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

In situ probing of the present-day zircon-bearing magma chamber at Krafla, Northeastern Iceland

Active felsic magmatism has been rarely probed in situ by drilling but one recent exception is quenched rhyolite sampled during the 2009 Iceland Deep Drilling Project (IDDP). We report finding of rare zircons of up to ∼100 µm in size in rhyolite glasses from the IDDP-1 well products and the host 1724 AD Viti granophyres. The applied SHRIMP U-Th dating for both the IDDP and the Viti granophyre zircons gives zero-age (±2 kyr), and therefore suggests that the IDDP-1 zircons have crystallized from an active magma intrusion rather than due to the 20–80 ka post-caldera magmatic episodes recorded by nearby domes and ridges. Ti-in-zircon geothermometer for Viti granophyre reveals zircon crystallization temperatures ∼800°C–900°C, whereas IDDP-1 rhyolite zircon cores show Ti content higher than 100 ppm, corresponding to temperatures up to ∼1,100°C according to the Ti-in-zircon thermometer. According to our thermochemical model at such elevated temperatures as 1,100°C, rhyolitic magma cannot be saturated with zircon and zircon crystallization is not possible. We explain this controversy by either kinetic effects or non-ideal Ti incorporation into growing zircons at low pressures that start to grow from nucleus at temperatures ∼930°C. High temperatures recorded by IDDP-1 zircon together with an occurrence of baddeleyite require that the rhyolite magma formed by partial melting of the host granophyre due to basaltic magma intrusion. Zr concentration profiles in glass around zircons are flat, suggesting residence in rhyolitic melt for >4 years. In our thermochemical modeling, three scenarios are considered. The host felsite rocks are intruded by: 1) a basaltic sill, 2) rhyolite magma 3) rhyolite sill connected to a deeper magmatic system. Based on the solution of the heat conduction equation accounting for the release of latent heat and effective thermal conductivity, these data confirm that the rhyolite magma could be produced by felsic crust melting as a result of injection of a basaltic or rhyolite sill during the Krafla Fires eruption (1975 AD)

B cells and monocytes from patients with active multiple sclerosis exhibit increased surface expression of both HERV-H Env and HERV-W Env, accompanied by increased seroreactivity

<p>Abstract</p> <p>Background</p> <p>The etiology of the neurogenerative disease multiple sclerosis (MS) is unknown. The leading hypotheses suggest that MS is the result of exposure of genetically susceptible individuals to certain environmental factor(s). Herpesviruses and human endogenous retroviruses (HERVs) represent potentially important factors in MS development. Herpesviruses can activate HERVs, and HERVs are activated in MS patients.</p> <p>Results</p> <p>Using flow cytometry, we have analyzed HERV-H Env and HERV-W Env epitope expression on the surface of PBMCs from MS patients with active and stable disease, and from control individuals. We have also analyzed serum antibody levels to the expressed HERV-H and HERV-W Env epitopes. We found a significantly higher expression of HERV-H and HERV-W Env epitopes on B cells and monocytes from patients with active MS compared with patients with stable MS or control individuals. Furthermore, patients with active disease had relatively higher numbers of B cells in the PBMC population, and higher antibody reactivities towards HERV-H Env and HERV-W Env epitopes. The higher antibody reactivities in sera from patients with active MS correlate with the higher levels of HERV-H Env and HERV-W Env expression on B cells and monocytes. We did not find such correlations for stable MS patients or for controls.</p> <p>Conclusion</p> <p>These findings indicate that both HERV-H Env and HERV-W Env are expressed in higher quantities on the surface of B cells and monocytes in patients with active MS, and that the expression of these proteins may be associated with exacerbation of the disease.</p

CCC meets ICU: Redefining the role of critical care of cancer patients

<p>Abstract</p> <p>Background</p> <p>Currently the majority of cancer patients are considered ineligible for intensive care treatment and oncologists are struggling to get their patients admitted to intensive care units. Critical care and oncology are frequently two separate worlds that communicate rarely and thus do not share novel developments in their fields. However, cancer medicine is rapidly improving and cancer is eventually becoming a chronic disease. Oncology is therefore characterized by a growing number of older and medically unfit patients that receive numerous novel drug classes with unexpected side effects.</p> <p>Discussion</p> <p>All of these changes will generate more medically challenging patients in acute distress that need to be considered for intensive care. An intense exchange between intensivists, oncologists, psychologists and palliative care specialists is warranted to communicate the developments in each field in order to improve triage and patient treatment. Here, we argue that "critical care of cancer patients" needs to be recognized as a medical subspecialty and that there is an urgent need to develop it systematically.</p> <p>Conclusion</p> <p>As prognosis of cancer improves, novel therapeutic concepts are being introduced and more and more older cancer patients receive full treatment the number of acutely ill patients is growing significantly. This development a major challenge to current concepts of intensive care and it needs to be redefined who of these patients should be treated, for how long and how intensively.</p

Defining Life: The Virus Viewpoint

Are viruses alive? Until very recently, answering this question was often negative and viruses were not considered in discussions on the origin and definition of life. This situation is rapidly changing, following several discoveries that have modified our vision of viruses. It has been recognized that viruses have played (and still play) a major innovative role in the evolution of cellular organisms. New definitions of viruses have been proposed and their position in the universal tree of life is actively discussed. Viruses are no more confused with their virions, but can be viewed as complex living entities that transform the infected cell into a novel organism—the virus—producing virions. I suggest here to define life (an historical process) as the mode of existence of ribosome encoding organisms (cells) and capsid encoding organisms (viruses) and their ancestors. I propose to define an organism as an ensemble of integrated organs (molecular or cellular) producing individuals evolving through natural selection. The origin of life on our planet would correspond to the establishment of the first organism corresponding to this definition

Cellular Proteins in Influenza Virus Particles

Virions are thought to contain all the essential proteins that govern virus egress from the host cell and initiation of replication in the target cell. It has been known for some time that influenza virions contain nine viral proteins; however, analyses of other enveloped viruses have revealed that proteins from the host cell can also be detected in virions. To address whether the same is true for influenza virus, we used two complementary mass spectrometry approaches to perform a comprehensive proteomic analysis of purified influenza virus particles. In addition to the aforementioned nine virus-encoded proteins, we detected the presence of 36 host-encoded proteins. These include both cytoplasmic and membrane-bound proteins that can be grouped into several functional categories, such as cytoskeletal proteins, annexins, glycolytic enzymes, and tetraspanins. Interestingly, a significant number of these have also been reported to be present in virions of other virus families. Protease treatment of virions combined with immunoblot analysis was used to verify the presence of the cellular protein and also to determine whether it is located in the core of the influenza virus particle. Immunogold labeling confirmed the presence of membrane-bound host proteins on the influenza virus envelope. The identification of cellular constituents of influenza virions has important implications for understanding the interactions of influenza virus with its host and brings us a step closer to defining the cellular requirements for influenza virus replication. While not all of the host proteins are necessarily incorporated specifically, those that are and are found to have an essential role represent novel targets for antiviral drugs and for attenuation of viruses for vaccine purposes

Microarray-Based Sketches of the HERV Transcriptome Landscape

Human endogenous retroviruses (HERVs) are spread throughout the genome and their long terminal repeats (LTRs) constitute a wide collection of putative regulatory sequences. Phylogenetic similarities and the profusion of integration sites, two inherent characteristics of transposable elements, make it difficult to study individual locus expression in a large-scale approach, and historically apart from some placental and testis-regulated elements, it was generally accepted that HERVs are silent due to epigenetic control. Herein, we have introduced a generic method aiming to optimally characterize individual loci associated with 25-mer probes by minimizing cross-hybridization risks. We therefore set up a microarray dedicated to a collection of 5,573 HERVs that can reasonably be assigned to a unique genomic position. We obtained a first view of the HERV transcriptome by using a composite panel of 40 normal and 39 tumor samples. The experiment showed that almost one third of the HERV repertoire is indeed transcribed. The HERV transcriptome follows tropism rules, is sensitive to the state of differentiation and, unexpectedly, seems not to correlate with the age of the HERV families. The probeset definition within the U3 and U5 regions was used to assign a function to some LTRs (i.e. promoter or polyA) and revealed that (i) autonomous active LTRs are broadly subjected to operational determinism (ii) the cellular gene density is substantially higher in the surrounding environment of active LTRs compared to silent LTRs and (iii) the configuration of neighboring cellular genes differs between active and silent LTRs, showing an approximately 8 kb zone upstream of promoter LTRs characterized by a drastic reduction in sense cellular genes. These gathered observations are discussed in terms of virus/host adaptive strategies, and together with the methods and tools developed for this purpose, this work paves the way for further HERV transcriptome projects

BMC Public Health

BACKGROUND: In 2009, the World Health Organization's Commission on Social Determinants of Health set out its recommendations for action, which included establishing equity from early childhood onwards by enabling all children and their mothers to benefit from a comprehensive package of quality programmes. In order to address social inequalities in health, it is recommended that action be taken from early childhood, and actions providing support for parenting are an effective lever in this respect. The aim of this review of systematic reviews is to analyse, on the one hand, the components and characteristics of effective interventions in parenting support and, on the other, the extent to which the reviews took into account social inequalities in health. METHODS: A total of 796 reviews were selected from peer-reviewed journals published between 2009 and 2016 in French or English. Of these, 21 reviews responding to the AMSTAR and selected ROBIS criteria were retained. These were analysed in relation to the consideration they gave to social inequalities in health according to PRISMA-equity. RESULTS: The reviews confirmed that parenting support programmes improved infants' sleep, increased mothers' self-esteem and reduced mothers' anger, anxiety and stress levels. The mainly authors noted that the contexts in which the interventions had taken place were described either scantly or not at all, making it difficult to evaluate them. Only half of the reviews had addressed the question of social inequalities in health. In particular, there had been little research conducted on the relational aspect and the social link. CONCLUSION: In terms of addressing social inequalities in perinatal health, the approach remains both modest and reductive. Understanding how, for whom and in what conditions interventions operate is one way of optimising their results. Further research is needed to study the interactions between the interventions and their contexts