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Synthetic lethality provides an attractive strategy for developing targeted cancer therapies. For example, cancer cells with high levels of microsatellite instability (MSI-H) are dependent on the Werner (WRN) helicase for survival. However, the mechanisms that regulate WRN spatiotemporal dynamics remain poorly understood. Here, we used single-molecule tracking (SMT) in combination with a WRN inhibitor to examine WRN dynamics within the nuclei of living cancer cells. WRN inhibition traps the helicase on chromatin, requiring p97/VCP for extraction and proteasomal degradation in a MSI-H dependent manner. Using a phenotypic screen, we identify the PIAS4-RNF4 axis as the pathway responsible for WRN degradation. Finally, we show that co-inhibition of WRN and SUMOylation has an additive toxic effect in MSI-H cells and confirm the in vivo activity of WRN inhibition using an MSI-H mouse xenograft model. This work elucidates a regulatory mechanism for WRN that may facilitate identification of new therapeutic modalities, and highlights the use of SMT as a tool for drug discovery and mechanism-of-action studies., (© 2024. The Author(s).)

Previous research has consistently shown that juvenile violent victimization is associated with an increased risk of future criminal involvement, a phenomenon commonly known as victim-offender overlap. Despite a growing interest in the factors underlying this overlap, potential roles of major life transitions and turning points that may interrupt and reshape the nature of this developmental association have garnered less academic attention. Analyzing nationally representative data from waves I, IV, and V of the National Longitudinal Study of Adolescent to Adult Health (Add Health; n  = 10,205), this study investigates the association between juvenile violent victimization and adult criminal outcomes (i.e., violent offending, non-violent offending, arrest, and incarceration) and whether this association is moderated by military service with and without combat experience in young adulthood. Employing a series of logistic regression analyses and adjusting for a host of covariates, measures of selection, and criminogenic traits, we found that juvenile violent victimization was significantly associated with greater odds of violent offending, arrest, and incarceration in adulthood. Among individuals with violent victimization histories, military service with no combat experience was associated with a 16% decrease in the odds of incarceration in adulthood. Combat experience, however, was associated with over seven times greater odds of violent offending in adulthood for these individuals. These findings have important implications for theory, research, and practice, and highlight the relevance of life transitions and turning points in general, and military service in particular, in mitigating or perpetuating the criminogenic impacts of violent victimization in the life course., Competing Interests: Data Availability StatementResearchers interested in obtaining Data Files from Add Health should contact Add Health, The University of North Carolina at Chapel Hill, Carolina Population Center, 206 W. Franklin Street, Chapel Hill, NC 27516-2524 (addhealthcontracts@unc.edu). Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

Objective: Faith leaders often serve as health-related role models yet many struggle with obesity and self-care engagement. The purpose of this scoping review was to examine how the faith leader literature has defined self-care and examined obesity and obesity-related chronic disease., Data Source: Studies were identified through database (eg, PubMed, CINAHL, PsycINFO), backward, and grey literature (eg, dissertations) searches., Inclusion/exclusion Criteria: Studies published in English with participants who were 18 years or older and examined leaders across all faiths. Studies also included an examination of self-care behaviors among faith leaders within the context of obesity or obesity-related chronic diseases., Data Extraction/synthesis: Data synthesis was qualitative and informed by the six-step framework developed by Arksey and O'Malley (2005) as well as updated recommendations by Daudt et al (2013). Of the 418 studies identified and screened, 20 met the eligibility criteria., Results: Studies were primarily cross-sectional and participants Christian faith-leaders in the US. Most studies did not define self-care or incorporate theory, but focused on vegetarian diets and physical activity engagement. Other self-care related behaviors (eg, sleep, days off), some unique to faith leaders (eg, sabbatical), were included but not systematically., Conclusions: Research with more diverse faith leaders and that uses theory is needed to guide development of strategies for engaging this population in self-care to reduce obesity and related chronic diseases., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.