Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva.

Currently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues owing to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2 (also known as ACVR1). From a screen of known biologically active compounds, we identified saracatinib as a potent ALK2 kinase inhibitor. In enzymatic and cell-based assays, saracatinib preferentially inhibited ALK2, compared with other receptors of the BMP/TGF-ß signaling pathway, and induced dorsalization in zebrafish embryos consistent with BMP antagonism. We further tested the efficacy of saracatinib using an inducible ACVR1Q207D-transgenic mouse line, which provides a model of heterotopic ossification (HO), as well as an inducible ACVR1R206H-knockin mouse, which serves as a genetically and physiologically faithful FOP model. In both models, saracatinib was well tolerated and potently inhibited the development of HO, even when administered transiently following soft tissue injury. Together, these data suggest that saracatinib is an efficacious clinical candidate for repositioning in FOP treatment, offering an accelerated path to clinical proof-of-efficacy studies and potentially significant benefits to individuals with this devastating condition.

Military deployment human exposure assessment: urine total and isotopic uranium sampling results.

Currently the Department of Defense (DoD) does not use exposure biomarkers to measure service members' exposure to environmental chemicals. Blood and urine exposure biomarkers for volatile organic compounds (VOC), selected heavy metals, depleted uranium (DU), and chemical warfare agents are currently available but have not been field tested or validated by the DoD in military deployments as a tool to document exposures. The Military Deployment Human Exposure Assessment Study, a prospective cohort of 46 soldiers deployed to Bosnia, was designed to field test blood and urine exposure biomarkers as a mechanism to document exposures to these chemicals during military deployments. Blood and urine were collected before, during, and after deployment. Standard questionnaire, environmental, and occupational monitoring data collection methods were conducted for comparison to the exposure biomarker results. This article compares and reports the pre-, during, and postdeployment urine total and isotopic uranium measurements and compares them to perceived exposures captured on questionnaire, to environmental data collected by the United Nations Environmental Program in Bosnia, and to standard U.S. urine uranium reference levels (CDC, 2003). Additionally, the questionnaire and environmental and occupational measurements are reported. The results of the study indicate that exposure biomarkers may be a valuable tool to the DoD in exposure and risk assessment with regard to environmental and occupational exposures to uranium.