FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK

The exceptionally powerful TeV gamma-ray emitters in the Large Magellanic Cloud

The Large Magellanic Cloud, a satellite galaxy of the Milky Way, has been observed with the High Energy Stereoscopic System (H.E.S.S.) above an energy of 100 billion electron volts for a deep exposure of 210 hours. Three sources of different types were detected: the pulsar wind nebula of the most energetic pulsar known N 157B, the radio-loud supernova remnant N 132D and the largest non-thermal X-ray shell - the superbubble 30 Dor C. The unique object SN 1987A is, surprisingly, not detected, which constrains the theoretical framework of particle acceleration in very young supernova remnants. These detections reveal the most energetic tip of a gamma-ray source population in an external galaxy, and provide via 30 Dor C the unambiguous detection of gamma-ray emission from a superbubble.Comment: Published in Science Magazine (Jan. 23, 2015). This ArXiv version has the supplementary online material incorporated as an appendix to the main pape

Employing the Metabolic “Branch Point Effect” to Generate an All-or-None, Digital-like Response in Enzymatic Outputs and Enzyme-Based Sensors

Here, we demonstrate a strategy to convert the graded Michaelis−Menten response typical of unregulated enzymes into a sharp, effectively all-or-none response. We do so using an approach analogous to the “branch point effect”, a mechanism observed in naturally occurring metabolic networks in which two or more enzymes compete for the same substrate. As a model system, we used the enzymatic reaction of glucose oxidase (GOx) and coupled it to a second, nonsignaling reaction catalyzed by the higher affinity enzyme hexokinase (HK) such that, at low substrate concentrations, the second enzyme outcompetes the first, turning off the latter’s response. Above an arbitrarily selected “threshold” substrate concentration, the nonsignaling HK enzyme saturates leading to a “sudden” activation of the first signaling GOx enzyme and a far steeper dose−response curve than that observed for simple Michaelis−Menten kinetics. Using the well-known GOx-based amperometric glucose sensor to validate our strategy, we have steepen the normally graded response of this enzymatic sensor into a discrete yes/no output similar to that of a multimeric cooperative enzyme with a Hill coefficient above 13. We have also shown that, by controlling the HK reaction we can precisely tune the threshold target concentration at which we observe the enzyme output. Finally, we demonstrate the utility of this strategy for achieving effective noise attenuation in enzyme logic gates. In addition to supporting the development of biosensors with digital-like output, we envisage that the use of all-or-none enzymatic responses will also improve our ability to engineer efficient enzyme-based catalysis reactions in synthetic biology applications

A Customized Pigmentation SNP Array Identifies a Novel SNP Associated with Melanoma Predisposition in the SLC45A2 Gene

As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P<0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value<0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date

Regulatory T cells and their role in rheumatic diseases: a potential target for novel therapeutic development

Regulatory T cells have an important role in limiting immune reactions and are essential regulators of self-tolerance. Among them, CD4+CD25high regulatory T cells are the best-described subset. In this article, we summarize current knowledge on the phenotype, function, and development of CD4+CD25high regulatory T cells. We also review the literature on the role of these T cells in rheumatic diseases and discuss the potential for their use in immunotherapy

Optimization of Enzymatic Biochemical Logic for Noise Reduction and Scalability: How Many Biocomputing Gates Can Be Interconnected in a Circuit?

We report an experimental evaluation of the "input-output surface" for a biochemical AND gate. The obtained data are modeled within the rate-equation approach, with the aim to map out the gate function and cast it in the language of logic variables appropriate for analysis of Boolean logic for scalability. In order to minimize "analog" noise, we consider a theoretical approach for determining an optimal set for the process parameters to minimize "analog" noise amplification for gate concatenation. We establish that under optimized conditions, presently studied biochemical gates can be concatenated for up to order 10 processing steps. Beyond that, new paradigms for avoiding noise build-up will have to be developed. We offer a general discussion of the ideas and possible future challenges for both experimental and theoretical research for advancing scalable biochemical computing

Design concepts for the Cherenkov Telescope Array CTA: an advanced facility for ground-based high-energy gamma-ray astronomy

Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA

Constraints on axionlike particles with H.E.S.S. from the irregularity of the PKS 2155-304 energy spectrum

Axionlike particles (ALPs) are hypothetical light (sub-eV) bosons predicted in some extensions of the Standard Model of particle physics. In astrophysical environments comprising high-energy gamma rays and turbulent magnetic fields, the existence of ALPs can modify the energy spectrum of the gamma rays for a sufficiently large coupling between ALPs and photons. This modification would take the form of an irregular behavior of the energy spectrum in a limited energy range. Data from the H.E.S.S. observations of the distant BL Lac object PKS 2155-304 (z=0.116) are used to derive upper limits at the 95% C.L. on the strength of the ALP coupling to photons, ggammaa<2.1×10-11GeV-1 for an ALP mass between 15 and 60 neV. The results depend on assumptions on the magnetic field around the source, which are chosen conservatively. The derived constraints apply to both light pseudoscalar and scalar bosons that couple to the electromagnetic fieldFil: Medina, Maria Clementina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto Argentino de Radioastronomia (i); ArgentinaFil: H.E.S. S. collaboration

7th Drug hypersensitivity meeting: part two

No abstract availabl