Environmental Exposures during Puberty: Window of Breast Cancer Risk and Epigenetic Damage.

During puberty, a woman's breasts are vulnerable to environmental damage ("window of vulnerability"). Early exposure to environmental carcinogens, endocrine disruptors, and unhealthy foods (refined sugar, processed fats, food additives) are hypothesized to promote molecular damage that increases breast cancer risk. However, prospective human studies are difficult to perform and effective interventions to prevent these early exposures are lacking. It is difficult to prevent environmental exposures during puberty. Specifically, young women are repeatedly exposed to media messaging that promotes unhealthy foods. Young women living in disadvantaged neighborhoods experience additional challenges including a lack of access to healthy food and exposure to contaminated air, water, and soil. The purpose of this review is to gather information on potential exposures during puberty. In future directions, this information will be used to help elementary/middle-school girls to identify and quantitate environmental exposures and develop cost-effective strategies to reduce exposures.

Cardiovascular and Self-Regulatory Consequences of SES-Based Social Identity Threat.

This work examined the effects of socioeconomic status (SES)-based social identity threat on cardiovascular indexes of challenge and threat and self-regulatory strength. Participants ( N = 104) took an exam described as either diagnostic of intellectual ability (identity threat) or framed as a problem-solving task (control) while we recorded cardiovascular reactivity and assessed participants' physical self-control. Under identity threat, lower SES students exhibited impaired performance, reduced self-control, and cardiovascular threat reactivity. In contrast, higher SES students under threat exhibited the reverse pattern-a boost in performance, no change in self-regulation, and cardiovascular challenge reactivity. Furthermore, while measures of general arousal (heart rate and pre-ejection period) were unrelated to performance, cardiovascular patterns of challenge and threat were significantly associated with performance under identity threat. Results provide evidence that SES-based stigma influences physiological and self-regulatory processes.

Obesity and Triple-Negative Breast Cancer: Disparities, Controversies, and Biology.

Once considered a problem of Western nations, obesity (body mass index ≥30 kg/m2) has rapidly increased since the 1970s to become a major threat to world health. Since 1970, the face of obesity has changed from a disease of affluence and abundance to a disease of poverty. During the last 10 years, studies have mechanistically linked obesity and an obese tumor microenvironment with signaling pathways that predict aggressive breast cancer biology. For example, in the United States, African American women are more likely than non-Hispanic European American women to be obese and to be diagnosed with triple-negative breast cancer (TNBC). In 2008, the Carolina Breast Study found that obesity (increased waist/hip ratio) was linked to an increased incidence of TNBC in premenopausal and postmenopausal African American women. Subsequently, several groups have investigated the potential link between obesity and TNBC in African American women. To date, the data are complex and sometimes contradictory. We review epidemiologic studies that investigated the potential association among obesity, metabolic syndrome, and TNBC in African American women and mechanistic studies that link insulin signaling to the obese breast microenvironment, tissue inflammation, and aggressive TNBC biology.

Genetic Gastric Cancer Susceptibility in the International Clinical Cancer Genomics Community Research Network.

Few susceptibility genes for gastric cancer have been identified. We sought to identify germline susceptibility genes from participants with gastric cancer from an international hereditary cancer research network. Adults with gastric cancer of any histology, and with a germline DNA sample (n = 51), were retrospectively selected. For those without previously identified germline mutations (n = 43), sequencing was performed for 706 candidate genes. Twenty pathogenic or likely pathogenic variants were identified among 18 participants. Eight of the 18 participants had previous positive clinical testing, including six with CDH1 pathogenic or likely pathogenic variants, and two with pathogenic MSH2 and TP53 variants. Of the remaining 10, six were in BRCA1 DNA damage response pathway genes (ATM, ATR, BRCA2, BRIP1, FANCC, TP53), other variants were identified in CTNNA1, FLCN, SBDS, and GNAS. Participants identified with pathogenic or likely pathogenic variants were younger at gastric cancer diagnosis than those without, 39.1 versus 48.0 years, and over 50% had a close family member with gastric cancer (p-values < 0.0001). In conclusion, many participants were identified with mutations in clinically-actionable genes. Age of onset and family history of gastric cancer were mutation status predictors. Our findings support multigene panels in identifying gastric cancer predisposition.

Accuracy of MR imaging-estimated proton density fat fraction for classification of dichotomized histologic steatosis grades in nonalcoholic fatty liver disease.

PURPOSE: To evaluate the diagnostic performance of previously proposed high-specificity magnetic resonance (MR) imaging-estimated proton density fat fraction (PDFF) thresholds for diagnosis of steatosis grade 1 or higher (PDFF threshold of 6.4%), grade 2 or higher (PDFF threshold of 17.4%), and grade 3 (PDFF threshold of 22.1%) by using histologic findings as a reference in an independent cohort of adults known to have or suspected of having nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: This prospective, cross-sectional, institutional review board-approved, HIPAA-compliant single-center study was conducted in an independent cohort of 89 adults known to have or suspected of having NAFLD who underwent contemporaneous liver biopsy. MR imaging PDFF was estimated at 3 T by using magnitude-based low-flip-angle multiecho gradient-recalled-echo imaging with T2* correction and multipeak modeling. Steatosis was graded histologically (grades 0, 1, 2, and 3, according to the Nonalcoholic Steatohepatitis Clinical Research Network scoring system). Sensitivity, specificity, and binomial confidence intervals were calculated for the proposed MR imaging PDFF thresholds. RESULTS: The proposed MR imaging PDFF threshold of 6.4% to diagnose grade 1 or higher steatosis had 86% sensitivity (71 of 83 patients; 95% confidence interval [CI]: 76, 92) and 83% specificity (five of six patients; 95% CI: 36, 100). The threshold of 17.4% to diagnose grade 2 or higher steatosis had 64% sensitivity (28 of 44 patients; 95% CI: 48, 78) and 96% specificity (43 of 45 patients; 95% CI: 85, 100). The threshold of 22.1% to diagnose grade 3 steatosis had 71% sensitivity (10 of 14 patients; 95% CI: 42, 92) and 92% specificity (69 of 75 patients; 95% CI: 83, 97). CONCLUSION: In an independent cohort of adults known to have or suspected of having NAFLD, the previously proposed MR imaging PDFF thresholds provided moderate to high sensitivity and high specificity for diagnosis of grade 1 or higher, grade 2 or higher, and grade 3 steatosis. Prospective multicenter studies are now needed to further validate these high-specificity thresholds.