Timing of surgery following SARS-CoV-2 infection: an international prospective cohort study.

Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay

Old drug, New target. Ellipticines selectively inhibit RNA Polymerase I transcription

Transcription by RNA polymerase I (Pol-I) is the main driving force behind ribosome biogenesis, a fundamental cellular process that requires the coordinated transcription of all three nuclear polymerases. Increased Pol-I transcription and the concurrent increase in ribosome biogenesis has been linked to the high rates of proliferation in cancers. The ellipticine family contains a number of potent anticancer therapeutic agents, some having progressed to stage I and II clinical trials; however, the mechanism by which many of the compounds work remains unclear. It has long been thought that inhibition of Top2 is the main reason behind the drugs antiproliferative effects. Here we report that a number of the ellipticines, including 9-hydroxyellipticine, are potent and specific inhibitors of Pol-I transcription, with IC(50) in vitro and in cells in the nanomolar range. Essentially, the drugs did not affect Pol-II and Pol-III transcription, demonstrating a high selectivity. We have shown that Pol-I inhibition occurs by a p53-, ATM/ATR-, and Top2-independent mechanism. We discovered that the drug influences the assembly and stability of preinitiation complexes by targeting the interaction between promoter recognition factor SL1 and the rRNA promoter. Our findings will have an impact on the design and development of novel therapeutic agents specifically targeting ribosome biogenesis

Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53

Increased transcription of ribosomal RNA genes (rDNA) by RNA Polymerase I is a common feature of human cancer, but whether it is required for the malignant phenotype remains unclear. We show that rDNA transcription can be therapeutically targeted with the small molecule CX-5461 to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B cell population. The therapeutic effect is a consequence of nucleolar disruption and activation of p53-dependent apoptotic signaling. Human leukemia and lymphoma cell lines also show high sensitivity to inhibition of rDNA transcription that is dependent on p53 mutational status. These results identify selective inhibition of rDNA transcription as a therapeutic strategy for the cancer specific activation of p53 and treatment of hematologic malignancies

The works of Aristotle translated into English /

V.1: Categoriae and De Interpretatione, by E.M. Edgehill. Analytica priora, by A.J. Jenkinson. Analytica posteriora by G.R.G. Mure. Topica and De sophisticis elenchis, by W.A. Pickard-Cambridge.-- v. 2: Physica, by R.P. Hardie and R.K. Gaye. De Caelo, by J.L. Stocks. De generatione et corruptione, by H.H. Joachim.-- v. 3:Meteorologica, by E.W. Webster. De mundo, by E.S. Forster. De anima, by J.S. Smith. Parva naturalia by J.I. Beare and G.R.T. Ross. De spiritu, by J.F. Dobson.-- v. 4: Historia animalium, by D'Arcy Wentworth Thompson. -- v. 5: De parvis animalium, by William Ogle. De motu and De incessu animalium, by A.S.L. Farquharson. De generatione animalium, by Arthur Platt. -- v. 6: Opuscula, by T. Loveday, L.D. Dowdall, E.S. Forster and H.H. Joachim. -- v. 7: Problemata, byE. S. Forster. -- v. 8: Metaphysica, by W.D. Ross. -- v. 9: Ethica nicomachea, by W.D. Ross. Magna moralia, by St. George Stock. Ethica eudemia de virtutibus et vitiis, by J. Solomon. -- v. 10: Politica, by Benjamin Jowett. Oeconomica, by E.S. Forster. Athenensium respublica, by Sir Frederick G. Kenyon.-- v. 11: Rhetorica, by W. Rhys Roberts. De rhetorica ad alexandrum, by E.S. Forster. De poetica, by Ingram Bywater. -- v. 12: Select fragments.Mode of access: Internet