Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805.

The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2(V617F) mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative neoplasms and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2(V617F) and JAK2 wild-type enzymes by a novel substituted quinoxaline, NVP-BSK805, which acts in an ATP-competitive manner. Within the JAK family, NVP-BSK805 displays more than 20-fold selectivity towards JAK2 in vitro, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2(V617F)-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, NVP-BSK805 exhibited good oral bioavailability and a long half-life. The inhibitor was efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2(V617F) cell-driven mouse mechanistic model. Furthermore, NVP-BSK805 potently suppressed recombinant human erythropoietin-induced polycythemia and extramedullary erythropoiesis in mice and rats.

Congenital anomalies, labor/delivery complications, maternal risk factors and their relationship with perfluorooctanoic acid (PFOA)-contaminated public drinking water.

BACKGROUND: We have previously examined the associations between perfluorooctanoic acid (PFOA) exposure, birth weight and gestational age in individuals exposed to PFOA-contaminated residential drinking water from the Little Hocking Water Association (LHWA). In this investigation, we expand the scope of our analysis to examine the associations between PFOA, congenital anomalies, labor and delivery complications and maternal risk factors. OBJECTIVES: To compare the likelihood of congenital anomalies, labor and delivery complications and maternal risk factors in neonates and their mothers residing in zip codes with public water service provided completely, partially or not at all by the LHWA. METHODS: Logistic regression analyses were performed on singleton neonatal birth outcome data supplied by the Ohio Department of Health to examine the associations between LHWA water service category and the outcomes of interest. When possible, models were adjusted for maternal age, preterm birth, neonatal sex, race, maternal education, alcohol use, tobacco use and diabetic status. RESULTS: Increased PFOA exposure, as assessed by water service category, was not associated with an overall increase in the likelihood of congenital anomalies or any specific diagnosis (adjusted OR: 1.4, 95% CI: 0.34-3.3). The overall likelihood of labor and delivery complications was significantly lower among mothers with water service provided by the LHWA, as compared to mothers not serviced by the LHWA (adjusted OR: 0.65, 95% CI: 0.46-0.92). A significant increase in the likelihood of anemia (crude OR: 11, 95% CI: 1.8-64) and dysfunctional labor (crude OR: 5.3, 95% CI: 1.2-24) was noted for mothers residing within zip codes serviced by the LHWA, but the number of reported cases was very small. CONCLUSION: At the levels measured in the LHWA, we conclude that PFOA is not associated with increased risk of congenital anomalies, most labor and delivery complications and maternal risk factors. Additional research is required to assess the observed associations between PFOA, anemia and dysfunctional labor.

The relationship between birth weight, gestational age and perfluorooctanoic acid (PFOA)-contaminated public drinking water.

BACKGROUND: Recent studies have examined the associations between perfluorooctanoic acid (PFOA) levels in cord blood and maternal plasma with lowered birth weight and gestational age in humans; however, no study has examined these effects in a population of known high PFOA exposure. Residents drinking PFOA-contaminated water from the Little Hocking Water Association (LHWA) in Washington County, Ohio have serum PFOA levels approximately 80 times those in the general U.S. population. OBJECTIVES: To compare birth weights and gestational ages of neonates born to mothers residing in zip codes with water service provided completely, partially or not at all by the LHWA. METHODS: Multiple logistic and linear regression analyses were performed on singleton neonatal birth weight data supplied by the Ohio Department of Health to examine the associations between LHWA water service category (used as a surrogate for PFOA exposure) with mean birth weight, mean gestational age, the likelihood of low birth weight (<2500 g), and the likelihood of preterm birth (<37 completed weeks of gestation). All models were adjusted for maternal age, gestational age, sex, race and population-level socioeconomic status. RESULTS: The incidence of low birth weight, preterm birth, mean birth weight and mean gestational age of neonates did not significantly differ among water service categories. CONCLUSION: Markedly elevated PFOA exposure, as categorized by water service category, is not associated with increased risk of lowered birth weight or gestational age. This study does not confirm earlier findings of an association between PFOA and lowered birth weight observed at normal population levels.