Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

PurposeBRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigatedfor the first time to our knowledgeassociations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction.Materials and MethodsWe genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights.ResultsIn male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 x 10(-6)). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 x 10(-9)). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively.ConclusionPRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.Peer reviewe

Hepatic alterations are accompanied by changes to bile acid transporter-expressing neurons in the hypothalamus after traumatic brain injury

Annually, there are over 2 million incidents of traumatic brain injury (TBI) and treatment options are non-existent. While many TBI studies have focused on the brain, peripheral contributions involving the digestive and immune systems are emerging as factors involved in the various symptomology associated with TBI. We hypothesized that TBI would alter hepatic function, including bile acid system machinery in the liver and brain. The results show activation of the hepatic acute phase response by 2 hours after TBI, hepatic inflammation by 6 hours after TBI and a decrease in hepatic transcription factors, Gli 1, Gli 2, Gli 3 at 2 and 24 hrs after TBI. Bile acid receptors and transporters were decreased as early as 2 hrs after TBI until at least 24 hrs after TBI. Quantification of bile acid transporter, ASBT-expressing neurons in the hypothalamus, revealed a significant decrease following TBI. These results are the first to show such changes following a TBI, and are compatible with previous studies of the bile acid system in stroke models. The data support the emerging idea of a systemic influence to neurological disorders and point to the need for future studies to better define specific mechanisms of action

Demarcating wetting states in textured microchannels under flow conditions by Poiseuille number

In this work, flow friction in microchannels decorated with micropillars was investigated experimentally, with an interest to understand the wetting transition through two simple means: Poiseuille number and scaling laws. Different wetting states were demarcated by qualitatively assessing the behaviour of Poiseuille number (Po = f.Re, where f is friction factor and Re is Reynolds number), which are further corroborated by confocal microscopy-based measurements and numerical simulations. The wetting transition ensued smoothly with an increase in Re, independent of the gas fraction (a ratio of area covered by the liquid-gas interface to the total projected area), for moderate gas fractions, whereas an early breakdown of the Cassie-Baxter state occurred irrespective of Re at high gas fractions. Additionally, the scaling laws were found to correlate well with the underlying state of the flow. Our observations revealed that the liquid-gas interface exhibits a partial slip, contrary to the common notion that it is shear free. It is inferred that an increase in effective flow area leads to a reduction in flow friction in textured microchannels. The present work underlines three important outcomes. The first is the identification of wetting states in flow conditions shown by tracking the Poiseuille number. The second is that the liquid-gas interface is deduced to behave like a partial slip boundary. The third is that a textured microchannel can be worse than an enlarged dimension microchannel

Slippage on a particle-laden liquid-gas interface in textured microchannels

Despite numerous investigations in the literature on slip flows in textured microchannels, experimental results were seldom in agreement with the theory. It is conjectured that contamination of the liquid-gas interface by impurities might be one of the sources of this discrepancy. However, the effect of impurities on slippage at the liquid-gas interface is neither understood nor previously reported. To this end, this work presents numerical investigation on the flow past a liquid-gas interface embedded with solid particles in textured microchannels. Initially, we present numerical simulations past transverse ribs with cylindrical particles on the liquid-gas interface. A reduction in effective slip length (or slip loss) with respect to the particle-free interface as a function of gas fraction, constriction ratio, and particle position was quantified. A significant slip loss (similar to 20-80%) was induced, owing to acceleration-deceleration cycles experienced by the liquid advecting across the particle-laden liquid-gas interface. Even a small number of solid particles adsorbed on a liquid-gas interface were shown to reduce the effective slip length considerably. This renders a textured microchannel with the particle-laden interface to be ineffective as compared to a completely wetted textured microchannel under certain conditions. Furthermore, a flow past two bi-dimensional textures, viz. posts and holes, with their interfaces embedded with spherical particles was also simulated. Our results show that texture configurations with an unbounded liquid-gas interface can mitigate the detrimental effects of particles adsorbed at the interface. The results presented here will help guide in designing efficient textured surfaces in future. Published by AIP Publishing