Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium.

Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. While venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug-responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e. OXPHOS) status with relatively high levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in LSCs and provide an avenue for clinical management of venetoclax resistance.

Provider-to-provider telehealth for sepsis patients in a cohort of rural emergency departments.

BACKGROUND: Telehealth has been proposed as one strategy to improve the quality of time-sensitive sepsis care in rural emergency departments (EDs). The purpose of this study was to measure the association between telehealth-supplemented ED (tele-ED) care, health care costs, and clinical outcomes among patients with sepsis in rural EDs. METHODS: Cohort study using Medicare fee-for-service claims data for beneficiaries treated for sepsis in rural EDs between February 1, 2017, and September 30, 2019. Our primary hospital-level analysis used multivariable generalized estimating equations to measure the association between treatment in a tele-ED-capable hospital and 30-day total costs of care. In our supporting secondary analysis, we conducted a propensity-matched analysis of patients who used tele-ED with matched controls from non-tele-ED-capable hospitals. Our primary outcome was total health care payments among index hospitalized patients between the index ED visit and 30 days after hospital discharge, and our secondary outcomes included hospital mortality, hospital length of stay, 90-day mortality, 28-day hospital-free days, and 30-day inpatient readmissions. RESULTS: In our primary analysis, sepsis patients in tele-ED-capable hospitals had 6.7% higher (95% confidence interval [CI] 2.1%-11.5%) total health care costs compared to those in non-tele-ED-capable hospitals. In our propensity-matched patient-level analysis, total health care costs were 23% higher (95% CI 16.5%-30.4%) in tele-ED cases than matched non-tele-ED controls. Clinical outcomes were similar. CONCLUSIONS: Tele-ED capability in a mature rural tele-ED network was not associated with decreased health care costs or improved clinical outcomes. Future work is needed to reduce rural-urban sepsis care disparities and formalize systems of regionalized care.