Gene-environment interactions and obesity traits among postmenopausal African-American and Hispanic women in the Women’s Health Initiative SHARe Study

Genome-wide association studies of obesity measures have identified associations with single nucleotide polymorphisms (SNPs). However, no large-scale evaluation of gene-environment interactions has been performed. We conducted a search of gene-environment (G×E) interactions in post-menopausal African-American and Hispanic women from the Women’s Health Initiative SNP Health Association Resource GWAS study. Single SNP linear regression on body mass index (BMI) and waist-to-hip circumference ratio (WHR) adjusted for multidimensional-scaling-derived axes of ancestry and age was run in race-stratified data with 871,512 SNPs available from African-Americans (N=8,203) and 786,776 SNPs from Hispanics (N=3,484). Tests of G×E interaction at all SNPs for recreational physical activity (met-hrs/wk), dietary energy intake (kcal/day), alcohol intake (categorical), cigarette smoking years, and cigarette smoking (ever vs. never) were run in African-Americans and Hispanics adjusted for ancestry and age at interview, followed by meta-analysis of G×E interaction terms. The strongest evidence for concordant G×E interactions in African-Americans and Hispanics was for smoking and marker rs10133840 (Q statistic P=0.70, beta=−0.01, P=3.81×10−7) with BMI as the outcome. The strongest evidence for G×E interaction within a cohort was in African-Americans with WHR as outcome for dietary energy intake and rs9557704 (SNP×kcal =−0.04, P=2.17×10−7). No results exceeded the Bonferroni–corrected statistical significance threshold

Umbilical Cord Serum Interleukin-6, C-Reactive Protein, and Myeloperoxidase Concentrations at Birth and Association with Neonatal Morbidities and Long-Term Neurodevelopmental Outcomes

To determine if umbilical cord serum concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), and myeloperoxidase (MPO), in pregnancies at risk for preterm birth (PTB), are associated with neonatal morbidities and/or altered neurodevelopmental outcomes in the children

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH)Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2009-223175, HEALTH-F2-2009-223175Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi: https://doi.org/10.13039/501100000024Funder: Quebec Breast cancer Foundation Genome QuebecFunder: U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM); doi: https://doi.org/10.13039/100000092Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))Funder: European Union’s Horizon 2020Funder: Deutsche Krebshilfe (German Cancer Aid); doi: https://doi.org/10.13039/501100005972Funder: BCAST - European Union’s Horizon 2020Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913Abstract: Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women

SUNY Brockport’s migration from Bepress to SUNY’s SOAR

SUNY’s SOAR repository provided the opportunity to move from a commercial digital platform (bepress) to a less costly openly available alternative. A small campus implementation team worked with OLIS under a tight 12 week deadline to migrate 11,000+ items to 2 new instances – SOAR and SDR. Preliminary work included analyzing existing collections, prioritizing order of moves, defining structure, and developing new collection development standards. Process involved metadata clean up, conversion, and multiple data integrity checks. The new repository instance was online by early September and is simple, spare, and serviceable. Next steps, future maintenance, and assessment will be outlined

Singleton term breech deliveries in nulliparous and multiparous women: A 5-year experience at The University of Miami/Jackson Memorial Hospital

Objective: The purpose of this retrospective study was to evaluate the feasibility of planned vaginal delivery, the maternal morbidity and mortality, and the short-term perinatal outcome in selected multiethnic women at term with singleton breech presentations. Study Design: Singleton breech deliveries were identified from the delivery database between January 1, 1989, and December 31, 1993. A retrospective chart review identified 310 nulliparous and 711 multiparous women at term (37-42 weeks) for a total of 1021. Parameters studied included the success rate of planned vaginal deliveries and the incidences of maternal morbidity, perinatal morbidity, and mortality as a whole stratified by parity and mode of delivery. The Student t test, χ 2 test, and Fisher exact test were used for statistical analysis. Results: Among 1021 women with singleton fetuses in a breech position at term, 191 were candidates for vaginal delivery, and 135 (70.7%) of these deliveries were successful. By parity, 12.3% of 310 nulliparous women and 21.5% of 711 multiparous women were candidates for vaginal delivery; 50% of the former and 75.8% of the latter underwent vaginal delivery. Maternal morbidity was more commonly associated with multiparity and cesarean delivery. Newborn intensive care admissions were equally distributed by parity, and significantly more were for vaginal than cesarean deliveries (17.4% vs 10.8%, P = .036 ). Premature rupture of the membranes complicated deliveries in 23.9% of the nulliparous women and only 6.5% of the multiparous women ( P = .000). Conclusion: In this multiethnic population 70.7% of candidates selected for attempted vaginal breech delivery at term were successful. The remaining 29.3% underwent cesarean delivery for labor disorders or nonreassuring fetal heart rate patterns. (Am J Obstet Gynecol 1999;181:247-52.

Mothers with AIDS

Over the past few years, reviewers have suggested that the phenomena of human immunodeficiency virus-Type I (HIV-1) infection and acquired immunodeficiency syndrome (AIDS) among heterosexuals, women, and ethnic minority groups have been largely understudied while at the same time accelerating in incidence (Mays & Cochran, 1988). National and regional epidemiological data collected since 1985 appear to support the latter point. While reported cases of AIDS among homosexual men leveled off in major metropolitan areas (Berkelman et al., 1989) and actually declined in some cities (Lindan, Rutherford, Payne, Hearst, & Lemp, 1989) between 1985 and 1988, the proportion of cases attributable to heterosexual transmission has been increasing more rapidly than those due to any other risk category (Creenberg et al., 1989; Friedland & Klein, 1987). It has been projected that by the early 1990s, heterosexual transmission will account for 5% of all adult AIDS cases in the United States, and the majority of these will occur in New York and Florida (Friedland & Klein, 1987)

Impact of a risk-based prevention policy on neonatal group B streptococcal disease

Objective: Neonatal group B streptococcal infections can be prevented by intrapartum antibiotic prophylaxis. Beginning in 1992, women with obstetric risk factors at University of Miami–Jackson Memorial Medical Center were targeted to receive intrapartum antibiotic prophylaxis. We evaluated these preventive efforts. Study Design: A case was defined as isolation of group B streptococci from a sterile site in an infant <7 days old born during the study period, 1992-1995. We reviewed systematic samples of women with preterm delivery and prolonged rupture of membranes to assess use of intrapartum antibiotic prophylaxis. Results: Group B streptococcal cases declined from 1.7 cases/1000 live births to 0.2 cases/1000 live births (Poisson regression, P = .002). Intrapartum antibiotic prophylaxis use increased from 13% of preterm deliveries in 1992 to 42% in 1995, and from 20% of deliveries with prolonged rupture of membranes in 1992 to 72% in 1995 (χ 2 test for linear trend P = .007 and P < .001, respectively). Conclusion: Provision of intrapartum antibiotic prophylaxis on the basis of risk factors was associated with decreased group B streptococcal disease. (Am J Obstet Gynecol 1998;179:1568-71.