Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Preliminary Results from the Software Product Management State-of-Practice Survey

Software product management (SPM) as a discipline includes many practices like product and release planning, market analysis, roadmapping, and product lifecycle management. Product management frameworks prescribe these practices but companies seldom adopt all of them. We conducted a state-of-practice survey with the aim to investigate how companies adopt SPM practices and how this practical experience fits together with the framework suggested by International Software Product Management Association (ISPMA). The results of this study showed that ISPMA SPM Framework describes core product management practices well but the impact of product management practices to the final product success remains ambiguous

Experimental validation of a risk assessment method

[Context and motivation] It is desirable that requirement engineering methods are reliable, that is, that methods can be repeated with the same results. Risk assessments methods, however, often have low reliability when they identify risk mitigations for a system based on expert judgement. [Question/problem] Our goal is to assess the reliability of an availability risk assessment method for telecominfrastructures, and to identify possibilities for improvement of its reliability. [Principal ideas/results] We propose an experimental validation of reliability, and report on its application. We give a detailed analysis of sources of variation, explain how we controlled them and validated their mitigations, and motivate the statistical procedure used to analyse the outcome. [Contribution] Our results can be used to improve the reliability of risk assessment methods. Our approach to validating reliability can be useful for the assessment of the reliability of other methods. Keywords: Reliability; Risk assessment; Expert judgement; Experiment design; Telecommunication

Short- and long-term influences of heavy metals on anionic drug efflux from renal proximal tubule.

We recently demonstrated in isolated killifish renal proximal tubules that two classes of nephrotoxicants, aminoglycoside antibiotics and radiocontrast agents, rapidly decrease transport mediated by multidrug resistance protein 2 (Mrp2) by causing endothelin (ET) release and signaling through an ET(B) receptor and protein kinase C (PKC). In the present study, we used killifish proximal tubules, fluorescein methotrexate, a fluorescent model substrate for Mrp2, and confocal microscopy to examine the effects of two heavy metal salts (CdCl(2) and HgCl(2)) on Mrp2 function. Three patterns of effects were seen. First, exposing tubules to 10 microM CdCl(2) or 100 nM HgCl(2) for 30 min reduced Mrp2-mediated transport. This reduction was abolished by the ET(B) receptor antagonist, RES-701-1, and by the PKC-selective inhibitor, bis-indolylmaleimide I; neither of these pharmacological tools by itself affected transport. As with aminoglycoside antibiotics and radiocontrast agents, the acute effects of 10 microM CdCl(2) or 100 nM HgCl(2) on transport were also blocked by nifedipine, suggesting that Ca(2+) also initiated cadmium and mercury action. Second, exposure to higher concentrations of CdCl(2) and HgCl(2) appeared to be toxic. Third, exposing tubules for 6 to 24 h to lower levels of CdCl(2) increased Mrp2-mediated transport and Mrp2 immunostaining at the luminal membrane of the proximal tubule cells. Together, these findings indicate that exposure of renal proximal tubules to heavy metals initially leads to reduced Mrp2 function but is followed by an induction in Mrp2-mediated transport after long-term exposure