A systems approach points to a therapeutic role for retinoids in asparaginase-associated pancreatitis.

Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP). Connectivity Map analysis of the transcriptomic data showed that asparaginase-induced gene signatures were potentially reversed by retinoids (vitamin A and its analogs). Analysis of a large electronic health record database (TriNetX) and the U.S. Federal Drug Administration Adverse Events Reporting System demonstrated a reduction in AAP risk with concomitant exposure to vitamin A. Furthermore, we performed a global metabolomic screening of plasma samples from 24 individuals with ALL who developed pancreatitis (cases) and 26 individuals with ALL who did not develop pancreatitis (controls), before and after a single exposure to asparaginase. Screening from this discovery cohort revealed that plasma carotenoids were lower in the cases than in controls. This finding was validated in a larger external cohort. A 30-day dietary recall showed that the cases received less dietary vitamin A than the controls did. In mice, asparaginase administration alone was sufficient to reduce circulating and hepatic retinol. Based on these data, we propose that circulating retinoids protect against pancreatic inflammation and that asparaginase reduces circulating retinoids. Moreover, we show that AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach taken for AAP provides an impetus to examine the role of dietary vitamin A supplementation in preventing or treating AAP.

Quantitative cancer assessment for vinyl chloride: indications of early-life sensitivity.

Complementary sources of information are analyzed to characterize the early-life cancer risk from inhaling vinyl chloride. A study of partial-lifetime exposures suggests that the lifetime cancer risk depends on age at exposure, with higher lifetime risks attributable to exposures at younger ages. Studies of newborn animal exposures further demonstrate that a brief exposure in newborns can, by the end of life, induce a higher incidence of tumors compared to long-term exposure occurring later in life, including tumor types not induced by exposure later in life. An empirical, quantitative approach is used to model early-life sensitivity to inhaled vinyl chloride, supplementing conventional approaches for estimating the increased cancer risk from lifetime exposure. A single estimate is not presumed to apply to the entire population; instead, the new approach makes distinctions about the cancer risks for different population segments. This assessment shows one way such information might be analyzed, presented, and used to assess actual exposure situations.