Mitochondria provide the first line of defense against the tumor-promoting effects of oxidative stress. Here we show that the prostate-specific homeoprotein NKX3.1 suppresses prostate cancer initiation by protecting mitochondria from oxidative stress. Integrating analyses of genetically engineered mouse models, human prostate cancer cells, and human prostate cancer organotypic cultures, we find that, in response to oxidative stress, NKX3.1 is imported to mitochondria via the chaperone protein HSPA9, where it regulates transcription of mitochondrial-encoded electron transport chain (ETC) genes, thereby restoring oxidative phosphorylation and preventing cancer initiation. Germline polymorphisms of NKX3.1 associated with increased cancer risk fail to protect from oxidative stress or suppress tumorigenicity. Low expression levels of NKX3.1 combined with low expression of mitochondrial ETC genes are associated with adverse clinical outcome, whereas high levels of mitochondrial NKX3.1 protein are associated with favorable outcome. This work reveals an extranuclear role for NKX3.1 in suppression of prostate cancer by protecting mitochondrial function. Significance: Our findings uncover a nonnuclear function for NKX3.1 that is a key mechanism for suppression of prostate cancer. Analyses of the expression levels and subcellular localization of NKX3.1 in patients at risk of cancer progression may improve risk assessment in a precision prevention paradigm, particularly for men undergoing active surveillance. See related commentary by Finch and Baena, p. 2132. This article is highlighted in the In This Issue feature, p. 2113
Background: Growing evidence suggests a possible sex disparity in COVID-19 disease related outcomes. Objective: To explore the sex disparity in COVID-19 cases and outcomes using New York City (NYC) population level data. Setting: NYC surveillance data from February 29 to June 12, 2020. Participants: Individuals tested for COVID-19 in metropolitan NYC. Outcome Measurements and Statistical Analysis: Outcomes of interest included rates of COVID-19 case positivity, hospitalization and death. Relative risks and case fatality rates were computed for all outcomes based on sex and were stratified by age groups. Results and Limitations: 911,310 individuals were included, of whom 434,273 (47.65%) were male and 477,037 (52.35%) were female. Men represented the majority of positive cases (n=106,275, 51.36%), a majority of hospitalizations (n=29,847, 56.44%), and a majority of deaths (n=13,054, 59.23%). Following population level adjustments for age and sex, testing rates of men and women were equivalent. The majority of positive cases and hospitalizations occurred in men for all age groups except age >75 years, and death was more likely in men of all age groups. Men were at a statistically significant greater relative risk of case positivity, hospitalization, and death across all age groups except those <18 years of age. The most significant difference for case positivity was observed in the 65-74 age group (RR 1.22, 95%CI 1.19-1.24), for hospitalization in the 45-65 age group (RR 1.85, 95% 1.80-1.90), and for death in the 18-44 age group (RR 3.30, 95% CI 2.82-3.87). Case fatality rates were greater for men in all age-matched comparisons to women. Limitations include the use of an evolving surveillance data set and absence of further demographic characteristics such as ethnographic data. Conclusion: Men have higher rates of COVID-19 positivity, hospitalization, and death despite greater testing of women; this trend remains after stratification by age.
Introduction Over 1,500 bladder cancers were diagnosed among US Veterans in 2010, the majority of which were non-muscle invasive bladder cancer (NMIBC). Little is known about NMIBC treatment within the Veterans Health Administration. The objective of the study was to assess the quality of care for Veterans with newly-diagnosed NMIBC within Veterans Integrated Service Network (VISN) 02. Materials and Methods We used ICD-9 and ICD-10 codes to identify patients with newly-diagnosed bladder cancer from 1/2016–8/2017. We risk-stratified the patients into low, intermediate, and high-risk based on the 2016 American Urological Association Guidelines on NMIBC. Our primary objectives were percentages of transurethral resection of bladder tumors (TURBTs) with detrusor, repeat TURBT in high-risk and T1 disease, high-risk NMIBC treated with induction intravesical therapy (IVT), and responders treated with maintenance IVT. We performed logistic regression for association between distance to diagnosing hospital and receipt of induction IVT in high-risk patients. Results There were 121 newly-diagnosed NMIBC patients; 16% low-risk, 28% intermediate-risk, and 56% high-risk. Detrusor was present in 80% of all initial TURBTs and 84% of high-risk patients. Repeat TURBT was performed in 56% of high-risk NMIBC and 60% of T1. Induction IVT was given to 66% of high-risk patients and maintenance IVT was given to 59% of responders. On multivariate logistic regression, distance to medical center was not associated with receipt of induction IVT (OR = 0.99, 95% CI [0.97,1.01], p = 0.52). Conclusions We observed high rates of sampling of detrusor in the first TURBT specimen, utilization of repeat TURBT, and administration of induction and maintenance intravesical BCG for high-risk patients among a regional cohort of US Veterans with NMIBC. While not a comparative study, our findings suggest high quality NMIBC care in VA VISN 02.
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