Novel Mouse Models of Bladder Cancer Identify a Prognostic Signature Associated with Risk of Disease Progression.

To study the progression of bladder cancer from non-muscle-invasive to muscle-invasive disease, we have developed a novel toolkit that uses complementary approaches to achieve gene recombination in specific cell populations in the bladder urothelium in vivo, thereby allowing us to generate a new series of genetically engineered mouse models (GEMM) of bladder cancer. One method is based on the delivery of adenoviruses that express Cre recombinase in selected cell types in the urothelium, and a second uses transgenic drivers in which activation of inducible Cre alleles can be limited to the bladder urothelium by intravesicular delivery of tamoxifen. Using both approaches, targeted deletion of the Pten and p53 tumor suppressor genes specifically in basal urothelial cells gave rise to muscle-invasive bladder tumors. Furthermore, preinvasive lesions arising in basal cells displayed upregulation of molecular pathways related to bladder tumorigenesis, including proinflammatory pathways. Cross-species analyses comparing a mouse gene signature of early bladder cancer with a human signature of bladder cancer progression identified a conserved 28-gene signature of early bladder cancer that is associated with poor prognosis for human bladder cancer and that outperforms comparable gene signatures. These findings demonstrate the relevance of these GEMMs for studying the biology of human bladder cancer and introduce a prognostic gene signature that may help to stratify patients at risk for progression to potentially lethal muscle-invasive disease. SIGNIFICANCE: Analyses of bladder cancer progression in a new series of genetically engineered mouse models has identified a gene signature of poor prognosis in human bladder cancer.

Pharmacokinetics of fluoxetine in pregnant baboons (Papio spp.).

Fluoxetine is used to treat a number of psychiatric conditions in humans and behavioral problems in animals. Its use in pregnancy must balance maternal benefit with potential risk to the fetus. Knowledge of adult and fetal drug disposition can assist clinicians in selecting therapy that minimizes adverse effects to the fetus. Nonhuman primate models are used frequently in drug dose-translation studies, and pregnancy in baboons has many similarities to human pregnancy. Accordingly, pharmacokinetic analysis of a series of fluoxetine and norfluoxetine administrations to pregnant baboons was performed. The mean maternal baboon steady-state clearance of fluoxetine (42 mL/min/kg) was considerably higher than that in humans. Norfluoxetine, the major active metabolite, had a higher metabolite-to-drug ratio (8.7) than that found in humans, particularly with oral dosing. These results are consistent with more extensive metabolism in baboons than in humans and leads to a higher clearance than would be expected from allometric scaling. Fetal-to-maternal fluoxetine and norfluoxetine ratios under steady-state conditions were similar to those in humans, with fetal concentrations of fluoxetine 42% and norfluoxetine 47% of maternal concentrations. The fetal clearance of fluoxetine (303 ± 176 mL/min) and norfluoxetine (450 mL/min) exceeded reported placental blood flow. Understanding these species-associated differences in metabolism is a prerequisite to extrapolating data between species. Nonetheless, nonhuman primates are likely to remain valuable models for pharmacokinetic studies during pregnancy, particularly those directed toward fetal neurodevelopmental effects. Our results also are applicable to determining appropriate dosing of nonhuman primates in clinical settings.