A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence

RBC-transfusion dependence is common in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis. The objective of this study was to determine the rates of RBC-transfusion independence after therapy with pomalidomide vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. Two hundred and fifty-two subjects (intent-to-treat (ITT) population) including 229 subjects confirmed by central review (modified ITT population) were randomly assigned (2:1) to pomalidomide or placebo. Trialists and subjects were blinded to treatment allocation. Primary end point was proportion of subjects achieving RBC-transfusion independence within 6 months. One hundred and fifty-two subjects received pomalidomide and 77 placebo. Response rates were 16% (95% confidence interval (CI), 11, 23%) vs 16% (8, 26% P=0.87). Response in the pomalidomide cohort was associated with ⩽4 U RBC/28 days (odds ratio (OR)=3.1; 0.9, 11.1), age ⩽65 (OR=2.3; 0.9, 5.5) and type of MPN-associated myelofibrosis (OR=2.6; 0.7, 9.5). Responses in the placebo cohort were associated with ⩽4 U RBC/28 days (OR=8.6; 0.9, 82.3), white blood cell at randomization >25 × 10(9)/l (OR=4.9; 0.8, 28.9) and interval from diagnosis to randomization >2 years (OR=4.9; 1.1, 21.9). Pomalidomide was associated with increased rates of oedema and neutropenia but these adverse effects were manageable. Pomalidomide and placebo had similar RBC-transfusion-independence response rates in persons with MPN-associated RBC-transfusion dependence

Low HDL Cholesterol, Smoking and IL-13 R130Q Polymorphism are Associated with Myocardial Infarction in Greek Cypriot Males. A Pilot Study

This study was carried out in Greek Cypriot males to identify risk factors that predispose to myocardial infarction (MI). Genetic and lipid risk factors were investigated for the first time in a Greek Cypriot male case-control study.Contrary to other studies, mean low density lipoprotein cholesterol did not differ between cases and controls. High density lipoprotein cholesterol on the other hand, although within normal range in cases and controls, was significantly higher in the control population. In agreement with many other studies, smoking was significantly more prevalent in cases compared with controls. In pooled cases and controls, smokers had a significantly lower HDL-C level compared with non-smokers. The frequency of the IL-13 R130Q homozygotes for the mutation (QQ), as well as the mutant allele were significantly higher in cases compared with controls. The IL-13 R130Q variant, or another locus, linked to it, may increase the risk of MI

Epigenetic abnormalities in myeloproliferative neoplasms: a target for novel therapeutic strategies

The myeloproliferative neoplasms (MPNs) are a group of clonal hematological malignancies characterized by a hypercellular bone marrow and a tendency to develop thrombotic complications and to evolve to myelofibrosis and acute leukemia. Unlike chronic myelogenous leukemia, where a single disease-initiating genetic event has been identified, a more complicated series of genetic mutations appear to be responsible for the BCR-ABL1-negative MPNs which include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Recent studies have revealed a number of epigenetic alterations that also likely contribute to disease pathogenesis and determine clinical outcome. Increasing evidence indicates that alterations in DNA methylation, histone modification, and microRNA expression patterns can collectively influence gene expression and potentially contribute to MPN pathogenesis. Examples include mutations in genes encoding proteins that modify chromatin structure (EZH2, ASXL1, IDH1/2, JAK2V617F, and IKZF1) as well as epigenetic modification of genes critical for cell proliferation and survival (suppressors of cytokine signaling, polycythemia rubra vera-1, CXC chemokine receptor 4, and histone deacetylase (HDAC)). These epigenetic lesions serve as novel targets for experimental therapeutic interventions. Clinical trials are currently underway evaluating HDAC inhibitors and DNA methyltransferase inhibitors for the treatment of patients with MPNs

Comparison of RTN and TDDS methods for trap extraction in trigate nanowires

session 3E: Reliability TestingInternational audienceIn this paper we present a direct comparison of the two basic techniques for trap extraction, the Random Telegraph Noise (RTN) and the Time Dependent Defect Spectroscopy (TDDS). By using the method of histograms, extracted from the measured drain current transients, we divided the recorded defects in three different categories. Results show that we night be able to detect traps deeper in the oxide and, also, near the dielectric/channel interface. As we scale down, we found a better correlation between the two methods, while the after stress results show a merging of the slopes compared to the bimodal distribution that appeared at the beginning

Immobilized Enzymes on Magnetic Beads for Separate Mass Spectrometric Investigation of Human Phase II Metabolite Classes

The human body hasevolved to remove xenobiotics through a multistepclearance process. Non-endogenous metabolites are converted througha series of phase I and different phase II enzymes into compoundswith higher hydrophilicity. These compounds are important for diverseresearch fields such as toxicology, nutrition, biomarker discovery,doping control, and microbiome metabolism. One of the challenges inthese research fields has been the investigation of the two majorphase II modifications, sulfation and glucuronidation, and the correspondingunconjugated aglycon independently. We have now developed a new methodologyutilizing an immobilized arylsulfatase and an immobilized & beta;-glucuronidaseto magnetic beads for treatment of human urine samples. The enzymeactivities remained the same compared to the enzyme in solution. Theseparate mass spectrometric investigation of each metabolite classin a single sample was successfully applied to obtain the dietaryglucuronidation and sulfation profile of 116 compounds. Our new chemicalbiology strategy provides a new tool for the investigation of metabolitesin biological samples with the potential for broad-scale applicationin metabolomics, nutrition, and microbiome studies

Condom effectiveness in reducing heterosexual HIV transmission: a systematic review and meta-analysis of studies on HIV serodiscordant couples

Objective: This systematic review and meta-analysis aimed to reassess the effectiveness of condoms in reducing heterosexual transmission of HIV. Methods: Medline, Scopus, and the ISI Web of Science databases were searched up to June 2014. Eligible studies were synthesized using random-effects models. Results: Twenty-five studies with 10,676 HIV serodiscordant heterosexual couples were analyzed. The risk of HIV transmission was considerably lower among couples that were always using condoms compared to never-users (RR: 0.29, 95% CI: 0.20–0.43) or inconsistent users (RR: 0.23, 0.13–0.40). The protective effect was slightly higher when the male rather than the female partner was infected (RR: 0.31, 0.20–0.48; vs. RR: 0.44, 0.24–0.80), and very high in Asian settings (RR: 0.06, 0.01–0.46). Conclusions: Though imperfect, condoms reduce HIV transmission by more than 70% when used consistently by HIV serodiscordant heterosexual couples. Social, cultural and biological differences need to be studied further to inform projection modelers and policy makers. © 2015 Informa UK Limited, trading as Taylor & Francis Group