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Current understanding points to unrepairable chromosomal damage as the critical determinant of accelerated senescence in cancer cells treated with radiation or chemotherapy. Nonetheless, the potent senescence inducer etoposide not only targets topoisomerase II to induce DNA damage but also produces abundant free radicals, increasing cellular reactive oxygen species (ROS). Toward examining roles for DNA damage and oxidative stress in therapy-induced senescence, we developed a quantitative flow cytometric senescence assay and screened 36 redox-active agents as enhancers of an otherwise ineffective dose of radiation. While senescence failed to correlate with total ROS, the radiation enhancers, etoposide and the other effective topoisomerase inhibitors each produced high levels of lipid peroxidation. The reactive aldehyde 4-hydroxy-2-nonenal, a lipid peroxidation end product, was sufficient to induce senescence in irradiated cells. In turn, sequestering aldehydes with hydralazine blocked effects of etoposide and other senescence inducers. These results suggest that lipid peroxidation potentiates DNA damage from radiation and chemotherapy to drive therapy-induced senescence.

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Background and Aims: Immunity to SARS‐CoV‐2 can be infection or vaccine‐induced. Cirrhosis is associated with vaccine hyporesponsiveness, but whether there is decreased immunity after SARS‐CoV‐2 infection in unvaccinated patients with cirrhosis is unknown. The objective of our study was to compare infection‐induced and vaccine‐induced immunity against COVID‐19 among patients with cirrhosis. Methods: This was a retrospective cohort study among US Veterans with cirrhosis between November 27, 2020, and November 16, 2021, comparing a vaccine‐induced immunity group, defined as participants without a documented SARS‐CoV‐2 infection but fully vaccinated with two doses of an mRNA vaccine, and infection‐associated immunity group, defined as unvaccinated participants who had a positive SARS‐CoV‐2 polymerase chain reaction (PCR). Both groups were propensity score matched for observed characteristics, including location, and the date of the immunity acquiring event, to control for the community prevalence of COVID‐19 variants. The outcome was a positive SARS‐CoV‐2 PCR more than 60 days after previous infection in the infection‐induced, or after full vaccination in the vaccine‐induced immunity group. Results: We compared 634 participants in the infection‐induced immunity group with 27,131 participants in the vaccine‐induced immunity group using inverse propensity of treatment weighting. Vaccine‐induced immunity was associated with a reduced odds of developing SARS‐CoV‐2 infection (adjusted hazard ratio [aHR], 0.18; 95% confidence interval [CI], 0.16–0.20, p < 0.0001). On multivariable logistic regression, vaccine‐induced immunity was associated with reduced odds of developing symptomatic (adjusted odds ratio [aOR], 0.36; 95% CI, 0.33–0.41, p < 0.0001), moderate/severe/critical (aOR, 0.27; 95% CI, 0.22–0.31, p < 0.0001), and severe or critical COVID‐19 (aOR, 0.20; 95% CI, 0.16–0.26, p < 0.001), compared with infection‐induced immunity. Conclusions: In participants with cirrhosis, vaccine‐induced immunity is associated with reduced risk of developing COVID‐19, compared with infection‐induced immunity.