Biology of advanced uveal melanoma and next steps for clinical therapeutics

Uveal melanoma is the most common intraocular malignancy although it is a rare subset of all melanomas. Uveal melanoma has distinct biology relative to cutaneous melanoma, with widely divergent patient outcomes. Patients diagnosed with a primary uveal melanoma can be stratified for risk of metastasis by cytogenetics or gene expression profiling, with approximately half of patients developing metastatic disease, predominately hepatic in location, over a 15-yr period. Historically, no systemic therapy has been associated with a clear clinical benefit for patients with advanced disease, and median survival remains poor. Here, as a joint effort between the Melanoma Research Foundation's ocular melanoma initiative, CURE OM and the National Cancer Institute, the current understanding of the molecular and immunobiology of uveal melanoma is reviewed, and on-going laboratory research into the disease is highlighted. Finally, recent investigations relevant to clinical management via targeted and immunotherpies are reviewed, and next steps in the development of clinical therapeutics are discussed

9-Genes Reinforce the Phylogeny of Holometabola and Yield Alternate Views on the Phylogenetic Placement of Strepsiptera

Background: The extraordinary morphology, reproductive and developmental biology, and behavioral ecology of twisted wing parasites (order Strepsiptera) have puzzled biologists for centuries. Even today, the phylogenetic position of these enigmatic “insects from outer space” [1] remains uncertain and contentious. Recent authors have argued for the placement of Strepsiptera within or as a close relative of beetles (order Coleoptera), as sister group of flies (order Diptera), or even outside of Holometabola.Methodology/Principal Findings Here, we combine data from several recent studies with new data (for a total of 9 nuclear genes and ∼13 kb of aligned data for 34 taxa), to help clarify the phylogenetic placement of Strepsiptera. Our results unequivocally support the monophyly of Neuropteroidea ( = Neuropterida + Coleoptera) + Strepsiptera, but recover Strepsiptera either derived from within polyphagan beetles (order Coleoptera), or in a position sister to Neuropterida. All other supra-ordinal- and ordinal-level relationships recovered with strong nodal support were consistent with most other recent studies. Conclusions/Significance: These results, coupled with the recent proposed placement of Strepsiptera sister to Coleoptera, suggest that while the phylogenetic neighborhood of Strepsiptera has been identified, unequivocal placement to a specific branch within Neuropteroidea will require additional study.Organismic and Evolutionary Biolog

Incentive motivation in first-episode psychosis: A behavioural study

<p>Abstract</p> <p>Background:</p> <p>It has been proposed that there are abnormalities in incentive motivational processing in psychosis, possibly secondary to subcortical dopamine abnormalities, but few empirical studies have addressed this issue.</p> <p>Methods:</p> <p>We studied incentive motivation in 18 first-episode psychosis patients from the Cambridge early psychosis service CAMEO and 19 control participants using the Cued Reinforcement Reaction Time Task, which measures motivationally driven behaviour. We also gathered information on participants' attentional, executive and spatial working memory function in order to determine whether any incentive motivation deficits were secondary to generalised cognitive impairment.</p> <p>Results:</p> <p>We demonstrated the anticipated "reinforcement-related speeding" effect in controls (17 out of 19 control participants responded faster during an "odd-one-out" task in response to a cue that indicated a high likelihood of a large points reward). Only 4 out of 18 patients showed this effect and there was a significant interaction effect between reinforcement probability and diagnosis on reaction time (F_1,35= 14.2, p = 0.001). This deficit was present in spite of preserved executive and attentional function in patients, and persisted even in antipsychotic medication free patients.</p> <p>Conclusion:</p> <p>There are incentive motivation processing abnormalities in first-episode psychosis; these may be secondary to dopamine dysfunction and are not attributable to generalised cognitive impairment.</p

Bioavailability in soils

The consumption of locally-produced vegetables by humans may be an important exposure pathway for soil contaminants in many urban settings and for agricultural land use. Hence, prediction of metal and metalloid uptake by vegetables from contaminated soils is an important part of the Human Health Risk Assessment procedure. The behaviour of metals (cadmium, chromium, cobalt, copper, mercury, molybdenum, nickel, lead and zinc) and metalloids (arsenic, boron and selenium) in contaminated soils depends to a large extent on the intrinsic charge, valence and speciation of the contaminant ion, and soil properties such as pH, redox status and contents of clay and/or organic matter. However, chemistry and behaviour of the contaminant in soil alone cannot predict soil-to-plant transfer. Root uptake, root selectivity, ion interactions, rhizosphere processes, leaf uptake from the atmosphere, and plant partitioning are important processes that ultimately govern the accumulation ofmetals and metalloids in edible vegetable tissues. Mechanistic models to accurately describe all these processes have not yet been developed, let alone validated under field conditions. Hence, to estimate risks by vegetable consumption, empirical models have been used to correlate concentrations of metals and metalloids in contaminated soils, soil physico-chemical characteristics, and concentrations of elements in vegetable tissues. These models should only be used within the bounds of their calibration, and often need to be re-calibrated or validated using local soil and environmental conditions on a regional or site-specific basis.Mike J. McLaughlin, Erik Smolders, Fien Degryse, and Rene Rietr

Vitamin D deficiency and anemia: a cross-sectional study

Vitamin D has been suggested to have an effect on erythropoiesis. We sought to evaluate the prevalence of anemia in a population of individuals with vitamin D deficiency compared with those with normal levels in a population of a large integrated healthplan. A cross-sectional analysis in the period 1 January 2004 through 31 December 2006 of subjects with documented concurrent levels of 25-hydroxyvitamin D and hemoglobin were evaluated. Vitamin D deficiency was defined as <30 ng/mL and anemia was defined as a hemoglobin <11 g/dL. A total of 554 subjects were included in the analysis. Anemia was present in 49% of 25-hydroxyvitamin D-deficient subjects compared with 36% with normal 25-hydroxyvitamin D levels (p < 0.01). Odds ratio for anemia in subjects with 25-hydroxyvitamin D deficiency using logistic regressions and controlling for age, gender, and chronic kidney disease was 1.9 (95% CI 1.3–2.7). 25-hydroxyvitamin D-deficient subjects had a lower mean Hb (11.0 vs. 11.7; p = 0.12 ) and a higher prevalence of erythrocyte stimulating agent use (47% vs. 24%; p < 0.05). This study demonstrates an association of vitamin D deficiency and a greater risk of anemia, lower mean hemoglobin, and higher usage of erythrocyte-stimulating agents. Future randomized studies are warranted to examine whether vitamin D directly affects erythropoiesis

Measurement of D-s(+) and D-s(*+) production in B meson decays and from continuum e(+)e(-) annihilation at √s=10.6 GeV

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APSNew measurements of Ds+ and Ds*+ meson production rates from B decays and from qq̅ continuum events near the Υ(4S) resonance are presented. Using 20.8 fb-1 of data on the Υ(4S) resonance and 2.6 fb-1 off-resonance, we find the inclusive branching fractions B(B⃗Ds+X)=(10.93±0.19±0.58±2.73)% and B(B⃗Ds*+X)=(7.9±0.8±0.7±2.0)%, where the first error is statistical, the second is systematic, and the third is due to the Ds+→φπ+ branching fraction uncertainty. The production cross sections σ(e+e-→Ds+X)×B(Ds+→φπ+)=7.55±0.20±0.34pb and σ(e+e-→Ds*±X)×B(Ds+→φπ+)=5.8±0.7±0.5pb are measured at center-of-mass energies about 40 MeV below the Υ(4S) mass. The branching fractions ΣB(B⃗Ds(*)+D(*))=(5.07±0.14±0.30±1.27)% and ΣB(B⃗Ds*+D(*))=(4.1±0.2±0.4±1.0)% are determined from the Ds(*)+ momentum spectra. The mass difference m(Ds+)-m(D+)=98.4±0.1±0.3MeV/c2 is also measured.This work was supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the Swiss NSF, A. P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

Search for rare quark-annihilation decays, B --> Ds(*) Phi

We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context of the Standard Model, these decays are expected to be highly suppressed since they proceed through annihilation of the b and u-bar quarks in the B- meson. Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected with the BABAR detector at SLAC. We find no evidence for these decays, and we set Bayesian 90% confidence level upper limits on the branching fractions BF(B- --> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid Communications

Psip1/p52 regulates posterior Hoxa genes through activation of lncRNA Hottip

Long noncoding RNAs (lncRNAs) have been implicated in various biological functions including the regulation of gene expression, however, the functionality of lncRNAs is not clearly understood and conflicting conclusions have often been reached when comparing different methods to investigate them. Moreover, little is known about the upstream regulation of lncRNAs. Here we show that the short isoform (p52) of a transcriptional co-activator—PC4 and SF2 interacting protein (Psip1), which is known to be involved in linking transcription to RNA processing, specifically regulates the expression of the lncRNA Hottip–located at the 5’ end of the Hoxa locus. Using both knockdown and knockout approaches we show that Hottip expression is required for activation of the 5’ Hoxa genes (Hoxa13 and Hoxa10/11) and for retaining Mll1 at the 5’ end of Hoxa. Moreover, we demonstrate that artificially inducing Hottip expression is sufficient to activate the 5’ Hoxa genes and that Hottip RNA binds to the 5’ end of Hoxa. By engineering premature transcription termination, we show that it is the Hottip lncRNA molecule itself, not just Hottip transcription that is required to maintains active expression of posterior Hox genes. Our data show a direct role for a lncRNA molecule in regulating the expression of developmentally-regulated mRNA genes in cis

After the floods: Differential impacts of rainfall anomalies on child stunting in India

none2si• Excessive rainfall increases the risk of child stunting in India. • Children from socially disadvantaged households display higher vulnerability to such shocks. • Investment in women’s education can significantly reduce the risk of child stunting.openDimitrova A.; Muttarak R.Dimitrova A.; Muttarak R