RESUMEN
Maintenance of the mitochondrial thiol redox state is essential for cell survival. However, we lack a comprehensive understanding of the redox response to mitochondrial glutathione depletion. We developed a mitochondria-penetrating peptide, mtCDNB, to specifically deplete mitochondrial glutathione. A genome-wide CRISPR/Cas9 screen in tandem with mtCDNB treatment was employed to uncover regulators of the redox response to mitochondrial glutathione depletion. We identified nucleoside diphosphate kinase 3 (NME3) as a regulator of mitochondrial dynamics. We show that NME3 is recruited to the mitochondrial outer membrane when under redox stress. In the absence of NME3, there is impaired mitophagy, which leads to the accumulation of dysfunctional mitochondria. NME3 knockouts depleted of mitochondrial glutathione have increased mitochondrial ROS production, accumulate mtDNA lesions, and present a senescence-associated secretory phenotype. Our findings suggest a novel role for NME3 in selecting mitochondria for degradation through mitophagy under conditions of mitochondrial redox stress.
RESUMEN
Introduction: KEYNOTE-394 showed pembrolizumab significantly improved overall survival, progression-free survival, and objective response rate with manageable safety versus placebo for patients from Asia with previously treated advanced hepatocellular carcinoma. We present results on health-related quality of life (HRQoL). Methods: HRQoL was evaluated using the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EuroQol-5D-3L (EQ-5D-3L) questionnaires. Key HRQoL endpoints were least squares mean (LSM) score changes from baseline to week 12 and time to deterioration (TTD) for EORTC QLQ-C30 global health status (GHS)/QoL. p values were one-sided and nominal without adjustment for multiplicity. Results: The HRQoL population included patients randomly assigned to pembrolizumab (n = 298) and placebo (n = 152). From baseline to week 12, a greater decline in EORTC QLQ-C30 GHS/QoL score was observed with placebo (LSM, -8.4; 95% CI: -11.7 to -5.1) versus pembrolizumab (-4.0; 95% CI: -6.4 to -1.6; difference vs. placebo: 4.4; 95% CI: 0.5-8.4; nominal p = 0.0142). Similarly, a greater decline in the EQ-5D-3L visual analog scale score was observed with placebo (-6.9; 95% CI: -9.4 to -4.5) versus pembrolizumab (-2.7; 95% CI: -4.5 to -1.0; difference vs. placebo: 4.2; 95% CI: 1.2-7.2; nominal p = 0.0030). TTD in EORTC QLQ-C30 GHS/QoL score was similar between arms (hazard ratio, 0.85; 95% CI: 0.58-1.25; nominal p = 0.1993). Conclusion: Patients receiving placebo showed a greater decline in HRQoL than those receiving pembrolizumab. Combined with efficacy and safety data from KEYNOTE-394 and the global KEYNOTE-240 and KEYNOTE-224 trials, our data support the clinically meaningful benefit and manageable tolerability of pembrolizumab as second-line therapy for patients with advanced hepatocellular carcinoma.
RESUMEN
Consultation following evidence-based practice (EBP) training enhances the uptake of EBPs. Yet, little is known about what occurs during consultation, and it is often difficult for providers to engage in consultation. This study examined provider engagement in consultation and the content and strategies used during consultation following training in Trauma-focused Cognitive Behavioral Therapy (TF-CBT) as part of a community-based learning collaborative (CBLC). Minute-to-minute live coding of consultation calls revealed most content was clinically-oriented and the most common strategies used by consultants were didactic in nature. Providers with more years of professional experience and those with greater TF-CBT knowledge attended significantly more consultation calls. Providers with a greater average weekly caseload and providers who were supervisors presented significantly more cases on calls. Providers with greater TF-CBT knowledge spoke significantly more minutes on calls. Consistent with previous work, findings highlight difficulties with provider engagement in consultation and that providers with more baseline expertise are most likely to be engaged. Findings suggest tailoring EBP training efforts to better engage providers at greatest risk for low engagement.
