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Finally, we observe no footprint of positive selection on P-element insertions in piRNA clusters, suggesting that the rapid evolution of piRNA-mediated repression in D. melanogaster was driven primarily by mutation. Our results reveal for the first time how the unique genetic architecture of piRNA production, in which numerous piRNA clusters can encode regulatory small RNAs upon transpositional insertion, facilitates the non-adaptive rapid evolution of repression. Published by Cold Spring Harbor Laboratory Press.In the central nervous system, melastatin transient receptor potential (TRPM) channels function as receptors for the neurosteroid pregnenolone sulfate (PregS). The expression and function of TRPM3 has been explored in adult retina, though its role during development is unknown. We found, during the second postnatal week in mice, TRPM3 immunofluorescence labeled distinct subsets of inner retinal neurons, including a subset of retinal ganglion cells (RGCs), similar to what has been reported in the adult. Labeling for a TRPM3 promoter-driven reporter confirmed expression of the TRPM3 gene in RGCs and revealed additional expression in nearly all Müller glial cells. Using two-photon calcium imaging, we show that PregS and the synthetic TRPM3 agonist CIM0216 induced prolonged calcium transients in RGCs, which were mostly absent in TRPM3 knockout (KO) mice. These prolonged calcium transients were not associated with strong membrane depolarizations but induced cFOS expression. To elucidate the impact of PregS-activat3 responds to PregS, producing prolonged calcium transients in a subset of retinal ganglion cells (RGCs) and increasing the frequency of spontaneous synaptic current onto RGCs. The PregS-mediated increase in spontaneous synaptic activity was absent in the TRPM3 KO retina. In addition, the absence of TRPM3 signaling reduced wave frequency. Thus, we show that TRPM3 and the endogenous neurosteroid, PregS, function in modulating spontaneous activity in the retina during development. Copyright © 2020 Webster et al.BACKGROUND The underlying etiology of colorectal cancer (CRC) includes both genetic variation and environmental exposures. The main aim of this study was to search for interaction effects between well-established environmental risk factors and published common genetic variants exerting main effects on CRC risk. METHODS We used a two-phase approach (i) Discovery phase (2,652 incident CRC cases and 10,608 controls from UK Biobank) and (ii) Validation phase (1,656 cases and 2,497 controls from the Study of Colorectal Cancer in Scotland). Interactions with nominal P less then 0.05 in phase I were taken forward for validation in phase II. Furthermore, we constructed a weighted genetic risk score (GRS) of CRC risk for each individual and studied interactions between the GRS and the environmental risk factors. RESULTS Seventy of the 1,500 tested interactions were nominally significant in phase I. After testing these 70 interactions in phase II, an interaction between rs11903757 (2q32.3/NABP1) and body mass index (BMI) was nominally significant (P=0.02) with the same direction of effects. The rs11903757*BMI interaction was also significant (ratio of odds ratios =1.26; 95% CI, 1.10-1.44; Pinteraction=6.03×10-4; Pheterogeneity=0.63) in a meta-analysis combining results from both phases. No interactions were significant in phase II after accounting for multiple testing. No interactions involving the GRS were found with statistical significance. [https://www.selleckchem.com/products/blasticidin-s-hcl.html this website] CONCLUSIONS Limited evidence of gene-environment interactions in CRC risk was observed. There are potential modifications of the rs11903757 effect by BMI on CRC risk. IMPACT Our findings might contribute to identifying subpopulations with different susceptibility to the effect of BMI on CRC risk. Copyright ©2020, American Association for Cancer Research.BACKGROUND Several oncogenic signals are involved in the synthesis, metabolism, transportation and modulation of cholesterol. However, the roles of genetic variants of the cholesterol pathway genes in cancer survival remain unclear. METHODS We investigated associations between 26,781 common single-nucleotide polymorphisms (SNPs) in 209 genes of the cholesterol pathway and non-small cell lung cancer (NSCLC) survival by utilizing genotyping datasets from two published genome-wide association studies (GWASs). We used multivariate Cox proportional hazards regression and expression quantitative trait loci (eQTL) analyses to identify survival-associated SNPs and their correlations with the corresponding mRNA expression, respectively. We also used Kaplan-Meier survival analysis and bioinformatics functional prediction to further evaluate the identified independent SNPs. RESULTS We found five independent SNPs (APOB rs1801701C&gt;T; CDH13 rs35859010 C&gt;T, rs1833970 T&gt;A, rs254315 T&gt;C and rs425904 T&gt;C) to be significantly associated with NSCLC survival in both discovery and replication datasets. When the unfavorable genotype (APOB rs1801701CC) and haplotypes (CDH13 rs35859010-rs1833970-rs254315-rs425904 C-A-T-C and T-T-T-T) were combined into a genetic score as the number of unfavorable genotypes/haplotypes (NUGH) in the multivariate analysis, an increased NUGH was associated with a worse survival (Ptrend less then 0.0001). In addition, both APOB rs1801701T less then C and CDH13 rs425904C less then T were correlated with mRNA expression of the genes in normal lung tissues from the genotype-tissue expression (GTEx) project. CONCLUSIONS Genetic variants of APOB and CDH13 in the cholesterol pathway were associated with NSCLC survival, possibly by affecting their gene expression. IMPACT Genetic variants of APOB and CDH13 in the cholesterol pathway may provide new scientific insights into NSCLC prognosis. Copyright ©2020, American Association for Cancer Research.BACKGROUND Although vitamin D inhibits breast tumor growth in experiments, the findings from population-based studies remain inconclusive. Our goals were to investigate the association between pre-diagnostic plasma 25-hydroxyvitamin D [25(OH)D] and breast cancer recurrence in the Nurses' Health Studies (NHS) and to explore the molecular underpinnings. METHODS Plasma 25(OH)D was measured with a high-affinity-protein-binding-assay/a radioimmunoassay. We profiled transcriptome-wide-gene-expression in breast tumors using microarrays. Hazard ratios (HRs) of breast cancer recurrence were estimated from covariate-adjusted-Cox-regressions. We examined differential gene expression in association with 25(OH)D. We derived a gene expression score for 25(OH)D, and assessed associations between the score and cancer recurrence. RESULTS Although 25(OH)D was not associated with breast cancer recurrence overall (HR=0.97; 95% confidence interval (CI) 0.88-1.08), the association varied by estrogen-receptor (ER) status (p-for-interaction=0.005). Importantly, among ER-positive stage I-to-III cancers, every 5ng/ml increase in 25(OH)D was associated with a 13% lower risk of recurrence (HR=0.87; 95%-CI 0.76-0.99). A null association was observed for ER-negative cancers. Pathway analysis identified multiple gene-sets (proliferation, migration, and inflammation) that were significantly down-regulated in ER-positive tumors of women with high 25(OH)D (≥30ng/ml), compared to those with low levels. 25(OH)D score derived was marginally associated with reduced risk of recurrence in ER-positive diseases in NHS, however, no association was noted in the replication dataset. CONCLUSIONS Our findings support an intriguing line of research to better understand the mechanisms underlying the role of vitamin D in breast tumor progression, particularly for the ER-positive subtype. IMPACT Vitamin D may present a personal-level secondary-prevention strategy for breast cancer. Copyright ©2020, American Association for Cancer Research.Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, and the cancer with the fastest increase in mortality in the USA, with more than 39,000 cases and 29,000 deaths in 2018. As with many cancers, survival is significantly improved by early detection. The median survival of patients with early HCC is &gt;60 months but less then 15 months when detected at an advanced stage. Surveillance of at risk patients improves outcome but fewer than 20% of those at risk for HCC receive surveillance, and current surveillance strategies have limited sensitivity and specificity. Ideally, blood based biomarkers with adequate sensitivity or specificity would be available for early detection of HCC; however, the most commonly used biomarker for HCC, alpha fetoprotein, has inadequate performance characteristics. There are several candidate serum proteomic, glycomic, and genetic markers that have gone through early stages of biomarker validation and have shown promise for the early detection of HCC, but these markers require validation in well curated cohorts. Ongoing prospective cohort studies will permit retrospective longitudinal (phase III biomarker study) validation of biomarkers. In this review, we highlight promising candidate biomarkers and biomarker panels that have completed phase II evaluation but require further validation prior to clinical use. Copyright ©2020, American Association for Cancer Research.BACKGROUND Breast cancer is a complex and multifactorial disease, and environmental factors have been suggested to increase its risk. However, prior research has largely focused on studying exposures to one factor/contaminant at a time, which does not reflect the real-world environment. METHODS Herein, we investigate associations between breast cancer and the Environmental Quality Index (EQI), a comprehensive assessment of five domains of environmental quality (air, water, land, sociodemographic, and built) at the county level. Breast cancer diagnoses for North Carolina women were obtained from the North Carolina Central Cancer Registry (2009-2014) and the county of residence at the time of diagnosis was linked with the EQI. We evaluated the odds of localized, regional, or distant metastatic breast cancer in categories of environmental quality using women with carcinoma in situ as registry-based controls. RESULTS Overall environmental quality was generally not associated with invasive breast cancer; however, all breast cancer types tended to be inversely associated with land quality, particularly in more rural communities [distant metastatic breast cancer was 5-8% more likely (OR 1.08; 95% CI 1.02, 1.14, p=0.02) compared to carcinoma in situ]. CONCLUSIONS Cumulatively, our results suggest that some broad measures of environmental quality are associated with invasive breast cancer but that associations vary by environmental domain, cancer stage, subtype, and urbanicity. IMPACT Our findings suggest that components of land quality (e.g. pesticide applications and animal facilities) warrant additional investigation in relation to invasive breast cancer. Copyright ©2020, American Association for Cancer Research.Rhabdomyosarcoma (RMS) is the most common childhood soft-tissue sarcoma. The largest subtype of RMS is embryonal rhabdomyosarcoma (ERMS) and accounts for 53% of all RMS. ERMS typically occurs in the head and neck region, bladder, or reproductive organs and portends a promising prognosis when localized; however, when metastatic the 5-yr overall survival rate is ∼43%. The genomic landscape of ERMS demonstrates a range of putative driver mutations, and thus the recognition of the pathological mechanisms driving tumor maintenance should be critical for identifying effective targeted treatments at the level of the individual patients. Here, we report genomic, phenotypic, and bioinformatic analyses for a case of a 3-yr-old male who presented with bladder ERMS. Additionally, we use an unsupervised agglomerative clustering analysis of RNA and whole-exome sequencing data across ERMS and undifferentiated pleomorphic sarcoma (UPS) tumor samples to determine several major endotypes inferring potential targeted treatments for a spectrum of pediatric ERMS patient cases.