Data resource profile: COVid VAXines effects on the aged (COVVAXAGE).

Background: To improve the assessment of COVID-19 vaccine use, safety, and effectiveness in older adults and persons with complex multimorbidity, the COVid VAXines Effects on the Aged (COVVAXAGE) database was established by linking CVS Health and Walgreens pharmacy customers to Medicare claims. Methods: We deterministically linked CVS Health and Walgreens customers who had a pharmacy dispensation/encounter paid for by Medicare to Medicare enrollment and claims records. Linked data include U.S. Medicare claims, Medicare enrollment files, and community pharmacy records. The data currently span 01/01/2016 to 08/31/2022. "Research-ready" files were created, with weekly indicators for vaccinations, censoring, death, enrollment, demographics, and comorbidities. Data are updated quarterly. Results: As of November 2022, records for 27,086,723 CVS Health and 23,510,025 Walgreens unique customer IDs were identified for potential linkage. Approximately 91% of customers were matched to a Medicare beneficiary ID (95% for those aged 65 years or older). In the final linked cohort, there were 38,250,873 unique beneficiaries representing ~60% of the Medicare population. Among those alive and enrolled in Medicare as of January 1, 2020 (n = 33,721,568; average age = 73 years, 74% White, 51% Medicare Fee-for-Service, and 11% dual-eligible for Medicaid), the average follow-up time was 130 weeks. The cohort contains 16,021,055 beneficiaries with evidence a first COVID-19 vaccine dose. Data are stored on the secure Medicare & Medicaid Resource Information Center Health & Aging Data Enclave. Data access: Investigators with funded or in-progress funding applications to the National Institute on Aging who are interested in learning more about the database should contact Dr Vincent Mor [Vincent_mor@brown.edu] and Dr Kaleen Hayes [kaley_hayes@brown.edu]. A data dictionary can be provided under reasonable request. Conclusions: The COVVAXAGE cohort is a large and diverse cohort that can be used for the ongoing evaluation of COVID-19 vaccine use and other research questions relevant to the Medicare population.

Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity.

Cancer heterogeneity impacts therapeutic response, driving efforts to discover over-arching rules that supersede variability. Here, we define pan-cancer binary classes based on distinct expression of YAP and YAP-responsive adhesion regulators. Combining informatics with in vivo and in vitro gain- and loss-of-function studies across multiple murine and human tumor types, we show that opposite pro- or anti-cancer YAP activity functionally defines binary YAPon or YAPoff cancer classes that express or silence YAP, respectively. YAPoff solid cancers are neural/neuroendocrine and frequently RB1-/-, such as retinoblastoma, small cell lung cancer, and neuroendocrine prostate cancer. YAP silencing is intrinsic to the cell of origin, or acquired with lineage switching and drug resistance. The binary cancer groups exhibit distinct YAP-dependent adhesive behavior and pharmaceutical vulnerabilities, underscoring clinical relevance. Mechanistically, distinct YAP/TEAD enhancers in YAPoff or YAPon cancers deploy anti-cancer integrin or pro-cancer proliferative programs, respectively. YAP is thus pivotal across cancer, but in opposite ways, with therapeutic implications.

Cancer Cells Hijack PRC2 to Modify Multiple Cytokine Pathways.

Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator induced in many cancers. It is thought to drive tumorigenesis by repressing division, stemness, and/or developmental regulators. Cancers evade immune detection, and diverse immune regulators are perturbed in different tumors. It is unclear how such cell-specific effects are coordinated. Here, we show a profound and cancer-selective role for PRC2 in repressing multiple cytokine pathways. We find that PRC2 represses hundreds of IFNγ stimulated genes (ISGs), cytokines and cytokine receptors. This target repertoire is significantly broadened in cancer vs non-cancer cells, and is distinct in different cancer types. PRC2 is therefore a higher order regulator of the immune program in cancer cells. Inhibiting PRC2 with either RNAi or EZH2 inhibitors activates cytokine/cytokine receptor promoters marked with bivalent H3K27me3/H3K4me3 chromatin, and augments responsiveness to diverse immune signals. PRC2 inhibition rescues immune gene induction even in the absence of SWI/SNF, a tumor suppressor defective in ~20% of human cancers. This novel PRC2 function in tumor cells could profoundly impact the mechanism of action and efficacy of EZH2 inhibitors in cancer treatment.