Induction of APOBEC3-mediated genomic damage in urothelium implicates BK polyomavirus (BKPyV) as a hit-and-run driver for bladder cancer.

Limited understanding of bladder cancer aetiopathology hampers progress in reducing incidence. Mutational signatures show the anti-viral apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) enzymes are responsible for the preponderance of mutations in bladder tumour genomes, but no causative viral agent has been identified. BK polyomavirus (BKPyV) is a common childhood infection that remains latent in the adult kidney, where reactivation leads to viruria. This study provides missing mechanistic evidence linking reactivated BKPyV-infection to bladder cancer risk. We used a mitotically-quiescent, functionally-differentiated model of normal human urothelium to examine BKPyV-infection. BKPyV-infection led to significantly elevated APOBEC3A and APOBEC3B protein, increased deaminase activity and greater numbers of apurinic/apyrimidinic sites in the host urothelial genome. BKPyV Large T antigen (LT-Ag) stimulated re-entry from G0 into the cell cycle through inhibition of retinoblastoma protein and activation of EZH2, E2F1 and FOXM1, with cells arresting in G2. The single-stranded DNA displacement loops formed in urothelial cells during BKPyV-infection interacted with LT-Ag to provide a substrate for APOBEC3-activity. Addition of interferon gamma (IFNγ) to infected urothelium suppressed expression of the viral genome. These results support reactivated BKPyV infections in adults as a risk factor for bladder cancer in immune-insufficient populations.

Does use of the Hepcon point-of-care coagulation monitor to optimise heparin and protamine dosage for cardiopulmonary bypass decrease bleeding and blood and blood product requirements in adult patients undergoing cardiac surgery?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether use of the Hepcon point-of-care coagulation monitor (Medtronic, Minneapolis, MN) to optimise and monitor heparin and protamine dosage for cardiopulmonary bypass could decrease bleeding and blood and blood product requirements in adult patients undergoing cardiac surgery. Altogether 680 papers were identified on Medline, and 879 on Embase using the reported search strategy. Two further relevant papers were found by hand-searching of reference lists. Fourteen papers represented the best evidence on the topic. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. We conclude that in patients undergoing cardiac surgery, use of the Hepcon coagulation monitor will increase the dose of heparin but decrease the dose of protamine administered compared to more empirical ACT-based dosing regimes. There is some evidence that this leads to less activation of the coagulation system and may be associated with decreased postoperative bleeding and blood product requirements but more work is required to quantify the magnitude of this effect.