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Immune checkpoint inhibitor-associated colitis (ICIC) affects approximately 15% of cancer patients treated with immunotherapy. Although histological evaluation is potentially valuable for both the diagnosis of ICIC and evaluation of disease activity, use in clinical practice is heterogeneous. We aimed to develop expert recommendations to standardize histological assessment of disease activity in patients with ICIC. Using the modified Research and Development/University of California Los Angeles (RAND/UCLA) appropriateness methodology, an international panel of 11 pathologists rated the appropriateness of 99 statements on a 9-point Likert scale during two rounds of anonymous voting. Results were discussed between rounds using moderated videoconferences. There are currently no disease-specific instruments for assessing histological features of ICIC. The panel considered that colonoscopy with at least three biopsies per segment from a total of at least five segments, including both endoscopically normal and inflamed areas, was appropriate for tissue acquisition. They agreed that biopsies should be oriented such that the long axis of the colonic crypts is visualized and should be stained with hematoxylin and eosin. Histological items that the panel voted were appropriate to evaluate in ICIC included the degree of structural/architectural change, chronic inflammatory infiltrate, lamina propria and intraepithelial neutrophils, crypt abscesses and destruction, erosions/ulcerations, apoptosis, surface intraepithelial lymphocytosis, and subepithelial collagen thickness. The appropriateness of routine immunohistochemistry was uncertain. These expert recommendations will help standardize assessment of histological activity in patients with ICIC. The panel also identified the development and validation of an ICIC-specific histological index as a research priority.

Research summary: The concern of crime in New York City public housing complexes motivated heightened police patrol of buildings and the enforcement of trespass laws. The 2013 federal court settlement of Davis et al. v. City of New York et al. mandated that the New York City Police Department (NYPD) implement a series of reforms, including the deployment of body‐worn cameras (BWCs) on officers, to address unconstitutional use of criminal trespass enforcement and stop and frisk practices in public housing developments. This study employed a stepped wedge quasi‐experimental design that involved the sequential crossover of public housing service area clusters from control to BWC implementation until all NYPD housing bureau officers were equipped with BWCs. Panel regression models at the individual officer and service area levels were used to estimate BWC program impacts on outcomes between 2015 and 2019. Logistic regression models were used to estimate the impact of the BWCs on the lawfulness of officer stop reports that were randomly selected for audit between 2017 and 2019. Results show that BWC deployment in public housing reduced excessive enforcement, citizen complaints, and use of force by NYPD housing officers. Findings further suggest that BWCs can help reduce constitutionally problematic stops and frisks of citizens. Policy implications: Problematic police activities in public housing contexts can be reformed using BWCs. When coupled with routine supervisory review of video footage, the deployment of BWCs on public housing officers can improve compliance with department directives to reduce enforcement actions and increase documentation of citizen stops. [ABSTRACT FROM AUTHOR]

Research Summary Policy Implications The evaluation literature suggests that focused deterrence strategies are effective in reducing gun violence. However, focused deterrence is notoriously difficult to implement and sustain. The history of focused deterrence implementation failure raises questions about its viability as a gun violence prevention strategy. Stockton, California, implemented focused deterrence three times during the past 25 years. In its most recent version, Stockton officials explicitly designed the strategy to be a permanent feature of the city's violence prevention portfolio. Although program caseloads diminished over the course of the COVID‐19 pandemic and the strategy faced leadership and resource challenges, Stockton's efforts prevented the program from being discontinued and, for those gang members who did receive treatment, delivered a robust gun violence prevention strategy. A quasi‐experimental evaluation shows that treated gang members were less likely to be shot and reduced their violent offending relative to similar untreated gang members. The focused deterrence impacts also appear to spill over to gang members who were socially connected to treated gang members. Although Stockton experienced an increase in homicides over the course of the COVID‐19 pandemic, the increase was not as steep as other comparable California cities.Focused deterrence strategies can be effective responses to gun violence problems when implemented properly. A priori planning is essential when jurisdictions prepare to adopt focused deterrence. Strategic management actions, such as maintaining a robust network of partnering agencies, developing accountability structures and sustainability plans, and conducting upfront and ongoing problem analysis, are critical elements that must be in place for focused deterrence to be effective and sustainable. [ABSTRACT FROM AUTHOR]

O-GlcNAcase (OGA) is the only human enzyme that catalyzes the hydrolysis (deglycosylation) of O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) from numerous protein substrates. OGA has broad implications in many challenging diseases including cancer. However, its role in cell malignancy remains mostly unclear. Here, we report that a cancer-derived point mutation on the OGA's noncatalytic stalk domain aberrantly modulates OGA interactome and substrate deglycosylation toward a specific set of proteins. Interestingly, our quantitative proteomic studies uncovered that the OGA stalk domain mutant preferentially deglycosylated protein substrates with +2 proline in the sequence relative to the O-GlcNAcylation site. One of the most dysregulated substrates is PDZ and LIM domain protein 7 (PDLIM7), which is associated with the tumor suppressor p53. We found that the aberrantly deglycosylated PDLIM7 suppressed p53 gene expression and accelerated p53 protein degradation by promoting the complex formation with E3 ubiquitin ligase MDM2. Moreover, deglycosylated PDLIM7 significantly up-regulated the actin-rich membrane protrusions on the cell surface, augmenting the cancer cell motility and aggressiveness. These findings revealed an important but previously unappreciated role of OGA's stalk domain in protein substrate recognition and functional modulation during malignant cell progression. [ABSTRACT FROM AUTHOR]