| Objectives: Contralateral, metachronous upper urinary tract (UUT) tumors afterprimary transitional cell carcinoma (TCC) of the UUT are reported rarely, and to theauthors’ knowledge the risk factors have not been determined to date. In addition, fewreports have described the characteristics of recurrent bladder tumors and contralateralUUT tumors and any relation between theses tumor types.Methods: Statistical analysis of data from882patients with documented primaryTCC was undertaken. After excluding bilateral involvement and distant metastases,11variables were analyzed by multivariate analysis in112patients to determine the riskfactors for recurrent urothelial tumors.Results: The incidence rates of recurrent bladder tumors and contralateral UUTtumors were31.2%and5.8%, respectively. Multiplicity was determined as a riskfactor for recurrent bladder tumors. Renal insufficiency and concurrent bladder tumorssignificantly predisposed patients to develop contralateral UUT tumors after primaryUUT-TCC. The time intervals and stage distributions differed significantly betweenrecurrent bladder tumors and contralateral UTT tumors. Patients who had recurrentbladder tumors had earlier stage tumors and had a shorter time to recur compared withpatients who had contralateral, metachronous UUT tumors.Conclusions: For patients with primary UUT-TCC, regular follow-up by cystoscopy isnecessary to detect recurrent bladder tumors. Intravenous urography orCT Urography should be performed for patients who have a high risk of developing contralateral UUT tumors. Glycogen synthase kinase3β (GSK3β) is a multifunctional serine/threonine proteinkinase that is involved in several biological processes including insulin and Wntsignaling pathways. GSK3β can be phosphorylated by the protein kinase B (PKB). Themutations of Arg4and Arg6to alanine at N-terminal GSK3β have been reported toimpair its ability to autophosphorylate at Ser9. Despite the extensive experimentalobservations, the detailed mechanism for the auto-inhibition of GSK3β has not beenrationalized at the molecular level. In this study, we have demonstrated the structuralconsequences of GSK3β R4A and R6A mutations and the atomic changes thatinfluenced the loss of PKB-binding affinity. Molecular dynamics simulation resultssuggested significant loss in atomic contacts in the R4A and R6A mutant systemscompared to the wild type system. Furthermore, we observed many notable changes(such as conformation, residues motions, hydrogen bonds and binding free energy) inthe mutated GSK3β-PKB complexes. Loss of binding affinity in the mutated systemsrendered the decrease of GSK3β phosphorylation, which, in turn, impaired theauto-inhibition of GSK3β. The significant outcomes obtained from this study canexplain the auto-inhibition of GSK3β and maybe facilitate type2diabetes mellitusresearches and in developing the potent drug therapies. |
