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Oral and parenteral anticoagulants: new kids on the block. Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms "anticoagulants", "blood coagulation inhibitors", "anticoagulants and venous thromboembolism", "anticoagulants and atrial fibrillation", and "'antithrombins." Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.

Which clotting factor is inhibited by betrixaban?

55200c606b348bb82c000013_139

alpha-Synuclein immunoreactivity in dementia with Lewy bodies: morphological staging and comparison with ubiquitin immunostaining. alpha-Synuclein is a presynaptic protein recently identified as a specific component of Lewy bodies (LB) and Lewy neurites. The aim of this study was to assess the morphology and distribution of alpha-synuclein immunoreactivity in cases of dementia with LB (DLB), and to compare alpha-synuclein with ubiquitin immunostaining. We examined substantia nigra, paralimbic regions (entorhinal cortex, cingulate gyrus, insula and hippocampus), and neocortex (frontal and occipital association cortices) with double alpha-synuclein and ubiquitin immunostaining in 25 cases meeting neuropathological criteria for DLB. alpha-Synuclein immunostaining was more specific than ubiquitin immunostaining in that it differentiated LB from globose tangles. It was also slightly more sensitive, staining 4-5% more intracytoplasmic structures, especially diffuse alpha-synuclein deposits that were ubiquitin negative. In addition to LB, alpha-synuclein staining showed filiform and globose neurites in the substantia nigra, CA2-3 regions of the hippocampus, and entorhinal cortex. A spectrum of alpha-synuclein staining was seen in substantia nigra: from diffuse "cloud-like" inclusions to aggregated intracytoplasmic inclusions with variable ubiquitin staining to classic LB. We hypothesize that these represent different stages in LB formation.

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

53189656b166e2b80600001c_015

Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. BACKGROUND: Homozygous familial hypercholesterolaemia is a rare, serious disorder caused by very low or absent plasma clearance of LDL, substantially raised LDL cholesterol, and accelerated development of cardiovascular disease. Conventional lipid-lowering treatments are modestly effective. Evolocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), reduced LDL cholesterol by 16% in a pilot study. We now report results with evolocumab in a randomised, double-blind, placebo-controlled phase 3 trial. METHODS: This randomised, double-blind, placebo-controlled phase 3 trial was undertaken at 17 sites in ten countries in North America, Europe, the Middle East, and South Africa. 50 eligible patients (aged > 12 years) with homozygous familial hypercholesterolaemia, on stable lipid-regulating therapy for at least 4 weeks, and not receiving lipoprotein apheresis, were randomly allocated by a computer-generated randomisation sequence in a 2:1 ratio to receive subcutaneous evolocumab 420 mg or placebo every 4 weeks for 12 weeks. Randomisation was stratified by LDL cholesterol at screening (<11 mmol/L or > 11 mmol/L) and implemented by a computerised interactive voice-response system. Patients, study personnel, and the funder were masked to treatment and to the efficacy results by the central laboratory not returning LDL cholesterol or any lipid results to the clinical sites after the baseline visit. The primary endpoint was percentage change in ultracentrifugation LDL cholesterol from baseline at week 12 compared with placebo, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01588496. FINDINGS: Of the 50 eligible patients randomly assigned to the two treatment groups, 49 actually received the study drug and completed the study (16 in the placebo group and 33 in the evolocumab group). Compared with placebo, evolocumab significantly reduced ultracentrifugation LDL cholesterol at 12 weeks by 30·9% (95% CI -43·9% to -18·0%; p<0·0001). Treatment-emergent adverse events occurred in ten (63%) of 16 patients in the placebo group and 12 (36%) of 33 in the evolocumab group. No serious clinical or laboratory adverse events occurred, and no anti-evolocumab antibody development was detected during the study. INTERPRETATION: In patients with homozygous familial hypercholesterolaemia receiving stable background lipid-lowering treatment and not on apheresis, evolocumab 420 mg administered every 4 weeks was well tolerated and significantly reduced LDL cholesterol compared with placebo. FUNDING: Amgen Inc.

Which enzyme is targeted by Evolocumab?

54e0d1491388e8454a000014_006

Orteronel for the treatment of prostate cancer. Orteronel (also known as TAK-700) is a novel hormonal therapy that is currently in testing for the treatment of prostate cancer. Orteronel inhibits the 17,20 lyase activity of the enzyme CYP17A1, which is important for androgen synthesis in the testes, adrenal glands and prostate cancer cells. Preclinical studies demonstrate that orteronel treatment suppresses androgen levels and causes shrinkage of androgen-dependent organs, such as the prostate gland. Early reports of clinical studies demonstrate that orteronel treatment leads to reduced prostate-specific antigen levels, a marker of prostate cancer tumor burden, and more complete suppression of androgen synthesis than conventional androgen deprivation therapies that act in the testes alone. Treatment with single-agent orteronel has been well tolerated with fatigue as the most common adverse event, while febrile neutropenia was the dose-limiting toxicity in a combination study of orteronel with docetaxel. Recently, the ELM-PC5 Phase III clinical trial in patients with advanced-stage prostate cancer who had received prior docetaxel was unblinded as the overall survival primary end point was not achieved. However, additional Phase III orteronel trials are ongoing in men with earlier stages of prostate cancer.

Which enzyme is inhibited by Orteronel?

54e0c3e71388e8454a000013_013

A cytochrome c methyltransferase from Crithidia oncopelti. The mitochondrial cytochrome c-557 of Crithidia oncopelti contains two lysine residues and an N-terminal proline residue that are methylated in vivo by the methyl group of methionine. The purified cytochrome can act as a methyl acceptor for a methyltransferase activity in the cell extract that uses S-adenosylmethionine as methyl donor. Crithidia cytochrome c-557 is by far the best substrate for this methyltransferase of those tested, in spite of the fact that methylation sites are already almost fully occupied. The radioactive uptake of [14C]methyl groups from S-adenosylmethionine occurred only at a lysine residue (-8) and the N-terminal proline residue. This methyltransferase appears to differ from that of Neurospora and yeast [Durban, Nochumson, Kim, Paik & Chan (1978) J. Biol. Chem. 253, 1427-1435; DiMaria, Polastro, DeLange, Kim & Paik (1979) J. Biol. Chem. 254, 4645-4652] in that lysine-72 of horse cytochrome c is a poor acceptor. Also, the Crithidia methyltransferase appears to be stable to carry lysine methylation much further to completion than do the enzymes from yeast and Neurospora, which produce very low degrees of methylation in native cytochromes c.

Which is the methyl donor of histone methyltransferases?

516e7fda298dcd4e51000081_024

Identification of protein interfaces between α-synuclein, the principal component of Lewy bodies in Parkinson disease, and the molecular chaperones human Hsc70 and the yeast Ssa1p. Fibrillar α-synuclein (α-Syn) is the principal component of Lewy bodies, which are evident in individuals affected by Parkinson disease (PD). This neuropathologic form of α-Syn plays a central role in PD progression as it has been shown to propagate between neurons. Tools that interfere with α-Syn assembly or change the physicochemical properties of the fibrils have potential therapeutic properties as they may be sufficient to interfere with and/or halt cell-to-cell transmission and the systematic spread of α-Syn assemblies within the central nervous system. Vertebrate molecular chaperones from the constitutive/heat-inducible heat shock protein 70 (Hsc/p70) family have been shown to hinder the assembly of soluble α-Syn into fibrils and to bind to the fibrils and very significantly reduce their toxicity. To understand how Hsc70 family members sequester soluble α-Syn, we set up experiments to identify the molecular chaperone-α-Syn surface interfaces. We cross-linked human Hsc70 and its yeast homologue Ssa1p and α-Syn using a chemical cross-linker and mapped the Hsc70- and Ssa1p-α-Syn interface. We show that the client binding domain of Hsc70 and Ssa1p binds two regions within α-Syn similar to a tweezer, with the first spanning residues 10-45 and the second spanning residues 97-102. Our findings define what is necessary and sufficient for engineering Hsc70- and Ssa1p-derived polypeptide with minichaperone properties with a potential as therapeutic agents in Parkinson disease through their ability to affect α-Syn assembly and/or toxicity.

Which is the primary protein component of Lewy bodies?

58a2e5f760087bc10a000007_018

ACS chemical neuroscience molecule spotlight on Telcagepant (MK-0974). Telcagepant (MK-0974) is a novel calcitonin gene-related peptide (CGRP) receptor antagonist currently undergoing clinical trials for migraine (http://www.merck.com/research/pipeline/home.html). MK-0974 is currently being studied in phase III clinical trials.

Which receptor is targeted by telcagepant?

55032efde9bde69634000035_002

Cognitive abilities of Alzheimer's disease transgenic mice are modulated by social context and circadian rhythm. In the present study, we used a new training paradigm in the intelliCage automatic behavioral assessment system to investigate cognitive functions of the transgenic mice harboring London mutation of the human amyloid precursor protein (APP.V717I). Three groups of animals: 5-, 12- and 18-24-month old were subjected to both Water Maze training and the IntelliCage-based appetitive conditioning. The spatial memory deficit was observed in all three groups of transgenic mice in both behavioral paradigms. However, the APP mice were capable to learn normally when co-housed with the wild-type (WT) littermates, in contrast to clearly impaired learning observed when the transgenic mice were housed alone. Furthermore, in the transgenic mice kept in the Intellicage alone, the cognitive deficit of the young animals was modulated by the circadian rhythm, namely was prominent only during the active phase of the day. The novel approach to study the transgenic mice cognitive abilities presented in this paper offers new insight into cognitive dysfunctions of the Alzheimer's disease mouse model.

Which disease the London mutation involved in?

58b6978822d300530900000a_001

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_012

Delamanid when other anti-tuberculosis-treatment regimens failed due to resistance or tolerability. INTRODUCTION: The limited availability of effective drugs causes difficulties in the management of multidrug-resistant tuberculosis (MDR-TB) and novel therapeutic agents are needed. Delamanid , a new nitro-hydro-imidazooxazole derivative, inhibits mycolic acid synthesis. This review covers the efficacy and safety of delamanid for MDR-TB. AREA COVERED: This paper reviews the pharmacological profile of delamanid and the results of clinical trials evaluating its efficacy for treating MDR-TB in combination with other anti-TB drugs. The drug's safety and tolerability profiles are also considered. EXPERT OPINION: Delamanid showed potent activity against drug-susceptible and -resistant Mycobacterium tuberculosis in both in vitro and in vivo studies. In clinical trials, the drug showed significant early bactericidal activity in pulmonary TB patients, and increased culture conversion after 2 months of treatment in combination with an optimized background regimen in MDR-TB patients. In addition, decreased mortality was observed in MDR-TB patients who received > 6 months of delamanid treatment. The drug was generally tolerable, but QT prolongation should be monitored carefully using electrocardiograms and potassium levels. Therefore, delamanid could be used as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.

Which disease can be treated with Delamanid?

56bc7d71ac7ad10019000018_005

Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy. Telomeres may regulate human disease by at least two independent mechanisms. First, replicative senescence occurs once short telomeres generate DNA-damage signals that produce a barrier to tumor progression. Second, telomere position effects (TPE) could change gene expression at intermediate telomere lengths in cultured human cells. Here we report that telomere length may contribute to the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a late-onset disease genetically residing only 25-60 kilobases from the end of chromosome 4q. We used a floxable telomerase to generate isogenic clones with different telomere lengths from affected patients and their unaffected siblings. DUX4, the primary candidate for FSHD pathogenesis, is upregulated over ten-fold in FSHD myoblasts and myotubes with short telomeres, and its expression is inversely proportional to telomere length. FSHD may be the first known human disease in which TPE contributes to age-related phenotype.

Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?

550f0e4c6a8cde6b72000003_006

methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit.

Which R package is used for the analysis of genome-wide DNA methylation profiles?

588f8e9794c1512c50000005_006

Delayed myelination is not a constant feature of Allan-Herndon-Dudley syndrome: report of a new case and review of the literature. INTRODUCTION: Allan-Herndon-Dudley syndrome is an X-linked condition caused by mutations of the monocarboxylate transporter 8 gene. This syndrome is characterized by axial hypotonia, severe mental retardation, dysarthria, athetoid movements, spastic paraplegia, and a typical thyroid hormone profile. In most of the cases reported so far, brain magnetic resonance imaging showed delayed myelination of the central white matter and this finding greatly affects the diagnosis of the syndrome. CASE REPORT: We present a new case studied with magnetic resonance imaging and spectroscopy and we reviewed all the articles published between 2004 and 2012 containing information on brain neuroimaging in this syndrome. An Italian boy, showing a classical phenotype of the syndrome, was diagnosed at 17months of age. Genetic analysis revealed a new frameshift mutation of the monocarboxylate transporter 8 gene. His brain magnetic resonance imaging and spectroscopy, performed at the age of 14months, were normal. DISCUSSION: Among the 33 cases reported in the literature, 3 cases had normal neuroimaging and in 7 of 14 cases, having a longitudinal follow-up, the initial finding of delayed myelination gradually improved. Our case and the review of the pertinent literature suggest that Allan-Herndon-Dudley syndrome should be suspected in males with the typical neurological and thyroid profile, even in cases with normal brain myelination.

Which hormone concentrations are altered in patients with the Allan–Herndon–Dudley syndrome?

530f900ee3eabad021000003_002

Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Andexanet alfa is a specific reversal agent for Factor Xa inhibitors. The molecule is a recombinant protein analog of factor Xa that binds to Factor Xa inhibitors and antithrombin:LMWH complex but does not trigger prothrombotic activity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) was able to dose-dependently reverse Factor Xa inhibition and restore thrombin generation for the duration of drug administration. Further trials are underway to examine its safety and efficacy in the population of patients experiencing FXa inhibitor-related bleeding.

Andexanet Alfa is an antidote of which clotting factor inhibitors?

5880b073c872c95565000003_013

The database of the smallest known auto-replicable RNA species: viroids and viroid-like RNAs. This is an online database in order to facilitate research on viroid, viroid-like RNAs and human hepatitis delta virus by presenting a large number of sequences and related data in a comprehensive and user-friendly format (e.g., position of their self-catalytic domains, open reading frame, prediction of the most stable secondary structures, etc.). This online database is available on the WWW at http://www.callisto.si. usherb.ca/jpperra

Which are the smallest known subviral pathogens of plants?

56e0447a51531f7e3300000b_013

Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. Accumulating lines of experimental evidence have revealed that hypoxia-inducible factors, HIF-1α and HIF-2α, are key regulators of the adaptation of cancer- and metastasis-initiating cells and their differentiated progenies to oxygen and nutrient deprivation during cancer progression under normoxic and hypoxic conditions. Particularly, the sustained stimulation of epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), stem cell factor (SCF) receptor KIT, transforming growth factor-β receptors (TGF-βRs) and Notch and their downstream signalling elements such as phosphatidylinositol 3'-kinase (PI3K)/Akt/molecular target of rapamycin (mTOR) may lead to an enhanced activity of HIFs. Moreover, the up-regulation of HIFs in cancer cells may also occur in the hypoxic intratumoral regions formed within primary and secondary neoplasms as well as in leukaemic cells and metastatic prostate and breast cancer cells homing in the hypoxic endosteal niche of bone marrow. The activated HIFs may induce the expression of numerous gene products such as induced pluripotency-associated transcription factors (Oct-3/4, Nanog and Sox-2), glycolysis- and epithelial-mesenchymal transition (EMT) programme-associated molecules, including CXC chemokine receptor 4 (CXCR4), snail and twist, microRNAs and angiogenic factors such as vascular endothelial growth factor (VEGF). These gene products in turn can play critical roles for high self-renewal ability, survival, altered energy metabolism, invasion and metastases of cancer cells, angiogenic switch and treatment resistance. Consequently, the targeting of HIF signalling network and altered metabolic pathways represents new promising strategies to eradicate the total mass of cancer cells and improve the efficacy of current therapies against aggressive and metastatic cancers and prevent disease relapse.

Which is the molecular target of the immunosuppressant drug Rapamycin?

53124bdae3eabad02100000b_002

Necrobiosis lipoidica diabeticorum. Localization in surgical scars. Necrobiosis lipoidica is a skin disorders with an interesting predisposition for areas of trauma such as the anterior shins. In this report a patient with diabetes mellitus and generalized necrobiosis lipoidica diabeticorum with localization in surgical scars is described. A brief review of other skin disorders occurring in scars is also included.

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

58bfd8e902b8c60953000018_017

Prospective comparison of the clinical impacts of heterogeneous vancomycin-intermediate methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-susceptible MRSA. Although methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) strains with reduced susceptibility to vancomycin (RVS-MRSA; including vancomycin-intermediate S. aureus [VISA] and heterogeneous VISA [hVISA]) have been linked with vancomycin treatment failure, it is unclear whether they are more pathogenic than vancomycin-susceptible MRSA (VS-MRSA). We prospectively assessed patients with clinical MRSA isolates during a 10-month period to determine clinical status (infection versus colonization) and therapeutic outcome before correlating these findings with the results of detailed in vitro assessment of vancomycin susceptibility, including population analysis profile (PAP) testing. hVISA and VISA were defined by standard PAP criteria (area-under-the-curve ratio compared to that of the reference hVISA strain Mu3 [>or=0.9]) and routine CLSI criteria (vancomycin MIC, 4 to 8 microg/ml), respectively. Among the 117 patients assessed, 58 had RVS-MRSA isolates (56 hVISA and 2 VISA) and 59 had VS-MRSA isolates; the patient demographics and comorbidities were similar. RVS-MRSA was associated with a lower rate of infection than VS-MRSA (29/58 versus 46/59; P = 0.003), including a lower rate of bacteremia (3/58 versus 20/59, respectively; P < 0.001). The cure rates in RVS-MRSA and VS-MRSA groups were not statistically different (16/26 versus 31/42; P = 0.43), but the post hoc assessment of treatment regimes and study size made detailed conclusions difficult. The results of the macro method Etest correlated well with the PAP results (sensitivity, 98.3%, and specificity, 91.5%), but broth microdilution and our preliminary RVS-MRSA detection method correlated poorly. All isolates were susceptible to linezolid and daptomycin. These data suggest that detailed prospective laboratory identification of RVS-MRSA isolates may be of limited value and that, instead, such in vitro investigation should be reserved for isolates from patients who are failing appropriate anti-MRSA therapy.

What is MRSA?

58a32efe60087bc10a000013_041

The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. T-cell expression of programmed death receptor-1 (PD-1) down-regulates the immune response against malignancy by interacting with cognate ligands (eg, PD-L1) on tumor cells; however, little is known regarding PD-1 and natural killer (NK) cells. NK cells exert cytotoxicity against multiple myeloma (MM), an effect enhanced through novel therapies. We show that NK cells from MM patients express PD-1 whereas normal NK cells do not and confirm PD-L1 on primary MM cells. Engagement of PD-1 with PD-L1 should down-modulate the NK-cell versus MM effect. We demonstrate that CT-011, a novel anti-PD-1 antibody, enhances human NK-cell function against autologous, primary MM cells, seemingly through effects on NK-cell trafficking, immune complex formation with MM cells, and cytotoxicity specifically toward PD-L1(+) MM tumor cells but not normal cells. We show that lenalidomide down-regulates PD-L1 on primary MM cells and may augment CT-011's enhancement of NK-cell function against MM. We demonstrate a role for the PD-1/PD-L1 signaling axis in the NK-cell immune response against MM and a role for CT-011 in enhancing the NK-cell versus MM effect. A phase 2 clinical trial of CT-011 in combination with lenalidomide for patients with MM should be considered.

The antibodies MK-3475 and CT-011 have shown promising results in treating malignancies. Which protein are they targeting?

517901bc8ed59a060a00003b_004

New insights into the promoterless transcription of DNA coligo templates by RNA polymerase III. Chemically synthesized DNA can carry small RNA sequence information but converting that information into small RNA is generally thought to require large double-stranded promoters in the context of plasmids, viruses and genes. We previously found evidence that circularized oligodeoxynucleotides (coligos) containing certain sequences and secondary structures can template the synthesis of small RNA by RNA polymerase III in vitro and in human cells. By using immunoprecipitated RNA polymerase III we now report corroborating evidence that this enzyme is the sole polymerase responsible for coligo transcription. The immobilized polymerase enabled experiments showing that coligo transcripts can be formed through transcription termination without subsequent 3' end trimming. To better define the determinants of productive transcription, a structure-activity relationship study was performed using over 20 new coligos. The results show that unpaired nucleotides in the coligo stem facilitate circumtranscription, but also that internal loops and bulges should be kept small to avoid secondary transcription initiation sites. A polymerase termination sequence embedded in the double-stranded region of a hairpin-encoding coligo stem can antagonize transcription. Using lessons learned from new and old coligos, we demonstrate how to convert poorly transcribed coligos into productive templates. Our findings support the possibility that coligos may prove useful as chemically synthesized vectors for the ectopic expression of small RNA in human cells.

What is a coligo?

5a87ea1861bb38fb2400000d_001

Defective Proteasome Delivery of Polyubiquitinated Proteins by Ubiquilin-2 Proteins Containing ALS Mutations. Ubiquilin proteins facilitate delivery of ubiquitinated proteins to the proteasome for degradation. Interest in the proteins has been heightened by the discovery that gene mutations in UBQLN2 cause dominant inheritance of amyotrophic lateral sclerosis (ALS). However, the mechanisms by which the mutations cause ALS are not known. Here we report on the underlying defect of ubiquilin-2 proteins containing ALS-linked mutations in affecting proteasome-mediated degradation. We found that overexpression of ubiquilin-2 proteins containing any one of five different ALS mutations slow degradation of Myc, a prototypic proteasome substrate. Examination of coprecipitating proteins indicated that the mutant proteins are generally capable of binding polyubiquitinated proteins, but defective in binding the proteasome. GST-pulldown studies revealed that many of the mutants bind weaker to the S5a subunit of the proteasome, compared with wild type (WT) ubiquilin-2 protein. The results suggest the mutant proteins are unable to deliver their captured cargo to the proteasome for degradation, which presumably leads to toxicity. Quantification of cell death is consistent with this idea. Measurement of protein turnover further indicated the mutant proteins have longer half-lives than WT ubiquilin-2. Our studies provide novel insight into the mechanism by which ALS-linked mutations in UBQLN2 interfere with protein degradation.

Which human disease is associated with mutated UBQLN2

58bc5e2202b8c60953000002_012

Targeting p53 for Novel Anticancer Therapy. Carcinogenesis is a multistage process, involving oncogene activation and tumor suppressor gene inactivation as well as complex interactions between tumor and host tissues, leading ultimately to an aggressive metastatic phenotype. Among many genetic lesions, mutational inactivation of p53 tumor suppressor, the "guardian of the genome," is the most frequent event found in 50% of human cancers. p53 plays a critical role in tumor suppression mainly by inducing growth arrest, apoptosis, and senescence, as well as by blocking angiogenesis. In addition, p53 generally confers the cancer cell sensitivity to chemoradiation. Thus, p53 becomes the most appealing target for mechanism-driven anticancer drug discovery. This review will focus on the approaches currently undertaken to target p53 and its regulators with an overall goal either to activate p53 in cancer cells for killing or to inactivate p53 temporarily in normal cells for chemoradiation protection. The compounds that activate wild type (wt) p53 would have an application for the treatment of wt p53-containing human cancer. Likewise, the compounds that change p53 conformation from mutant to wt p53 (p53 reactivation) or that kill the cancer cells with mutant p53 using a synthetic lethal mechanism can be used to selectively treat human cancer harboring a mutant p53. The inhibitors of wt p53 can be used on a temporary basis to reduce the normal cell toxicity derived from p53 activation. Thus, successful development of these three classes of p53 modulators, to be used alone or in combination with chemoradiation, will revolutionize current anticancer therapies and benefit cancer patients.

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

55421ee7ccca0ce74b000002_011

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

Which enzyme does MLN4924 inhibit?

56ed03862ac5ed1459000004_023

microRNAs: a new frontier in kallikrein research. microRNAs (miRNAs) are a recently discovered class of small non-coding RNAs that regulate gene expression. Rapidly accumulating evidence has revealed that miRNAs are associated with cancer. The human tissue kallikrein gene family is the largest contiguous family of proteases in the human genome, containing 15 genes. Many kallikreins have been reported as potential tumor markers. In this review, recent bioinformatics and experimental evidence is presented indicating that kallikreins are potential miRNA targets. The available experimental approaches to investigate these interactions and the potential diagnostic and therapeutic applications are also discussed. miRNAs represent a possible regulatory mechanism for controlling kallikrein expression at the post-transcriptional level. Many miRNAs were predicted to target kallikreins and a single miRNA can target more than one kallikrein. Recent evidence suggests that miRNAs can also exert 'quantitative' control of kallikreins by utilizing multiple targeting sites in the kallikrein mRNA. More research is needed to experimentally verify the in silico predictions and to investigate the possible role in tumor initiation and/or progression.

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

511a3573df1ebcce7d000018_015

Diagnosing diabetic foot osteomyelitis: is the combination of probe-to-bone test and plain radiography sufficient for high-risk inpatients? AIMS: To investigate the accuracy of the sequential combination of the probe-to-bone test and plain X-rays for diagnosing osteomyelitis in the foot of patients with diabetes. METHODS: We prospectively compiled data on a series of 338 patients with diabetes with 356 episodes of foot infection who were hospitalized in the Diabetic Foot Unit of La Paloma Hospital from 1 October 2002 to 31 April 2010. For each patient we did a probe-to-bone test at the time of the initial evaluation and then obtained plain X-rays of the involved foot. All patients with positive results on either the probe-to-bone test or plain X-ray underwent an appropriate surgical procedure, which included obtaining a bone specimen that was processed for histology and culture. We calculated the sensitivity, specificity, predictive values and likelihood ratios of the procedures, using the histopathological diagnosis of osteomyelitis as the criterion standard. RESULTS: Overall, 72.4% of patients had histologically proven osteomyelitis, 85.2% of whom had positive bone culture. The performance characteristics of both the probe-to-bone test and plain X-rays were excellent. The sequential diagnostic approach had a sensitivity of 0.97, specificity of 0.92, positive predictive value of 0.97, negative predictive value of 0.93, positive likelihood ratio of 12.8 and negative likelihood ratio of 0.02. Only 6.6% of patients with negative results on both diagnostic studies had osteomyelitis. CONCLUSIONS: Clinicians seeing patients in a setting similar to ours (specialized diabetic foot unit with a high prevalence of osteomyelitis) can confidently diagnose diabetic foot osteomyelitis when either the probe-to-bone test or a plain X-ray, or especially both, are positive.

Which disease can be diagnosed with the "probe to bone" test?

5a6f853ab750ff4455000055_005

Auto-regulatory RNA editing fine-tunes mRNA re-coding and complex behaviour in Drosophila. Auto-regulatory feedback loops are a common molecular strategy used to optimize protein function. In Drosophila, many messenger RNAs involved in neuro-transmission are re-coded at the RNA level by the RNA-editing enzyme, dADAR, leading to the incorporation of amino acids that are not directly encoded by the genome. dADAR also re-codes its own transcript, but the consequences of this auto-regulation in vivo are unclear. Here we show that hard-wiring or abolishing endogenous dADAR auto-regulation dramatically remodels the landscape of re-coding events in a site-specific manner. These molecular phenotypes correlate with altered localization of dADAR within the nuclear compartment. Furthermore, auto-editing exhibits sexually dimorphic patterns of spatial regulation and can be modified by abiotic environmental factors. Finally, we demonstrate that modifying dAdar auto-editing affects adaptive complex behaviours. Our results reveal the in vivo relevance of auto-regulatory control over post-transcriptional mRNA re-coding events in fine-tuning brain function and organismal behaviour.

Which is the major RNA editing enzyme in Drosophila melanogaster?

58e9e7aa3e8b6dc87c00000d_009

Ackee (Blighia sapida) hypoglycin A toxicity: dose response assessment in laboratory rats. Hypoglycin A, the toxin found in the ackee fruit, has been reported in the literature as the causative agent in incidences of acute toxicity termed Jamaican vomiting sickness or toxic hypoglycemic syndrome. Hypoglycin A toxicity in this study was determined by feeding male and female Sprague-Dawley rats a control diet and ackee diets that contained 4-3840 ppm of hypoglycin. The fixed dose method was used to quantify the acute toxic dose of hypoglycin A and was determined by feeding a diet consisting of the lowest hypoglycin A concentration; this was increased to the next highest dose after 24h until toxicity was observed. The maximum tolerated dose (MTD) of hypoglycin A was determined by feeding rats the ackee and control diets over a 30-day period. The acute toxic dose for male and female rats was 231.19+/-62.5 5mg hypoglycinA/kgBW and 215.99+/-63.33 mg hypoglycinA/kgBW, respectively. This was considerably greater than the dose of 100 mg hypoglycin/kgBW reported in a previous study when aqueous hypoglycin was administered orally. The MTD of hypoglycin A in both male and female rats was 1.50+/-0.07 mg hypoglycinA/kgBW/day. These findings suggest that the form in which hypoglycin in ackee is administered could affect the toxicological properties it exhibits. Therefore, for the purpose of a hazard assessment, it may be best administered within the matrix of the fruit, which is the form that humans consume it.

What fruit causes Jamaican vomiting sickness?

5895f7e978275d0c4a000001_009

A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia. Achondroplasia is the most common type of genetic dwarfism. It is characterized by disproportionate short stature and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. Recent studies mapped the achondroplasia gene on chromosome region 4p16.3 and identified a common mutation in the gene encoding the fibroblast growth factor receptor 3 (FGFR3). In an analysis of 19 achondroplasia families from a variety of ethnic backgrounds we confirmed the presence of the G380R mutation in 21 of 23 achondroplasia chromosomes studied. In contrast, the G380R mutation was not found in any of the 8 hypochondroplasia chromosomes studied. Furthermore, linkage studies in a 3-generation family with hypochondroplasia show discordant segregation with markers in the 4p16.3 region suggesting that at least some cases of hypochondroplasia are caused by mutations in a gene other than FGFR3.

Mutation of which gene is associated with Achondroplasia?

52b2e498f828ad283c000010_003

Brigatinib Effective in ALK+ NSCLC. Results from a phase I/II trial indicate that the investigational ALK inhibitor brigatinib is active in patients with ALK-rearranged non-small cell lung cancer. Patients who had previously received crizotinib-as well as those who hadn't-responded to the drug, which was also active in patients with brain metastases.

What disease is the ALK tyrosine kinase associated with?

5a871a6861bb38fb24000009_001

Acute coronary syndromes: targeting inflammation-what has the VISTA-16 trial taught us? The VISTA-16 trial of varespladib, a secretory phospholipase A2 (sPLA2) inhibitor, in patients with an acute coronary syndrome was terminated prematurely owing to futility and a signal towards harm. Despite these discouraging results, therapies that target inflammation to modify pathways in atherogenesis remain an area of active investigation.

Which enzyme is inhibited by Varespladib?

56c1f00def6e39474100003f_001

The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. The 53BP1-dependent end-joining pathway plays a critical role in double strand break repair and is uniquely responsible for cellular sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We and others have investigated the downstream effectors of 53BP1, including replication timing regulatory factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP), in the past few years to elucidate how loss of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 patients. However, questions regarding the upstream regulation of the 53BP1 pathway remain unanswered. In this study, we identified the Tudor-interacting repair regulator (TIRR) that specifically associates with the ionizing radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable complex, which is required for their expression. Moreover, the 53BP1-TIRR complex dissociates after DNA damage, and this dissociation may be ataxia telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi resistance in BRCA1-deficient cells. Collectively, our data identified a novel 53BP1-TIRR complex in DNA damage response. TIRR may play both positive and negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and thus positively regulates 53BP1. On the other hand, its association with 53BP1 prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an inhibitor of 53BP1.

Which protein is regulated by Tudor interacting repair regulator (TIRR)?

5a774fdcfaa1ab7d2e000008_011

Transcription-associated mutation in Bacillus subtilis cells under stress. Adaptive (stationary phase) mutagenesis is a phenomenon by which nondividing cells acquire beneficial mutations as a response to stress. Although the generation of adaptive mutations is essentially stochastic, genetic factors are involved in this phenomenon. We examined how defects in a transcriptional factor, previously reported to alter the acquisition of adaptive mutations, affected mutation levels in a gene under selection. The acquisition of mutations was directly correlated to the level of transcription of a defective leuC allele placed under selection. To further examine the correlation between transcription and adaptive mutation, we placed a point-mutated allele, leuC427, under the control of an inducible promoter and assayed the level of reversion to leucine prototrophy under conditions of leucine starvation. Our results demonstrate that the level of Leu(+) reversions increased significantly in parallel with the induced increase in transcription levels. This mutagenic response was not observed under conditions of exponential growth. Since transcription is a ubiquitous biological process, transcription-associated mutagenesis may influence evolutionary processes in all organisms.

In which phase of cell cycle does stress-induced transcription-associated mutagenesis (TAM) occur?

5544de7a5beec11c10000005_001

Wilson's disease: update on integrated Chinese and Western medicine. Wilson's disease (WD), or hepatolenticular degeneration, is an autosomal recessive inheritance disorder of copper metabolism caused by ATP7B gene mutation. As WD is an inherited disease of the nervous system that is not curable; early diagnosis with early and life-long treatment leads to better prognoses. Currently, the recommended treatment for WD is integrated Chinese and Western medicine. A number of studies indicate that treatment of integrative medicine can not only enforce the de-copper effect but also improve liver function, intelligence, and other factors. This article reviewed in detail the advantages of WD treated with Chinese and Western medicine together.

What is the mode of inheritance of Wilson's disease?

52bf1b0a03868f1b06000009_003

Acrokeratosis paraneoplastica: Bazex syndrome. Bazex syndrome, or acrokeratosis paraneoplastica, is a cutaneous paraneoplastic syndrome characterized by psoriasiform lesions associated with, usually, a squamous cell carcinoma of the upper aerodigestive tract. We present a case of Bazex syndrome associated with metastatic cervical squamous cell carcinoma with an unknown primary. The features of the condition are discussed in the light of current knowledge.

Name synonym of Acrokeratosis paraneoplastica.

56bc751eac7ad10019000013_006

Multiple microRNAs regulate human FOXP2 gene expression by targeting sequences in its 3' untranslated region. BACKGROUND: Mutations in the human FOXP2 gene cause speech and language impairments. The FOXP2 protein is a transcription factor that regulates the expression of many downstream genes, which may have important roles in nervous system development and function. An adequate amount of functional FOXP2 protein is thought to be critical for the proper development of the neural circuitry underlying speech and language. However, how FOXP2 gene expression is regulated is not clearly understood. The FOXP2 mRNA has an approximately 4-kb-long 3' untranslated region (3' UTR), twice as long as its protein coding region, indicating that FOXP2 can be regulated by microRNAs (miRNAs). FINDINGS: We identified multiple miRNAs that regulate the expression of the human FOXP2 gene using sequence analysis and in vitro cell systems. Focusing on let-7a, miR-9, and miR-129-5p, three brain-enriched miRNAs, we show that these miRNAs regulate human FOXP2 expression in a dosage-dependent manner and target specific sequences in the FOXP2 3' UTR. We further show that these three miRNAs are expressed in the cerebellum of the human fetal brain, where FOXP2 is known to be expressed. CONCLUSIONS: Our results reveal novel regulatory functions of the human FOXP2 3' UTR sequence and regulatory interactions between multiple miRNAs and the human FOXP2 gene. The expression of let-7a, miR-9, and miR-129-5p in the human fetal cerebellum is consistent with their roles in regulating FOXP2 expression during early cerebellum development. These results suggest that various genetic and environmental factors may contribute to speech and language development and related neural developmental disorders via the miRNA-FOXP2 regulatory network.

Which gene is responsible for proper speech development?

5ace12be0340b9f058000007_014

[Difficulties associated with Lambert-Eaton syndrome]. INTRODUCTION: The diagnosis and treatment of the neurological paraneoplastic syndromes associated with lung cancer can pose a challenge both to general physicians and neurologists as well as pulmonologists. CASE REPORT: A 53 year-old heavy smoker presented with a Lambert-Eaton myasthenic syndrome (LEMS). Bronchoscopy was normal but radiological examinations revealed a lymph node in site 4R. The pathological diagnosis after mediastinoscopy was negative. Twenty-five months later, an opacity on chest X-ray led to a biopsy which revealed a squamous cell carcinoma. A lobectomy was performed for a pT2N0M0 lesion. A significant improvement of neurological symptoms was seen. The myasthenic syndrome reappeared 21 months later. A local and general relapse was diagnosed. The patient died 10 months later despite chemotherapy. CONCLUSION: LEMS occurs because of an immunological reaction against voltage-dependent calcium channels. LEMS is generally associated with small cell lung cancer occurring in three percent of cases. However, the case that we report shows the unusual association of LEMS with non small-cell lung cancer and highlights the difficulties associated in the management of this condition.

Which type of lung cancer is the most strongly associated with Lambert-Eaton syndrome?

5147c088d24251bc05000026_003

Extrachromosomal element capture and the evolution of multiple replication origins in archaeal chromosomes. In all three domains of life, DNA replication begins at specialized loci termed replication origins. In bacteria, replication initiates from a single, clearly defined site. In contrast, eukaryotic organisms exploit a multitude of replication origins, dividing their genomes into an array of short contiguous units. Recently, the multiple replication origin paradigm has also been demonstrated within the archaeal domain of life, with the discovery that the hyperthermophilic archaeon Sulfolobus has three replication origins. However, the evolutionary mechanism driving the progression from single to multiple origin usage remains unclear. Here, we demonstrate that Aeropyrum pernix, a distant relative of Sulfolobus, has two origins. Comparison with the Sulfolobus origins provides evidence for evolution of replicon complexity by capture of extrachromosomal genetic elements. We additionally identify a previously unrecognized candidate archaeal initiator protein that is distantly related to eukaryotic Cdt1. Our data thus provide evidence that horizontal gene transfer, in addition to its well-established role in contributing to the information content of chromosomes, may fundamentally alter the manner in which the host chromosome is replicated.

Do archaeal genomes contain one or multiple origins of replication?

52fe58f82059c6d71c00007a_005

The physiological target for LeuRS translational quality control is norvaline. The fidelity of protein synthesis depends on the capacity of aminoacyl-tRNA synthetases (AARSs) to couple only cognate amino acid-tRNA pairs. If amino acid selectivity is compromised, fidelity can be ensured by an inherent AARS editing activity that hydrolyses mischarged tRNAs. Here, we show that the editing activity of Escherichia coli leucyl-tRNA synthetase (EcLeuRS) is not required to prevent incorrect isoleucine incorporation. Rather, as shown by kinetic, structural and in vivo approaches, the prime biological function of LeuRS editing is to prevent mis-incorporation of the non-standard amino acid norvaline. This conclusion follows from a reassessment of the discriminatory power of LeuRS against isoleucine and the demonstration that a LeuRS editing-deficient E. coli strain grows normally in high concentrations of isoleucine but not under oxygen deprivation conditions when norvaline accumulates to substantial levels. Thus, AARS-based translational quality control is a key feature for bacterial adaptive response to oxygen deprivation. The non-essential role for editing under normal bacterial growth has important implications for the development of resistance to antimicrobial agents targeting the LeuRS editing site.

Which is the physiological target for LeuRS translational quality control?

56ae57350a360a5e4500000a_003

Tecfidera(®): an approach for repurposing. As a case study of patent coverage for a repurposed drug, Biogen Idec's approach for Tecfidera(®), an oral formulation of dimethyl fumarate, was analyzed. While mixtures of fumarates have been used for over 50 years to treat psoriasis, Tecifidera is approved for the treatment of relapsing-remitting multiple sclerosis. Biogen pursued claims to pharmaceutical formulations and useful doses for treating multiple sclerosis, an approach that is relevant to pharmaceutical lifecycle management in general. A survey of recent US, EP, and PCT patent applications indicate other companies are developing competing fumarate formulations. While it is possible to pursue secondary patents for compounds without composition of matter coverage, regulatory data exclusivity provides additional protection to delay competitors.

What is the drug Tecfidera used against?

5aa824a8fcf4565872000002_001

New anticoagulants: focus on venous thromboembolism. Anticoagulation is recommended for prophylaxis and treatment of venous thromboembolism (VTE) (deep vein thrombosis and pulmonary embolism) and/or arterial thromboembolism. The therapeutic arsenal of anticoagulants available to clinicians is mainly composed by unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux and oral vitamin K antagonists (VKA) (i.e. warfarin and acenocumarol). These anticoagulants are effective, but they require parenteral administration (UFH, LMWH, fondaparinux) and/or frequent anticoagulant monitoring (intravenous UFH, oral VKA). Novel anticoagulants in clinical testing include orally active direct factor II inhibitors [dabigatran etexilate (BIBR 1048), AZD0837)], parenteral direct factor II inhibitors (flovagatran sodium), orally active direct factor X inhibitors [rivaroxaban (BAY 59-7939), apixaban, betrixaban, YM150, DU-176b, LY-517717, GW813893, TAK-442, PD 0348292] and new parenteral FXa inhibitors [idraparinux, idrabiotaparinux (biotinilated idraparinux; SSR 126517), ultra-low-molecular-weight heparins (ULMWH: AVE5026, RO-14)]. These new compounds have the potential to complement heparins and fondaparinux for short-term anticoagulation and/or to replace VKA for long-term anticoagulation in most patients. Dabigatran and rivaroxaban have been the firsts of the new oral anticoagulants to be licensed for the prevention of VTE after hip and knee replacement surgery. In the present review, we discuss the pharmacology of new anticoagulants, the key points necessary for interpreting the results of studies on VTE prophylaxis and treatment, the results of clinical trials testing these new compounds and their potential advantages and drawbacks over existing therapies.

Which clotting factor is inhibited by betrixaban?

55200c606b348bb82c000013_097

Fibrosis of the thyroid gland caused by an IgG4-related sclerosing disease: three years of follow-up. Immunoglobulin G4-related sclerosing disease (IgG4-RSD) represents a recently identified inflammatory disorder in which infiltration of IgG4 plasma cells causes fibrosis in organs. While IgG4-RSD is well documented in the pancreas and other organs, it is poorly characterized in the thyroid gland. We report a case of a 48-year-old female with a fibrotic thyroid mass associated with a retroperitoneal fibrosis. Diagnosed early as Riedel disease, the high serum IgG4, immunohistopathology and decreased fibrosis with corticosteroid therapy, finally confirm for the first time, the origin of IgG4-RSD fibrosis of the thyroid.

Which antibodies cause Riedel thyroiditis?

56c1f040ef6e394741000055_011

Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.

What is the target of daratumumab?

5880aef4c872c95565000001_041

Arabidopsis homologs of components of the SWR1 complex regulate flowering and plant development. The SWR1 complex (SWR1C) in yeast catalyzes the replacement of nucleosomal H2A with the H2AZ variant, which ensures full activation of underlying genes. We compared the phenotype of mutants in the homologs of SWR1C components in Arabidopsis thaliana. Mutations in Arabidopsis SWC6 (AtSWC6), SUPPRESSOR OF FRIGIDA 3 (SUF3) and PHOTOPERIOD-INDEPENDENT EARLY FLOWERING 1 (PIE1), homologs of SWC6, ARP6 and SWR1, respectively, caused similar developmental defects, including leaf serration, weak apical dominance, flowers with extra petals and early flowering by reduction in expression of FLOWERING LOCUS C (FLC), a strong floral repressor. Chromatin immunoprecipitation assays showed that AtSWC6 and SUF3 bind to the proximal region of the FLC promoter, and protoplast transfection assays showed that AtSWC6 colocalizes with SUF3. Protein interaction analyses suggested the formation of a complex between PIE1, SUF3, AtSWC6 and AtSWC2. In addition, H2AZ, a substrate of SWR1C, interacts with both PIE1 and AtSWC2. Finally, knockdown of the H2AZ genes by RNA interference or artificial microRNA caused a phenotype similar to that of atswc6 or suf3. Our results strongly support the presence of an SWR1C-like complex in Arabidopsis that ensures proper development, including floral repression through full activation of FLC.

Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?

58a6db8660087bc10a00002c_025

Recent developments in the diagnosis of Marfan syndrome and related disorders. Marfan syndrome is a multisystem disorder of connective tissue that is inherited in an autosomal dominant fashion, and results from mutation of the FBN1 gene on human chromosome 15. There are a number of conditions of the connective tissue with a similar phenotype that can be confused with Marfan syndrome. Modifications of the diagnostic criteria have recently been published, facilitating the differentiation of Marfan syndrome from these conditions. It is still difficult to use modern genetic testing for diagnosis because Marfan syndrome can be caused by many different mutations in FBN1, a large gene with 65 coding segments, while mutations in other genes can cause overlapping phenotypes. Several clinical trials of drug therapy, including the antihypertensive drug losartan, are in progress.

Which gene mutations cause the Marfan syndrome?

58d8e6818acda3452900000a_023

Paediatric investigation plans for pain: painfully slow! PURPOSE: To examine the early impact of the Paediatric Regulation, which entered into force in Europe on 27 January 2007, on the development of pharmaceutical drugs in the therapeutic field of pain submitted to the Paediatric Committee (PDCO) and to the European Medicines Agency (EMA). METHODS: Paediatric Investigations Plans (PIPs) submitted with a Decision (outcome) reached between September 2007 and March 2010 were included in the analysis. RESULTS: Of the 17 Paediatric Investigation Plans submitted, 14 have resulted in an EMA Decision, 3 were withdrawn by the applicants, 8 were granted a full waiver from development, and 1 resulted in a negative opinion. Decisions as issued included 15 clinical trials, with at least 1,282 children to be recruited into studies across five different products. Neonates were included in four of the products. CONCLUSIONS: The small number of submissions indicates a lack of new drugs being developed for the management of pain. Ethical concerns that too many vulnerable children will be recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use. Now is an opportune time for clinicians, academics, learned societies and industry to collaborate for the benefit of children in pain.

How many clinical trials for off-label drugs in neonates are cited in the literature.

5150b807d24251bc05000072_001

Septin ring assembly is regulated by Spt20, a structural subunit of the SAGA complex. Accurate cell division requires the proper assembly of high-order septin structures. In fission yeast (Schizosaccharomyces pombe), Spn1-Spn4 are assembled into a primary septin ring at the division site, and the subsequent recruitment of Mid2 to the structure results in a stable septin ring. However, not much is known about the regulation of this key process. Here, we found that deletion of Spt20, a structural subunit of the Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional activation complex, caused a severe cell separation defect. The defect was mainly due to impaired septin ring assembly, as 80% of spt20Δ cells lost septin rings at the division sites. Spt20 regulates septin ring assembly partially through the transcriptional activation of mid2(+). Spt20 also interacted with Spn2 and Mid2 in vitro and was associated with other components of the ring in vivo. Spt20 colocalized with the septin ring, but did not separate when the septin ring split. Importantly, Spt20 regulated the stability of the septin ring and was required for the recruitment of Mid2. The transcription-dependent and -independent roles of Spt20 in septin ring assembly highlight a multifaceted regulation of one process by a SAGA subunit.

What does the SAGA complex acronym stands for?

56b76f496e3f8eaf4c000002_002

Molecular basis of congenital hypopigmentary disorders in humans: a review. Many specific gene products are sequentially made and utilized by the melanocyte as it emigrates from its embryonic origin, migrates into specific target sites, synthesizes melanin(s) within a specialized organelle, transfers pigment granules to neighboring cells, and responds to various exogenous cues. A mutation in many of the respective encoding genes can disrupt this process of melanogenesis and can result in hypopigmentary disorders. Following are examples highlighting this scenario. A subset of neural crest derived cells emigrate from the dorsal surface of the neural tube, become committed to the melanoblast lineage, and are targeted along the dorsal lateral pathway. The specific transcription factors PAX3 and MITF (microphthalmia transcription factor) appear to play a regulatory role in early embryonic development of the pigment system and in associated diseases (the Waardenburg syndromes). During the subsequent development and commitment of the melanoblast, concomitant expression of the receptors for fibroblasts growth factor (FGFR2), endothelin-B (EDNRB), and steel factor (cKIT) also appears essential for the continued survival of migrating melanoblasts. Lack or dysfunction of these receptors result in Apert syndrome, Hirschsprung syndrome and piebaldism, respectively. Once the melanocyte resides in its target tissue, a plethora of melanocyte specific enzymes and structural proteins are coordinately expressed to form the melanosome and to convert tyrosine to melanin within it. Mutations in the genes encoding these proteins results in a family of congenital hypopigmentary diseases called oculocutaneous albinism (OCA). The tyrosinase gene family of proteins (tyrosinase, TRP1, and TRP2) regulate the type of eumelanin synthesized and mutations affecting them result in OCA1, OCA3, and slaty (in the murine system), respectively. The P protein, with 12 transmembrane domains localized to the melanosome, has no assigned function as of yet but is responsible for OCA2 when dysfunctional. There are other genetically based syndromes, phenotypically resembling albinism, in which the synthesis of pigmented melanosomes, as well as specialized organelles of other cell types, is compromised. The Hermansky-Pudlak syndrome (HPS) and the Chediak-Higashi syndrome (CHS) are two such disorders. Eventually, the functional melanocyte must be maintained in the tissue throughout life. In some cases it is lost either normally or prematurely. White hair results in the absence of melanocytes repopulating the germinative hair follicle during subsequent anagen stages. Vitiligo, in contrast, results from the destruction and removal of the melanocyte in the epidermis and mucous membranes.

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

58cbb98c02b8c60953000034_106

[Regulation of melanogenesis: the role of cAMP and MITF]. The article presents the melanogenesis pathway and the role of cyclic adenosine monophosphate (cAMP) and microphthalmia transcription factor (MITF) in regulation of this process. Products of melanogenesis are eu- and/or pheomelanins synthesized in a multistage process of tyrosine oxidation and polymerization. The conversions require the presence of tyrosinase (TYR, key enzyme), tyrosine hydroxylase isoform I (THI) and tyrosinase related proteins (TRP1 and TRP2). Many types of signal molecules and transcription factors participate in regulation of melanin synthesis, but the most important are cAMP and MITF. cAMP is the second messenger in the intracellular signal cascade, which is synthesized from adenosine triphosphate (ATP) by adenylyl cyclase, activated among others by the melanocortin receptor and the αS subunit of G protein. The signal molecule cAMP regulates MITF, TYR, THI, GTP-cyclohydroxylase I (GTP-CHI) transcription and phenylalanine hydroxylase (PAH) phosphorylation at Ser16 by protein kinase A (PKA). Mutations of genes encoding proteins belonging to the cAMP signal cascade may lead to McCune-Albright and Carney syndromes. MITF is one of the most important nuclear transcription factors regulating melanogenesis. Currently 10 isoforms of human MITF are known, but in melanocytes only MITF-M, MITF-Mdel, MITF-A and MITF-H occur. MITF transcription factor regulates melanogenesis by activation of tyrosinase, TRP1 and TRP2 transcription. It also affects expression of other factors regulating melanosome maturation, biogenesis and transport. Moreover, it regulates melanocyte proliferation and protection against apoptosis. Mutations of the MITF gene may lead to hereditary diseases: Waardenburg type II and Tietz syndromes.

Which mutated gene is associated with Waardenburg and Tietz syndromes?

58a57f9460087bc10a00001f_021

A polymorphism study of the human Agouti gene and its association with MC1R. To determine whether the Agouti Signalling Protein (ASP) gene is associated with skin and hair coloration in humans, the complete coding region of ASP was screened for polymorphisms. Analysis of ASP in Caucasian, African-American, Spanish Basque, Hispanic, Apache and Australian Aboriginal populations revealed no amino acid substitutions. A single polymorphism in the 3' untranslated region occurred at a frequency of 0.2 in African-Americans. Variants of the Melanocortin 1 Receptor (MC1R) gene have been found to be associated with red hair and fair skin in humans. Red hair individuals are usually compound heterozygotes or homozygous for one of a number of MC1R polymorphisms associated with red hair. Some individuals however are heterozygous for only one of these polymorphisms and dizygotic twins can be concordant for MC1R variants but discordant for hair colour. A recent study has also identified rare redheads carrying no MC1R variants indicating that polymorphisms of the human MC1R gene are required but not sufficient for the red hair phenotype. To address the question of whether ASP also contributes to the red hair phenotype, individuals previously identified as having unexpected MC1R genotypes were screened for polymorphisms at the ASP locus. No polymorphisms were found in any of these individuals. Results indicate that the human ASP gene is unlikely to function in normal human pigmentation in the same way as MC1R.

Which gene is responsible for red hair?

5ace19420340b9f05800000a_041

libFLASM: a software library for fixed-length approximate string matching. BACKGROUND: Approximate string matching is the problem of finding all factors of a given text that are at a distance at most k from a given pattern. Fixed-length approximate string matching is the problem of finding all factors of a text of length n that are at a distance at most k from any factor of length ℓ of a pattern of length m. There exist bit-vector techniques to solve the fixed-length approximate string matching problem in time [Formula: see text] and space [Formula: see text] under the edit and Hamming distance models, where w is the size of the computer word; as such these techniques are independent of the distance threshold k or the alphabet size. Fixed-length approximate string matching is a generalisation of approximate string matching and, hence, has numerous direct applications in computational molecular biology and elsewhere. RESULTS: We present and make available libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching under both the edit and the Hamming distance models. Moreover we describe how fixed-length approximate string matching is applied to solve real problems by incorporating libFLASM into established applications for multiple circular sequence alignment as well as single and structured motif extraction. Specifically, we describe how it can be used to improve the accuracy of multiple circular sequence alignment in terms of the inferred likelihood-based phylogenies; and we also describe how it is used to efficiently find motifs in molecular sequences representing regulatory or functional regions. The comparison of the performance of the library to other algorithms show how it is competitive, especially with increasing distance thresholds. CONCLUSIONS: Fixed-length approximate string matching is a generalisation of the classic approximate string matching problem. We present libFLASM, a free open-source C++ software library for solving fixed-length approximate string matching. The extensive experimental results presented here suggest that other applications could benefit from using libFLASM, and thus further maintenance and development of libFLASM is desirable.

Which library is used for fixed-length approximate string matching?

587f7a69d8d850a152000001_002

Phase 1 study in Japan of siltuximab, an anti-IL-6 monoclonal antibody, in relapsed/refractory multiple myeloma. Siltuximab, a chimeric monoclonal antibody with high affinity and specificity for interleukin-6, has been shown to enhance anti-multiple myeloma activity of bortezomib and corticosteroid in vitro. We evaluated the safety, pharmacokinetics, immunogenicity, and antitumor effect of siltuximab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma. This open-label, phase 1, dose-escalating study used two doses of siltuximab: 5.5 and 11.0 mg/kg (administered on day 1 of each 21-day cycle). In total, nine patients were treated. The most common grade 3/4 adverse events, lymphopenia (89 %) and thrombocytopenia (44 %), occurred in patients receiving both doses of siltuximab; however, no dose-limiting toxicities (DLTs) were observed. Following intravenous administration of siltuximab at 5.5 and 11.0 mg/kg, the maximum serum concentration and the area under the curve from 0 to 21 days and from 0 to infinity increased in an approximately dose-proportional manner. Mean half-life, total systemic clearance, and volume of distribution were similar at doses of 5.5 and 11.0 mg/kg. Across both doses, six of the nine patients had complete or partial response (22 and 44 %, respectively). In conclusion, as no DLT was observed, the recommended dose for this combination is 11.0 mg/kg once every 3 weeks. The study is registered at http://www.clinicaltrials.gov as NCT01309412.

Which interleukin is blocked by Siltuximab?

56c1f02aef6e39474100004b_001

[Clincal features and treatment of multiple myeloma]. The diagnosis and treatment of multiple myeloma (MM) are progressing continuously. This article aims at summarizing the current status in the diagnosis and treatment of MM, emphasizing a clinical point of view. Prognostic factors can be determined by clinical parameters, molecular analyses and patient characteristics (e.g. age and comorbidities). The international staging system (ISS) and cytogenetics, such as the high-risk aberrations 17p deletion, translocation (4;14) and insertion 1q21 > 2 copies, are key factors in risk stratification of MM patients. Induction therapy based on novel agents, namely bortezomib, followed by subsequent high-dose melphalan and autologous stem cell transplantation is considered the standard of care for younger, newly diagnosed MM patients ( < 70 years). Transplant-ineligible patients should receive thalidomide or bortezomib-based chemotherapy. The combination of bortezomib, melphalan and prednisone (VMP) was shown to significantly improve overall survival (OS) compared to melphalan and prednisone (MP, 56.4 vs. 43.1 months, p = < 0.01). Recent results suggest that lenalidomide-based therapy not incorporating alkylating agents might be a competitive alternative with a favorable toxicity profile for transplant-ineligible patients. Maintenance therapies are of increasing clinical significance in MM as they have the ability to prolong overall survival; however, thalidomide maintenance therapy should not be used in MM patients with high-risk cytogenetics as it shortens OS. Refractory or relapsed MM treatment continues to improve with the development of second and third generation immunomodulatory agents and proteasome inhibitors. For example, pomalidomide and dexamethasone vs. high-dose dexamethasone significantly improved OS (12.7 vs. 8.1 months, p = 0.03). Novel therapy strategies include targeted and stroma-directed approaches. Antibodies targeting CS-1 (elotuzumab) and CD38 (daratumumab) in particular are currently undergoing advanced clinical phase II/III trials.

Which molecule is targeted by Daratumumab?

56c04412ef6e39474100001b_026

Lipopolysaccharide (LPS) induces the apoptosis and inhibits osteoblast differentiation through JNK pathway in MC3T3-E1 cells. Bone degradation is a serious complication of chronic inflammatory diseases such as septic arthritis, osteomyelitis, and infected orthopedic implant failure. Up to date, effective therapeutic treatments for bacteria-caused bone destruction are limited. In our previous study, we found that LPS promoted osteoclast differentiation and activity through activation of mitogen-activated protein kinases (MAPKs) pathway such as c-Jun N-terminal kinases (JNK) and extracellular signal regulated kinase (ERK1/2). The current study was to evaluate the mechanism of LPS on the apoptosis and osteoblast differentiation in MC3T3-E1 cells. MC3T3-E1 osteoblasts were non-treated, treated with LPS. After treatment, the cell viability, the activity of alkaline phosphatase (ALP) and caspase-3 were measured. The expressions of osteoblast-specific genes and Bax, Bcl-2, and caspase-3 were determined by real-time quantitative polymerase chain reaction (qPCR). Protein levels of Bax, Bcl-2, caspase-3, and phosphorylation of MAPKs were measured using Western blotting assays. The MAPK signaling pathway was blocked by pretreatment with JNK inhibitor SP600125. LPS treatment induced a significant decrease in cell metabolism, viability, and ALP activity in MC3T3-E1 cells. LPS also significantly decreased mRNA expressions of osteoblast-related genes in MC3T3-E1 cells. On the other hand, LPS significantly upregulated mRNA expressions and protein levels of Bax and caspase-3 as well as activation of caspase-3, whereas decreased Bcl-2 expression in MC3T3-E1 cells. Furthermore, LPS significantly promoted MAPK pathway including the phosphorylation of JNK and the phosphorylation of ERK1/2; moreover, pretreatment with JNK inhibitor not only attenuated both of phosphorylation-JNK and ERK1/2 enhanced by LPS in MC3T3-E1 cells, but also reversed the downregulated expressions of osteoblast-specific genes including ALP and BSP induced by LPS. In conclusion, LPS could induce osteoblast apoptosis and inhibit osteoblast differentiation via activation of JNK pathway.

Which MAP kinase phosphorylates the transcription factor c-jun?

5518e7da622b194345000004_007

Facial nerve preservation surgery for koos grade 3 and 4 vestibular schwannomas. BACKGROUND: Facial nerve preservation surgery for large vestibular schwannomas is a novel strategy for maintaining normal nerve function by allowing residual tumor adherent to this nerve or root-entry zone. OBJECTIVE: To report, in a retrospective study, outcomes for large Koos grade 3 and 4 vestibular schwannomas. METHODS: After surgical treatment for vestibular schwannomas in 52 patients (2004-2013), outcomes included extent of resection, postoperative hearing, and facial nerve function. Extent of resection defined as gross total, near total, or subtotal were 7 (39%), 3 (17%), and 8 (44%) in 18 patients after retrosigmoid approaches, respectively, and 10 (29.5%), 9 (26.5%), and 15 (44%) for 34 patients after translabyrinthine approaches, respectively. RESULTS: Hearing was preserved in 1 (20%) of 5 gross total, 0 of 2 near-total, and 1 (33%) of 3 subtotal resections. Good long-term facial nerve function (House-Brackmann grades of I and II) was achieved in 16 of 17 gross total (94%), 11 of 12 near-total (92%), and 21 of 23 subtotal (91%) resections. Long-term tumor control was 100% for gross total, 92% for near-total, and 83% for subtotal resections. Postoperative radiation therapy was delivered to 9 subtotal resection patients and 1 near-total resection patient. Follow-up averaged 33 months. CONCLUSION: Our findings support facial nerve preservation surgery in becoming the new standard for acoustic neuroma treatment. Maximizing resection and close postoperative radiographic follow-up enable early identification of tumors that will progress to radiosurgical treatment. This sequential approach can lead to combined optimal facial nerve function and effective tumor control rates.

Which disease can be categorized using the Koos grading system?

5886519c3b87a8a738000007_004

Distinction between upper and lower gastrointestinal perforation: usefulness of the periportal free air sign on computed tomography. PURPOSE: To evaluate the usefulness of the periportal free air (PPFA) sign on computed tomography (CT) to distinguish upper from lower gastrointestinal (GI) tract perforation. MATERIALS AND METHODS: During a 30-month period, we retrospectively analyzed abdominal CT images of 53 consecutive patients with surgically proven GI tract perforation. We divided the patients into two groups, i.e. upper and lower GI tract perforation groups. According to the distribution of free air, we divided the peritoneal cavity into supramesocolic compartment and inframesocolic compartment. We observed the presence or absence of free air in each compartment in each group. When there was free air in the periportal area, it was defined as periportal free air (PPFA) and the sign was positive. To evaluate the usefulness of the PPFA sign, we compared the PPFA sign with the falciform ligament sign and the ligamentum teres sign, both of which are well-known CT signs of pneumoperitoneum. Statistical analyses were performed with univariate and multivariate analyses using SPSS version 11.5 for significant findings among the CT signs. RESULTS: Free air was seen in supramesocolic compartment in 29 of 30 (97%) patients in the upper GI perforation group and in 17 of 23 (74%) in the lower GI perforation group. Free air in inframesocolic compartment did not show significant difference in either group (p=.16). The PPFA sign was seen in 28 of 30 (93%) patients with upper GI tract perforation, but in only 8 of 23 (35%) patients with lower GI tract perforation (p<.0001). The falciform ligament sign was seen in 24 of 30 (80%) patients with upper GI tract perforation and in 10 of 23 (43%) patients with lower GI tract perforation (p=.020). The ligamentum teres sign was seen in 16 of 30 (53%) patients with upper GI tract perforation and in 2 of 23 (8%) patients with lower GI tract perforation (p=.008). Multivariate logistic regression analysis showed that the PPFA sign was the only variable, which adjusted odds ratio of 15.5 (p=.002). CONCLUSION: The PPFA sign is a useful finding which can help to distinguish upper from lower GI tract perforation. When this sign is present, upper GI tract perforation is strongly suggested.

Falciform ligament sign is characteristic to which disease?

5a72329e2dc08e987e000006_006

Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes. Focal cortical dysplasias are a well-recognized cause of medically intractable seizures. The clinical relevance of certain subgroups of the International League Against Epilepsy (ILAE) classification scheme remains to be determined. The aim of the present work is to assess the effect of the focal cortical dysplasia type Ib and Ic histologic subtypes on surgical outcome with respect to seizure frequency. This study also provides an opportunity to compare the predictive value of the ILAE and Palmini et al classification schemes with regard to the type I focal cortical dysplasias. We retrospectively reviewed 91 focal cortical dysplasia patients (55% female; median age: 19 years (interquartile range 8-34); median seizure duration: 108 months (interquartile range 36-204)) with chronic epilepsy who underwent surgery. We compared the pathological subtypes, evaluating the patients' post-surgical outcome with respect to seizure frequency according to the Engel's classification and the ILAE outcome classification. Both the ILAE classification scheme and Palmini et al classification scheme were utilized to classify the histologic subtype. Using χ(2) and Fisher's exact tests, we compared the post-surgical outcomes among these groups. Of the 91 patients, there were 50 patients with ILAE focal cortical dysplasia type Ib, 41 with ILAE focal cortical dysplasia type Ic, 63 with Palmini et al focal cortical dysplasia type IA, and 28 with Palmini et al focal cortical dysplasia type IB. After surgery, 44 patients (48%) were seizure-free. Crude analysis revealed no significant difference between patients with subtypes of ILAE focal cortical dysplasia type I or Palmini et al focal cortical dysplasia type I concerning postoperative outcome according to the Engel and ILAE scoring systems on seizure frequency. Our findings revealed no significant difference concerning surgical outcome with respect to seizure frequency for the histologic subtypes of ILAE focal cortical dysplasia type I (Ib vs Ic) or Palmini et al focal cortical dysplasia type I (IA vs IB). In isolation, the histologic subtype of focal cortical dysplasia type I does not appear predictive of postoperative outcome.

Which disorder is rated by Palmini classification?

56c1f020ef6e394741000047_013

[Paraneoplastic hypoglycemia: The hopes of pathophysiological documentation]. Doege-Potter syndrome is a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. These tumors are rare and usually asymptomatic. The syndrome of hypoglycemia is seen in less than 5% of the cases, and the associated tumors are large with a high mitotic rate. The cause of hypoglycemia is related to insulin-like growth factors produced by these tumors called "big" IGF-2. Several biological tests can demonstrate the increase of "big" IGF-2 plasma levels confirming the diagnosis of non-islet cell tumor induced hypoglycemia. The diagnosis is suggested by imaging but diagnostic confirmation is provided by the surgery, which remains the treatment of choice. Resection in many cases is the cure leading to hypoglycemia resolution. Recurrences and malignant transformations are possible which imposes a long-term monitoring. We report a case with relapsed malignant pleural fibrous tumor for which the pathophysiological mechanism of hypoglycemia could be documented as a paraneoplastic syndrome.

What is the most common feature of the Doege–Potter syndrome?

5a761ac3aacfb9cd4c000002_003

Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Melanin pigmentation protects the skin from the damaging effects of ultraviolet radiation (UVR). There are two types of melanin, the red phaeomelanin and the black eumelanin, both of which are present in human skin. Eumelanin is photoprotective whereas phaeomelanin, because of its potential to generate free radicals in response to UVR, may contribute to UV-induced skin damage. Individuals with red hair have a predominance of phaeomelain in hair and skin and/or a reduced ability to produce eumelanin, which may explain why they fail to tan and are at risk from UVR. In mammals the relative proportions of phaeomelanin and eumelanin are regulated by melanocyte stimulating hormone (MSH), which acts via its receptor (MC1R), on melanocytes, to increase the synthesis of eumelanin and the product of the agouti locus which antagonises this action. In mice, mutations at either the MC1R gene or agouti affect the pattern of melanogenesis resulting in changes in coat colour. We now report the presence of MC1R gene sequence variants in humans. These were found in over 80% of individuals with red hair and/or fair skin that tans poorly but in fewer than 20% of individuals with brown or black hair and in less than 4% of those who showed a good tanning response. Our findings suggest that in humans, as in other mammals, the MC1R is a control point in the regulation of pigmentation phenotype and, more importantly, that variations in this protein are associated with a poor tanning response.

Which gene is responsible for red hair?

5ace19420340b9f05800000a_001

Marfan's syndrome with aortic valve endocarditis. Marfans syndrome is an Autosomal dominant disorder of the connective tissues resulting in abnormalities of the musculoskeletal system, cardiovascular system and eyes. It has a prevalence of 1 in 100,000 population1 and occurs in all ethnic groups. It may be familial or due to new mutation (30%), in the fibrillin gene on arm of chromosome 15. It is estimated that one person in every 3000-5000 has Marfans syndrome may have cardiovascular abnormalities and may be complicated by infective endocartditis. About 90% of Marfan patients will develop cardiac complications2. The patient under discussion has musculoskeletal (Tall stature, reduced upper-lower segment ratio, arm-span to height ratio > 1.05, high arched palate) and Cardiovascular features (Severe aortic regurgitation complicated with infective endocarditis).

What tissue is commonly affected in Marfan's syndrome

58dd0dde8acda34529000027_003

Peroxiredoxin 2 and peroxide metabolism in the erythrocyte. Peroxiredoxin 2 (Prx2) is an antioxidant enzyme that uses cysteine residues to decompose peroxides. Prx2 is the third most abundant protein in erythrocytes, and competes effectively with catalase and glutathione peroxidase to scavenge low levels of hydrogen peroxide, including that derived from hemoglobin autoxidation. Low thioredoxin reductase activity in the erythrocyte is able to keep up with this basal oxidation and maintain the Prx2 in its reduced form, but exposure to exogenous hydrogen peroxide causes accumulation of the disulfide-linked dimer. The high cellular concentration means that although turnover is slow, erythrocyte Prx2 can act as a noncatalytic scavenger of hydrogen peroxide and a sink for hydrogen peroxide before turnover becomes limiting. The consequences of Prx2 oxidation for the erythrocyte are not well characterized, but mice deficient in this protein develop severe hemolytic anemia associated with Heinz body formation. Prx2, also known as calpromotin, regulates ion transport by associating with the membrane and activating the Gárdos channel. How Prx2 redox transformations are linked to membrane association and channel activation is yet to be established. In this review, we discuss the functional properties of Prx2 and its role as a major component of the erythrocyte antioxidant system.

What type of enzyme is peroxiredoxin 2 (PRDX2)?

52bf1f1303868f1b06000014_006

Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery. BACKGROUND: Plasma kallikrein plays a major role in the contact (kallikrein-kinin) cascade producing bradykinin. Bradykinin is a vasodilator, which increases vascular permeability, activates inflammation and produces pain. Plasma kallikrein is also crosslinked to the coagulation system and the complement cascade. OBJECTIVE: Ecallantide (DX-88) is a potent and specific inhibitor of plasma kallikrein. Ecallantide is a recombinantly produced and engineered small protein based on the first Kunitz domain of human tissue factor pathway inhibitor. It was identified through phage display technology. METHODS: The search terms 'ecallantide', 'DX-88' and 'hereditary angioedema' were entered into Pubmed/Medline, ClinicalTrials and Google. RESULTS/CONCLUSION: At present, the drug is being studied for two major indications. First, the results for the treatment of hereditary angioedema are promising. Second, a prospective randomised multi-centre trial for the reduction of blood loss during on-pump cardiothoracic surgery will be terminated in October 2008.

DX-88 is investigational name of which drug?

54f1e031c409818c32000001_005

p73 plays a role in erythroid differentiation through GATA1 induction. The TP73 gene gives rise to transactivation domain-p73 isoforms (TAp73) as well as DeltaNp73 variants with a truncated N terminus. Although TAp73alpha and -beta proteins are capable of inducing cell cycle arrest, apoptosis, and differentiation, DeltaNp73 acts in many cell types as a dominant-negative repressor of p53 and TAp73. It has been proposed that p73 is involved in myeloid differentiation, and its altered expression is involved in leukemic degeneration. However, there is little evidence as to which p73 variants (TA or DeltaN) are expressed during differentiation and whether specific p73 isoforms have the capacity to induce, or hinder, this differentiation in leukemia cells. In this study we identify GATA1 as a direct transcriptional target of TAp73alpha. Furthermore, TAp73alpha induces GATA1 activity, and it is required for erythroid differentiation. Additionally, we describe a functional cooperation between TAp73 and DeltaNp73 in the context of erythroid differentiation in human myeloid cells, K562 and UT-7. Moreover, the impaired expression of GATA1 and other erythroid genes in the liver of p73KO embryos, together with the moderated anemia observed in p73KO young mice, suggests a physiological role for TP73 in erythropoiesis.

How many TAp73 isoforms have been identified in humans?

5173bdb38ed59a060a000020_055

MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. The basic-helix-loop-helix-leucine zipper (bHLHZip) protein MITF (microphthalmia-associated transcription factor) is a master regulator of melanocyte development. Mutations in the MITF have been found in patients with the dominantly inherited hypopigmentation and deafness syndromes Waardenburg syndrome type 2A (WS2A) and Tietz syndrome (TS). Additionally, both somatic and germline mutations have been found in MITF in melanoma patients. Here, we characterize the DNA-binding and transcription activation properties of 24 MITF mutations found in WS2A, TS and melanoma patients. We show that most of the WS2A and TS mutations fail to bind DNA and activate expression from melanocyte-specific promoters. Some of the mutations, especially R203K and S298P, exhibit normal activity and may represent neutral variants. Mutations found in melanomas showed normal DNA-binding and minor variations in transcription activation properties; some showed increased potential to form colonies. Our results provide molecular insights into how mutations in a single gene can lead to such different phenotypes.

Which mutated gene is associated with Waardenburg and Tietz syndromes?

58a57f9460087bc10a00001f_019

Stable carbon isotopes and the study of prehistoric human diet. Mass spectrometric analysis of the stable carbon isotope composition (13C/12C or delta 13C) of bone collagen from human remains recovered at archaeological sites provides a direct chemical method for investigating dietary patterns of prehistoric human populations. This methodology is based on the facts that (1) different food items within the human diet have distinct delta 13C values, and (2) the delta 13C value of human bone collagen is determined by the delta 13C value of the diet. Studies of the development of subsistence patterns based on corn agriculture, one of the most significant developments in North American prehistory, can benefit from the use of stable carbon isotope techniques because corn has a high delta 13C value relative to other components of the human diet. Measurements of delta 13C of bone collagen from prehistoric human skeletal remains from southeastern Missouri and northeastern Arkansas indicate that intensive corn agriculture began in this region around A.D. 1000, that the incorporation of corn into the human diet was a rapid phenomenon, and that 35 to 77% of the human diet from A.D. 1000 to A.D. 1600 consisted of corn. Results from an isochronous population in southeastern South Dakota (A.D. 1400) suggest that 78 to 90% of the diet of this group consisted of corn, with no difference between males and females. Coupled with more traditional archaeological methods, stable carbon isotope analysis of bone collagen can significantly enhance reconstruction of dietary patterns of prehistoric humans.

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

55054f8af73303d458000002_019

Clinics in diagnostic imaging (175). Corpus callosum glioblastoma multiforme (GBM): butterfly glioma. A 54-year-old man presented with change in behaviour, nocturnal enuresis, abnormal limb movement and headache of one week's duration. The diagnosis of butterfly glioma (glioblastoma multiforme) was made based on imaging characteristics and was further confirmed by biopsy findings. As the corpus callosum is usually resistant to infiltration by tumours, a mass that involves and crosses the corpus callosum is suggestive of an aggressive neoplasm. Other neoplastic and non-neoplastic conditions that may involve the corpus callosum and mimic a butterfly glioma, as well as associated imaging features, are discussed.

What is the most common histological diagnosis of "butterfly glioma"?

5a7234352dc08e987e000007_001

First trimester maternal serum PAPP-A and free β-HCG levels in hyperemesis gravidarum. OBJECTIVE: To evaluate whether hyperemesis gravidarum (HG) affects first-trimester maternal serum PAPP-A and free β-hCG levels. METHOD: An observational study was conducted in 115 cases of HG and 110 control pregnancies who attended the first-trimester prenatal screening program between January 2006 and July 2010. RESULTS: Maternal serum TSH levels were lower and free T4, and transaminases (ALT, AST) levels were higher in pregnancies complicated with HG compared with controls (p < 0.05 for all). In HG cases, median values of maternal serum PAPP-A were significantly higher with respect to normal pregnancies (1.2 vs 1.0 MoM; p = 0.009). Similarly, median values of free β-hCG were 1.3 MoM in HG pregnancies and 1.0 MoM in controls (p = 0.006). Multivariate analysis revealed that PAPP-A and hCG were independently associated with HG after controlling for TSH, free T4, AST, and ALT. CONCLUSION: HG is associated with elevated levels of PAPP-A and free β-hCG, and such changes are independent of serum indicators of thyroid and liver function.

Which protein is associated with hyperemesis gravidarum during pregrancy?

58da1aa08acda34529000012_002

Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Astrocytomas are the leading cause of brain cancer in humans. Because these tumours are highly infiltrative, current treatments that rely on targeting the tumour mass are often ineffective. A mouse model for astrocytoma would be a powerful tool for dissecting tumour progression and testing therapeutics. Mouse models of astrocytoma have been designed to express oncogenic proteins in astrocytes, but have had limited success due to low tumour penetrance or limited tumour progression. We present here a mouse model of astrocytomas involving mutation of two tumour-suppressor genes, Nf1 and Trp53. Humans with mutations in NF1 develop neurofibromatosis type I (NF1) and have increased risk of optic gliomas, astrocytomas and glioblastomas. The TP53 tumour suppressor is often mutated in a subset of astrocytomas that develop at a young age and progress slowly to glioblastoma (termed secondary glioblastomas, in contrast to primary glioblastomas that develop rapidly de novo). This mouse model shows a range of astrocytoma stages, from low-grade astrocytoma to glioblastoma multiforme, and may accurately model human secondary glioblastoma involving TP53 loss. This is the first reported mouse model of astrocytoma initiated by loss of tumour suppressors, rather than overexpression of transgenic oncogenes.

Which is the gene mutated in type 1 neurofibromatosis?

5343fc1aaeec6fbd07000003_026

SERCA2a: a prime target for modulation of cardiac contractility during heart failure. Heart failure is one of the leading causes of sudden death in developed countries. While current therapies are mostly aimed at mitigating associated symptoms, novel therapies targeting the subcellular mechanisms underlying heart failure are emerging. Failing hearts are characterized by reduced contractile properties caused by impaired Ca(2+) cycling between the sarcoplasm and sarcoplasmic reticulum (SR). Sarcoplasmic/ endoplasmic reticulum Ca(2+)ATPase 2a (SERCA2a) mediates Ca(2+) reuptake into the SR in cardiomyocytes. Of note, the expression level and/or activity of SERCA2a, translating to the quantity of SR Ca(2+) uptake, are significantly reduced in failing hearts. Normalization of the SERCA2a expression level by gene delivery has been shown to restore hampered cardiac functions and ameliorate associated symptoms in pre-clinical as well as clinical studies. SERCA2a activity can be regulated at multiple levels of a signaling cascade comprised of phospholamban, protein phosphatase 1, inhibitor-1, and PKCα. SERCA2 activity is also regulated by post-translational modifications including SUMOylation and acetylation. In this review, we will highlight the molecular mechanisms underlying the regulation of SERCA2a activity and the potential therapeutic modalities for the treatment of heart failure.

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

54cb9c94f693c3b16b000005_004

Gene deletion in a patient with chronic granulomatous disease and McLeod syndrome: fine mapping of the Xk gene locus. In a patient suffering from X-linked chronic granulomatous disease (X-CGD)--a disorder of phagocytesuperoxide generation--and McLeod syndrome, characterized by the absence of the red cell Kell antigen, we identified a deletion of the entire X-CGD gene by means of DNA hybridization with a cDNA probe. Our findings suggest that the X-CGD and McLeod loci are physically close in the p21 region of the X chromosome proximal to the Duchenne muscular dystrophy locus.

Mutation of which gene is associated with McLeod syndrome?

531464a6e3eabad021000014_065

Non-invasive prenatal testing for fetal sex determination: is ultrasound still relevant? Early prenatal diagnosis of fetal sex is necessary to optimize pregnancy management in families known to be at risk of some heritable disorders. The demonstration of cell-free fetal DNA (cffDNA) in the mother's blood has made it possible to identify Y chromosome sequences in maternal blood and to determine fetal sex noninvasively, during the first trimester. This procedure can significantly reduce the number of invasive procedures for women with fetuses at risk of sex-linked diseases and optimize the management of these pregnancies. Fetal sex can be diagnosed by ultrasound with the same sensitivity and specificity, but later in pregnancy. We performed a review of the published literature evaluating the use of cffDNA and ultrasound for prenatal determination of fetal sex during the first trimester of pregnancy. We present the feasibility of the two methods and their impact on clinical practice. We applied a sensitive search of multiple bibliographic databases including Pubmed (MEDLINE), EMBASE, the Cochrane Library and Web of science between 1998 and 2013. Sixteen reports of the determination of fetal sex in maternal blood and 13 reports of the determination by ultrasound met our inclusion criteria. We found a sensitivity and specificity of nearly 100% from 8 weeks of gestation for cffDNA and from 13 weeks of gestation for ultrasound respectively. Based on this review, we conclude that fetal sex can be determined with a high level of accuracy by analyzing cffDNA and at an earlier gestation than ultrasound. Ten years after the first feasibility study, the French National Authority for Health (HAS) released a technological assessment report on the determination of fetal sex in maternal blood, which has resulted in validating this test for reimbursement by the national health insurance fund for the following indications: X-linked recessive disease and congenital adrenal hyperplasia.

How early during pregnancy does non-invasive cffDNA testing allow sex determination of the fetus?

57136a7e1174fb1755000006_004

Effect of cytochrome P450 3A4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with multiple myeloma or non-Hodgkin's lymphoma. BACKGROUND AND OBJECTIVE: Bortezomib, an antineoplastic agent with proteasome inhibitory activity, is extensively metabolized by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C19. Drugs that affect these enzymes may therefore have an impact on the pharmacological profile of bortezomib. This study evaluated the effects of co-administration of a potent CYP3A4 inducer (rifampicin [rifampin]) and a weak CYP3A4 inducer (dexamethasone) on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib. PATIENTS AND METHODS: Patients aged > 18 years with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma received intravenous bortezomib 1.3 mg/m2, administered on days 1, 4, 8 and 11 of a 21-day cycle, for 3 cycles. In stage 1, patients were randomized (1 : 1) to receive bortezomib alone or in combination with oral rifampicin 600 mg once daily on days 4-10 during cycle 3 only. If the mean area under the plasma concentration-time curve (AUC) of bortezomib was reduced by > 30% during rifampicin co-administration, then stage 2 was initiated, in which patients received bortezomib with dexamethasone 40 mg once daily on days 1-4 and days 9-12 during cycle 3 only. Blood samples were collected on days 11 through 14 of cycles 2 and 3 before and after bortezomib administration, at prespecified time points, for pharmacokinetic and pharmacodynamic (proteasome inhibition) assessments. RESULTS: Twelve patients in the bortezomib-alone arm, six patients in the bortezomib plus rifampicin arm and seven patients in the bortezomib plus dexamethasone arm were included in the pharmacokinetics-evaluable set. Rifampicin reduced the mean AUC from 0 to 72 hours (AUC(72h)) of bortezomib by approximately 45% (223 ng · h/mL in cycle 2 vs 123 ng · h/mL in cycle 3), while dexamethasone had no effect (mean AUC(72h): 179 ng · h/mL in cycle 2 vs 170 ng · h/mL in cycle 3). Proteasome inhibition parameters in peripheral blood were unaffected by rifampicin or dexamethasone. Safety profiles were similar across the treatment arms and consistent with previous experience of bortezomib. CONCLUSIONS: In patients with multiple myeloma or non-Hodgkin's lymphoma, co-administration of rifampicin decreased the exposure to bortezomib but did not affect the proteasome inhibition or safety profiles; co-administration of dexamethasone did not affect the exposure to bortezomib, proteasome inhibition or safety profiles. Concomitant administration of bortezomib with strong CYP3A4 inducers such as rifampicin is not recommended, as it may result in a reduction of the clinical effect, whereas concomitant administration of weak CYP3A4 inducers such as dexamethasone does not affect the pharmacological profile of bortezomib.

What disease is Velcade (bortezomib) mainly used for?

51631154298dcd4e5100004e_007

RANKL expression, function, and therapeutic targeting in multiple myeloma and chronic lymphocytic leukemia. Bone destruction is a prominent feature of multiple myeloma, but conflicting data exist on the expression and pathophysiologic involvement of the bone remodeling ligand RANKL in this disease and the potential therapeutic benefits of its targeted inhibition. Here, we show that RANKL is expressed by primary multiple myeloma and chronic lymphocytic leukemia (CLL) cells, whereas release of soluble RANKL was observed exclusively with multiple myeloma cells and was strongly influenced by posttranscriptional/posttranslational regulation. Signaling via RANKL into multiple myeloma and CLL cells induced release of cytokines involved in disease pathophysiology. Both the effects of RANKL on osteoclastogenesis and cytokine production by malignant cells could be blocked by disruption of RANK-RANKL interaction with denosumab. As we aimed to combine neutralization of RANKL with induction of antibody-dependent cellular cytotoxicity of natural killer (NK) cells against RANKL-expressing malignant cells and as denosumab does not stimulate NK reactivity, we generated RANK-Fc fusion proteins with modified Fc moieties. The latter displayed similar capacity compared with denosumab to neutralize the effects of RANKL on osteoclastogenesis in vitro, but also potently stimulated NK cell reactivity against primary RANKL-expressing malignant B cells, which was dependent on their engineered affinity to CD16. Our findings introduce Fc-optimized RANK-Ig fusion proteins as attractive tools to neutralize the detrimental function of RANKL while at the same time potently stimulating NK cell antitumor immunity.

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

52bf1d9e03868f1b06000010_005

Differential control of TAp73 and DeltaNp73 protein stability by the ring finger ubiquitin ligase PIR2. p73 is a p53-related transcription factor with fundamental roles in development and tumor suppression. Transcription from two different promoters on the p73 gene results in generation of transcriptionally active TAp73 isoforms and dominant negative DeltaNp73 isoforms with opposing pro- and anti-apoptotic functions. Therefore, the relative ratio of each isoform is an important determinant of the cell fate. Proteasomal degradation of p73 is mediated by polyubiquitination-dependent and -independent processes both of which appear, thus far, to lack selectivity for the TAp73 and DeltaNp73 isoforms. Here, we describe the characterization of another transcriptional target of TAp73; a ring finger domain ubiquitin ligase p73 Induced RING 2 protein (PIR2). Although PIR2 was initially identified a p53-induced gene (p53RFP), low abundance of PIR2 transcript in mouse embryonic fibroblasts of TAp73 KO mice compared with WT mice and comparison of PIR2 mRNA and protein levels following TAp73 or p53 overexpression substantiate TAp73 isoforms as strong inducers of PIR2. Although PIR2 expression was induced by DNA damage, its expression did not alter apoptotic response or cell cycle profile per se. However, coexpression of PIR2 with TAp73 or DeltaNp73 resulted in an increase of the TA/DeltaNp73 ratio, due to preferential degradation of DeltaNp73. Finally, PIR2 was able to relieve the inhibitory effect of DeltaNp73 on TAp73 induced apoptosis following DNA damage. These results suggest that PIR2, by being induced by TAp73 and degrading DeltaNp73, differentially regulates TAp73/DeltaNp73 stability, and, hence, it may offer a therapeutic approach to enhance the chemosensitivity of tumor cells.

How many TAp73 isoforms have been identified in humans?

5173bdb38ed59a060a000020_040

Co-amplification of MYCN and a DEAD box gene (DDX1) in primary neuroblastoma. DEAD box proteins are putative RNA helicases that have been implicated in cellular processes involving alteration of RNA secondary structure, such as translation initiation and splicing. These proteins share eight conserved amino acid motifs, including Asp(D)-Glu-(E)-Ala(A)-Asp(D) which is part of a more extended motif. Recently, we have shown that the novel DDX1 gene containing a DEAD box motif maps to the same chromosome band as MYCN at 2p24 and is co-amplified with MYCN in retinoblastoma cell lines. Here, we show that the DDX1 gene is co-amplified with the MYCN gene in 2 of three neuroblastoma cell lines and that DDX1 RNA levels correlate with DDX1 gene copy number. Since amplification of MYCN is an indicator of poor prognosis in neuroblastoma, it was of interest to determine whether co-amplification with DDX1 occurred in clinical samples of neuroblastoma and whether such a finding carried any additional prognostic significance. We determined the gene copy number of DDX1 in 32 neuroblastoma patient samples (representative of all stages): 13 were MYCN amplified and 19 had normal copy numbers of the MYCN gene. Of the 13 neuroblastomas that were MYCN amplified, seven were also DDX1 amplified. Of the 19 that were not MYCN amplified, none were DDX1 amplified. This is the first example of a gene that is co-amplified with MYCN at a high frequency in neuroblastoma. While there was a trend towards a worse clinical outcome with co-amplification, the numbers were too small to reach significance.

Which is the conserved motif of DEAD box proteins?

5a885daa61bb38fb24000018_001

Human alpha-galactosidase A: high plasma activity expressed by the -30G-->A allele. Human alpha-galactosidase A (EC 3.2.1.22; alpha-Gal A) is the lysosomal exoglycosidase responsible for the hydrolysis of terminal alpha-galactosyl residues from glycoconjugates and is the defective enzyme causing Fabry disease (McKusick 301500). An unusally elevated level of plasma alpha-Gal A activity (> 2.5 times the normal mean) was detected in two unrelated normal males and the elevated activities were inherited as X-linked traits in their families. Sequencing of the alpha-Gal A coding region, intron/exon boundaries and 5'-flanking region from the proband identified a single mutation, a G-->A transition 30 nt upstream from the initiation of translation codon in exon 1. The -30G-->A mutation occurred in a putative NF kappa B/Ets consensus binding site that was recently shown to inhibit protein binding to the 5'-untranslated region of the gene, providing a possible explanation for its high activity. To further characterize the mutation, the mRNA and protein expressed by this variant allele were studied. Purified plasma and lymphoblast alpha-Gal A activity from individuals with the -30G-->A mutation had normal physical and kinetic properties. In vitro translation of mRNAs from the cloned normal and high plasma activity alleles resulted in similar levels of alpha-Gal A protein, indicating that this mutation did not enhance translation. These findings suggest that the -30G-->A mutation in the 5'-untranslated region of the alpha-Gal A gene enhances transcription, presumably by interfering with the binding of negatively-acting transcription factors which normally decrease alpha-Gal A expression in various cells. Preliminary studies of the frequency of the -30G-->A mutation in 395 unrelated normal males of mixed ancestry revealed two additional unrelated individuals who had high plasma enzymatic activity and the mutation, confirming the effect of this mutation on enzyme expression and suggesting that about 0.5% of normal individuals have high plasma alpha-Gal A activity due to this variant allele.

Which is the defective protein causing the lysosomal storage disease Fabry?

51405cd123fec90375000005_003

Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus: a review of the evidence. OBJECTIVE: To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM). DATA SOURCES: PubMed was searched using the search terms empagliflozin, BI 10773, and BI10773, for entries between January 1, 2000, and December 1, 2014. Reference lists from retrieved articles were searched manually for additional peer-reviewed publications. STUDY SELECTION AND DATA EXTRACTION: All publications reporting clinical trials of empagliflozin were eligible for inclusion. DATA SYNTHESIS: Empagliflozin is a new once-daily oral SGLT2 inhibitor with a mechanism of action that is independent of β-cell function and the insulin pathway. Data from a comprehensive phase III clinical trial program have demonstrated its efficacy as monotherapy, as add-on to other glucose-lowering agents, and in different patient populations. In these studies, empagliflozin resulted in improvements in blood glucose levels as well as reductions in body weight and blood pressure. Empagliflozin was well tolerated and was not associated with an increased risk of hypoglycemia versus placebo. CONCLUSION: The oral antidiabetes agent, empagliflozin, can be used as monotherapy or alongside other glucose-lowering treatments, including insulin, to treat T2DM.

For which type of diabetes can empagliflozin be used?

571e14fbbb137a4b0c000001_001

Battle of the eternal rivals: restoring functional p53 and inhibiting Polo-like kinase 1 as cancer therapy. Polo-like kinase 1, a pivotal regulator of mitosis and cytokinesis, is highly expressed in a broad spectrum of tumors and its expression correlates often with poor prognosis, suggesting its potential as a therapeutic target. p53, the guardian of the genome, is the most important tumor suppressor. In this review, we address the intertwined relationship of these two key molecules by fighting each other as eternal rivals in many signaling pathways. p53 represses the promoter of Polo-like kinase 1, whereas Polo-like kinase 1 inhibits p53 and its family members p63 and p73 in cancer cells lacking functional p53. Plk1 inhibitors target all rapidly dividing cells irrespective of tumor cells or non-transformed normal but proliferating cells. Upon treatment with Plk1 inhibitors, p53 in tumor cells is activated and induces strong apoptosis, whereas tumor cells with inactive p53 arrest in mitosis with DNA damage. Thus, inactive p53 is not associated with a susceptible cytotoxicity of Polo-like kinase 1 inhibition and could rather foster the induction of polyploidy/aneuploidy in surviving cells. In addition, compared to the mono-treatment, combination of Polo-like kinase 1 inhibition with anti-mitotic or DNA damaging agents boosts more severe mitotic defects, effectually triggers apoptosis and strongly inhibits proliferation of cancer cells with functional p53. In this regard, restoration of p53 in tumor cells with loss or mutation of p53 will reinforce the cytotoxicity of combined Polo-like kinase 1 therapy and provide a proficient strategy for combating relapse and metastasis of cancer.

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

55421ee7ccca0ce74b000002_018

Subviral pathogens of plants: the viroids. Research during the last 15 years has conclusively shown that viroids are not only fundamentally different from viruses at the molecular level, but that they are most likely not directly related to viruses in an evolutionary sense. Today, viroids are among the most thoroughly studied biological macromolecules. Their molecular structures have been elucidated to a large extent, but much needs to be learned regarding the correlation between molecular structure and biological function. The availability of the tools of recombinant DNA technology in viroid research promises rapid progress in these areas of inquiry.

Which are the smallest known subviral pathogens of plants?

56e0447a51531f7e3300000b_008

Chicken trunk neural crest migration visualized with HNK1. The development of the nervous system involves cells remaining within the neural tube (CNS) and a group of cells that delaminate from the dorsal neural tube and migrate extensively throughout the developing embryo called neural crest cells (NCC). These cells are a mesenchymal highly migratory group of cells that give rise to a wide variety of cell derivatives: melanocytes, sensory neurons, bone, Schwann cells, etc. But not all NCC can give rise to all derivatives, they have fate restrictions based on their axial level of origin: cranial, vagal, trunk and sacral. Our aim was to provide a thorough presentation on how does trunk neural crest cell migration looks in the chicken embryo, in wholemount and in sections using the unique chicken marker HNK1. The description presented here makes a good guideline for those interested in viewing trunk NCC migration patterns. We show how before HH14 there are few trunk NCC delaminating and migrating, but between HH15 through HH19 trunk NCC delaminate in large numbers. Melanocytes precursors begin to enter the dorsolateral pathway by HH17. We found that by HH20 HNK1 is not a valid good marker for NCC and that HNK1 is a better marker than Sox10 when looking at neural crest cells morphology and migration details.

Where do the Schwann cells and melanocytes originate from?

58b56fe422d3005309000007_001

The biology of chronic myelogenous leukemia: implications for imatinib therapy. Chronic myelogenous leukemia (CML) results from the neoplastic transformation of primitive hematopoietic stem cells, and has been classified as a myeloproliferative disorder. The hallmark of CML is the presence of a balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11.2), which is known as the Philadelphia (Ph) chromosome. This translocation results in the formation of the bcr-abl fusion gene, which, in turn, is translated into a chimeric Bcr-Abl protein with deregulated tyrosine kinase activity. Constitutive Bcr-Abl expression has been shown to be necessary and sufficient for the transformed phenotype of CML cells. CML is unique among human cancers in that a single genetic defect, the Ph chromosome, is responsible for the transformed phenotype. Since this discovery more than 40 years ago, our understanding of the clinical course, therapy, and prognosis of patients with CML has changed significantly. These changes have culminated in the emergence of imatinib, the first rationally designed, molecularly targeted therapy for human malignancy. In this review, the authors describe the molecular biology of CML and the development of imatinib as a therapeutic agent for the treatment of CML.

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

5324a8ac9b2d7acc7e000018_036

Mutational spectrum in the cardioauditory syndrome of Jervell and Lange-Nielsen. Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive syndrome characterised by profound congenital sensorineural deafness and prolongation of the QT interval on the electrocardiogram, representing abnormal ventricular repolarisation. In a study of ten British and Norwegian families with JLNS, we have identified all of the mutations in the KCNQ1 gene, including two that are novel. Of the nine mutations identified in this group of 10 families, five are nonsense or frameshift mutations. Truncation of the protein proximal to the recently identified C-terminal assembly domain is expected to preclude assembly of KCNQ1 monomers into tetramers and explains the recessive inheritance of JLNS. However, study of a frameshift mutation, with a dominant effect phenotypically, suggests the presence of another assembly domain nearer to the N-terminus.

What is the mode of inheritance of long QT Jervell and Lange-Nielsen syndrome?

52eea4dcc8da89891000000c_002

The combination of irreversible EGFR TKIs and SAHA induces apoptosis and autophagy-mediated cell death to overcome acquired resistance in EGFR T790M-mutated lung cancer. To overcome T790M-mediated acquired resistance of lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), second generation TKIs such as BIBW2992 (afatinib) and third generation TKIs including WZ4002 have been developed. However, clinical data on their efficacy in treating T790M mutant tumors are lacking. Histone deacetylase (HDAC) inhibitors have been reported to arrest cell growth and to lead to differentiation and apoptosis of various cancer cells, both in vitro and in vivo. In the present study, we assessed whether the combination of suberoylanilide hydroxamic acid (SAHA, vorinostat), a potent HDAC inhibitor, and BIBW2992 or WZ4002 could overcome EGFR TKI resistance associated with T790M mutation in lung cancer cells. While treatment with BIBW2992 or WZ4002 alone slightly reduced the viability of PC-9G and H1975 cells, which possess T790M mutation, combining them with SAHA resulted in significantly decreased cell viability through the activation of the apoptotic pathway. This combination also enhanced autophagy occurrence and inhibition of autophagy significantly reduced the apoptosis induced by the combination treatment, showing that autophagy is required for the enhanced apoptosis. Caspase-independent autophagic cell death was also induced by the combination treatment with SAHA and either BIBW2992 or WZ4002. Finally, the combined treatment with SAHA and either BIBW2992 or WZ4002 showed an enhanced anti-tumor effect on xenografts of H1975 cells in vivo. In conclusion, the combination of new generation EGFR TKIs and SAHA may be a new strategy to overcome the acquired resistance to EGFR TKIs in T790M mutant lung cancer.

Which gene harbors the mutation T790M?

56d1f790f22319765a000001_017

Development of a surveillance system for methicillin-resistant Staphylococcus aureus in German hospitals. OBJECTIVE: To determine the appropriate method to calculate the rate of methicillin-resistant Staphylococcus aureus (MRSA) infection and colonization (hereafter, MRSA rates) for interhospital comparisons, such that the large number of patients who are already MRSA positive on admission is taken into account. DESIGN: A prospective, multicenter, hospital-based surveillance of MRSA-positive case patients from January through December 2004. SETTING: Data from 31 hospitals participating in the German national nosocomial infections surveillance system (KISS) were recorded during routine surveillance by the infection control team at each hospital. RESULTS: Data for 4,215 MRSA-positive case patients were evaluated. From this data, the following values were calculated. The median incidence density was 0.71 MRSA-positive case patients per 1,000 patient-days, and the median nosocomial incidence density was 0.27 patients with nosocomial MRSA infection or colonization per 1,000 patient-days (95% CI, 0.18-0.34). The median average daily MRSA burden was 1.13 MRSA patient-days per 100 patient-days (95% CI, 0.86-1.51), with the average daily MRSA burden defined as the total number of MRSA patient-days divided by the total number of patient-days times 100. The median MRSA-days-associated nosocomial MRSA infection and colonization rate, which describes the MRSA infection risk for other patients in hospitals housing large numbers of MRSA-positive patients and/or many patients who were MRSA positive on admission, was 23.1 cases of nosocomial MRSA infection and colonization per 1,000 MRSA patient-days (95% CI, 17.4-28.6). The values were also calculated for various MRSA screening levels. CONCLUSIONS: The MRSA-days-associated nosocomial MRSA rate allows investigators to assess the extent of MRSA colonization and infection at each hospital, taking into account cases that have been imported from other hospitals, as well as from the community. This information provides an appropriate incentive for hospitals to introduce further infection control measures.

What is MRSA?

58a32efe60087bc10a000013_070

Solitary fibrous tumor of the pleura with associated Doege-Potter syndrome. Doege-Potter syndrome is a paraneoplastic syndrome characterized by tumor-associated hypoglycemia secondary to a solitary fibrous tumor of the pleura. We present a case of an 84-year-old man, who presented with acute mental confusion and therapy-resistant hypoglycemia. Diagnostic imaging revealed a large sharply defined pleural tumor based on the left diaphragm, after surgical resection the diagnosis was made of a malignant solitary fibrous tumor of the pleura and restoration of the glucose homeostasis was observed.

What is the most common feature of the Doege–Potter syndrome?

5a761ac3aacfb9cd4c000002_010

iLIR database: A web resource for LIR motif-containing proteins in eukaryotes. Atg8-family proteins are the best-studied proteins of the core autophagic machinery. They are essential for the elongation and closure of the phagophore into a proper autophagosome. Moreover, Atg8-family proteins are associated with the phagophore from the initiation of the autophagic process to, or just prior to, the fusion between autophagosomes with lysosomes. In addition to their implication in autophagosome biogenesis, they are crucial for selective autophagy through their ability to interact with selective autophagy receptor proteins necessary for the specific targeting of substrates for autophagic degradation. In the past few years it has been revealed that Atg8-interacting proteins include not only receptors but also components of the core autophagic machinery, proteins associated with vesicles and their transport, and specific proteins that are selectively degraded by autophagy. Atg8-interacting proteins contain a short linear LC3-interacting region/LC3 recognition sequence/Atg8-interacting motif (LIR/LRS/AIM) motif which is responsible for their interaction with Atg8-family proteins. These proteins are referred to as LIR-containing proteins (LIRCPs). So far, many experimental efforts have been carried out to identify new LIRCPs, leading to the characterization of some of them in the past 10 years. Given the need for the identification of LIRCPs in various organisms, we developed the iLIR database ( https://ilir.warwick.ac.uk ) as a freely available web resource, listing all the putative canonical LIRCPs identified in silico in the proteomes of 8 model organisms using the iLIR server, combined with a Gene Ontology (GO) term analysis. Additionally, a curated text-mining analysis of the literature permitted us to identify novel putative LICRPs in mammals that have not previously been associated with autophagy.

Which web resource for LIR motif-containing proteins in eukaryotes has been developed?

5a8056a2faa1ab7d2e00001f_002

Structural insight into maintenance methylation by mouse DNA methyltransferase 1 (Dnmt1). Methylation of cytosine in DNA plays a crucial role in development through inheritable gene silencing. The DNA methyltransferase Dnmt1 is responsible for the propagation of methylation patterns to the next generation via its preferential methylation of hemimethylated CpG sites in the genome; however, how Dnmt1 maintains methylation patterns is not fully understood. Here we report the crystal structure of the large fragment (291-1620) of mouse Dnmt1 and its complexes with cofactor S-adenosyl-L-methionine and its product S-adenosyl-L-homocystein. Notably, in the absence of DNA, the N-terminal domain responsible for targeting Dnmt1 to replication foci is inserted into the DNA-binding pocket, indicating that this domain must be removed for methylation to occur. Upon binding of S-adenosyl-L-methionine, the catalytic cysteine residue undergoes a conformation transition to a catalytically competent position. For the recognition of hemimethylated DNA, Dnmt1 is expected to utilize a target recognition domain that overhangs the putative DNA-binding pocket. Taking into considerations the recent report of a shorter fragment structure of Dnmt1 that the CXXC motif positions itself in the catalytic pocket and prevents aberrant de novo methylation, we propose that maintenance methylation is a multistep process accompanied by structural changes.

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

51585b28d24251bc0500008d_016

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_012

UV-enhanced reactivation of a UV-damaged reporter gene suggests transcription-coupled repair is UV-inducible in human cells. The genetic disorders xeroderma pigmentosum (XP) and Cockayne syndrome (CS) exhibit deficiencies in the repair of UV-induced DNA damage. CS fibroblasts retain proficient nucleotide excision repair (NER) of inactive (or bulk) DNA, but are deficient in the transcription-coupled repair (TCR) of active genes. In contrast, XP complementation group C (XP-C) fibroblasts retain proficient TCR, but are deficient in bulk DNA repair. The remaining NER-deficient XP groups exhibit deficiencies in both repair pathways. Ad5HCMVsp1lacZ is a recombinant adenovirus vector that is unable to replicate in human fibroblasts, but can efficiently infect and express the beta-galactosidase reporter gene in these cells. We have examined the host cell reactivation (HCR) of beta-galactosidase activity for UV-irradiated Ad5HCMVsp1lacZ in non-irradiated and UV-irradiated normal, XP-B, XP-C, XP-D, XP-F, XP-G, CS-A and CS-B fibroblasts. HCR of beta-galactosidase activity for UV-irradiated Ad5HCMVsp1lacZ was reduced in non-irradiated cells from each of the repair-deficient groups examined (including XP-C) relative to that in non-irradiated normal cells. Prior irradiation of cells with low UV fluences resulted in an enhancement of HCR for normal and XP-C strains, but not for the remaining XP and CS strains. HCR of the UV-damaged reporter gene in UV-irradiated XP and CS strains was similar to measurements of TCR reported previously for these cells. These results suggest that UV treatment results in an induced repair of UV-damaged DNA in the transcribed strand of an active gene in XP-C and normal cells through an enhancement of TCR or a mechanism which involves the TCR pathway.

Which gene strand is targeted by transcription-coupled repair (TCR)?

5545186cbf90a13052000002_007

Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies. Fibrillin is the major component of extracellular microfibrils and is widely distributed in connective tissue throughout the body. Mutations in the fibrillin-1 (FBN1) gene, on chromosome 15q21.1, have been found to cause Marfan syndrome, a dominantly inherited disorder characterised by clinically variable skeletal, ocular, and cardiovascular abnormalities. Fibrillin-1 mutations have also been found in several other related connective tissue disorders, such as severe neonatal Marfan syndrome, dominant ectopia lentis, familial ascending aortic aneurysm, isolated skeletal features of Marfan syndrome, and Shprintzen-Goldberg syndrome. Mutations are spread throughout the gene and, with the exception of neonatal Marfan syndrome, show no obvious clustering or phenotypic association.

Which gene mutations cause the Marfan syndrome?

58d8e6818acda3452900000a_054

Common variation in Kallikrein genes KLK5, KLK6, KLK12, and KLK13 and risk of prostate cancer and tumor aggressiveness. The human tissue Kallikrein family consists of 15 genes with the majority shown to be differentially expressed in cancers and/or indicators of cancer prognosis. We sought to elucidate the role of common genetic variation in four of the Kallikrein genes, KLK5, KLK6, KLK12, and KLK13, in prostate cancer risk and tumor aggressiveness. Genotyping of all 22 tagging single nucleotide polymorphisms (tagSNPs) in the KLK5, KLK6, KLK12, and KLK13 genes was performed in approximately 1,000 prostate cancer cases and 1,300 male controls from Australia. Data from any positive results were also accessed for 1,844 cases and 1,886 controls from a previously published prostate cancer genome-wide association study set from the United Kingdom. For one SNP in KLK12, rs3865443, there was evidence for association with prostate cancer risk of similar direction and magnitude in the replication set to that seen in the Australian cohort. We conducted genotyping of a further 309 prostate cancer cases, and combined analyses revealed an increased risk of prostate cancer for carriers of the rare homozygous genotype for rs3865443 (OR 1.28, 95% CI 1.04-1.57; P = 0.018). No other tagSNPs in the KLK5, KLK6, and KLK13 genes were consistently associated with prostate cancer risk or tumor aggressiveness. Analysis of a combined sample of 3,153 cases and 3,199 controls revealed the KLK12 tagSNP rs3865443 to be marginally statistically significantly associated with risk of prostate cancer. Considering the total number of SNPs investigated in this study, this finding should be interpreted cautiously and requires additional validation from very large datasets such as those of the Prostate Cancer Association group to investigate cancer associated alterations (PRACTICAL) Consortium.

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

511a3573df1ebcce7d000018_002

Mouse Xist expression begins at zygotic genome activation and is timed by a zygotic clock. The imprinted mouse Xist (X-inactive specific transcript) gene is involved in the initiation of X-chromosome inactivation. Only the paternal Xist is expressed in preimplantation development beginning from the 4-cell stage, preceding and in correlation with paternal X-inactivation in the extraembryonic lineage of the blastocyst. To better understand the mechanisms regulating Xist expression in early development, we investigated the precise timing of its onset. We set up a single-cell RT-PCR for the simultaneous analysis on single embryos of Xist and Hprt (internal control) cDNAs and a Y-chromosome specific DNA sequence, Zfy (for embryo sexing). Applying this procedure, we demonstrate that Xist expression begins at the G2-phase of 2-cell female embryos, earlier than previously reported and at the same time of the major wave of zygotic genome activation (ZGA). We then examined, if Xist expression at the 2-cell stage is dependent on the lapse of time spent since fertilization, as previously reported for zygotic genes. One-cell embryos at the G2-phase of the first cell-cycle were cultured with cytochalasin D (inhibitor of cytokinesis but not of DNA synthesis or nuclear progression) for a time equivalent to the 4-cell stage in control, untreated embryos. We show that Xist activation occurs at a scheduled time following fertilization despite the embryos being blocked at the 1-cell stage, suggesting the existence of a zygotic clock involved in the regulation of the transcription of this imprinted gene.

Which is the transcript responsible for X-chromosome inactivation?

5353aedb288f4dae47000006_026

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

Andexanet Alfa is an antidote of which clotting factor inhibitors?

5880b073c872c95565000003_093

Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia. Imatinib mesylate (IM) binds to the BCR-ABL protein, inhibiting its kinase activity and effectively controlling diseases driven by this kinase. IM resistance has been associated with kinase mutations or increased BCR-ABL expression. However, disease progression may be mediated by other mechanisms that render tumor cells independent of BCR-ABL. To demonstrate this potential, IM-resistant cells were found in chronic myelogenous leukemia patients with continuous BCR-ABL gene expression but undetectable BCR-ABL protein expression. These cells were unresponsive to IM and acquired BCR-ABL-independent signaling characteristics. IM resistance in some patients may be mediated through loss of kinase target dependence.

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

5324a8ac9b2d7acc7e000018_077

The duration of pacing-induced atrial fibrillation is reduced in vivo by inhibition of small conductance Ca(2+)-activated K(+) channels. Atrial fibrillation (AF) is associated with increased morbidity and is in addition the most prevalent cardiac arrhythmia. Compounds used in pharmacological treatment has traditionally been divided into Na(+) channel inhibitors, β-blockers, K(+) channel inhibitors, and Ca(2+) channel inhibitors, whereas newer multichannel blockers such as amiodarone and ranolazine have been introduced later. This study was devoted to the evaluation of an acute pacing-induced in vivo model of AF in rats. Antiarrhythmic effects of well-known compounds such as lidocaine, dofetilide, and ranolazine were confirmed in this model. In addition, antiarrhythmic effects of different inhibitors of Ca(2+)-activated small conductance K(+) (SK) channels were demonstrated. Intravenous application of 5 mg/kg of the negative SK channel modulator NS8593 reduced AF duration by 64.5%, and the lowest significantly effective dose was 1.5 mg/kg. A dose-effect relationship was established based on 6 different dose groups. Furthermore, it was demonstrated that the antiarrhythmic effect of NS8593 and other tested drugs was associated with an increase in atrial effective refractory period. The functional role of SK channels was confirmed by 2 other SK channel inhibitors, UCL1684 and apamin, thereby confirming the hypothesis that these channels might constitute a new promising target for antiarrhythmic treatment.

Which is the most prevalent form of arrhythmia worldwide?

54d8ea2c4b1fd0d33c000002_007

Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome. Deficiency in the serine protease inhibitor LEKTI is the etiological origin of Netherton syndrome, which causes detachment of the stratum corneum and chronic inflammation. Here we show that the membrane protease matriptase initiates Netherton syndrome in a LEKTI-deficient mouse model by premature activation of a pro-kallikrein cascade. Auto-activation of pro-inflammatory pro-kallikrein-related peptidases that are associated with stratum corneum detachment was either low or undetectable, but they were efficiently activated by matriptase. Ablation of matriptase from LEKTI-deficient mice dampened inflammation, eliminated aberrant protease activity, prevented detachment of the stratum corneum, and improved the barrier function of the epidermis. These results uncover a pathogenic matriptase-pro-kallikrein pathway that could operate in several human skin and inflammatory diseases.

Which protein is causing Netherton syndrome?

54ff45966ad7dcbc12000010_008

Novel Abl kinase inhibitors in chronic myeloid leukemia in blastic phase and Philadelphia chromosome-positive acute lymphoblastic leukemia. Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome, which is associated with a balanced translocation involving chromosomes 9 and 22 to produce a fusion gene (bcr-abl) that gives rise to a constitutively activated Abl tyrosine kinase. This kinase led to the discovery of several small-molecule inhibitors, imatinib being the first and most successful of these. Resistance to imatinib results in some patients from Abl kinase point mutations. Overcoming imatinib resistance represents one of the biggest challenges facing clinicians in the modern management of CML. In this review, we discuss the current understanding of CML pathophysiology and mechanisms of imatinib resistance and how advancing this knowledge has led to the design of novel therapies in the area of blastic phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia with previous imatinib failure.

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

5324a8ac9b2d7acc7e000018_069

Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.

Which clotting factor is inhibited by betrixaban?

55200c606b348bb82c000013_132

Dysregulation of 4q35- and muscle-specific genes in fetuses with a short D4Z4 array linked to facio-scapulo-humeral dystrophy. Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the DUX4 retrogene from the last D4Z4 repeated unit is thought to underlie FSHD pathophysiology. However, no one knows what triggers muscle defect and when alteration arises. To gain further insights into the molecular mechanisms of the disease, we evaluated at the molecular level, the perturbation linked to the FSHD genotype with no a priori on disease onset, severity or penetrance and prior to any infiltration by fibrotic or adipose tissue in biopsies from fetuses carrying a short pathogenic D4Z4 array (n = 6) compared with fetuses with a non-pathogenic D4Z4 array (n = 21). By measuring expression of several muscle-specific markers and 4q35 genes including the DUX4 retrogene by an RT-PCR and western blotting, we observed a global dysregulation of genes involved in myogenesis including MYOD1 in samples with <11 D4Z4. The DUX4-fl pathogenic transcript was detected in FSHD biopsies but also in controls. Importantly, in FSHD fetuses, we mainly detected the non-spliced DUX4-fl isoform. In addition, several other genes clustered at the 4q35 locus are upregulated in FSHD fetuses. Our study is the first to examine fetuses carrying an FSHD-linked genotype and reveals an extensive dysregulation of several muscle-specific and 4q35 genes at early development stage at a distance from any muscle defect. Overall, our work suggests that even if FSHD is an adult-onset muscular dystrophy, the disease might also involve early molecular defects arising during myogenesis or early differentiation.

Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?

550f0e4c6a8cde6b72000003_026

PHYLUCE is a software package for the analysis of conserved genomic loci. UNLABELLED: Targeted enrichment of conserved and ultraconserved genomic elements allows universal collection of phylogenomic data from hundreds of species at multiple time scales (<5 Ma to > 300 Ma). Prior to downstream inference, data from these types of targeted enrichment studies must undergo preprocessing to assemble contigs from sequence data; identify targeted, enriched loci from the off-target background data; align enriched contigs representing conserved loci to one another; and prepare and manipulate these alignments for subsequent phylogenomic inference. PHYLUCE is an efficient and easy-to-install software package that accomplishes these tasks across hundreds of taxa and thousands of enriched loci. AVAILABILITY AND IMPLEMENTATION: PHYLUCE is written for Python 2.7. PHYLUCE is supported on OSX and Linux (RedHat/CentOS) operating systems. PHYLUCE source code is distributed under a BSD-style license from https://www.github.com/faircloth-lab/phyluce/ PHYLUCE is also available as a package (https://binstar.org/faircloth-lab/phyluce) for the Anaconda Python distribution that installs all dependencies, and users can request a PHYLUCE instance on iPlant Atmosphere (tag: phyluce). The software manual and a tutorial are available from http://phyluce.readthedocs.org/en/latest/ and test data are available from doi: 10.6084/m9.figshare.1284521. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Which software package is available for the analysis of conserved genomic loci?

587e07023ec846c24f000001_003

Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells. Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.

Which enzyme is inhibited by Imetelstat?

56c048acef6e39474100001c_010