecular basis of OCA has been studied extensively in different population groups, but very little information is available on Indian patients. Our investigation covering thirteen ethnic groups of India, some representing >20 million people, revealed that among 25 OCA families 12 were affected with OCA1, and that these cases were primarily due to founder mutations in TYR. We detected nine mutations and eight SNPs in TYR, of which six mutations (five point mutations & one gross deletion) were novel. In contrast to most reports describing compound heterozygotes, the presence of homozygotes in 10 out of the 12 pedigrees underscores the lack of intermixing between these ethnic groups in India. Haplotype analysis suggested a few founder chromosomes causing the disease in the majority of the patients. Direct detection of the mutations prevalent in specific ethnic groups could be used for carrier detection and genetic counselling.

Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?

58cbb98c02b8c60953000034_044

Oculocutaneous albinism type 1: the last 100 years. Research on human albinism has been central to many of the major discoveries in human genetics. These include the first evidence that Mendel's rules of genetic segregation apply to humans, first published in 1903. Contrary to initial thought that albinism is caused by mutations in a single gene, we now know that the genetics of albinism are complex. The complexity of albinism was hinted at, in early publications, but has only recently been fully appreciated with the advent of molecular techniques. Currently, 12 different genes have been identified, that when mutated, result in a different type of albinism. Oculocutaneous albinism type 1 (OCA1), resulting from mutations of the tyrosinase gene, is genetically and biochemically the best understood type of albinism. Though much of the research in albinism has involved OCA1, there are many unanswered questions about OCA1 and albinism, in general. The next 100 yr should still provide many surprises as did the first 100 yr.

Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?

58cbb98c02b8c60953000034_117

Monitoring and reversal strategies for new oral anticoagulants. Thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban, apixaban and edoxaban form a new class of non-vitamin K antagonist oral anticoagulants and have been extensively studied in patients with venous thromboembolism and atrial fibrillation. They offer anticoagulation that is as effective and at least as safe compared to warfarin without the need for routine laboratory monitoring; however, no reversal strategies are currently validated in case of a non-vitamin K antagonist oral anticoagulant-associated bleed. In emergency situations, laboratory drug measurement and well-defined management for non-vitamin K antagonist oral anticoagulant-induced hemorrhage may improve clinical outcome. In this review, the merits and limitations of the routine coagulation tests and some of the more specific laboratory assays are compared. Furthermore, prohemostatic measures are reviewed and the recommended strategies in case of bleeding are summarized. Specific reversal agents are currently under development (idarucizumab for dabigatran, andexanet alfa for Xa inhibitors, and PER977 for both Xa- and thrombin inhibitors), which will facilitate clinical management of severe bleeding and emergency surgery.

Andexanet Alfa is an antidote of which clotting factor inhibitors?

5880b073c872c95565000003_057

Host factors are more important in predicting recurrent Clostridium difficile infection than ribotype and use of antibiotics. OBJECTIVE: A frequent complication of Clostridium difficile infection (CDI) is recurrent disease. The aim of this study was to determine whether early recurrence risk was higher after infection with ribotype 027 (outbreak strain) compared with infection with endemic strain types of C. difficile. METHODS: Consecutive patients diagnosed with CDI between May 2013 and March 2014 were included (outbreak strain, and non-outbreak strains). Patients who developed recurrent CDI within 30 days after completion of CDI treatment, were compared with patients without a recurrence. Medical charts were reviewed for demographic and clinical characteristics. General practitioners were contacted to complete data about the occurrence of recurrent CDI, and the use of medication after hospital discharge. RESULTS: In total, 135 patients were at risk for the development of recurrent CDI; 74 patients were infected by ribotype 027, and 61 patients by other ribotypes. Thirty-nine patients (29%) developed recurrent CDI within 30 days after completion of CDI treatment. In multivariable analysis, age > 70 years (HR 3.05, 95% CI 1.54-6.03), and a duration of CDI treatment > 11 days (HR 1.92, 95% CI 1.00-3.69) were clearly associated with recurrence; infection with ribotype 027 showed a HR of 1.72 (95% CI 0.88-3.33). CONCLUSION: During this outbreak of C. difficile in a tertiary care centre, age and a prolonged duration of CDI therapy (which is most likely a marker of underlying disease severity) were the main risk factors for recurrent CDI. This points to host factors as more important predictors for recurrent CDI than strain type or antibiotic use.

Which main ribotype of Clostridium difficile is responsible of the recent outbreak?

5a87d73861bb38fb2400000b_005

Infantile neuroaxonal dystrophy and PLA2G6-associated neurodegeneration: An update for the diagnosis. Infantile neuroaxonal dystrophy is a rare neurodegenerative disorder characterized by infantile onset of rapid motor and cognitive regression and hypotonia evolving into spasticity. Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment. Phenotypic spectrum continues to evolve and genotype-phenotype correlations are currently limited. Due to the overlapping phenotypes and heterogeneity of clinical findings characterization of the syndrome is not always achievable. We reviewed the most recent clinical and neuroradiological information in the way to make easier differential diagnosis with other degenerative disorders in the paediatric age. Recognizing subtle signs and symptoms is a fascinating challenge to drive towards better diagnostic and genetic investigations.

Which gene is mutated in the Karak syndrome?

588f9950ed9bbee70d000002_012

The melanocortin 1 receptor (MC1R): more than just red hair. The melanocortin 1 receptor, a seven pass transmembrane G protein coupled receptor, is a key control point in melanogenesis. Loss-of-function mutations at the MC1R are associated with a switch from eumelanin to phaeomelanin production, resulting in a red or yellow coat colour. Activating mutations, in animals at least, lead to enhanced eumelanin synthesis. In man, a number of loss-of-function mutations in the MC1R have been described. The majority of red-heads (red-haired persons) are compound heterozygotes or homozygotes for up to five frequent loss-of-function mutations. A minority of redheads are, however, only heterozygote. The MC1R is, therefore, a major determinant of sun sensitivity and a genetic risk factor for melanoma and non-melanoma skin cancer. Recent work suggests that the MC1R also shows a clear heterozygote effect on skin type, with up to 30% of the population harbouring loss-of-function mutations. Activating mutations of the MC1R in man have not been described. The MC1R is particularly informative and a tractable gene for studies of human evolution and migration. In particular, study of the MC1R may provide insights into the lightening of skin colour observed in most European populations. The world wide pattern of MC1R diversity is compatible with functional constraint operating in Africa, whereas the greater allelic diversity seen in non-African populations is consistent with neutral predictions rather than selection. Whether this conclusion is as a result of weakness in the statistical testing procedures applied, or whether it will be seen in other pigment genes will be of great interest for studies of human skin colour evolution.

Which gene is responsible for red hair?

5ace19420340b9f05800000a_015

Use of flumazenil in intoxicated patients with coma. A double-blind placebo-controlled study in ICU. In a double-blind placebo-controlled prospective clinical trial we studied the efficacy and safety of the benzodiazepine antagonist, flumazenil. In 23 patients admitted to the Intensive Care Unit with coma due to overdose with benzodiazepines or other sedatives, flumazenil i.v. (up to 2 mg or placebo) was given. In 13 patients given flumazenil the Glasgow Coma Scale (GCS) increased significantly from 4.9 to 7.8 (p less than 0.05). Six of these 13 patients, including mainly benzodiazepine mono-intoxications, needed only one series of injections (up to 1.0 mg flumazenil); the GCS increased thereby from 4.5 to 10.7 within a maximum of 5 min (p less than 0.01). In the remaining 7 patients, needing two series of injections of flumazenil (up to 2.0 mg), GCS did not rise significantly and coma was related to intoxications with nonbenzodiazepine sedatives, flunitrazepam and in one patient, encephalitis. In the 10 patients receiving placebo, the GCS did not change. A significant increase in the GCS from 5.5 to 10.8 (p less than 0.001) was, however, observed when flumazenil (up to 1.0 mg) was given after placebo. In patients with EEG monitoring the changes in waveform pattern paralleled the clinical response. Effects could be detected within 1-2 min after flumazenil injection and lasted up to 45 min. There were no adverse reactions or benzodiazepine withdrawal symptoms. We conclude that flumazenil is an effective and safe drug in the treatment of benzodiazepine overdose. The use of flumazenil is of diagnostic value in mixed-drug intoxications or coma of unknown origin and is of therapeutic importance for reversal of benzodiazepine intoxications.

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

514a0a57d24251bc05000051_045

The p73 gene is an anti-tumoral target of the RARbeta/gamma-selective retinoid tazarotene. Tazarotene, a member of the new class of acetylenic retinoids, has been shown to be effective in the treatment of several hyperproliferative skin diseases, including non-melanoma skin cancer. Its effectiveness is thought to rely on the ability to activate retinoic acid receptors beta and gamma and to induce a number of downstream anti-proliferative genes. Here, we show that the p53-related gene p73 is a target of tazarotene. Indeed, tazarotene modulates the expression of the p73 gene in immortalized keratinocyte cell lines by inducing the pro-apoptotic and anti-proliferative TAp73 isoforms and by repressing the anti-apoptotic and pro-proliferative DeltaNp73 isoforms. This occurs at the transcriptional level through a coordinated action on P1p73 and P2p73 promoters that control the expression of TA and DeltaN isoforms, respectively. The selective downregulation of DeltaNp73 expression by small interfering RNA led to an enhancement of tazarotene-induced bax activation and apoptosis, whereas the downregulation of both TA and DeltaN isoforms impairs tazarotene-mediated apoptosis. These results indicate the relevance of p73 gene products in tazarotene-induced growth inhibition and effectiveness in the treatment of skin tumors.

How many TAp73 isoforms have been identified in humans?

5173bdb38ed59a060a000020_076

TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity. The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73(-/-)) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73(-/-) mice show a high incidence of spontaneous tumors. Moreover, TAp73(-/-) mice are infertile and produce oocytes exhibiting spindle abnormalities. These data suggest a link between TAp73 activities and the common molecular machinery underlying meiosis and mitosis. Previous studies have indicated that the spindle assembly checkpoint (SAC) complex, whose activation leads to mitotic arrest, also regulates meiosis. In this study, we demonstrate in murine and human cells that TAp73 is able to interact directly with several partners of the SAC complex (Bub1, Bub3, and BubR1). We also show that TAp73 is involved in SAC protein localization and activities. Moreover, we show that decreased TAp73 expression correlates with increases of SAC protein expression in patients with lung cancer. Our results establish TAp73 as a regulator of SAC responses and indicate that TAp73 loss can lead to mitotic arrest defects. Our data suggest that SAC impairment in the absence of functional TAp73 could explain the genomic instability and increased aneuploidy observed in TAp73-deficient cells.

How many TAp73 isoforms have been identified in humans?

5173bdb38ed59a060a000020_012

Slings in iatrogenic male incontinence: Current status. OBJECTIVES: The increasing number of prostatectomies entails an increasing number of patients suffering from iatrogenic incontinence despite improved surgical techniques. The severity of this problem often requires invasive treatments such as periurethral injection of bulking agents, artificial urinary sphincter (AUS) implantation, and sub-urethral sling positioning. The artificial urethral sphincter has represented, until today, the gold standard but, in the recent years, sling systems have been investigated as minimally invasive alternative options. Today, three different sling procedures are commonly performed: bone-anchored, readjustable, and trans-obturator slings systems. The aim of this review is to critically report the current status of sling systems in the treatment of iatrogenic male incontinence. MATERIALS AND METHODS: MEDLINE and PubMed databases were searched and all articles between 1974 and 2009 were evaluated. RESULTS: With regard to bone-anchored, readjustable, and trans-obturator slings systems, cure rates ranged between 58.0% and 86.0%, 55.5% and 73.0%, and 40.0% and 63.0%, respectively, while major complication rates ranged between 0 and 14.5%, 10.0 and 22.2%, and 0 and 10.0%, respectively. CONCLUSIONS: Suburethral slings are the only alternative techniques which can be favorably compared with the AUS, showing more advantages with respect to AUS implantations which are mainly represented by a quick and less invasive approach, low morbidity, and low costs. In spite of the difficulty in identifying the most effective sling procedure, overall, sling systems can be recommended for patients with persistent mild or moderate incontinence. However, the indication can also be extended to patients with severe incontinence, after appropriate counseling, allowing AUS implantation in the event of sling failure.

What is the gold standard treatment for Iatrogenic male incontinence?

5325fdf0600967d132000001_001

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).

Andexanet Alfa is an antidote of which clotting factor inhibitors?

5880b073c872c95565000003_054

SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson's disease. We have recently shown that the Na(+)/Ca(2+) exchanger (NCX) is involved in nitric oxide (NO)-induced cytotoxicity in cultured astrocytes and neurons. However, there is no in vivo evidence suggesting the role of NCX in neurodegenerative disorders associated with NO. NO is implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease. This study examined the effect of SEA0400, the specific NCX inhibitor, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a model of Parkinson's disease, in C57BL/6J mice. MPTP treatment (10 mg/kg, four times at 2-h intervals) decreased dopamine levels in the midbrain and impaired motor coordination, and these effects were counteracted by S-methylthiocitrulline, a selective neuronal NO synthase inhibitor. SEA0400 protected against the dopaminergic neurotoxicity (determined by dopamine levels in the midbrain and striatum, tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum, striatal dopamine release, and motor deficits) in MPTP-treated mice. SEA0400 had no radical-scavenging activity. SEA0400 did not affect MPTP metabolism and MPTP-induced NO production and microglial activation, while it attenuated MPTP-induced increases in extracellular signal-regulated kinase (ERK) phosphorylation and lipid peroxidation product, thiobarbituric acid reactive substance. These findings suggest that SEA0400 protects against MPTP-induced neurotoxicity probably by blocking ERK phosphorylation and lipid peroxidation which are downstream of NCX-mediated Ca(2+) influx.

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

5506c3e38e1671127b00000a_012

Recommendations for the management of facioscapulohumeral muscular dystrophy in 2011. Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disease, characterized by an autosomal dominant mode of inheritance, facial involvement, and selectivity and asymmetry of muscle involvement. In general, FSHD typically presents before age 20 years. Usually, FSHD muscle involvement starts in the face and then progresses to the shoulder girdle, the humeral muscles and the abdominal muscles, and then the anterolateral compartment of the leg. Disease severity is highly variable and progression is very slow. About 20% of FSHD patients become wheelchair-bound. Lifespan is not shortened. The diagnosis of FSHD is based on a genetic test by which a deletion of 3.3kb DNA repeats (named D4Z4 and mapping to the subtelomeric region of chromosome 4q35) is identified. The progressive pattern of FSHD requires that the severity of symptoms as well as their physical, social and psychological impact be evaluated on a regular basis. A yearly assessment is recommended. Multidisciplinary management of FSHD--consisting of a combination of genetic counselling, functional assessment, an assessment by a physical therapist, prescription of symptomatic therapies and prevention of known complications of this disease--is required. Prescription of physical therapy sessions and orthopedic appliances are to be adapted to the patient's deficiencies and contractures.

What is the mode of inheritance of Facioscapulohumeral muscular dystrophy (FSHD)?

52e8e93498d023950500001e_001

Chromosome condensation and sister chromatid pairing in budding yeast. We have developed a fluorescent in situ hybridization (FISH) method to examine the structure of both natural chromosomes and small artificial chromosomes during the mitotic cycle of budding yeast. Our results suggest that the pairing of sister chromatids: (a) occurs near the centromere and at multiple places along the chromosome arm as has been observed in other eukaryotic cells; (b) is maintained in the absence of catenation between sister DNA molecules; and (c) is independent of large blocks of repetitive DNA commonly associated with heterochromatin. Condensation of a unique region of chromosome XVI and the highly repetitive ribosomal DNA (rDNA) cluster from chromosome XII were also examined in budding yeast. Interphase chromosomes were condensed 80-fold relative to B form DNA, similar to what has been observed in other eukaryotes, suggesting that the structure of interphase chromosomes may be conserved among eukaryotes. While additional condensation of budding yeast chromosomes were observed during mitosis, the level of condensation was less than that observed for human mitotic chromosomes. At most stages of the cell cycle, both unique and repetitive sequences were either condensed or decondensed. However, in cells arrested in late mitosis (M) by a cdc15 mutation, the unique DNA appeared decondensed while the repetitive rDNA region appeared condensed, suggesting that the condensation state of separate regions of the genome may be regulated differently. The ability to monitor the pairing and condensation of sister chromatids in budding yeast should facilitate the molecular analysis of these processes as well as provide two new landmarks for evaluating the function of important cell cycle regulators like p34 kinases and cyclins. Finally our FISH method provides a new tool to analyze centromeres, telomeres, and gene expression in budding yeast.

In which yeast chromosome does the rDNA cluster reside?

5710e131a5ed216440000001_016

Phylogenomics supports microsporidia as the earliest diverging clade of sequenced fungi. BACKGROUND: Microsporidia is one of the taxa that have experienced the most dramatic taxonomic reclassifications. Once thought to be among the earliest diverging eukaryotes, the fungal nature of this group of intracellular pathogens is now widely accepted. However, the specific position of microsporidia within the fungal tree of life is still debated. Due to the presence of accelerated evolutionary rates, phylogenetic analyses involving microsporidia are prone to methodological artifacts, such as long-branch attraction, especially when taxon sampling is limited. RESULTS: Here we exploit the recent availability of six complete microsporidian genomes to re-assess the long-standing question of their phylogenetic position. We show that microsporidians have a similar low level of conservation of gene neighborhood with other groups of fungi when controlling for the confounding effects of recent segmental duplications. A combined analysis of thousands of gene trees supports a topology in which microsporidia is a sister group to all other sequenced fungi. Moreover, this topology received increased support when less informative trees were discarded. This position of microsporidia was also strongly supported based on the combined analysis of 53 concatenated genes, and was robust to filters controlling for rate heterogeneity, compositional bias, long branch attraction and heterotachy. CONCLUSIONS: Altogether, our data strongly support a scenario in which microsporidia is the earliest-diverging clade of sequenced fungi.

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

5547a01cf35db75526000005_005

Fresh approaches stem MRSA tide. The theory of positive deviance holds that in any group, some people are more effective than others even when they have the same resources at hand. The object is to identify those people, see what they're doing differently and share it with the larger group. The Plexus Institute and the Robert Wood Johnson Foundation recently collaborated on a six-hospital positive-deviance study that reduced methicillin-resistant Staphylococcus aureus (MRSA) infection rates by 70 percent. What these hospitals learned may help others cut their MRSA rates.

What is MRSA?

58a32efe60087bc10a000013_076

Ultrasound: a noninvasive screening test for detrusor instability. OBJECTIVE: To determine whether transvaginal ultrasound measurement of bladder wall thickness can be used as a screening test for detrusor instability in women with urinary symptoms. DESIGN: A blinded prospective study. SETTING: A London teaching hospital. PARTICIPANTS: One hundred and eight-four symptomatic women presenting to a urodynamic clinic. MAIN OUTCOME MEASURE: The detection of detrusor instability by means of videocystourethrography (VCU) and ambulatory urodynamics in women with a mean bladder wall thickness of greater than 5 mm measured by transvaginal ultrasound. RESULTS: One hundred and eight women had a mean bladder wall thickness of greater than 5 mm. Ninety-four percent (102) of these women had detrusor instability either when undergoing VCU or ambulatory urodynamics. Seventeen women had a bladder wall thickness of less than 3.5 mm of whom three were found to have detrusor instability on VCU. CONCLUSION: The measurement of a mean bladder wall thickness greater than 5 mm with transvaginal ultrasound is a sensitive screening method for diagnosing detrusor instability in symptomatic women without outflow obstruction.

How is bladder wall thickness measured?

5324bdba9b2d7acc7e00001a_010

RON-regulated innate immunity is protective in an animal model of multiple sclerosis. The tyrosine kinase receptor RON and its ligand, macrophage stimulating protein (MSP), exert inhibitory effects on systemic innate immunity, but their CNS expression and impact on human neuroinflammatory diseases are unknown were RON and MSP present in human brain perivascular macrophages and microglia, but RON mRNA and protein abundance in the CNS were diminished in both MS patients and the MS animal model, experimental autoimmune encephalomyelitis (EAE). Treatment of differentiated human monocytoid cells with MSP resulted in significant reduction of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and MMP-9 mRNA levels, whereas minimal effects were observed in human astrocytes. After induction of EAE, RON knockout and heterozygote animals exhibited significantly increased CNS proinflammatory gene (TNF-alpha, MMP-12) expression compared with wild-type littermate controls, although IL-4 levels were suppressed in both RON-deficient groups. Neurological disease in RON-deficient animals showed a more rapid onset with overall worsened severity, together with exacerbated demyelination, axonal injury, and neuroinflammation after EAE induction. The proto-oncogene, c-Cbl, which modulates ubiquitylation of RON, was increased in glia in both MS brains and EAE spinal cords. Thus, the MSP-RON pathway represents a novel regulatory mechanism within the CNS by which innate immunity and its pathogenic effects could be targeted for future therapeutic interventions.

Which is the most widely used model for the study of multiple sclerosis (MS)?

5139b31dbee46bd34c000004_014

Transrectal ultrasound versus cystography in the evaluation of anatomical stress urinary incontinence. Thirty-two female patients with clinical and urodynamic findings of genuine stress urinary incontinence were evaluated before and 6 months after surgery for stress urinary incontinence. Twenty-nine control patients had identical evaluations before and 6 months after surgery which did not involve the urethrovesical junction. Twenty-four patients with primary bladder instability had similar evaluations and served as a second control group. Anatomical landmarks indicating support to the urethrovesical junction were evaluated by the position of the urethra at the most dependent point in the bladder on straining and the urethral descent on straining to beneath the posterior ramus of the symphysis pubis on bead chain cystography. The urethrovesical junction drop on straining was evaluated by transrectal ultrasonography. Cystographic and ultrasonographic tests for the position of the urethrovesical junction at the most dependent position in the bladder during straining were very sensitive in women with stress urinary incontinence (94 and 87% respectively) but much less specific (45 and 48% respectively). When evaluating anatomical support to the urethrovesical junction and its descent on straining, these tests were both highly sensitive (97 and 94% respectively) and specific (76 and 96% respectively) in women with genuine stress urinary incontinence. Simple clinical tests for support of the urethrovesical junction, such as the Q tip test, are non-specific in patients with stress urinary incontinence. Transrectal ultrasonography is a simple and quick out-patient procedure. The availability of ultrasound equipment in most clinics and the high sensitivity and specificity of the test make it an attractive and cost-effective alternative to X-ray cystography in the pre-operative evaluation of anatomical support to the urethrovesical junction.

Which type of urinary incontinence is diagnosed with the Q tip test?

5a67b2f7b750ff445500000f_008

Identification of defects in the fibrillin gene and protein in individuals with the Marfan syndrome and related disorders. The Marfan syndrome is an autosomal dominant disorder with pleiotropic manifestations that involve the cardiovascular, ocular, and skeletal systems. Through a number of investigational approaches, the gene encoding for fibrillin, the FBN1 gene on chromosome 15, has been identified as the defective gene causing the Marfan syndrome. Fibrillin is the large glycoprotein with a repetitive domain structure and is a major protein component of microfibrils, a fibrillar system closely associated with elastin in connective tissue. Mutational analysis of defects in the FBN1 gene in patients with the Marfan syndrome has revealed that most mutations are private or unique in an affected individual or family. Analysis of fibrillin protein or gene defects in individuals with related phenotypes has revealed that a perinatal lethal syndrome, termed neonatal Marfan syndrome, is due to FBN1 gene mutations. In addition, fibroblast cell strains from a subset of patients with idiopathic scoliosis have fibrillin protein defects. Last, fibroblasts from calves affected with bovine Marfan syndrome display defects in the fibrillin protein. These studies have wide-ranging implications in the diagnosis, treatment, and prevention of Marfan syndrome and related disorders.

Which gene mutations cause the Marfan syndrome?

58d8e6818acda3452900000a_056

Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online. Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.

Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?

58cbb98c02b8c60953000034_021

Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Ixazomib is the first investigational oral proteasome inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) occurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 patients received in 4 expansion cohorts. Patients received a median of 4 cycles (range, 1-39); 18% received > 12 cycles. Eighty-eight percent had drug-related adverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), and rash (40%); drug-related grade > 3 events included thrombocytopenia (37%) and neutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% (no grade > 3). Two patients died on the study (both considered unrelated to treatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma exposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 response-evaluable patients, 15% achieved partial response or better (76% stable disease or better). These findings have informed the subsequent clinical development of ixazomib in multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00932698.

Which type of myeloma is ixazomib being evaluated for?

56ed0ffe2ac5ed1459000008_014

Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BACKGROUND: Patisiran is an investigational RNA interference (RNAi) therapeutic in development for the treatment of hereditary ATTR (hATTR) amyloidosis, a progressive disease associated with significant disability, morbidity, and mortality. METHODS: Here we describe the rationale and design of the Phase 3 APOLLO study, a randomized, double-blind, placebo-controlled, global study to evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy. Eligible patients are 18-85 years old with hATTR amyloidosis, investigator-estimated survival of > 2 years, Neuropathy Impairment Score (NIS) of 5-130, and polyneuropathy disability score  < IIIb. Patients are randomized 2:1 to receive either intravenous patisiran 0.3 mg/kg or placebo once every 3 weeks. The primary objective is to determine the efficacy of patisiran at 18 months based on the difference in the change in modified NIS+7 (a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function) between the patisiran and placebo groups. Secondary objectives are to evaluate the effect of patisiran on Norfolk-Diabetic Neuropathy quality of life questionnaire score, nutritional status (as evaluated by modified body mass index), motor function (as measured by NIS-weakness and timed 10-m walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 questionnaire). Exploratory objectives include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden. Safety of patisiran will be assessed throughout the study. DISCUSSION: APOLLO represents the largest randomized, Phase 3 study to date in patients with hATTR amyloidosis, with endpoints that capture the multisystemic nature of this disease. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov ( NCT01960348 ); October 9, 2013.

What is the name of the RNAi investigational drug being developed against hereditary amyloidosis?

5a735b383b9d13c708000002_001

Molecular basis of oculocutaneous albinism type 1 in Lebanese patients. Oculocutaneous albinism type 1 (OCA1) results from mutations in the tyrosinase gene, which lead to partial or complete loss of activity of the corresponding enzyme. A large number of mutations have been identified worldwide, providing insight into the pathogenesis of the disorder. We performed ophthalmic and dermatological exams on 30 Lebanese subjects with oculocutaneous albinism, then screened for mutations in the tyrosinase gene in an effort to establish the molecular basis of the disorder in our population and correlate it with phenotypic findings. The five exons of the gene together with the exon-intron boundaries and part of the promoter region were sequenced. Mutations were found in a total of 14 patients (47%) while no mutation was identified in the sequenced regions in 53% of patients. Fourteen different mutations were identified of which eight were novel while six had been previously reported. Mutations were mainly seen in patients with clinical findings, suggestive of OCA1A (64% of patients with OCA1A versus 25% of patients with OCA1B); therefore, the absence of mutations in some of the other patients may indicate the involvement of other genes.

Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?

58cbb98c02b8c60953000034_081

Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. The dynamin-related protein Opa1 is localized to the mitochondrial intermembrane space, where it facilitates fusion between mitochondria. Apoptosis causes Opa1 release into the cytosol and causes mitochondria to fragment. Loss of mitochondrial membrane potential also causes mitochondrial fragmentation but not Opa1 release into the cytosol. Both conditions induce the proteolytic cleavage of Opa1, suggesting that mitochondrial fragmentation is triggered by Opa1 inactivation. The opposite effect was observed with knockdown of the mitochondrial intermembrane space protease Yme1. Knockdown of Yme1 prevents the constitutive cleavage of a subset of Opa1 splice variants but does not affect carbonyl cyanide m-chlorophenyl hydrazone or apoptosis-induced cleavage. Knockdown of Yme1 also increases mitochondrial connectivity, but this effect is independent of Opa1 because it also occurs in Opa1 knockdown cells. We conclude that Yme1 constitutively regulates a subset of Opa1 isoforms and an unknown mitochondrial morphology protein, whereas the loss of membrane potential induces the further proteolysis of Opa1.

Which is the cellular localization of the protein Opa1?

5717d64f29809bbe7a000001_003

Selexipag for the treatment of pulmonary arterial hypertension. INTRODUCTION: Selexipag is a first-in-class orally available selective non-prostanoid IP receptor agonist. This review was based on a PubMed search and focuses on the potential role of selexipag in the treatment of pulmonary arterial hypertension (PAH). AREAS COVERED: Selexipag is rapidly hydrolyzed to an active metabolite, ACT-333679. Both selexipag and its metabolite are highly selective for the IP receptor compared with other prostanoid receptors. This selectivity for the IP receptor offers the potential for improved tolerability with selexipag, as side effects (e.g., nausea and vomiting) that might result from activation of the other prostanoid receptors may be minimized. In addition, the selexipag metabolite has a half-life of 7.9 h, thus permitting oral dosing twice daily. Selexipag showed effects on pharmacodynamic end points obtained with right heart catheterization in a Phase II trial in patients with PAH, and is being evaluated in the ongoing Phase III trial (GRIPHON trial, Clinicaltrials.gov NCT01106014). EXPERT OPINION: The signal of a beneficial effect of selexipag on disease progression may become more robust for long term under prolonged exposure. Pending the GRIPHON trial results, selexipag could provide a convenient first-line prostacyclin treatment option for patients with PAH.

Selexipag is used for which disease?

56c1f045ef6e394741000058_002

Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.

Which gene harbors the mutation T790M?

56d1f790f22319765a000001_008

NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits cancer cell proliferation has not been defined, although it is accompanied by DNA rereplication and attendant DNA damage. Here we show that stabilization of the DNA replication factor Cdt1, a substrate of cullins 1 and 4, is critical for MLN4924 to trigger DNA rereplication and inhibit cell proliferation. Even only 1 hour of exposure to MLN4924, which was sufficient to elevate Cdt1 for 4-5 hours, was found to be sufficient to induce DNA rereplication and to activate apoptosis and senescence pathways. Cells in S phase were most susceptible, suggesting that MLN4924 will be most toxic on highly proliferating cancers. Although MLN4924-induced cell senescence seems to be dependent on induction of p53 and its downstream effector p21(Waf1), we found that p53(-/-) and p21(-/-) cells were even more susceptible than wild-type cells to MLN4924. Our results suggested that apoptosis, not senescence, might be more important for the antiproliferative effect of MLN4924. Furthermore, our findings show that transient exposure to this new investigational drug should be useful for controlling p53-negative cancer cells, which often pose significant clinical challenge.

Which enzyme does MLN4924 inhibit?

56ed03862ac5ed1459000004_016

CAFE: an R package for the detection of gross chromosomal abnormalities from gene expression microarray data. SUMMARY: The current methods available to detect chromosomal abnormalities from DNA microarray expression data are cumbersome and inflexible. CAFE has been developed to alleviate these issues. It is implemented as an R package that analyzes Affymetrix *.CEL files and comes with flexible plotting functions, easing visualization of chromosomal abnormalities. AVAILABILITY AND IMPLEMENTATION: CAFE is available from https://bitbucket.org/cob87icW6z/cafe/ as both source and compiled packages for Linux and Windows. It is released under the GPL version 3 license. CAFE will also be freely available from Bioconductor. CONTACT: [email protected] or [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Which R package is used for the detection of chromosomal abnormalities from microarray data?

5880a8ec0a76a87357000001_001

Different intracellular compartmentalization of TA and DeltaNp73 in non-small cell lung cancer. The p53 homologue p73 is overexpressed in many tumors, including lung cancer. We have evaluated the differential expression and subcellular localization of the functionally distinct apoptotic (TA) and anti-apoptotic (DeltaN) isoforms of p73 in non-small cell lung cancer (NSCLC), their possible association with p53 expression and determined the methylation status of the two p73 gene promoters (P1 and P2) in this tumor type. Immunohistochemical analysis showed that both isoforms are expressed in the majority of cases. However, the oncogenic DeltaN variant, derived from the transcripts DeltaN'p73 (from P1) and/or DeltaNp73 (from P2), is localized mainly in the nucleus, while the anti-oncogenic TAp73 isoform (derived from a P1 transcript) is sequestered in the cytoplasm in almost all cases analyzed. Significant correlation was found between p53 and DeltaNp73 expression (p=0.041). Methylation analysis conducted on 41 tumor samples showed that the P1 promoter is almost invariably unmethylated (39/41 cases) whereas P2 was found completely methylated in 17 cases and partially or totally unmethylated in 24 samples. No correlation was found between the methylation status of P1 and P2 and p73 expression. Our results demonstrate that both isoforms contribute to p73 overexpression in NSCLC and suggest that their different intracellular localization may reflect an alteration of the functional p53-p73 network that might contribute to lung cancer development.

How many TAp73 isoforms have been identified in humans?

5173bdb38ed59a060a000020_008

OikoBase: a genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica. We report the development of OikoBase (http://oikoarrays.biology.uiowa.edu/Oiko/), a tiling array-based genome browser resource for Oikopleura dioica, a metazoan belonging to the urochordates, the closest extant group to vertebrates. OikoBase facilitates retrieval and mining of a variety of useful genomics information. First, it includes a genome browser which interrogates 1260 genomic sequence scaffolds and features gene, transcript and CDS annotation tracks. Second, we annotated gene models with gene ontology (GO) terms and InterPro domains which are directly accessible in the browser with links to their entries in the GO (http://www.geneontology.org/) and InterPro (http://www.ebi.ac.uk/interpro/) databases, and we provide transcript and peptide links for sequence downloads. Third, we introduce the transcriptomics of a comprehensive set of developmental stages of O. dioica at high resolution and provide downloadable gene expression data for all developmental stages. Fourth, we incorporate a BLAST tool to identify homologs of genes and proteins. Finally, we include a tutorial that describes how to use OikoBase as well as a link to detailed methods, explaining the data generation and analysis pipeline. OikoBase will provide a valuable resource for research in chordate development, genome evolution and plasticity and the molecular ecology of this important marine planktonic organism.

Mention the only available genomics and developmental transcriptomics resource for the urochordate Oikopleura dioica

56ae6e650a360a5e4500000e_008

Effect of ingested human antibodies induced by RTS, S/AS01 malaria vaccination in children on Plasmodium falciparum oocyst formation and sporogony in mosquitoes. BACKGROUND: The circumsporozoite protein (CS protein) on the malaria parasites in mosquitoes plays an important role in sporogony in mosquitoes. The RTS,S/AS01 malaria vaccine candidate, which has shown significant efficacy against clinical malaria in a large Phase 3 trial, targets the Plasmodium falciparum CS protein, but the ability of serum from vaccinated individuals to inhibit sporogony in mosquitoes has not been evaluated. METHODS: Previously a double-blind, randomized trial of RTS,S/AS01 vaccine, as compared with rabies vaccine, in five- to 17-month old children in Tanzania was conducted. In this study, polyclonal human antibodies were purified from the pools of sera taken one month after the third vaccination. IgGs were purified from four pools of sera from 25 RTS,S/AS01 vaccinated children each, and two pools of sera from 25 children vaccinated with rabies vaccine each. The ability of antibodies to inhibit P. falciparum oocyst formation and/or sporogony in the mosquito host was evaluated by a standard membrane-feeding assay. The test antibodies were fed on day 0 (at the same time as the gametocyte feed), or on days 3 or 6 (serial-feed experiments). The oocyst and sporozoite counts were performed on days 8 and 16, respectively. In addition, two human anti-CS monoclonal antibodies (mAb) and a control mAb were also evaluated. RESULTS: Polyclonal anti-CS IgG preparations from RTS,S-vaccinated children tested at concentrations of 149-210 ELISA units (EU)/ml did not show significant inhibition in oocyst and sporozoite formation when the antibodies were fed with gametocytes at the same time, or later (serial-feed experiments). Similarly, anti-CS mAbs tested at 6,421 or 7,122 EU/ml did not show reduction in oocyst and sporozoite formation. CONCLUSIONS: This study does not support the concept that anti-CS antibodies induced by the RTS,S/AS01 vaccines in humans noticeably reduce malaria transmission by blocking P. falciparum sporozoite development or salivary gland invasion in mosquitoes when taken up during feeding.

RTS S AS01 vaccine was developed to prevent which disease?

56bc77a3ac7ad10019000015_021

Identification and characterization of a novel XK splice site mutation in a patient with McLeod syndrome. BACKGROUND: McLeod syndrome is a rare X-linked neuroacanthocytosis syndrome with hematologic, muscular, and neurologic manifestations. McLeod syndrome is caused by mutations in the XK gene whose product is expressed at the red blood cell (RBC) surface but whose function is currently unknown. A variety of XK mutations has been reported but no clear phenotype-genotype correlation has been found, especially for the point mutations affecting splicing sites. STUDY DESIGN AND METHODS: A man suspected of neuroacanthocytosis was evaluated by neurologic examination, electromyography, muscle biopsy, muscle computed tomography, and cerebral magnetic resonance imaging. The McLeod RBC phenotype was disclosed by blood smear and immunohematology analyses and then confirmed at the biochemical level by Western blot analysis. The responsible XK mutation was characterized at the mRNA level by reverse transcription-polymerase chain reaction (PCR), identified by genomic DNA sequencing, and verified by allele-specific PCR. RESULTS: A novel XK splice site mutation (IVS1-1G>A) has been identified in a McLeod patient who has developed hematologic, neuromuscular, and neurologic symptoms. This is the first reported example of a XK point mutation affecting the 3' acceptor splice site of Intron 1, and it was demonstrated that this mutation indeed induces aberrant splicing of XK RNA and lack of XK protein at the RBC membrane. CONCLUSION: The detailed characterization at the molecular biology level of this novel XK splice site mutation associated with the clinical description of the patient contributes to a better understanding of the phenotype-genotype correlation in the McLeod syndrome.

Mutation of which gene is associated with McLeod syndrome?

531464a6e3eabad021000014_009

[Successful therapy of ulcerated necrobiosis lipoidica non diabeticorum with cyclosporine A]. Necrobiosis lipoidica is an inflammatory granulomatous skin disease of unknown etiology which is associated with diabetes mellitus in about 60% of the patients. In 15-35% of the affected patients painful ulcerations may occur after minimal trauma which can be extremely refractory to therapy. Because of the unknown pathomechanisms, current therapeutic options are limited. We report on a 68-year-old patient with an 18 year history of ulcerated necrobiosis lipoidica non diabeticorum of both lower limbs, which responded to systemic cyclosporine A. Based on this case, we discuss the role of cyclosporine A in patients with necrobiosis lipoidica in the context of the disease etiology.

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

58bfd8e902b8c60953000018_008

Contrave, a bupropion and naltrexone combination therapy for the potential treatment of obesity. Contrave, under development by Orexigen Therapeutics Inc for the potential treatment of obesity, is an oral, sustained-release combination of the dopamine and norepinephrine reuptake antagonist bupropion and the opioid antagonist naltrexone. The proposed dual mechanism of action of the compound involves complementary stimulation of central melanocortin pathways, resulting in increased energy expenditure and reduced appetite. At the time of publication, Contrave was being assessed in phase III clinical trials. Preliminary data demonstrated placebo-subtracted weight losses of 3 to 7% and improvements in obesity-related comorbidities and cardiovascular risk factors. The primary adverse effect leading to discontinuation of treatment was nausea. Assuming that the results of the Contrave phase III clinical program reaffirm the efficacy and safety of the drug combination, this agent could be approved and launched to become a market leader in the anti-obesity therapeutic arena.

What is Contrave prescribed for?

58a32edd60087bc10a000012_002

Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype-phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy. Mutations in the gene encoding fibrillin 1 (FBN1) cause Marfan syndrome (MFS), and related connective tissue disorders. The disease spectrum is wide and while many genotype-phenotype correlations have been reported, few have been consistent. In this study FBN1 was analyzed in 113 patients with MFS or Marfan-like features. Fifty-three mutations were identified in 52 individuals, 41 of which were novel. The mutations comprised 26 missense, 11 splice site, 7 frameshift, 6 nonsense, 1 in-frame deletion, and 2 whole exon deletions. In common with previous studies, genotype-phenotype analysis showed that a FBN1 mutation was more likely to be identified in patients fulfilling Ghent criteria (P = 0.005) and in those who had ectopia lentis (EL) (P < 0.0001). Other previously reported genotype-phenotype correlations were also considered and a new inverse association between a mutation in exons 59-65, and EL emerged (P = 0.002).

Which gene mutations cause the Marfan syndrome?

58d8e6818acda3452900000a_032

Adult bone marrow transplantation after stroke in adult rats. We transplanted adult whole bone marrow prelabeled with bromodeoxyuridine (BrdU) into the ischemic boundary zone of the adult rat brain at 1 day after 2 h of middle cerebral artery occlusion (MCAo). Approximately 3.3% of 10(6) transplanted bone marrow cells were BrdU reactive at 14 days after MCAo. BrdU-reactive cells expressed neuronal and astrocytic proteins, neuronal nuclei protein (NeuN, 1%), and glial fibrillary acidic protein (GFAP, 5%) immunoreactivities, respectively. In addition, bone marrow transplantation promoted proliferation of ependymal and subependymal cells, identified by nestin (a neuroepithelial stem cell marker), within the ventricular zone and subventricular zone (VZ/SVZ). These data suggest that intracerebral transplantation of bone marrow could potentially be used to induce plasticity in ischemic brain.

Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?

5540ca8a0083d1bf0e000003_010

Dasatinib inhibits the proliferation and function of CD4+CD25+ regulatory T cells. CD4+CD25+ regulatory T cells (Tregs) can influence various immune responses. Little is known about the effects of the Abl/Src kinase inhibitor dasatinib on Tregs which regulate anti-tumor/leukaemia immune responses. The present study demonstrated that dasatinib inhibited proliferation of Tregs and CD4+CD25- T cells in a dose-dependent manner, which was associated with the decreased production of corresponding cytokines. Treatment of Tregs with dasatinib inhibited the suppressive capacity of Tregs. The mechanisms of this inhibition included arrest of cells in the G0/G1 phase of cell cycle, down-regulation of the transcription factor forkhead box P3, glucocorticoid-induced tumour necrosis factor receptor and the cytotoxic T lymphocyte associated protein 4 as well as inhibition of signaling events through Src and nuclear factor kappaB. Dasatinib showed an inhibitory effect on the proliferation and function of both Tregs and CD4+CD25- T cells at therapeutically relevant concentrations of the drug. Clinical administration of dasatinib might influence not only the graft-versus-leukaemia effect but also the graft-versus-host-disease in patients receiving dasatinib after allogeneic stem cell transplantation and/or donor lymphocytes infusion as the function of both Tregs and effector T cells are hampered in a similar way by dasatinib.

Does dasatinib promote or inhibit T-cell proliferation?

56c85ed65795f9a73e000012_005

Smell testing is abnormal in 'lubag' or X-linked dystonia-parkinsonism: a pilot study. We administered a culturally corrected University of Pennsylvania Smell Identification Test (ccUPSIT) consisting of 25 odor items to 20 patients with 'Lubag' or X-linked dystonia-parkinsonism and 20 control subjects matched by sex, age, educational background, smoking history, and geographical origin. The mean ccUPSIT score of Lubag patients (18 +/- 3.19) was statistically lower (P = 0.003) than controls (20.5 +/- 3.02). The smell scores did not correlate with phenotype, severity of dystonia, or duration of disease. Nine of 20 Lubag patients (45%) had ccUPSIT scores below the mean, with the lowest score being 11. This pilot study suggests that olfactory dysfunction may occur in Lubag patients.

What is the synonym of the lubag disease?

54df695b1388e8454a000004_011

Inhibition by adriamycin of calmodulin-sensitive and phospholipid-sensitive calcium-dependent phosphorylation of endogenous proteins from heart. Adriamycin, a lipid-interacting anti-cancer agent, was found to inhibit phospholipid-sensitive Ca2+-dependent phosphorylation of endogenous proteins from the cytosol of the guinea-pig heart. The drug, unexpectedly, also inhibited phosphorylation of separate endogenous proteins in the cardiac cytosol and membranes catalysed by the calmodulin-sensitive species of Ca2+-dependent protein kinase. In both phosphorylation systems, the inhibition by adriamycin was reversed by either phospholipid (phosphatidylserine or cardiolipin) or calmodulin respectively. Adriamycin also inhibited phosphorylation of histone (exogenous protein) catalysed by purified cardiac phospholipid-sensitive Ca2+-dependent protein kinase, but not that by cyclic AMP-dependent and cyclic GMP-dependent protein kinases. It appears that Ca2+-dependent protein phosphorylation systems, regulated either by phospholipid or calmodulin, may represent hitherto unrecognized sites of action of adriamycin. It remains to be seen whether inhibition by adriamycin of these systems is related to the severe cardiotoxicity, the major adverse effect of the drug that limits its clinical usefulness.

What is the major adverse effect of adriamycin(doxorubicin)?

53551206a0726bee57000001_001

[Prenatal gene diagnosis of oculocutaneous albinism type I]. OBJECTIVE: Mutation analysis and prenatal gene diagnosis for the mutated tyrosinase (TYR) gene in two families with oculocutaneous albinism type I (OCA1). METHODS: To define the fetus genotypes and gene mutation sites, the PCR and sequencing techniques were applied to amplify and analyze the regions of exon, exon-intron and promoter of TYR gene in probands and their parents of 2 families. RESULTS: The patient or proband of family 1 showed as a compound heterozygote with mutants R278X and 929insC. However, the fetus did not get any one of the two mutations, and so was with a normal genotype and phenotype. The parents of proband in family 2 were heterozygous with IVS4+ 3A>T or G253E respectively, but their fetus was heterozygous only with IVS4+3A>T but without G253E, and so was a carrier as his father. CONCLUSION: In the mainland of China, the prenatal gene diagnosis of OCA1 is reported for the first time.

Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?

58cbb98c02b8c60953000034_056

Evaluation of the oral direct factor Xa inhibitor - betrixaban. INTRODUCTION: For over 60 years vitamin K antagonists have been the mainstay of oral therapy for treatment and prevention of venous and arterial thromboembolic disease. The emergence of two new classes of orally administered anticoagulants, direct thrombin and factor Xa inhibitors have drastically changed the landscape in the management of these disease states. Betrixaban , an orally administered direct factor Xa inhibitor, is entering a Phase III trial and undergoing investigation for similar indications as apixaban, dabigatran and rivaroxaban. AREAS COVERED: The chemical development of betrixaban, pharmacokinetic differences between betrixaban and currently available novel anticoagulants and future considerations for clinical use. EXPERT OPINION: Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.

Which clotting factor is inhibited by betrixaban?

55200c606b348bb82c000013_151

Comprehensive analysis of the genes responsible for neuroacanthocytosis in mood disorder and schizophrenia. Neuroacanthocytosis syndromes are mainly comprised of two diseases: chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). There is a high incidence of psychiatric disorders such as mood disorder and schizophrenia among neuroacanthocytosis patients. We hypothesized that neuroacanthocytosis-related-genes might be associated with susceptibility to these psychiatric disorders. We performed a comprehensive mutation screen of VPS13A and XK, the gene responsible for ChAc and MLS, respectively, in 85 mood disorder subjects and XK in 86 schizophrenia subjects and compared the variants to 100 or more control alleles. We also performed copy number variation (CNV) analysis in 72 mood disorder subjects and 86 schizophrenia subjects. We identified three non-synonymous, two synonymous and six intron variants in mood disorder subjects and a novel GAT triplet repeat polymorphism in VPS13A. By CNV analysis, we identified a heterozygous exon 60-61 deletion in VPS13A in one mood disorder subject. We identified one non-synonymous and one intron variant in mood disorder and schizophrenia subjects, respectively, in XK. The presence of a pathogenic mutation or a potentially functional variant in mood disorder or schizophrenia subjects suggests that neuroacanthocytosis-related-genes might be involved in the pathogenesis of these psychiatric disorders.

Mutation of which gene is associated with McLeod syndrome?

531464a6e3eabad021000014_002

[Turner's syndrome--correlation between karyotype and phenotype]. Turner's syndrome is defined as a congenital disease determining by quantitative and/or structural aberrations of one from two X chromosomes with frequent presence of mosaicism. Clinically it is characterized by growth and body proportion abnormalities, gonadal dysgenesis resulting in sexual infantilism, primary amenorrhoea, infertility, characteristic stigmata, anomalies of heart, renal and bones and the presence of some diseases like Hashimoto thyroiditis with hypothyroidism, diabetes mellitus type 2, osteoporosis, hypertension. Turner's syndrome occurs in 1:2000 to 1:2500 female livebirth. The most frequent X chromosome aberrations in patients with phenotype of Turner syndrome are as follows: X monosomy - 45,X; mosaicism (50-75%), including 45,X/46,XX (10-15%), 45,X/46,XY (2-6%), 45,X/46,X,i(Xq), 45,X/46,X,del(Xp), 45,X/46,XX/47,XXX; aberration of X structure: total or partial deletion of short arm of X chromosome (46,X,del(Xp)) isochromosom of long arm of X chromosome (46,X,(i(Xq)), ring chromosome (46, X,r(X)), marker chromosome (46,X+m). Searching of X chromosome and mapping and sequencing of genes located at this chromosome (such as SHOX, ODG2, VSPA, SOX 3) have made possible to look for linkage between phenotypes and adequate genes or regions of X chromosome. In this paper current data concerning correlation between phenotype and karyotype in patients with TS have been presented.

What chromosome is affected in Turner's syndrome?

58bca2f302b8c6095300000c_025

Preventing deaths from cryptococcal meningitis: from bench to bedside. Cryptococcal meningitis (CM), a fungal disease caused by Cryptococcus spp., is the most common form of meningitis and a leading cause of death among persons with HIV/AIDS in sub-Saharan Africa. Detection of cryptococcal antigen, which is present several weeks before overt signs of meningitis develop, provides an opportunity to detect infection early. Screening persons with HIV for cryptococcal infection when they access healthcare can identify asymptomatic infected patients allowing for prompt treatment and prevention of death. A newly developed point-of-care assay for cryptococcal antigen, as well as growing evidence supporting the utility and cost-effectiveness of screening, are further reasons to consider broad implementation of cryptococcal screening in countries with a high burden of cryptococcal disease.

Which is the main reason for the increase in the incidence of cryptococcal disease?

5ace37d50340b9f058000011_011

Contributions of CTCF and DNA methyltransferases DNMT1 and DNMT3B to Epstein-Barr virus restricted latency. Establishment of persistent Epstein-Barr virus (EBV) infection requires transition from a program of full viral latency gene expression (latency III) to one that is highly restricted (latency I and 0) within memory B lymphocytes. It is well established that DNA methylation plays a critical role in EBV gene silencing, and recently the chromatin boundary protein CTCF has been implicated as a pivotal regulator of latency via its binding to several loci within the EBV genome. One notable site is upstream of the common EBNA gene promoter Cp, at which CTCF may act as an enhancer-blocking factor to initiate and maintain silencing of EBNA gene transcription. It was previously suggested that increased expression of CTCF may underlie its potential to promote restricted latency, and here we also noted elevated levels of DNA methyltransferase 1 (DNMT1) and DNMT3B associated with latency I. Within B-cell lines that maintain latency I, however, stable knockdown of CTCF, DNMT1, or DNMT3B or of DNMT1 and DNMT3B in combination did not result in activation of latency III protein expression or EBNA gene transcription, nor did knockdown of DNMTs significantly alter CpG methylation within Cp. Thus, differential expression of CTCF and DNMT1 and -3B is not critical for maintenance of restricted latency. Finally, mutant EBV lacking the Cp CTCF binding site exhibited sustained Cp activity relative to wild-type EBV in a recently developed B-cell superinfection model but ultimately was able to transition to latency I, suggesting that CTCF contributes to but is not necessarily essential for the establishment of restricted latency.

Which enzyme is involved in the maintenance of DNA (cytosine-5-)-methylation?

51585b28d24251bc0500008d_009

LOLA: enrichment analysis for genomic region sets and regulatory elements in R and Bioconductor. UNLABELLED: Genomic datasets are often interpreted in the context of large-scale reference databases. One approach is to identify significantly overlapping gene sets, which works well for gene-centric data. However, many types of high-throughput data are based on genomic regions. Locus Overlap Analysis (LOLA) provides easy and automatable enrichment analysis for genomic region sets, thus facilitating the interpretation of functional genomics and epigenomics data. AVAILABILITY AND IMPLEMENTATION: R package available in Bioconductor and on the following website: http://lola.computational-epigenetics.org.

Which R / bioconductor package is used for enrichment analysis of genomic regions?

587e3e302420191125000002_001

Biodistribution and pharmacokinetics of dapivirine-loaded nanoparticles after vaginal delivery in mice. PURPOSE: To assess the potential of polymeric nanoparticles (NPs) to affect the genital distribution and local and systemic pharmacokinetics (PK) of the anti-HIV microbicide drug candidate dapivirine after vaginal delivery. METHODS: Dapivirine-loaded, poly(ethylene oxide)-coated poly(epsilon-caprolactone) (PEO-PCL) NPs were prepared by a nanoprecipitation method. Genital distribution of NPs and their ability to modify the PK of dapivirine up to 24 h was assessed after vaginal instillation in a female mouse model. Also, the safety of NPs upon daily administration for 14 days was assessed by histological analysis and chemokine/cytokine content in vaginal lavages. RESULTS: PEO-PCL NPs (180-200 nm) were rapidly eliminated after administration but able to distribute throughout the vagina and lower uterus, and capable of tackling mucus and penetrate the epithelial lining. Nanocarriers modified the PK of dapivirine, with higher drug levels being recovered from vaginal lavages and vaginal/lower uterine tissues as compared to a drug suspension. Systemic drug exposure was reduced when NPs were used. Also, NPs were shown safe upon administration for 14 days. CONCLUSIONS: Dapivirine-loaded PEO-PCL NPs were able to provide likely favorable genital drug levels, thus attesting the potential value of using this vaginal drug delivery nanosystem in the context of HIV prophylaxis.

Which infection can be prevented with Dapivirine?

5880b812c872c95565000006_015

[Thromboembolic prophylaxis 2011: is warfarin on the wane?]. Warfarin has been the effective treatment in the prophylaxis of cardioembolism, in particular in patients with atrial fibrillation, for more than 50 years. Nevertheless, many patients with atrial fibrillation are not currently treated because of the numerous limits of oral anticoagulation and in those treated the quality of anticoagulation is often poor. Novel oral anticoagulant drugs, the direct thrombin antagonist dabigatran and factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban, and betrixaban are more predictable and convenient anticoagulants in comparison with warfarin, mainly because of the non-requirement of regular laboratory monitoring and dose adjustments. Current data from phase III clinical trials are available for dabigatran, rivaroxaban and apixaban, which show to be at least noninferior in efficacy to warfarin for the prevention of stroke in patients with atrial fibrillation. This review focuses on the potential of novel anticoagulants to replace warfarin in patients with atrial fibrillation. Also the place in therapy and the potential limitations of the new agents in clinical practice represent important issues to be considered. The promise of new oral anticoagulants gives us the hope that warfarin will finally be replaced in a near future, but more importantly that anticoagulant undertreatment of atrial fibrillation will be partially overcome.

Which clotting factor is inhibited by betrixaban?

55200c606b348bb82c000013_061

Mice lacking sister chromatid cohesion protein PDS5B exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome. PDS5B is a sister chromatid cohesion protein that is crucial for faithful segregation of duplicated chromosomes in lower organisms. Mutations in cohesion proteins are associated with the developmental disorder Cornelia de Lange syndrome (CdLS) in humans. To delineate the physiological roles of PDS5B in mammals, we generated mice lacking PDS5B (APRIN). Pds5B-deficient mice died shortly after birth. They exhibited multiple congenital anomalies, including heart defects, cleft palate, fusion of the ribs, short limbs, distal colon aganglionosis, abnormal migration and axonal projections of sympathetic neurons, and germ cell depletion, many of which are similar to abnormalities found in humans with CdLS. Unexpectedly, we found no cohesion defects in Pds5B(-/-) cells and detected high PDS5B expression in post-mitotic neurons in the brain. These results, along with the developmental anomalies of Pds5B(-/-) mice, the presence of a DNA-binding domain in PDS5B in vertebrates and its nucleolar localization, suggest that PDS5B and the cohesin complex have important functions beyond their role in chromosomal dynamics.

Which syndrome is caused by deletion of Pds5b in mice?

5889eb503b87a8a73800000b_001

Reversal agents for use with direct and indirect anticoagulants. PURPOSE: The properties of three oral anticoagulant-specific reversal agents are reviewed, and guidance is presented to assist pharmacists in planning for the agents' introduction to the market. SUMMARY: Idarucizumab, which received Food and Drug Administration approval in October 2015, is a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant effect of dabigatran, as evidenced by reduced unbound dabigatran concentrations and normalized coagulation tests. Preliminary Phase III trial results demonstrated a median maximum reversal of 100%, a median time to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis in 92% of patients requiring anticoagulation reversal before an urgent procedure. Andexanet alfa is a factor Xa (FXa) decoy that binds to direct and indirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet alfa reduced anti-FXa activity by more than 90%, reduced the concentration of unbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is a reversal agent under development for reversal of anticoagulation with direct and indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its effect through hydrogen bonding. Concerns for thromboembolic events directly related to administration of idarucizumab, andexanet alfa, or ciraparantag have not arisen. Pharmacists need to begin preparing for the introduction of these specific reversal agents through protocol development and provider education; in addition, pharmacy departments need to plan for procurement and storage. The specific reversal agents should be incorporated into antithrombotic stewardship or other clinical pharmacy programs for surveillance. CONCLUSION: As agents that provide rapid reversal of direct oral anticoagulant activity become available, advance planning will help hospitals to optimize their use.

Andexanet Alfa is an antidote of which clotting factor inhibitors?

5880b073c872c95565000003_023

Elotuzumab and daratumumab: emerging new monoclonal antibodies for multiple myeloma. Multiple myeloma (MM) has been mostly incurable due to its highly complex and heterogeneous molecular abnormalities and the support from myeloma microenvironment factors. A therapeutic strategy which effectively targets relevant and specific molecule to myeloma cells, and which is potent in overcoming tumor microenvironment-mediated drug resistance needs to be developed. One of the promising fields is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This review focuses on the basic and clinical aspects of two emerging and promising novel MoAbs for MM, elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are relatively specific to myeloma cells and expressed in more than 90% of MM patients, and mediate adhesion of myeloma cells to bone marrow stromal cells. We also discuss the unique characteristics of the two MoAbs by comparing with other MoAbs being developed for MM.

Which molecule is targeted by Daratumumab?

56c04412ef6e39474100001b_025

Remission of ulcerated necrobiosis lipoidica diabeticorum after bariatric surgery. A 32-year-old woman with type 2 diabetes mellitus suffering from morbid obesity with BMI 45,14 kg/m(2) was operated on. Not only the type 2DM but also one of its complication known as necrobiosis lipoidica diabeticorum remitted postoperatively. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals but an epidemic that threatens global well-being. It causes or exacerbates many health problems, and in particular, it is associated with the type 2 diabetes. Necrobiosis lipoidica is a granulomatous skin disease of unknown etiology, associated mainly with diabetes mellitus. We presented in this paper a morbid obese case of necrobiosis lipoidica diabeticorum with dramatic good response to bariatric surgery.

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

58bfd8e902b8c60953000018_002

Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. OBJECTIVE: To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs. METHODS: In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12. RESULTS: Treatment with tofacitinib at a dose of > 3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P < 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%). CONCLUSION: Tofacitinib monotherapy at > 3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.

Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?

53357193d6d3ac6a34000047_026

Protective effect of JTV519, a new 1,4-benzothiazepine derivative, on prolonged myocardial preservation. BACKGROUND: JTV519 is know to protect cardiomyocytes from calcium overloading-induced damage. The aim of this study was to investigate the potential protective effect of JTV519 on myocardium subjected to prolonged ischemia and the underlying mechanism of such protection. The effect of JTV519 was also compared with that of diltiazem, a 1,5-benzothiazepine derivative. METHODS: Isolated rat hearts were randomly divided into three groups. Control hearts were arrested with histidine-tryptophan-ketoglutarat (HTK) cardioplegic solution alone. In the JTV519 group of hearts, cardiac arrest was achieved with JTV519 (10(-3) mmol/L) in the HTK solution. Hearts in the diltiazem group were arrested with diltiazem (0.5 mmol/L) in the HTK solution. All the hearts were then subjected to 6-hour storage in HTK solution at 4 degrees C. RESULTS: After a 30-minute reperfusion, the left ventricular developed pressure in the JTV519 and diltiazem groups were improved significantly compared with the control group. There was a significantly lower left ventricular end-diastolic pressure level and higher recovery of coronary flow in the JTV519 group than in the control group. The postischemic intracellular calcium concentration was attenuated by adding JTV519 or diltiazem to HTK cardioplegia. CONCLUSION: As an adjunct to cardioplegia, JTV519 showed a significant protective effect on myocardium undergoing 6 hours of ischemia. The beneficial protective effects of JTV519 are correlated with its ability to inhibit the postischemic rise in intracellular calcium.

The drug JTV519 is derivative of which group of chemical compounds?

54f9b74306d9727f76000004_029

Rilonacept in the treatment of chronic inflammatory disorders. Rilonacept (IL-1 Trap/Arcalyst) is a long-acting interleukin-1 (IL-1) blocker developed by Regeneron Pharmaceuticals. Initially, Regeneron entered into a joint development effort with Novartis to develop rilonacept for the treatment of rheumatoid arthritis (RA) but this was discontinued following the review of phase II clinical data showing that IL-1 blockade appeared to have limited benefit in RA. In February 2008, Regeneron received Orphan Drug approval from the Food and Drug Administration for rilonacept in the treatment of two cryopyrin-associated periodic syndromes (CAPS) disorders, namely, familial cold-induced autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), for children and adults 12 years and older. CAPS is a group of inherited inflammatory disorders consisting of FCAS, MWS, neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous and articular (CINCA) syndrome, all associated with heterozygous mutations in the NLRP3 (CIAS1) gene, which encodes the protein NLRP3 or cryopyrin. Prior to the discovery of the NLRP3 (CIAS1) mutations and the advent of IL-1-targeted therapy, treatment was aimed at suppressing inflammation but with limited success. The dramatic success of selective blockade of IL-1beta, initially with the IL-1 receptor antagonist (IL-1Ra; Kineret(R) or anakinra/ Amgen, Inc.), not only provided supportive evidence for the role of IL-1beta in CAPS but also demonstrated the efficacy of targeting IL-1beta for treatment of these conditions. A high-affinity protein called rilonacept has been produced by cytokine Trap technology and was developed by Regeneron. The desirable longer half-life of rilonacept offers potential alternatives to patients who do not tolerate daily injections very well or have difficulty with drug compliance. The initial evidence for the beneficial effects of rilonacept for MWS and FCAS suggests that it would also be a suitable treatment for CNICA/NOMID. It is yet to be determined whether rilonacept would be an effective treatment for other chronic inflammatory conditions such as gout, familial Mediterranean fever and systemic juvenile idiopathic arthritis.

What is the indication of ARCALYST?

58df47f08acda3452900002f_001

Lack of immune responses to Mycobacterium tuberculosis DosR regulon proteins following Mycobacterium bovis BCG vaccination. Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis (TB), despite its variable protective efficacy. Relatively little is known about the immune response profiles following BCG vaccination in relation to protection against TB. Here we tested whether BCG vaccination results in immune responses to DosR (Rv3133c) regulon-encoded proteins. These so-called TB latency antigens are targeted by the immune system during persistent Mycobacterium tuberculosis infection and have been associated with immunity against latent M. tuberculosis infection. In silico analysis of the DosR regulon in BCG and M. tuberculosis showed at least 97% amino acid sequence homology, with 41 out of 48 genes being identical. Transcriptional profiling of 14 different BCG strains, under hypoxia and nitric oxide exposure in vitro, revealed a functional DosR regulon similar to that observed in M. tuberculosis. Next, we assessed human immune responses to a series of immunodominant TB latency antigens and found that BCG vaccination fails to induce significant responses to latency antigens. Similar results were obtained with BCG-vaccinated BALB/c mice. In contrast, responses to latency antigens were observed in individuals with suspected exposure to TB (as indicated by positive gamma interferon responses to TB-specific antigens ESAT-6 and CFP-10) and in mice vaccinated with plasmid DNA encoding selected latency antigens. Since immune responses to TB latency antigens have been associated with control of latent M. tuberculosis infection, our findings support the development of vaccination strategies incorporating DosR regulon antigens to complement and improve the current BCG vaccine.

How many genes constitute the DosR regulon, controlled by the dormancy survival regulator (DosR) in Mycobacterium tuberculosis?

58edf567eda5a57672000011_003

Prediction of novel microRNA genes in cancer-associated genomic regions--a combined computational and experimental approach. The majority of existing computational tools rely on sequence homology and/or structural similarity to identify novel microRNA (miRNA) genes. Recently supervised algorithms are utilized to address this problem, taking into account sequence, structure and comparative genomics information. In most of these studies miRNA gene predictions are rarely supported by experimental evidence and prediction accuracy remains uncertain. In this work we present a new computational tool (SSCprofiler) utilizing a probabilistic method based on Profile Hidden Markov Models to predict novel miRNA precursors. Via the simultaneous integration of biological features such as sequence, structure and conservation, SSCprofiler achieves a performance accuracy of 88.95% sensitivity and 84.16% specificity on a large set of human miRNA genes. The trained classifier is used to identify novel miRNA gene candidates located within cancer-associated genomic regions and rank the resulting predictions using expression information from a full genome tiling array. Finally, four of the top scoring predictions are verified experimentally using northern blot analysis. Our work combines both analytical and experimental techniques to show that SSCprofiler is a highly accurate tool which can be used to identify novel miRNA gene candidates in the human genome. SSCprofiler is freely available as a web service at http://www.imbb.forth.gr/SSCprofiler.html.

Which method is used for prediction of novel microRNA genes in cancer-associated genomic regions?

5895f18ce370baff39000001_001

chromDraw: an R package for visualization of linear and circular karyotypes. Species-specific sets of chromosomes-karyotypes-are traditionally depicted as linear ideograms with individual chromosomes represented by vertical bars. However, linear visualization has its limitations when the shared collinearity and/or chromosomal rearrangements differentiating two or more karyotypes need to be demonstrated. In these instances, circular visualization might provide easier comprehension and interpretation of inter-species chromosomal collinearity. The chromDraw graphical tool was developed as a user-friendly graphical tool for visualizing both linear and circular karyotypes based on the same input data matrix. The output graphics, saved in two different formats (EPS and SVG), can be easily imported to and modified in presentation and image-editing computer programs. The tool is freely distributed under GNU General Public License (GPL) and can be installed from Bioconductor or from the chromDraw home page.

Which R package is used for visualization of linear and circular karyotypes?

588f2de394c1512c50000001_002

Hearing dysfunction in heterozygous Mitf(Mi-wh) /+ mice, a model for Waardenburg syndrome type 2 and Tietz syndrome. The human deafness-pigmentation syndromes, Waardenburg syndrome (WS) type 2a, and Tietz syndrome are characterized by profound deafness but only partial cutaneous pigmentary abnormalities. Both syndromes are caused by mutations in MITF. To illuminate differences between cutaneous and otic melanocytes in these syndromes, their development and survival in heterozygous Microphthalmia-White (Mitf(Mi-wh) /+) mice were studied and hearing function of these mice characterized. Mitf(Mi-wh) /+ mice have a profound hearing deficit, characterized by elevated auditory brainstem response thresholds, reduced distortion product otoacoustic emissions, absent endocochlear potential, loss of outer hair cells, and stria vascularis abnormalities. Mitf(Mi-wh) /+ embryos have fewer melanoblasts during embryonic development than their wild-type littermates. Although cochlear melanocytes are present at birth, they disappear from the Mitf(Mi-wh) /+ cochlea between P1 and P7. These findings may provide insight into the mechanism of melanocyte and hearing loss in human deafness-pigmentation syndromes such as WS and Tietz syndrome and illustrate differences between otic and follicular melanocytes.

Which mutated gene is associated with Waardenburg and Tietz syndromes?

58a57f9460087bc10a00001f_042

Coilin displays differential affinity for specific RNAs in vivo and is linked to telomerase RNA biogenesis. Coilin is widely known as the protein marker of the Cajal body, a subnuclear domain important to the biogenesis of small nuclear ribonucleoproteins and telomerase, complexes that are crucial to pre-messenger RNA splicing and telomere maintenance, respectively. Extensive studies have characterized the interaction between coilin and the various other protein components of CBs and related subnuclear domains; however, only a few have examined interactions between coilin and nucleic acid. We have recently published that coilin is tightly associated with nucleic acid, displays RNase activity in vitro, and is redistributed to the ribosomal RNA (rRNA)-rich nucleoli in cells treated with the DNA-damaging agents cisplatin and etoposide. Here, we report a specific in vivo association between coilin and rRNA, U small nuclear RNA (snRNA), and human telomerase RNA, which is altered upon treatment with DNA-damaging agents. Using chromatin immunoprecipitation, we provide evidence of coilin interaction with specific regions of U snRNA gene loci. We have also utilized bacterially expressed coilin fragments in order to map the region(s) important for RNA binding and RNase activity in vitro. Additionally, we provide evidence of coilin involvement in the processing of human telomerase RNA both in vitro and in vivo.

Which protein is the main marker of Cajal bodies?

58eb9542eda5a57672000007_001

Molecular basis of oculocutaneous albinism type 1 in Lebanese patients. Oculocutaneous albinism type 1 (OCA1) results from mutations in the tyrosinase gene, which lead to partial or complete loss of activity of the corresponding enzyme. A large number of mutations have been identified worldwide, providing insight into the pathogenesis of the disorder. We performed ophthalmic and dermatological exams on 30 Lebanese subjects with oculocutaneous albinism, then screened for mutations in the tyrosinase gene in an effort to establish the molecular basis of the disorder in our population and correlate it with phenotypic findings. The five exons of the gene together with the exon-intron boundaries and part of the promoter region were sequenced. Mutations were found in a total of 14 patients (47%) while no mutation was identified in the sequenced regions in 53% of patients. Fourteen different mutations were identified of which eight were novel while six had been previously reported. Mutations were mainly seen in patients with clinical findings, suggestive of OCA1A (64% of patients with OCA1A versus 25% of patients with OCA1B); therefore, the absence of mutations in some of the other patients may indicate the involvement of other genes.

Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?

58cbb98c02b8c60953000034_080

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_007

A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease. The interpretation of non-coding variants still constitutes a major challenge in the application of whole-genome sequencing in Mendelian disease, especially for single-nucleotide and other small non-coding variants. Here we present Genomiser, an analysis framework that is able not only to score the relevance of variation in the non-coding genome, but also to associate regulatory variants to specific Mendelian diseases. Genomiser scores variants through either existing methods such as CADD or a bespoke machine learning method and combines these with allele frequency, regulatory sequences, chromosomal topological domains, and phenotypic relevance to discover variants associated to specific Mendelian disorders. Overall, Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes, allowing effective detection and discovery of regulatory variants in Mendelian disease.

Which method is available for whole genome identification of pathogenic regulatory variants in mendelian disease?

5a67c497b750ff4455000012_007

The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism. Mutations in the gene for tyrosinase, the key enzyme in melanin synthesis, are responsible for oculocutaneous albinism type 1, and more than 100 mutations of this gene have been identified. The c.1205G > A variant of the tyrosinase gene (rs1126809) predicts p.R402Q and expression studies show thermolabile enzyme activity for the variant protein. The Q402 allele has been associated with autosomal recessive ocular albinism when it is in trans with a tyrosinase gene mutation associated with oculocutaneous albinism type 1. We have identified 12 families with oculocutaneous albinism type 1 that exhibit segregation of the c.1205G > A variant with a known pathologic mutation on the homologous chromosome, and demonstrate no genetic association between autosomal recessive oculocutaneous albinism and the Q402 variant. We conclude that the codon 402 variant of the tyrosinase gene is not associated with albinism.

Which mutated enzyme is responsible for oculocutaneous 1 (OCA1)-type albinism?

58cbb98c02b8c60953000034_060

Progesterone/RANKL is a major regulatory axis in the human breast. Estrogens and progesterones are major drivers of breast development but also promote carcinogenesis in this organ. Yet, their respective roles and the mechanisms underlying their action in the human breast are unclear. Receptor activator of nuclear factor κB ligand (RANKL) has been identified as a pivotal paracrine mediator of progesterone function in mouse mammary gland development and mammary carcinogenesis. Whether the factor has the same role in humans is of clinical interest because an inhibitor for RANKL, denosumab, is already used for the treatment of bone disease and might benefit breast cancer patients. We show that progesterone receptor (PR) signaling failed to induce RANKL in PR(+) breast cancer cell lines and in dissociated, cultured breast epithelial cells. In clinical specimens from healthy donors and intact breast tissue microstructures, hormone response was maintained and RANKL expression was under progesterone control, which increased RNA stability. RANKL was sufficient to trigger cell proliferation and was required for progesterone-induced proliferation. The findings were validated in vivo where RANKL protein expression in the breast epithelium correlated with serum progesterone levels and the protein was expressed in a subset of luminal cells that express PR. Thus, important hormonal control mechanisms are conserved across species, making RANKL a potential target in breast cancer treatment and prevention.

To the ligand of which receptors does Denosumab (Prolia) bind?

52bf1d9e03868f1b06000010_001

c-Jun-mediated anticancer mechanisms of tylophorine. Tylophorine, a phenanthroindolizidine alkaloid, is the major medicinal constituent of herb Tylophora indica. Tylophorine treatment increased the accumulation of c-Jun protein, a component of activator protein 1 (AP1), in carcinoma cells. An in vitro kinase assay revealed that the resultant c-Jun phosphorylation was primarily mediated via activated c-Jun N-terminal protein kinase (JNK). Moreover, flow cytometry indicated that ectopically overexpressed c-Jun in conjunction with tylophorine significantly increased the number of carcinoma cells that were arrested at the G1 phase. The tylophorine-mediated downregulation of cyclin A2 protein levels is known to be involved in the primary G1 arrest. Chromatin immunoprecipitation and reporter assays revealed that tylophorine enhanced the c-Jun downregulation of the cyclin A2 promoter activity upon increased binding of c-Jun to the deregulation AP1 site and decreased binding to the upregulation activating transcription factor (ATF) site in the cyclin A2 promoter, thereby reducing cyclin A2 expression. Further, biochemical studies using pharmacological inhibitors and RNA silencing approaches demonstrated that tylophorine-mediated elevation of the c-Jun protein level occurs primarily via two discrete prolonged signaling pathways: (i) the NF-κB/PKCδ_(MKK4)_JNK cascade, which phosphorylates c-Jun and increases its stability by slowing its ubiquitination, and (ii) the PI3K_PDK1_PP2A_eEF2 cascade, which sustains eukaryotic elongation factor 2 (eEF2) activity and thus c-Jun protein translation. To the best of our knowledge, this report is the first to demonstrate the involvement of c-Jun in the anticancer activity of tylophorine and the release of c-Jun translation from a global translational blockade via the PI3K_PDK1_eEF2 signaling cascade.

Which MAP kinase phosphorylates the transcription factor c-jun?

5518e7da622b194345000004_021

JAMM: a peak finder for joint analysis of NGS replicates. MOTIVATION: Although peak finding in next-generation sequencing (NGS) datasets has been addressed extensively, there is no consensus on how to analyze and process biological replicates. Furthermore, most peak finders do not focus on accurate determination of enrichment site widths and are not widely applicable to different types of datasets. RESULTS: We developed JAMM (Joint Analysis of NGS replicates via Mixture Model clustering): a peak finder that can integrate information from biological replicates, determine enrichment site widths accurately and resolve neighboring narrow peaks. JAMM is a universal peak finder that is applicable to different types of datasets. We show that JAMM is among the best performing peak finders in terms of site detection accuracy and in terms of accurate determination of enrichment sites widths. In addition, JAMM's replicate integration improves peak spatial resolution, sorting and peak finding accuracy. AVAILABILITY AND IMPLEMENTATION: JAMM is available for free and can run on Linux machines through the command line: http://code.google.com/p/jamm-peak-finder.

Which peak calling algorithm employs mixture model clustering under the hood?

587f760792a5b8ad44000005_003

Detection of epidermal growth factor receptor mutation in lung cancer by droplet digital polymerase chain reaction. BACKGROUND: Two types of epidermal growth factor receptor (EGFR) mutations in exon 19 and exon 21 (ex19del and L858R) are prevalent in lung cancer patients and sensitive to targeted EGFR inhibition. A resistance mutation in exon 20 (T790M) has been found to accompany drug treatment when patients relapse. These three mutations are valuable companion diagnostic biomarkers for guiding personalized treatment. Quantitative polymerase chain reaction (qPCR)-based methods have been widely used in the clinic by physicians to guide treatment decisions. The aim of this study was to evaluate the technical and clinical sensitivity and specificity of the droplet digital polymerase chain reaction (ddPCR) method in detecting the three EGFR mutations in patients with lung cancer. METHODS: Genomic DNA from H1975 and PC-9 cells, as well as 92 normal human blood specimens, was used to determine the technical sensitivity and specificity of the ddPCR assays. Genomic DNA of formalin-fixed, paraffin-embedded specimens from 78 Chinese patients with lung adenocarcinoma were assayed using both qPCR and ddPCR. RESULTS: The three ddPCR assays had a limit of detection of 0.02% and a wide dynamic range from 1 to 20,000 copies measurement. The L858R and ex19del assays had a 0% background level in the technical and clinical settings. The T790M assay appeared to have a 0.03% technical background. The ddPCR assays were robust for correct determination of EGFR mutation status in patients, and the dynamic range appeared to be better than qPCR methods. The ddPCR assay for T790M could detect patient samples that the qPCR method failed to detect. About 49% of this patient cohort had EGFR mutations (L858R, 15.4%; ex19del, 29.5%; T790M, 6.4%). Two patients with the ex19del mutation also had a naïve T790M mutation. CONCLUSION: These data suggest that the ddPCR method could be useful in the personalized treatment of patients with lung cancer.

Which gene harbors the mutation T790M?

56d1f790f22319765a000001_004

GBshape: a genome browser database for DNA shape annotations. Many regulatory mechanisms require a high degree of specificity in protein-DNA binding. Nucleotide sequence does not provide an answer to the question of why a protein binds only to a small subset of the many putative binding sites in the genome that share the same core motif. Whereas higher-order effects, such as chromatin accessibility, cooperativity and cofactors, have been described, DNA shape recently gained attention as another feature that fine-tunes the DNA binding specificities of some transcription factor families. Our Genome Browser for DNA shape annotations (GBshape; freely available at http://rohslab.cmb.usc.edu/GBshape/) provides minor groove width, propeller twist, roll, helix twist and hydroxyl radical cleavage predictions for the entire genomes of 94 organisms. Additional genomes can easily be added using the GBshape framework. GBshape can be used to visualize DNA shape annotations qualitatively in a genome browser track format, and to download quantitative values of DNA shape features as a function of genomic position at nucleotide resolution. As biological applications, we illustrate the periodicity of DNA shape features that are present in nucleosome-occupied sequences from human, fly and worm, and we demonstrate structural similarities between transcription start sites in the genomes of four Drosophila species.

Which is the genome browser database for DNA shape annotations?

587e1bfdfc7e8dd84f000002_005

Over-expression of CLN3P, the Batten disease protein, inhibits PANDER-induced apoptosis in neuroblastoma cells: further evidence that CLN3P has anti-apoptotic properties. Juvenile neuronal ceroid-lipofuscinosis (JNCL) or Batten/Spielmeyer-Vogt-Sjogren disease (OMIM #204200) is one of a group of nine clinically related inherited neurodegenerative disorders (CLN1-9). JNCL results from mutations in CLN3 on chromosome 16p12.1. The neuronal loss in Batten disease has been shown to be due to a combination of apoptosis and autophagy suggesting that CLN3P, the defective protein, may have an anti-neuronal death function. PANDER (PANcreatic-DERived factor) is a novel cytokine that was recently cloned from pancreatic islet cells. PANDER is specifically expressed in the pancreatic islets, small intestine, testis, prostate, and neurons of the central nervous system, and has been demonstrated to induce apoptosis. In this study, we over-expressed CLN3P in SH-SY5Y neuroblastoma cells and monitored the effects on PANDER-induced apoptosis. CLN3P significantly increased the survival rate of the SH-SY5Y cells in this system. This study provides additional evidence that the function of CLN3P is related to preventing neuronal apoptosis.

What is the effect of a defective CLN3 gene?

56b710f276d8bf8d13000003_003

Phenotypic and molecular analyses of X-linked dystonia-parkinsonism ("lubag") in women. BACKGROUND: X-linked dystonia-parkinsonism (XDP) or "lubag" is an X-linked recessive disorder that afflicts Filipino men, and rarely, women. Genetic confirmation is performed through haplotyping or detection of disease-specific changes in the DYT3 gene. OBJECTIVE: To describe the phenotypes and molecular data of 8 symptomatic female patients with XDP from 5 kindreds. METHODS: Case series. RESULTS: The average age of onset of symptoms was 52 years (range, 26-75 years). Six of 8 patients had parkinsonism, whereas only 1 had dystonia. The initial symptom was focal tremor or parkinsonism in 4, chorea in 3, and focal dystonia (cervical) in 1. Seven of 8 patients had slow or no progression of their symptoms and required no treatment. The patient with disabling parkinsonism was responsive to carbidopa/levodopa. Seven were heterozygous for the XDP haplotype, whereas 1 was homozygous. CONCLUSIONS: The phenotypes of female patients with XDP may include parkinsonism, dystonia, myoclonus, tremor, and chorea. The dystonia, if present, is mild and usually nonprogressive. Similar to men with XDP, parkinsonism is a frequent symptom in women. In contrast to men, affected women have a more benign phenotype, older age of onset, and milder course. Extreme X-inactivation mosaic may be a cause of symptoms in women with XDP, but a homozygously affected woman has also been observed.

What is the synonym of the lubag disease?

54df695b1388e8454a000004_009

The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. OBJECTIVE: Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. JAKs are important kinases in lymphocyte differentiation; however, their function in dendritic cells (DCs) is unknown. In this study, the function of JAKs in DCs was investigated with tofacitinib. METHODS: The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide (LPS) stimulation were investigated. In addition, its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells. RESULTS: Tofacitinib decreased expression of CD80/CD86 in a concentration-dependent manner in LPS-stimulated DCs; however, it did not affect HLA-DR expression. Tofacitinib suppressed tumour necrosis factor, interleukin (IL)-6 and IL-1β production without affecting transforming growth factor (TGF)-β and IL-10 production. Meanwhile, CD80/CD86 expression in DCs was enhanced by type I interferon (IFN) stimulation, and the LPS-induced CD80/CD86 expression was inhibited by an antibody to type I IFN receptor. Furthermore, tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor (IRF)-7, which is a transcription factor involved in CD80/CD86 and type I IFN expression. Tofacitinib also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2. CONCLUSIONS: Tofacitinib, a JAK1/JAK3 inhibitor, affected the activities of human DCs. It decreased CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signalling. These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs.

Which JAK (Janus kinase) inhibitor is approved for treatment of rheumatoid arthritis?

53357193d6d3ac6a34000047_006

Diagnostic accuracy of the Berlin questionnaire, STOP-BANG, STOP, and Epworth sleepiness scale in detecting obstructive sleep apnea: A bivariate meta-analysis. Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder; however, it remains underdiagnosed and undertreated. Although screening tools such as the Berlin questionnaire (BQ), STOP-BANG questionnaire (SBQ), STOP questionnaire (STOP), and Epworth sleepiness scale (ESS) are widely used for OSA, the findings regarding their diagnostic accuracy are controversial. Therefore, this meta-analysis investigated and compared the summary sensitivity, specificity, and diagnostic odds ratio (DOR) among the BQ, SBQ, STOP, and ESS according to the severity of OSA. Electronic databases, namely the Embase, PubMed, PsycINFO, ProQuest dissertations and theses A&I databases, and China knowledge resource integrated database, were searched from their inception to July 15, 2016. We included studies examining the sensitivity and specificity of the BQ, SBQ, STOP, and ESS against the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI). The revised quality assessment of diagnostic accuracy studies was used to evaluate the methodological quality of studies. A random-effects bivariate model was used to estimate the summary sensitivity, specificity, and DOR of the tools. We identified 108 studies including a total of 47 989 participants. The summary estimates were calculated for the BQ, SBQ, STOP, and ESS in detecting mild (AHI/RDI  >  5 events/h), moderate (AHI/RDI  >  15 events/h), and severe OSA (AHI/RDI  >  30 events/h). The performance levels of the BQ, SBQ, STOP, and ESS in detecting OSA of various severity levels are outlined as follows: for mild OSA, the pooled sensitivity levels were 76%, 88%, 87%, and 54%; pooled specificity levels were 59%, 42%, 42%, and 65%; and pooled DORs were 4.30, 5.13, 4.85, and 2.18, respectively. For moderate OSA, the pooled sensitivity levels were 77%, 90%, 89%, and 47%; pooled specificity levels were 44%, 36%, 32%, and 621%; and pooled DORs were 2.68, 5.05, 3.71, and 1.45, respectively. For severe OSA, the pooled sensitivity levels were 84%, 93%, 90%, and 58%; pooled specificity levels were 38%, 35%, 28%, and 60%; and pooled DORs were 3.10, 6.51, 3.37, and 2.10, respectively. Therefore, for mild, moderate, and severe OSA, the pooled sensitivity and DOR of the SBQ were significantly higher than those of other screening tools (P < .05); however, the specificity of the SBQ was lower than that of the ESS (P < .05). Moreover, age, sex, body mass index, study sample size, study populations, presence of comorbidities, PSG or portable monitoring performance, and risk of bias in the domains of the index test and reference standard were significant moderators of sensitivity and specificity (P < .05). Compared with the BQ, STOP, and ESS, the SBQ is a more accurate tool for detecting mild, moderate, and severe OSA. Sleep specialists should use the SBQ to conduct patient interviews for the early diagnosis of OSA in clinical settings, particularly in resource-poor countries and sleep clinics where PSG is unavailable.

Which disease risk can be estimated with the Stop-Bang questionnaire?

5a742d620384be9551000002_003

MARS: improving multiple circular sequence alignment using refined sequences. BACKGROUND: A fundamental assumption of all widely-used multiple sequence alignment techniques is that the left- and right-most positions of the input sequences are relevant to the alignment. However, the position where a sequence starts or ends can be totally arbitrary due to a number of reasons: arbitrariness in the linearisation (sequencing) of a circular molecular structure; or inconsistencies introduced into sequence databases due to different linearisation standards. These scenarios are relevant, for instance, in the process of multiple sequence alignment of mitochondrial DNA, viroid, viral or other genomes, which have a circular molecular structure. A solution for these inconsistencies would be to identify a suitable rotation (cyclic shift) for each sequence; these refined sequences may in turn lead to improved multiple sequence alignments using the preferred multiple sequence alignment program. RESULTS: We present MARS, a new heuristic method for improving Multiple circular sequence Alignment using Refined Sequences. MARS was implemented in the C++ programming language as a program to compute the rotations (cyclic shifts) required to best align a set of input sequences. Experimental results, using real and synthetic data, show that MARS improves the alignments, with respect to standard genetic measures and the inferred maximum-likelihood-based phylogenies, and outperforms state-of-the-art methods both in terms of accuracy and efficiency. Our results show, among others, that the average pairwise distance in the multiple sequence alignment of a dataset of widely-studied mitochondrial DNA sequences is reduced by around 5% when MARS is applied before a multiple sequence alignment is performed. CONCLUSIONS: Analysing multiple sequences simultaneously is fundamental in biological research and multiple sequence alignment has been found to be a popular method for this task. Conventional alignment techniques cannot be used effectively when the position where sequences start is arbitrary. We present here a method, which can be used in conjunction with any multiple sequence alignment program, to address this problem effectively and efficiently.

Which algorithm has been developed in order to improve multiple circular sequence alignment using refined sequences?

5a6a3464b750ff4455000026_003

Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. BACKGROUND: Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase. METHODS: A total of 532 patients with late--chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated. RESULTS: Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred. CONCLUSIONS: Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.

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

5324a8ac9b2d7acc7e000018_094

Genetic and molecular aspects of acromelic dysplasia. The acromelic dysplasia group includes three rare disorders: Weill-Marchesani syndrome (WMS), Geleophysic dysplasia (GD) and Acromicric dysplasia (AD) all characterized by short stature, short hands and stiff joints. The clinical overlap between the three disorders is striking. Indeed, in addition to the diagnostic criteria, they all share common features including delayed bone age, cone shaped epiphyses, thick skin and heart disease. In contrast, a microspherophakic lens seems to be a characteristic feature of WMS whereas hepatomegaly and a severe outcome are encountered only in the most severe forms of GD. Finally, WMS is transmitted either by an autosomal dominant or an autosomal recessive (AR) mode of inheritance, GD by an autosomal recessive mode of inheritance and AD by an autosomal dominant mode of inheritance. Using genetic approaches, we have identified the molecular basis of WMS and GD which both involved the same superfamily of proteins, the ADAMTS [A Disintegrin-like And Metalloproteinase domain (reprolysin type) with ThromboSpondin type 1 repeats (TSR)]. We have found ADAMTS10 mutations in the recessive form of WMS and Fibrillin 1 mutations in the dominant form of WMS. More recently, we have identified ADAMTSL2 mutations in GD. The function of ADAMTS1 0 and AD AMTSL 2 are unknown. But the findings of FBN1 and ADAMTS10 mutations in WMS suggest a direct link between the two proteins. Using a yeast double hybrid screen, we have identified LTBP1 (Latent TGFbeta Binding protein 1) as a partner of ADAMTSL2. The combination of these findings suggests that ADAMTS10 and ADAMTSL2 are both involved in the microfibrillar network.

What is the mode of inheritance of Acromicric dysplasia?

53318685d6d3ac6a3400003d_002

Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain. The role of serotonin in CNS function and in many neuropsychiatric diseases (e.g., schizophrenia, affective disorders, degenerative dementias) support the development of a reliable measure of serotonin receptor binding in vivo in human subjects. To this end, the regional distribution and intrasubject test-retest variability of the binding of [18F]altanserin were measured as important steps in the further development of [18F]altanserin as a radiotracer for positron emission tomography (PET) studies of the serotonin 5-HT2A receptor. Two high specific activity [18F]altanserin PET studies were performed in normal control subjects (n = 8) on two separate days (2-16 days apart). Regional specific binding was assessed by distribution volume (DV), estimates that were derived using a conventional four compartment (4C) model, and the Logan graphical analysis method. For both analysis methods, levels of [18F]altanserin binding were highest in cortical areas, lower in the striatum and thalamus, and lowest in the cerebellum. Similar average differences of 13% or less were observed for the 4C model DV determined in regions with high receptor concentrations with greater variability in regions with low concentrations (16-20%). For all regions, the absolute value of the test-retest differences in the Logan DV values averaged 12% or less. The test-retest differences in the DV ratios (regional DV values normalized to the cerebellar DV) determined by both data analysis methods averaged less than 10%. The regional [18F]altanserin DV values using both of these methods were significantly correlated with literature-based values of the regional concentrations of 5-HT2A receptors determined by postmortem autoradiographic studies (r2 = 0.95, P < 0.001 for the 4C model and r2 = 0.96, P < 0.001 for the Logan method). Brain uptake studies in rats demonstrated that two different radiolabeled metabolites of [18F]altanserin (present at levels of 3-25% of the total radioactivity in human plasma 10-120 min postinjection) were able to penetrate the blood-brain barrier. However, neither of these radiolabeled metabolites bound specifically to the 5-HT2A receptor and did not interfere with the interpretation of regional [18F]altanserin-specific binding parameters obtained using either a conventional 4C model or the Logan graphical analysis method. In summary, these results demonstrate that the test-retest variability of [18F]altanserin-specific binding is comparable to that of other PET radiotracers and that the regional specific binding of [18F]altanserin in human brain was correlated with the known regional distribution of 5-HT2A receptors. These findings support the usefulness of [18F]altanserin as a radioligand for PET studies of 5-HT2A receptors.

Which receptors can be evaluated with the [18F]altanserin?

55242d512c8b63434a000006_037

Stress responses in alfalfa (Medicago sativa L). XXII. cDNA cloning and characterization of an elicitor-inducible isoflavone 7-O-methyltransferase. Medicarpin, the major phytoalexin in alfalfa, is synthesized via the isoflavonoid branch of phenylpropanoid metabolism. The methyl group at the 9 position of medicarpin is generally accepted to arise via the methylation of the 4' position (B-ring) of daidzein. Surprisingly, the isoflavone-O-methyltransferase (IOMT), which is induced along with other enzymes involved in medicarpin biosynthesis, methylates the A-ring 7-hydroxyl group of daidzein in vitro, a reaction that probably does not occur in vivo. Utilizing internal amino acid sequence information from purified alfalfa IOMT, we have isolated three full-length IOMT cDNA clones. A search of the protein databases revealed sequence similarities to O-methyltransferases from various sources. The highest match (50.5% identity) was found between IOMT8 and 6a-hydroxymaackiain 3-O-methyltransferase from Pisum sativum. The molecular weight of alfalfa IOMT expressed in Escherichia coli was similar to that of purified IOMT from alfalfa cell cultures (41 kDa by SDS-PAGE). The recombinant enzyme catalyzed the O-methylation of A-ring hydroxyl group(s) of isoflavones, and could also methylate the pterocarpan (+) 6a-hydroxymaackiain. Alfalfa contains multiple IOMT genes, and closely related sequences are present in the genomes of chickpea and cowpea, species that also produce B-ring methylated isoflavonoids in vivo. Northern blot analysis indicated that IOMT transcripts are rapidly induced following elicitation, prior to the increase in IOMT activity and medicarpin accumulation. The possible role of the isoflavone 7-OMT in the synthesis of formononetin in vivo is discussed.

Which is the major phytoalexin in alfalfa (Medicago sativa L.)?

5543829fed966d112c000009_001