Targeting intermediary metabolism enhances the efficacy of BH3 mimetic therapy in hematologic malignancies.

BH3 mimetics are novel targeted drugs with remarkable specificity, potency and enormous potential to improve cancer therapy. However, acquired resistance is an emerging problem. We report the rapid development of resistance in chronic lymphocytic leukemia cells isolated from patients exposed to increasing doses of navitoclax (ABT-263), a BH3 mimetic. To mimic such rapid development of chemoresistance, we developed simple resistance models to three different BH3 mimetics, targeting BCL-2 (ABT-199), BCL-XL (A-1331852) or MCL-1 (A-1210477), in relevant hematologic cancer cell lines. In these models, resistance could not be attributed to either consistent changes in expression levels of the anti-apoptotic proteins or interactions among different pro- and anti-apoptotic BCL-2 family members. Using genetic silencing, pharmacological inhibition and metabolic supplementation, we found that targeting glutamine uptake and its downstream signaling pathways, namely glutaminolysis, reductive carboxylation, lipogenesis, cholesterogenesis and mammalian target of rapamycin signaling resulted in marked sensitization of the chemoresistant cells to BH3 mimetic-mediated apoptosis. Furthermore, our findings highlight the possibility of repurposing widely used drugs, such as statins, to target intermediary metabolism and improve the efficacy of BH3 mimetic therapy.

Accuracy and Efficiency of Recording Pediatric Early Warning Scores Using an Electronic Physiological Surveillance System Compared With Traditional Paper-Based Documentation.

Pediatric Early Warning Scores are advocated to assist health professionals to identify early signs of serious illness or deterioration in hospitalized children. Scores are derived from the weighting applied to recorded vital signs and clinical observations reflecting deviation from a predetermined "norm." Higher aggregate scores trigger an escalation in care aimed at preventing critical deterioration. Process errors made while recording these data, including plotting or calculation errors, have the potential to impede the reliability of the score. To test this hypothesis, we conducted a controlled study of documentation using five clinical vignettes. We measured the accuracy of vital sign recording, score calculation, and time taken to complete documentation using a handheld electronic physiological surveillance system, VitalPAC Pediatric, compared with traditional paper-based charts. We explored the user acceptability of both methods using a Web-based survey. Twenty-three staff participated in the controlled study. The electronic physiological surveillance system improved the accuracy of vital sign recording, 98.5% versus 85.6%, P < .02, Pediatric Early Warning Score calculation, 94.6% versus 55.7%, P < .02, and saved time, 68 versus 98 seconds, compared with paper-based documentation, P < .002. Twenty-nine staff completed the Web-based survey. They perceived that the electronic physiological surveillance system offered safety benefits by reducing human error while providing instant visibility of recorded data to the entire clinical team.