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Survival of pediatric AML remains poor despite maximized myelosuppressive therapy. The pneumocystis jiroveci pneumonia (PJP)-treating medication atovaquone (AQ) suppresses oxidative phosphorylation (OXPHOS) and reduces AML burden in patient-derived xenograft (PDX) mouse models, making it an ideal concomitant AML therapy. Poor palatability and limited product formulations have historically limited routine use of AQ in pediatric AML patients. Patients with de novo AML were enrolled at two hospitals. Daily AQ at established PJP dosing was combined with standard AML therapy, based on the Medical Research Council backbone. AQ compliance, adverse events (AEs), ease of administration score (scale: 1 (very difficult)-5 (very easy)) and blood/marrow pharmacokinetics (PK) were collected during Induction 1. Correlative studies assessed AQ-induced apoptosis and effects on OXPHOS. PDX models were treated with AQ. A total of 26 patients enrolled (ages 7.2 months–19.7 years, median 12 years); 24 were evaluable. A total of 14 (58%) and 19 (79%) evaluable patients achieved plasma concentrations above the known anti-leukemia concentration (>10 µM) by day 11 and at the end of Induction, respectively. Seven (29%) patients achieved adequate concentrations for PJP prophylaxis (>40 µM). Mean ease of administration score was 3.8. Correlative studies with AQ in patient samples demonstrated robust apoptosis, OXPHOS suppression, and prolonged survival in PDX models. Combining AQ with chemotherapy for AML appears feasible and safe in pediatric patients during Induction 1 and shows single-agent anti-leukemic effects in PDX models. AQ appears to be an ideal concomitant AML therapeutic but may require intra-patient dose adjustment to achieve concentrations sufficient for PJP prophylaxis. Full article

The Early Cretaceous Yellow Cat Member of the terrestrial Cedar Mountain Formation in Utah, USA. has been interpreted as a “time-rich” unit because of its dinosaur fossils, prominent paleosols, and the results of preliminary chemostratigraphic and geochronologic studies. Herein, we refine prior interpretations with: (1) a new composite C-isotope chemostratigraphic profile from the well-known Utahraptor Ridge dinosaur site, which exhibits δ¹³C features tentatively interpreted as the Valanginian double-peak carbon isotope excursion (the so-called “Weissert Event”) and some unnamed Berriasian features; and (2) a new cryptotephra zircon eruption age of 135.10 ± 0.30/0.31/0.34 Ma (2σ) derived from the CA-ID-TIMS U-Pb analyses of zircons from a paleosol cryptotephra. Our interpretations of δ¹³C features on our chemostratigraphic profile, in the context of our new radiometric age, are compatible with at least one prior age model for the “Weissert Event” and the most recent revision of the Cretaceous time scale. Our results also support the interpretation that the Yellow Cat Member records a significant part of Early Cretaceous time. Full article