SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown. Here we show that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response. Mechanistically, SARS-CoV-2 proteins ORF6 and NSP13 cause degradation of the DNA damage response kinase CHK1 through proteasome and autophagy, respectively. CHK1 loss leads to deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, DNA damage, pro-inflammatory pathways activation and cellular senescence. Supplementation of deoxynucleosides reduces that. Furthermore, SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing DNA repair. Key observations are recapitulated in SARS-CoV-2-infected mice and patients with COVID-19. We propose that SARS-CoV-2, by boosting ribonucleoside triphosphate levels to promote its replication at the expense of dNTPs and by hijacking damage-induced long non-coding RNAs’ biology, threatens genome integrity and causes altered DNA damage response activation, induction of inflammation and cellular senescence

Transferability to clinical practice of the results of controlled clinical trials: The case of antiemetic prophylactic treatment for cancer chemotherapy-induced nausea and vomiting

Background: There is convincing evidence from randomized clinical trials that the use of 5-HT3 antagonists has brought about a substantial improvement in the control of chemotherapy-induced nausea and vomiting. However, no data exist to indicate how this new research evidence can be applied to the individual patient. Patients and methods. We carried out a prospective, observational study on the use and effectiveness of antiemetic drugs in patients undergoing cancer chemotherapy in 33 Italian oncology departments. Results: A total of 1,956 consecutive patients entered the study; 1,238 of them underwent a one-day chemotherapy and 718 a chemotherapy fractionated over several consecutive days. The 5-HT3 antagonists, used either alone or in combination with a corticosteroid, have almost completely supplanted all other types of antiemetic regimens for preventing cancer chemotherapy-induced emesis. In fact, 80% of patients, irrespective of whether their emesis was acute or delayed, or of the emetogenic potential of the cancer chemotherapy they received, have been treated with these compounds. However, the practice of participating oncologists with respect to prescriptions has been far from consistent with the evidence provided by randomized controlled trials. Both overtreatment and undertreatment have occurred in many patients, creating unjustified costs and placing the patients at greater risk for emesis. However, when antiemetics are properly used their effectiveness is similar to that seen in randomized controlled trials. Conclusions: Powerful barriers exist between the evidence provided by sound research and clinical practice, and this issue hampers progress toward the optimal use of antiemetic drugs

Is an antiemetic prophylactic treatment needed for patients submitted to consecutive days of 5-fluorouracil? An observational study

Aims and Background. The necessity of an antiemetic prophylaxis in patients treated with chemotherapy of low emetogenic potential, such as 5-fluorouracil +/- folinic acid fractionated over several consecutive days, is controversial. The aim of the study was to evaluate the therapeutic behavior of oncologists on this issue. Methods. All consecutive in and out patients who started chemotherapy in 33 Italian oncological departments from June 24 to July 6, 1996, were studied. The antiemetic prescription pattern and its effectiveness, in patients submitted to 5-fluorouracil +/- folinic acid were evaluated. Results. Of the 1956 patients submitted to cancer chemotherapy, 259 patients received 5-fluorouracil +/- folinic acid. Of these, 186 patients were treated for 5 consecutive days, 47 for 4 days, 20 for 3 days and 6 for 2 days. A total of 219 (84.5%) received an antiemetic prophylaxis: 43.4% a 5-HT3 antagonist +/- steroids, 37.5% an antidopaminergic drug, 10.9% a steroid +/- antidopaminergic drug, and 8.2% other drugs. Only 40 patients (15.5%) did not receive an antiemetic prophylaxis. Overall complete protection from vomiting/nausea was 225/259 (86.9%)/163/259 (62.9%). The complete protection from vomiting/nausea during the 5 days in the 186 patients was not significantly different among patients receiving or not an antiemetic prophylaxis (88.1%/64.9% vs 88.9%/55.6%). At unifactorial analysis, the previous experience of vomiting/nausea caused by chemotherapy was found to be a significant prognostic factor. In fact, overall complete protection from vomiting/nausea was significantly inferior in patients who had previous experience of vomiting/nausea (65.1%/35.0%) with respect to those who did not (91.2%/75.4%, P 0.001, respectively). Conclusions. The study showed that in clinical practice patients submitted to 5-fluorouracil +/- folinic acid obtained a similar high protection from vomiting and nausea regardless of whether or not antiemetic prophylaxis was given. It would be therefore reasonable not to treat patients undergoing such chemotherapy, whereas patients with previous experience of vomiting/nausea caused by chemotherapy should be given an antiemetic prophylaxis