Comparison of oxidative properties, light absorbance, total and elemental mass concentration of ambient PM2.5 collected at 20 European sites.

OBJECTIVE: It has been proposed that the redox activity of particles may represent a major determinant of their toxicity. We measured the in vitro ability of ambient fine particles [particulate matter with aerodynamic diameters<or=2.5 microm (PM2.5)] to form hydroxyl radicals (.OH) in an oxidant environment, as well as to deplete physiologic antioxidants (ascorbic acid, glutathione) in the naturally reducing environment of the respiratory tract lining fluid (RTLF). The objective was to examine how these toxicologically relevant measures were related to other PM characteristics, such as total and elemental mass concentration and light absorbance. DESIGN: Gravimetric PM2.5 samples (n=716) collected over 1 year from 20 centers participating in the European Community Respiratory Health Survey were available. Light absorbance of these filters was measured with reflectometry. PM suspensions were recovered from filters by vortexing and sonication before dilution to a standard concentration. The oxidative activity of these particle suspensions was then assessed by measuring their ability to generate .OH in the presence of hydrogen peroxide, using electron spin resonance and 5,5-dimethyl-1-pyrroline-N-oxide as spin trap, or by establishing their capacity to deplete antioxidants from a synthetic model of the RTLF. RESULTS AND CONCLUSION: PM oxidative activity varied significantly among European sampling sites. Correlations between oxidative activity and all other characteristics of PM were low, both within centers (temporal correlation) and across communities (annual mean). Thus, no single surrogate measure of PM redox activity could be identified. Because these novel measures are suggested to reflect crucial biologic mechanisms of PM, their use may be pertinent in epidemiologic studies. Therefore, it is important to define the appropriate methods to determine oxidative activity of PM

Association of MC1R Variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study

&lt;p&gt;&lt;b&gt;Background&lt;/b&gt; Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods&lt;/b&gt; We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, &#8805;2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Results&lt;/b&gt; Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10−6 &#8804; P &#8804; .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; Ptrend = 1.86 × 10−8). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 &#8804; P &#8804; .04), hair color (.006 &#8804; P &#8804; .06), and number of nevi (6.9 × 10−6 &#8804; P &#8804; .02).&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusion&lt;/b&gt; Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.&lt;/p&gt

Pathway-Based Analysis of a Melanoma Genome-Wide Association Study: Analysis of Genes Related to Tumour-Immunosuppression

Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (pemp = 0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (pemp = 0.006) and secretion of suppressive factors (pemp = 0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges

Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormonally active factors, gene polymorphisms, and gene expression: The NewGeneris cohort

Background: Leukemia incidence has increased in recent decades among European children, suggesting that early-life environmental exposures play an important role in disease development. Objectives: We investigated the hypothesis that childhood susceptibility may increase as a result of in utero exposure to carcinogens and hormonally acting factors. Using cord blood samples from the NewGeneris cohort, we examined associations between a range of biomarkers of carcinogen exposure and hormonally acting factors with micronuclei (MN) frequency as a proxy measure of cancer risk. Associations with gene expression and genotype were also explored. Methods: DNA and protein adducts, gene expression profiles, circulating hormonally acting factors, and GWAS (genome-wide association study) data were investigated in relation to genomic damage measured by MN frequency in lymphocytes from 623 newborns enrolled between 2006 and 2010 across Europe. Results: Malondialdehyde DNA adducts (M1dG) were associated with increased MN frequency in binucleated lymphocytes (MNBN), and exposure to androgenic, estrogenic, and dioxin-like compounds was associated with MN frequency in mononucleated lymphocytes (MNMONO), although no monotonic exposure-outcome relationship was observed. Lower frequencies of MNBN were associated with a 1-unit increase expression of PDCD11, LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was significantly higher in association with the highest versus lowest category of bulky and M1dG-DNA adducts for five and six genes, respectively. Gene expression levels were significantly lower for 11 genes in association with the highest versus lowest category of plasma AR CALUX® (chemically activated luciferase expression for androgens) (8 genes), ERα CALUX® (for estrogens) (2 genes), and DR CALUX® (for dioxins). Several SNPs (single-nucleotide polymorphisms) on chromosome 11 near FOLH1 significantly modified associations between androgen activity and MNBN frequency. Polymorphisms in EPHX1/2 and CYP2E1 were associated with MNBN. Conclusion: We measured in utero exposure to selected environmental carcinogens and circulating hormonally acting factors and detected associations with MN frequency in newborns circulating T lymphocytes. The results highlight mechanisms that may contribute to carcinogen-induced leukemia and require further research

International union of basic and clinical pharmacology. LXXXIV: leukotriene receptor nomenclature, distribution, and pathophysiological functions

The seven-transmembrane G protein-coupled receptors activated by leukotrienes are divided into two subclasses based on their ligand specificity for either leukotriene B(4) or the cysteinyl leukotrienes (LTC(4), LTD(4), and LTE(4)). These receptors have been designated BLT and CysLT receptors, respectively, and a subdivision into BLT(1) and BLT(2) receptors and CysLT(1) and CysLT(2) receptors has been established. However, recent findings have also indicated the existence of putative additional leukotriene receptor subtypes. Furthermore, other ligands interact with the leukotriene receptors. Finally, leukotrienes may also activate other receptor classes, such as purinergic receptors. The aim of this review is to provide an update on the pharmacology, expression patterns, and pathophysiological roles of the leukotriene receptors as well as the therapeutic developments in this area of research

Recommendations for epidemiological studies on COPD

International audienceThe prevalence of chronic obstructive pulmonary disease (COPD) has been extensively studied, especially in Western Europe and North America. Few of these data are directly comparable because of differences between the surveys regarding composition of study populations, diagnostic criteria of the disease and definitions of the risk factors. Few community studies have examined phenotypes of COPD and included other ways of characterising the disease beyond that of spirometry. The objective of the present Task Force report is to present recommendations for the performance of general population studies in COPD in order to facilitate comparable and valid estimates on COPD prevalence by various risk factors. Diagnostic criteria in epidemiological settings, and standardised methods to examine the disease and its potential risk factors are discussed. The paper also offers practical advice for planning and performing an epidemiological study on COPD. The main message of the paper is that thorough planning is worth half the study. It is crucial to stick to standardised methods and good quality control during sampling. We recommend collecting biological markers, depending on the specific objectives of the study. Finally, studies of COPD in the population at large should assess various phenotypes of the disease

Antibiotic research and development: business as usual?

The global burden of antibiotic resistance is tremendous and, without new anti-infective strategies, will continue to increase in the coming decades. Despite the growing need for new antibiotics, few pharmaceutical companies today retain active antibacterial drug discovery programmes. One reason is that it is scientifically challenging to discover new antibiotics that are active against the antibiotic-resistant bacteria of current clinical concern. However, the main hurdle is diminishing economic incentives. Increased global calls to minimize the overuse of antibiotics, the cost of meeting regulatory requirements and the low prices of currently marketed antibiotics are strong deterrents to antibacterial drug development programmes. New economic models that create incentives for the discovery of new antibiotics and yet reconcile these incentives with responsible antibiotic use are long overdue. DRIVE-AB is a \u20ac9.4 million public-private consortium, funded by the EU Innovative Medicines Initiative, that aims to define a standard for the responsible use of antibiotics and to develop, test and recommend new economic models to incentivize investment in producing new anti-infective agents

Experimental access to Transition Distribution Amplitudes with the P̄ANDA experiment at FAIR

Baryon-to-meson Transition Distribution Amplitudes (TDAs) encoding valuable new information on hadron structure appear as building blocks in the collinear factorized description for several types of hard exclusive reactions. In this paper, we address the possibility of accessing nucleon-to-pion (\u3c0N) TDAs from \uafpp \u2192 e+e 12\u3c00 reaction with the future PANDA detector at the FAIR facility. At high center- of-mass energy and high invariant mass squared of the lepton pair q2, the amplitude of the signal channel pp\uaf \u2192 e+e 12\u3c00 admits a QCD factorized description in terms of \u3c0N TDAs and nucleon Distribution Amplitudes (DAs) in the forward and backward kinematic regimes. Assuming the validity of this factorized description, we perform feasibility studies for measuring \uafpp \u2192 e+e 12\u3c00 with the PANDA detector. Detailed simulations on signal reconstruction efficiency as well as on rejection of the most severe background channel, i.e. pp\uaf \u2192 \u3c0+\u3c0 12\u3c00 were performed for the center-of-mass energy squared s = 5 GeV2 and s = 10 GeV2, in the kinematic regions 3.0 0.5 in the proton-antiproton center-of-mass frame. Results of the simulation show that the particle identification capabilities of the PANDA detector will allow to achieve a background rejection factor of 5 \ub7 107 (1 \ub7 107) at low (high) q2 for s = 5 GeV2, and of 1 \ub7 108 (6 \ub7 106) at low (high) q2 for s = 10 GeV2, while keeping the signal reconstruction efficiency at around 40%. At both energies, a clean lepton signal can be reconstructed with the expected statistics corresponding to 2 fb 121 of integrated luminosity. The cross sections obtained from the simulations are used to show that a test of QCD collinear factorization can be done at the lowest order by measuring scaling laws and angular distributions. The future measurement of the signal channel cross section with PANDA will provide a new test of the perturbative QCD description of a novel class of hard exclusive reactions and will open the possibility of experimentally accessing \u3c0N TDAs

GEMAS: Indium in agricultural and grazing land soil of Europe - Its source and geochemical distribution patterns

Indium is a very rare element, which is usually not reported in geochemical data sets. It is classified as a critical metal, with important applications in the electronics industry, especially in the production of solar panels and liquid-crystal displays (LCDs).Over 4000 samples of agricultural and grazing land soil have been collected for the "Geochemical Mapping of Agricultural and Grazing Land Soil of Europe" (GEMAS) project, carried out by the EuroGeoSurveys Geochemistry Expert Group. Indium concentrations in soil have been analysed using aqua regia extraction followed by ICP-MS. Median values of In for both land use types are nearly identical, 0.0176. mg/kg for agricultural soil and 0.0177. mg/kg for grazing land soil.The spatial distribution patterns of In in European soil are mainly controlled by geology and the presence of Zn and Sn mineralisation. The preference of In to accumulate in the fine-grained fraction of soil with high clay content dominates the major anomaly patterns on the geochemical maps. In the Mediterranean region, secondary In enrichment is visible in karst areas. A notable feature of the In spatial distribution is the large difference between northern and southern Europe, with median values of 0.012 and 0.021. mg. In/kg, respectively, suggesting that, in addition to lithology, weathering and climate are important factors influencing In soil enrichment over time. \ua9 2015 Elsevier B.V