Interaction among apoptosis-associated sequence variants and joint effects on aggressive prostate cancer

<p>Abstract</p> <p>Background</p> <p>Molecular and epidemiological evidence demonstrate that altered gene expression and single nucleotide polymorphisms in the apoptotic pathway are linked to many cancers. Yet, few studies emphasize the interaction of variant apoptotic genes and their joint modifying effects on prostate cancer (PCA) outcomes. An exhaustive assessment of all the possible two-, three- and four-way gene-gene interactions is computationally burdensome. This statistical conundrum stems from the prohibitive amount of data needed to account for multiple hypothesis testing.</p> <p>Methods</p> <p>To address this issue, we systematically prioritized and evaluated individual effects and complex interactions among 172 apoptotic SNPs in relation to PCA risk and aggressive disease (i.e., Gleason score ≥ 7 and tumor stages III/IV). Single and joint modifying effects on PCA outcomes among European-American men were analyzed using statistical epistasis networks coupled with multi-factor dimensionality reduction (SEN-guided MDR). The case-control study design included 1,175 incident PCA cases and 1,111 controls from the prostate, lung, colo-rectal, and ovarian (PLCO) cancer screening trial. Moreover, a subset analysis of PCA cases consisted of 688 aggressive and 488 non-aggressive PCA cases. SNP profiles were obtained using the NCI Cancer Genetic Markers of Susceptibility (CGEMS) data portal. Main effects were assessed using logistic regression (LR) models. Prior to modeling interactions, SEN was used to pre-process our genetic data. SEN used network science to reduce our analysis from > 36 million to < 13,000 SNP interactions. Interactions were visualized, evaluated, and validated using entropy-based MDR. All parametric and non-parametric models were adjusted for age, family history of PCA, and multiple hypothesis testing.</p> <p>Results</p> <p>Following LR modeling, eleven and thirteen sequence variants were associated with PCA risk and aggressive disease, respectively. However, none of these markers remained significant after we adjusted for multiple comparisons. Nevertheless, we detected a modest synergistic interaction between <it>AKT3 rs2125230-PRKCQ rs571715 </it>and disease aggressiveness using SEN-guided MDR (p = 0.011).</p> <p>Conclusions</p> <p>In summary, entropy-based SEN-guided MDR facilitated the logical prioritization and evaluation of apoptotic SNPs in relation to aggressive PCA. The suggestive interaction between <it>AKT3-PRKCQ </it>and aggressive PCA requires further validation using independent observational studies.</p

Increasing duration of heatwaves poses a threat to oyster sustainability in the Gulf of Mexico

The future of the wild oyster fishery in the northern Gulf of Mexico is largely uncertain due to changing environmental conditions and declining abundance of harvestable oysters. Specifically, rising temperatures can directly impact the physiological thresholds of the eastern oyster (Crassostrea virginica) at all life history stages and alter the narrow ecological niche this oyster occupies. The impact of rising temperatures is likely most pronounced during atmospheric heatwaves, defined as three or more days above the 90th percentile of daily maximum air temperatures, which have been shown to be increasing in frequency. Increasing exposure to high temperature extremes may contribute to and exacerbate an already declining oyster fishery. Critical to fishery health is recruitment i.e., the addition of new harvestable biomass, which is a dynamic process strongly driven by temperature. Here, we examine the relationship between heatwave characteristics and the prediction of poor oyster recruitment, measured as the abundance of post-larval oysters (e.g. spat) below the site-specific median density observed in historically productive oyster fisheries over 46-years (1976 – 2020) in Mobile Bay, Alabama and 21-years (1993 – 2014) in Apalachicola Bay, Florida. We acquired daily maximum air temperature measurements measured over 50 years (1970 – 2020) at weather monitoring stations adjacent to the bays to identify site specific annual heatwave events (maximum yearly air temperature, yearly and consecutive heatwave days, and number of annual heatwaves). Then, years with extreme heatwaves that exceeded the 75th percentile for the 50-year measurements were compared to years with non-extreme heatwave events. Years with extreme total heatwave days and extreme consecutive heatwave days were correlated with low post-larval oyster density. Across both bay systems, if consecutive heatwave days exceeded 11 days, then poor recruitment of oysters occurred 83 % of the time. Extreme heatwave duration as an indicator for poor recruitment has the potential to be a powerful tool for fishery managers to forecast recruitment and inform sustainable oyster harvest based on year-to-year variability in heatwave duration and long-term warming trends. Our findings illustrate how extreme temperatures can exacerbate multiple physiological and ecological stressors resulting in the loss of a keystone species for healthy and resilient coastal ecosystems