The prison-based Therapeutic Community: Resident recommendations for program improvement.

INTRODUCTION: The prison-based Therapeutic Community (TC) is widely used within correctional institutions to address substance use disorders (SUDs). While most evaluations of the prison-based TC find the program to be effective, recent mixed evidence and the continued surge of the opioid crisis call for deeper investigation into program operations, barriers to engagement, and sources of treatment effect heterogeneity. Notably lacking from prior evaluations, and critical to our understanding of variable program engagement, is first-hand experiences and perceptions from program participants. METHODS: To assess prison-based TC resident perceptions of the program and their recommendations for improvement, we utilize data from the Therapeutic Community Prison Inmate Network Study (TC-PINS), a longitudinal data collection effort conducted in one prison-based TC unit within a Pennsylvania state prison. Specifically, we assess resident responses to the open-ended item "What can the TC do better?" Analyzing 470 responses to this question by 177 residents, two independent coders identified seven substantive categories of recommended changes or improvements to their TC program. RESULTS: Residents provided tangible recommendations for improvement of their prison-based TC program based on their experiences and perceptions. Importantly, a number of their recommendations directly counter the intended model of the TC, which highlights imperative issues underlying the translation of the TC model within the prison environment. Resident suggestions include enhanced structure, increased individualization, expanded curriculum, stricter enforcement of rules, and improved or more experienced staff. Additionally, many question the coercive nature of TC program participation within this prison system. CONCLUSIONS: Resident recommendations for program improvement unveil important sources of treatment effect heterogeneity and highlight tangible program changes that can be implemented to reduce barriers to treatment engagement. We provide suggested changes to this prison-based TC based on resident perceptions and discuss both the importance and relative ease of eliciting this critical participant feedback.

A Descriptive Account of the Nature and Extent of Transgender Homicide in America, 2010 to 2021.

There is a growing acknowledgment of transgender homicide as a serious social and public health issue; indeed, the American Medical Association has even referred to violence against transgender people as an "epidemic." Addressing this issue, however, requires understanding the patterns associated with this violence. Yet, reliable data for doing so does not currently exist, especially in recent years. As such, the prevalence of these incidents and their key features are not easily understood. The current study addresses this issue using a comprehensive nationwide database on 305 instances of homicide directed against transgender people between 2010 and 2021, collected through extensive open-source data collection methods. The descriptive analyses of these incidents demonstrate pronounced increases in homicide victimization over time, and clear geographic clustering by state, such that roughly one in four incidents occurred in just three states: Texas, Florida, and California. After accounting for the estimated size of the transgender population, Louisiana, Mississippi, and Missouri emerge as the most dangerous states with the highest risk of homicide victimization. The results also clearly demonstrate the intersectional nature of transgender homicide, in finding that most homicide victims are young Black or Hispanic transgender women. We conclude by emphasizing the need for multipronged policy responses to this issue that recognize the uniquely dangerous intersection of social problems that contribute to the vulnerable social position of many transgender people, including their vulnerability to homicide victimization.

IGF-1R nuclear import and recruitment to chromatin involves both alpha and beta subunits.

Mature type 1 insulin-like growth factor receptors (IGF-1Rs) are heterotetrameric structures comprising two extracellular α-subunits disulphide-bonded to two transmembrane ß-subunits with tyrosine kinase activity. IGF-1R is a well-known cell surface mediator of malignant growth, with an incompletely understood role upon nuclear import as a transcriptional regulator. Previous characterisation of nuclear IGF-1R focused on IGF-1Rß. Here, we aimed to clarify the source of nuclear IGF-1R and investigate whether α-subunits contribute to nuclear IGF-1R function. Using prostate cancer cell lines DU145 and 22Rv1 we detected nuclear α- and ß-subunits, with increase in nuclear signal upon IGF-treatment and reduction in response to IGF-1R inhibitor BMS-754807. Following biotinylation of cell surface proteins, biotinylated α- and ß-subunits were detected in nuclear extracts of both cell lines. Furthermore, α- and ß-subunits reciprocally co-precipitated from nuclear extract. Finally, we detected recruitment of both subunits to regulatory regions of chromatin, including the promoter of the oncogene JUN, that we previously identified in ChIP-seq as sites of IGF-1Rß enrichment. These data confirm the cell surface origin of nuclear IGF-1R, suggest the presence of nuclear αß complexes and reveal that both IGF-1Rα- and ß-subunits contribute to pro-tumorigenic functions of nuclear IGF-1R. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-021-00407-8.

Targeting IGF Perturbs Global Replication through Ribonucleotide Reductase Dysfunction.

Inhibition of IGF receptor (IGF1R) delays repair of radiation-induced DNA double-strand breaks (DSB), prompting us to investigate whether IGF1R influences endogenous DNA damage. Here we demonstrate that IGF1R inhibition generates endogenous DNA lesions protected by 53BP1 bodies, indicating under-replicated DNA. In cancer cells, inhibition or depletion of IGF1R delayed replication fork progression accompanied by activation of ATR-CHK1 signaling and the intra-S-phase checkpoint. This phenotype reflected unanticipated regulation of global replication by IGF1 mediated via AKT, MEK/ERK, and JUN to influence expression of ribonucleotide reductase (RNR) subunit RRM2. Consequently, inhibition or depletion of IGF1R downregulated RRM2, compromising RNR function and perturbing dNTP supply. The resulting delay in fork progression and hallmarks of replication stress were rescued by RRM2 overexpression, confirming RRM2 as the critical factor through which IGF1 regulates replication. Suspecting existence of a backup pathway protecting from toxic sequelae of replication stress, targeted compound screens in breast cancer cells identified synergy between IGF inhibition and ATM loss. Reciprocal screens of ATM-proficient/deficient fibroblasts identified an IGF1R inhibitor as the top hit. IGF inhibition selectively compromised growth of ATM-null cells and spheroids and caused regression of ATM-null xenografts. This synthetic-lethal effect reflected conversion of single-stranded lesions in IGF-inhibited cells into toxic DSBs upon ATM inhibition. Overall, these data implicate IGF1R in alleviating replication stress, and the reciprocal IGF:ATM codependence we identify provides an approach to exploit this effect in ATM-deficient cancers. SIGNIFICANCE: This study identifies regulation of ribonucleotide reductase function and dNTP supply by IGFs and demonstrates that IGF axis blockade induces replication stress and reciprocal codependence on ATM. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2128/F1.large.jpg.

An Approach to Improving Student Success in Science, Technology, Engineering, and Mathematics (STEM) Career Pathways.

In this article, we report on an 11-year study that explores approaches to improve student success in college by a five-week summer program in Mathematics and Language Arts for entering freshmen. To recruit students into the program, we invited students accepted at the university and listed as underrepresented and economically disadvantaged (Pell-eligible) by the Office of Institutional Research at California State University, Northridge. The program consisted of all-day Math and English enhancement in mixed ability groups. Results of this program examining Math and English performance at California State University, Northridge showed that students completing the summer programs during the 11-year study period had improved pass rates in Math and English at California State University, Northridge compared with students in a control group who did not participate in the summer program. The results show that intensive pre-college enhancement for entering freshmen can improve student success in college. Student graduation data from the early cohorts (2010, 2011, 2012) were obtained from Institutional Research. The summary results showed that students from the accepted/attending group had substantially increased GPAs and graduation rates, essentially closing the achievement gap. Increased interest in biomedical research careers was also developed by the program, as demonstrated by a five-fold number of summer enrichment participants entering the PhD, MARC (Minority Access to Research Careers) and RISE (Research Initiative for Scientific Enhancement) programs than students who did not attend summer enrichment.

Nuclear IGF1R Interacts with Regulatory Regions of Chromatin to Promote RNA Polymerase II Recruitment and Gene Expression Associated with Advanced Tumor Stage.

Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response to IGF1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here, we investigated the significance of nuclear IGF1R in clinical cancers and cell line models. In prostate cancers, IGF1R was predominantly membrane localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF1R, and nuclear IGF1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF1R-binding sites at or near transcription start sites of genes including JUN and FAM21, most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF1 also enriched RNAPol2 on promoters containing IGF1R-binding sites. These functions were inhibited by IGF1/II-neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected IGF1R on JUN and FAM21 promoters in fresh prostate cancers that contained abundant nuclear IGF1R, with evidence of correlation between nuclear IGF1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs.Significance: These findings reveal a noncanonical nuclear role for IGF1R in tumorigenesis, with implications for therapeutic evaluation of IGF inhibitory drugs. Cancer Res; 78(13); 3497-509. ©2018 AACR.