Our study found that men with a family history of breast or prostate cancer had elevated prostate cancer risks, including risk of lethal disease. These findings have translational relevance for cancer risk prediction in men.
Short application of the volatile anesthetic isoflurane at reperfusion after ischemia exerts strong protection of the heart against injury. Mild depolarization and acidification of the mitochondrial matrix are involved in the protective mechanisms of isoflurane, but the molecular basis for these changes is not clear. In this study, mitochondrial respiration, membrane potential, matrix pH, matrix swelling, ATP synthesis and -hydrolysis, and H2O2 release were assessed in isolated mitochondria. We hypothesized that isoflurane induces mitochondrial depolarization and matrix acidification through direct action on both complex I and ATP synthase. With complex I-linked substrates, isoflurane (0.5 mM) inhibited mitochondrial respiration by 28±10%, and slightly, but significantly depolarized membrane potential and decreased matrix pH. With complex II- and complex IV-linked substrates, respiration was not changed, but isoflurane still decreased matrix pH and depolarized mitochondrial membrane potential. Depolarization and matrix acidification were attenuated by inhibition of ATP synthase with oligomycin, but not by inhibition of mitochondrial ATP- and Ca2+-sensitive K+ channels or uncoupling proteins. Isoflurane did not induce matrix swelling and did not affect ATP synthesis and hydrolysis, but decreased H2O2 release in the presence of succinate in an oligomycin- and matrix pH-sensitive manner. Isoflurane modulated H+ flux through ATP synthase in an oligomycin-sensitive manner. Our results indicate that isoflurane-induced mitochondrial depolarization and acidification occur due to inhibition of the electron transport chain at the site of complex I and increased proton flux through ATP synthase. K+ channels and uncoupling proteins appear not to be involved in the direct effects of isoflurane on mitochondria.
Background Research on psychosocial stress and risk of breast cancer has produced conflicting results. Few studies have assessed this relation by breast cancer subtype or specifically among Black women, who experience unique chronic stressors. Methods We used prospective data from the Black Women’s Health Study, an ongoing cohort study of 59,000 US Black women, to assess neighborhood- and individual-level psychosocial factors in relation to risk of breast cancer. We used factor analysis to derive two neighborhood score variables after linking participant addresses to US Census data (2000 and 2010) on education, employment, income and poverty, female-headed households, and Black race for all households in each residential block group. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for established breast cancer risk factors. Results During follow-up from 1995 to 2017, there were 2167 incident invasive breast cancer cases (1259 estrogen receptor positive (ER +); 687 ER negative (ER−)). For ER− breast cancer, HRs were 1.26 (95% CI 1.00–1.58) for women living in the highest quartile of neighborhood disadvantage relative to women in the lowest quartile, and 1.24 (95% CI 0.98–1.57) for lowest versus highest quartile of neighborhood socioeconomic status (SES). For ER+ breast cancer, living in the lowest quartile of neighborhood SES was associated with a reduced risk of ER+ breast cancer (HR = 0.83, 95% CI 0.70–0.98). With respect to individual-level factors, childhood sexual abuse (sexual assault ≥ 4 times vs. no abuse: HR = 1.35, 95% CI 1.01–1.79) and marital status (married/living together vs. single: HR = 1.29, 95% CI 1.08–1.53) were associated with higher risk of ER+, but not ER− breast cancer. Conclusion Neighborhood disadvantage and lower neighborhood SES were associated with an approximately 25% increased risk of ER− breast cancer in this large cohort of Black women, even after control for multiple behaviors and lifestyle factors. Further research is need to understand the underlying reasons for these associations. Possible contributing factors are biologic responses to the chronic stress/distress experienced by individuals who reside in neighborhoods characterized by high levels of noise, crime and unemployment or the direct effects of environmental toxins.
BackgroundColorectal cancer (CRC) incidence rates have increased in younger individuals worldwide. We examined the most recent early- and late-onset CRC rates for the US.MethodsAge-standardized incidence rates (ASIR, per 100,000) of CRC were calculated using the US Cancer Statistics Database’s high-quality population-based cancer registry data from the entire US population. Results were cross-classified by age (20-49 [early-onset] and 50-74 years [late-onset]), race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, American Indian/Alaskan Native, Asian/Pacific Islander), sex, anatomic location (proximal, distal, rectal), and histology (adenocarcinoma, neuroendocrine).ResultsDuring 2001 through 2018, early-onset CRC rates significantly increased among American Indians/Alaskan Natives, Hispanics, and Whites. Compared to Whites, early-onset CRC rates are now 21% higher in American Indians/Alaskan Natives and 6% higher in Blacks. Rates of early-onset colorectal neuroendocrine tumors have increased in Whites, Blacks, and Hispanics; early-onset colorectal neuroendocrine tumor rates are 2-times higher in Blacks compared to Whites. Late-onset colorectal adenocarcinoma rates are decreasing, while late-onset colorectal neuroendocrine tumor rates are increasing, in all racial/ethnic groups. Late-onset CRC rates remain 29% higher in Blacks and 15% higher in American Indians/Alaskan Natives compared to Whites. Overall, CRC incidence was higher in men than women, but incidence of early-onset distal colon cancer was higher in women.ConclusionsThe early-onset CRC disparity between Blacks and Whites has decreased, due to increasing rates in Whites—rates in Blacks have remained stable. However, rates of colorectal neuroendocrine tumors are increasing in Blacks. Blacks and American Indians/Alaskan Natives have the highest rates of both early- and late-onset CRC.ImpactOngoing prevention efforts must ensure access to and uptake of CRC screening for Blacks and American Indians/Alaskan Natives.
Background Black Americans have the highest incidence of colorectal cancer (CRC) of any racial/ethnic group in the US. High intake of red and processed meats has been associated with an increased CRC risk in predominately White populations. However, three prior studies in Black populations, who have been reported to have high intake of red and processed meats, have reported no association. Data on a possible association with CRC risk of saturated and monounsaturated fatty acids, the primary types of fat in red and processed meat, are inconclusive. Objective We prospectively assessed intakes of processed and unprocessed red meat and saturated and monounsaturated fatty acids in relation to CRC risk, utilizing data from the Black Women's Health Study (BWHS, 1995–2018). Methods Dietary data were derived from validated food frequency questionnaires completed in 1995 and 2001. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. Results Among 52,695 BWHS participants aged 21–69 at baseline and followed for up to 22 years, 564 women developed incident CRC. Unprocessed red meat intake was associated with a 33% increased CRC risk per 100 g/d (HR = 1.33, 95%CI: 1.03–1.71). Examining CRC anatomic sites, unprocessed red meat was associated with 2-times increased rectal cancer risk (HR = 2.22, 95% CI: 1.15–4.26). There was no evidence of an interaction with age (pinteraction = 0.4), but unprocessed red meat intake was only associated with a significant increased risk of late-onset CRC (≥50 years of age, HR = 1.38, 95%CI: 1.04–1.83). Processed red meat and total saturated and monounsaturated fatty acid intakes were not associated with CRC risk. Conclusions Unprocessed red meat intake was associated with an increased CRC risk in the present study, the first positive evidence that red meat plays a role in the etiology of CRC in Black women. The findings suggest prevention opportunities.
Purpose To investigate the association between pre- or perinatal factors and breast cancer risk among African American women. Methods Participants in the Black Women’s Health Study, a prospective cohort of 59,000 African American women, reported birth weight, preterm birth, twin or triplet status, maternal age at birth, birth order, and having been breastfed during infancy at various times during follow-up from 1997 to 2015. Numbers of incident cases ranged from 312 for breastfed analyses to 1,583 for twin or triplet analyses. Using multivariable Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between each factor and breast cancer risk overall and by estrogen receptor (ER) status. Results Compared to birth weights of 5 lbs. 8 oz.−8 lbs. 13 oz., low (<5 lbs. 8 oz.) and high (>8 lbs. 13 oz.) birth weights were associated with increased breast cancer risk; HRs (95% CI) were 1.19 (0.98–1.44) and 1.26 (0.97–1.63), respectively. Associations were similar by ER status. Having been born to a mother aged ≥35 years vs. <20 years was associated with risk of ER+ (HR=1.59, 95% CI 1.10–2.29), but not ER- breast cancer. Other perinatal factors were not associated with breast cancer. Conclusion African American women with a low or high birth weight or born to older mothers may have increased breast cancer risk. Trends towards delayed child birth and higher birth weights, coupled with disproportionately high rates of low birth weight among African Americans, may contribute to increases in breast cancer incidence.
The recent development of a Hepatitis C virus (HCV) infectious virus cell culture model system has facilitated the development of whole-virus screening assays which can be used to interrogate the entire virus life cycle. Here, we describe the development of an HCV growth assay capable of identifying inhibitors against all stages of the virus life cycle with assay throughput suitable for rapid screening of large-scale chemical libraries. Novel features include, 1) the use of an efficiently-spreading, full-length, intergenotypic chimeric reporter virus with genotype 1 structural proteins, 2) a homogenous assay format compatible with miniaturization and automated liquid-handling, and 3) flexible assay end-points using either chemiluminescence (high-throughput screening) or Cellomics ArrayScan™ technology (high-content screening). The assay was validated using known HCV antivirals and through a large-scale, high-throughput screening campaign that identified novel and selective entry, replication and late-stage inhibitors. Selection and characterization of resistant viruses provided information regarding inhibitor target and mechanism. Leveraging results from this robust whole-virus assay represents a critical first step towards identifying inhibitors of novel targets to broaden the spectrum of antivirals for the treatment of HCV.
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