PURPOSE SARS-CoV-2 (COVID-19) is a systemic infection. Patients with cancer are immunocompromised and may be vulnerable to COVID-related morbidity and mortality. The objectives of this study were to determine if patients with cancer have worse outcomes compared with patients without cancer and to identify demographic and clinical predictors of morbidity and mortality among patients with cancer. METHODS We used data from adult patients who tested positive for COVID-19 and were admitted to two New York–Presbyterian hospitals between March 3 and May 15, 2020. Patients with cancer were matched 1:4 to controls without cancer in terms of age, sex, and number of comorbidities. Using Kaplan-Meier curves and the log-rank test, we compared morbidity (intensive care unit admission and intubation) and mortality outcomes between patients with cancer and controls. Among those with cancer, we identified demographic and clinical predictors of worse outcomes using Cox proportional hazard models. RESULTS We included 585 patients who were COVID-19 positive, of whom 117 had active malignancy, defined as those receiving cancer-directed therapy or under active surveillance within 6 months of admission. Presenting symptoms and in-hospital complications were similar between the cancer and noncancer groups. Nearly one half of patients with cancer were receiving therapy, and 45% of patients received cytotoxic or immunosuppressive treatment within 90 days of admission. There were no statistically significant differences in morbidity or mortality ( P = .894) between patients with and without cancer. CONCLUSION We observed that patients with COVID-19 and cancer had similar outcomes compared with matched patients without cancer. This finding suggests that a diagnosis of active cancer alone and recent anticancer therapy do not predict worse COVID-19 outcomes and therefore, recommendations to limit cancer-directed therapy must be considered carefully in relation to cancer-specific outcomes and death.

In metazoans, the mechanism by which DNA is synthesized during homologous recombination repair of double-strand breaks is poorly understood. Specifically, the identities of the polymerase(s) that carry out repair synthesis and how they are recruited to repair sites are unclear. Here, we have investigated the roles of several different polymerases during homologous recombination repair in Drosophila melanogaster. Using a gap repair assay, we found that homologous recombination is impaired in Drosophila lacking DNA polymerase zeta and, to a lesser extent, polymerase eta. In addition, the Pol32 protein, part of the polymerase delta complex, is needed for repair requiring extensive synthesis. Loss of Rev1, which interacts with multiple translesion polymerases, results in increased synthesis during gap repair. Together, our findings support a model in which translesion polymerases and the polymerase delta complex compete during homologous recombination repair. In addition, they establish Rev1 as a crucial factor that regulates the extent of repair synthesis.

The majority of colorectal cancers (CRCs) show hyperactivated WNT signaling due to inactivating mutations in the APC tumor suppressor. Genetically restoring Apc suppresses WNT and induces rapid and sustained tumor regression, implying that re-engaging this endogenous tumor suppressive mechanism may be an effective therapeutic strategy. Here, using new animal models, human cell lines, and ex vivo organoid cultures, we show that Tankyrase (TNKS) inhibition can control WNT hyperactivation and provide long-term tumor control in vivo, but that effective responses are critically dependent on how APC is disrupted. Mutant APC proteins truncated within the Mutation Cluster Region (MCR) region physically engage the destruction complex and suppress the WNT transcriptional program, while early APC truncations (i.e. Apc Min) show limited interaction with AXIN1 and β-catenin, and do not respond to TNKS blockade. Together, this work shows that TNKS inhibition, like APC restoration, can reestablish endogenous control of WNT/β-catenin signaling, but that APC genotype is a crucial determinant of this response.

Tankyrase (TNKS) 1/2 are positive regulators of WNT signaling by controlling the activity of the ß-catenin destruction complex. TNKS inhibitors provide an opportunity to suppress hyperactive WNT signaling in tumors, however, they have shown limited anti-proliferative activity as a monotherapy in human cancer cell lines. Here we perform a kinome-focused CRISPR screen to identify potential effective drug combinations with TNKS inhibition. We show that the loss of CDK4, but not CDK6, synergizes with TNKS1/2 blockade to drive G1 cell cycle arrest and senescence. Through precise modelling of cancer-associated mutations using cytidine base editors, we show that this therapeutic approach is absolutely dependent on suppression of canonical WNT signaling by TNKS inhibitors and is effective in cells from multiple epithelial cancer types. Together, our results suggest that combined WNT and CDK4 inhibition might provide a potential therapeutic strategy for difficult-to-treat epithelial tumors.

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Objectives Although non-O blood type is an established risk factor for venous thromboembolism in the general population, the impact of ABO blood type (ABO) on venous thromboembolism risk in individuals with persistent antiphospholipid antibodies (aPL) has not been studied. We sought to investigate the relationship between ABO and venous thromboembolism in aPL-positive individuals. We also sought to explore potential interactions between ABO and sex or race to determine whether ABO contributes to race or sex differences with respect to the development of venous thromboembolism. Methods We identified all patients over 18 years old followed at a tertiary medical center between January 2000 and January 2015 with serological aPL criteria and ABO data. Episodes of venous thromboembolism were recorded. Logistic regression models were fitted to estimate odds ratios (ORs) of venous thromboembolism for non-O (A, B, or AB blood types) versus O blood type. Results There were 226 patients included in the final analysis, of whom 75 (33%) had reported venous thromboembolism. In the overall sample, there was a non-significant difference between venous thromboembolism in patients with non-O blood type compared to O blood type (OR 1.64, 95% confidence interval (CI) 0.94, 2.88; P = 0.08). Men with non-O blood type had a significantly higher risk of venous thromboembolism as compared to men with O-type blood (OR 4.94, 95% CI 1.37, 17.85; P = 0.02), but there was no significant association between ABO and venous thromboembolism among women (OR 0.96, 95% CI 0.50, 1.83; P = 0.52). Conclusions Non-O blood type may be an under-recognized risk factor for venous thromboembolism among men with persistent aPL antibodies, whereas the risk associated with non-O blood type seen in the general population may be attenuated in aPL-positive women.

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