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PURPOSE: Compared to white women, Black women have increased risk of developing hypertensive diseases of pregnancy (HDOP) and have a higher incidence of aggressive breast cancer subtypes. Few studies of HDOP and breast cancer risk have included large numbers of Black women. This study examined the relation of HDOP to incidence of breast cancer overall and by estrogen receptor (ER) status in Black women. METHODS: We followed 42,982 parous women in the Black Women's Health Study, a nationwide prospective study of Black women. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) to assess associations of self-reported HDOP, including preeclampsia and gestational hypertension, with breast cancer incidence overall and by ER subtype, adjusted for age and established breast cancer risk factors. RESULTS: Over 20 years of follow-up, we identified 2376 incident breast cancer cases. History of HDOP (11.7%) was not associated with breast cancer risk overall (HR 0.98; 95% CI 0.87, 1.11). HRs for invasive ER+ and ER- breast cancer were 1.11 (95% CI 0.93, 1.34) and 0.81 (95% CI 0.61, 1.07), respectively. CONCLUSIONS: HDOP was not associated with risk of overall breast cancer in Black women. A suggestive inverse association with ER- breast cancer may reflect an anti-tumorigenic hormone profile in HDOP, but those results require confirmation in other studies.
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Neoplasias da Mama , Hipertensão , Negro ou Afro-Americano , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Feminino , Humanos , Incidência , Gravidez , Estudos Prospectivos , Fatores de Risco , Saúde da MulherRESUMO
Pulmonary arterial hypertension (PAH) is a morbid disease characterized by progressive right ventricle (RV) failure due to elevated pulmonary artery pressures (PAP). In PAH, histologically complex vaso-occlusive lesions in the pulmonary vasculature contribute to elevated PAP. However, the mechanisms underlying dysfunction of the microvascular endothelial cells (MVECs) that comprise a significant portion of these lesions are not well understood. We recently showed that MVECs isolated from the Sugen/hypoxia (SuHx) rat experimental model of PAH (SuHx-MVECs) exhibit increases in migration/proliferation, mitochondrial reactive oxygen species (ROS; mtROS) production, intracellular calcium levels ([Ca2+]i), and mitochondrial fragmentation. Furthermore, quenching mtROS with the targeted antioxidant MitoQ attenuated basal [Ca2+]i, migration and proliferation; however, whether increased mtROS-induced [Ca2+]i entry affected mitochondrial morphology was not clear. In this study, we sought to better understand the relationship between increased ROS, [Ca2+]i, and mitochondrial morphology in SuHx-MVECs. We measured changes in mitochondrial morphology at baseline and following inhibition of mtROS, with the targeted antioxidant MitoQ, or transient receptor potential vanilloid-4 (TRPV4) channels, which we previously showed were responsible for mtROS-induced increases in [Ca2+]i in SuHx-MVECs. Quenching mtROS or inhibiting TRPV4 attenuated fragmentation in SuHx-MVECs. Conversely, inducing mtROS production in MVECs from normoxic rats (N-MVECs) increased fragmentation. Ca2+ entry induced by the TRPV4 agonist GSK1017920A was significantly increased in SuHx-MVECs and was attenuated with MitoQ treatment, indicating that mtROS contributes to increased TRPV4 activity in SuHx-MVECs. Basal and maximal respiration were depressed in SuHx-MVECs, and inhibiting mtROS, but not TRPV4, improved respiration in these cells. Collectively, our data show that, in SuHx-MVECs, mtROS production promotes TRPV4-mediated increases in [Ca2+]i, mitochondrial fission, and decreased mitochondrial respiration. These results suggest an important role for mtROS in driving MVEC dysfunction in PAH.
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Células Endoteliais/patologia , Hipóxia/complicações , Indóis/toxicidade , Pulmão/patologia , Mitocôndrias/patologia , Hipertensão Arterial Pulmonar/patologia , Pirróis/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Inibidores da Angiogênese/toxicidade , Animais , Cálcio/metabolismo , Células Cultivadas , Células Endoteliais/metabolismo , Pulmão/metabolismo , Masculino , Mitocôndrias/metabolismo , Consumo de Oxigênio , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/metabolismo , Ratos , Ratos Wistar , Remodelação VascularRESUMO
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevations in pulmonary arterial pressure, in part due to formation of occlusive lesions in the distal arterioles of the lung. These complex lesions may comprise multiple cell types, including endothelial cells (ECs). To better understand the molecular mechanisms underlying EC dysfunction in PAH, lung microvascular endothelial cells (MVECs) were isolated from normoxic rats (N-MVECs) and rats subjected to SU5416 plus hypoxia (SuHx), an experimental model of PAH. Compared with N-MVECs, MVECs isolated from SuHx rats (SuHx-MVECs) appeared larger and more spindle shaped morphologically and expressed canonical smooth muscle cell markers smooth muscle-specific α-actin and myosin heavy chain in addition to endothelial markers such as Griffonia simplicifolia and von Willebrand factor. SuHx-MVEC mitochondria were dysfunctional, as evidenced by increased fragmentation/fission, decreased oxidative phosphorylation, and increased reactive oxygen species (ROS) production. Functionally, SuHx-MVECs exhibited increased basal levels of intracellular calcium concentration ([Ca2+]i) and enhanced migratory and proliferative capacity. Treatment with global (TEMPOL) or mitochondria-specific (MitoQ) antioxidants decreased ROS levels and basal [Ca2]i in SuHx-MVECs. TEMPOL and MitoQ also decreased migration and proliferation in SuHx-MVECs. Additionally, inhibition of ROS-induced Ca2+ entry via pharmacologic blockade of transient receptor potential vanilloid-4 (TRPV4) attenuated [Ca2]i, migration, and proliferation. These findings suggest a role for mitochondrial ROS-induced Ca2+ influx via TRPV4 in promoting abnormal migration and proliferation in MVECs in this PAH model.
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Cálcio/metabolismo , Endotélio Vascular/patologia , Hipertensão Pulmonar/patologia , Hipóxia/fisiopatologia , Indóis/toxicidade , Artéria Pulmonar/patologia , Pirróis/toxicidade , Canais de Cátion TRPV/metabolismo , Doenças Vasculares/patologia , Inibidores da Angiogênese/toxicidade , Animais , Células Cultivadas , Endotélio Vascular/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Masculino , Microvasos/metabolismo , Microvasos/patologia , Artéria Pulmonar/metabolismo , Ratos , Ratos Wistar , Canais de Cátion TRPV/genética , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismoRESUMO
BACKGROUND: High mammographic density is one of the strongest breast cancer risk factors; however, determinants of high mammographic density are understudied in Black women. We assessed growth and development factors across the lifecourse in relation to mammographic density. METHODS: Within the Black Women's Health Study (BWHS), we used Cumulus software to assess percent mammographic density from digital screening mammograms for 5,905 women ages 40-74. We fit linear regression models to quantify the association of lifecourse characteristics including birth weight, childhood somatotype, age at menarche, body mass index (BMI) at age 18, height, BMI at mammography, and adulthood waist-to-hip ratio with density overall and by age. We also performed a path analysis to assess the total and mediating effects of the growth and development factors on density. RESULTS: BMI at age 18, height, BMI at mammography, and waist-to-hip ratio were significantly and inversely associated with density. On path analysis, total effects of childhood somatotype (standardized ï¢ = -0.05, p <0.001), BMI at age 18 (standardized ï¢ = -0.13, p <0.001), BMI at mammography (standardized ï¢ = -0.22, p <0.001), and waist-to-hip ratio (standardized ï¢ = -0.04, p <0.001) were associated with density. CONCLUSIONS: Several factors across the lifecourse - greater childhood somatotype, BMI at age 18, height, BMI at mammography, and waist-to-hip ratio - were associated with lower mammographic density in this cohort of Black women. IMPACT: Body size closer to the time of mammography may be more meaningful in determining mammographic density, though early life adiposity also influences mammographic density.
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OBJECTIVE: To quantify racial disparities in mortality and post-hospitalization outcomes among incarcerated individuals that were hospitalized during their incarceration period. METHODS: We designed a retrospective cohort study using administrative and hospital data collected from a preferred healthcare referral center for all Massachusetts jails and prisons between January 2011 and December 2018 with linkage to Massachusetts Vital Records and Statistics. We identified 4260 incarcerated individuals with complete data on race/ethnicity that were hospitalized during the study period. The primary study indicators were age, race, ethnicity, length of hospital stay, Elixhauser comorbidity score, incarceration facility type, and number of hospital admissions. The primary outcome was time to death. RESULTS: Of the incarcerated individuals that were hospitalized, 2606 identified as White, 1214 identified as Black, and 411 people who identified as some other race. The hazard of death significantly increased by 3% (OR: 1.03; 95% CI: 1.02-1.03) for each additional yearly increase in age. After adjusting for the interaction between race and age, Black race was significantly associated with 3.01 increased hazard (95% CI: 1.75-5.19) of death for individuals hospitalized while incarcerated compared to White individuals hospitalized while incarcerated. Hispanic ethnicity and being incarcerated in a prison facility was not associated with time to mortality, while increased mean Elixhauser score (HR: 1.07; 95% CI: 1.06-1.08) and ≥ 3 hospital admissions (HR: 2.47; 95% CI: 2.07-2.95) increased the hazard of death. CONCLUSIONS: Our findings suggest disparities exist in the mortality outcomes among Black and White individuals who are hospitalized during incarceration, with an increased rate of death among Black individuals. Despite hypothesized equal access to healthcare within correctional facilities, our findings suggest that incarcerated and hospitalized Black individuals may experience worse disparities than their White counterparts, which has not been previously explored or reported in the literature. In addition to decarceration, advocacy, and political efforts, increased efforts to support research access to datasets of healthcare outcomes, including hospitalization and death, for incarcerated people should be encouraged. Further research is needed to identify and address the implicit and explicit sources of these racial health disparities across the spectrum of healthcare provision.
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Background and Aims: Individuals who are incarcerated often have limited access to first-line treatment and comprehensive health care. In this study, we aimed to compare the frequency of readmissions among patients with inflammatory bowel disease (IBD) receiving care at a community hospital who were and were not incarcerated at the time of hospitalization. Methods: We analyzed records from Lemuel Shattuck Hospital for all patients admitted between January 1, 2011, and December 31, 2019. Patients with IBD were identified using International Classification of Diseases codes. The primary outcome was all-cause readmission at 1 year following an IBD-related admission. Secondary outcomes were (1) all-cause readmission at 30 days, (2) IBD-related readmission at 30 days, and (3) IBD-related readmission at 1 year. Our indicator of interest was incarceration. Multivariable logistic regression models were built to describe predictors of all-cause readmissions at 1 year. Results: Among the 6511 individuals hospitalized at Lemuel Shattuck Hospital between 2011 and 2019, 90 individuals (1.4%) had International Classification of Diseases codes for IBD, either ulcerative colitis (n = 44) and/or Crohn's disease (n = 39). Half (n = 46) of patients with IBD were incarcerated during hospital admission. Individuals who were incarcerated had a higher rate of all-cause readmissions at 1 year than those who were not incarcerated at the time of hospitalization (76.0% vs 41.5%, P = .005). Multivariable analysis showed patients who were incarcerated had 3.98 (95% confidence interval: 1.39-12.78) increased odds of all-cause readmission within 1 year. Conclusion: Our results suggest individuals with IBD who are incarcerated may experience worse health outcomes than individuals who are not incarcerated, adding to a body of literature documenting the negative impact of incarceration on health.
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PURPOSE: Acute radiation dermatitis (ARD) is common after radiation therapy for breast cancer, with data indicating that ARD may disproportionately affect Black or African American (AA) patients. We evaluated the effect of skin of color (SOC) on physician-reported ARD in patients treated with radiation therapy. METHODS AND MATERIALS: We identified patients treated with whole breast or chest wall ± regional nodal irradiation or high tangents using 50 Gy in 25 fractions from 2015 to 2018. Baseline skin pigmentation was assessed using the Fitzpatrick scale (I = light/pale white to VI = black/very dark brown) with SOC defined as Fitzpatrick scale IV to VI. We evaluated associations among SOC, physician-reported ARD, late hyperpigmentation, and use of oral and topical treatments for RD using multivariable models. RESULTS: A total of 325 patients met eligibility, of which 40% had SOC (n = 129). On multivariable analysis, Black/AA race and chest wall irradiation had a lower odds of physician-reported grade 2 or 3 ARD (odds ratio [OR], 0.110; 95% confidence interval [CI], 0.030-0.397; P = .001; OR, 0.377; 95% CI, 0.161-0.883; P = .025), whereas skin bolus (OR, 8.029; 95% CI, 3.655-17.635; P = 0) and planning target volume D0.03cc (OR, 1.001; 95% CI, 1.000-1.001; P = .028) were associated with increased odds. On multivariable analysis, SOC (OR, 3.658; 95% CI, 1.236-10.830; P = .019) and skin bolus (OR, 26.786; 95% CI, 4.235-169.432; P = 0) were associated with increased odds of physician-reported late grade 2 or 3 hyperpigmentation. There was less frequent use of topical steroids to treat ARD and more frequent use of oral analgesics in SOC versus non-SOC patients (43% vs 63%, P < .001; 50% vs 38%, P = .05, respectively). CONCLUSIONS: Black/AA patients exhibited lower odds of physician-reported ARD. However, we found higher odds of late hyperpigmentation in SOC patients, independent of self-reported race. These findings suggest that ARD may be underdiagnosed in SOC when using the physician-rated scale despite this late evidence of radiation-induced skin toxicity.
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Hiperpigmentação , Lesões por Radiação , Radiodermite , Parede Torácica , Humanos , Parede Torácica/efeitos da radiação , Pigmentação da Pele , Mama , Radiodermite/etiologia , Lesões por Radiação/complicações , Hiperpigmentação/etiologiaRESUMO
Mitophagy, a mitochondria-specific form of autophagy, removes dysfunctional mitochondria and is hence an essential process contributing to mitochondrial quality control. PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin are critical molecules involved in stress-induced mitophagy, but the intracellular signaling mechanisms by which this pathway is regulated are unclear. We tested the hypothesis that signaling through RhoA, a small GTPase, induces mitophagy via modulation of the PINK1/Parkin pathway as a protective mechanism against ischemic stress. We demonstrate that expression of constitutively active RhoA as well as sphingosine-1-phosphate induced activation of endogenous RhoA in cardiomyocytes result in an accumulation of PINK1 at mitochondria. This is accompanied by translocation of Parkin to mitochondria and ubiquitination of mitochondrial proteins leading to recognition of mitochondria by autophagosomes and their lysosomal degradation. Expression of RhoA in cardiomyocytes confers protection against ischemia, and this cardioprotection is attenuated by siRNA-mediated PINK1 knockdown. In vivo myocardial infarction elicits increases in mitochondrial PINK1, Parkin, and ubiquitinated mitochondrial proteins. AAV9-mediated RhoA expression potentiates these responses and a concurrent decrease in infarct size is observed. Interestingly, induction of mitochondrial PINK1 accumulation in response to RhoA signaling is neither mediated through its transcriptional upregulation nor dependent on depolarization of the mitochondrial membrane, the canonical mechanism for PINK1 accumulation. Instead, our results reveal that RhoA signaling inhibits PINK1 cleavage, thereby stabilizing PINK1 protein at mitochondria. We further show that active RhoA localizes at mitochondria and interacts with PINK1, and that the mitochondrial localization of RhoA is regulated by its downstream effector protein kinase D. These findings demonstrate that RhoA activation engages a unique mechanism to regulate PINK1 accumulation, induce mitophagy and protect against ischemic stress, and implicates regulation of RhoA signaling as a potential strategy to enhance mitophagy and confer protection under stress conditions.