Curative responses in the treatment of multiple myeloma (MM) are limited by the emergence of therapeutic resistance. To address this problem, we set out to identify druggable mechanisms that convey resistance to proteasome inhibitors (PIs; e.g., bortezomib), which are cornerstone agents in the treatment of MM. In isogenic pairs of PI sensitive and resistant cells, we observed stark differences in cellular bioenergetics between the divergent phenotypes. PI resistant cells exhibited increased mitochondrial respiration driven by glutamine as the principle fuel source. To target glutamine-induced respiration in PI resistant cells, we utilized the glutaminase-1 inhibitor, CB-839. CB-839 inhibited mitochondrial respiration and was more cytotoxic in PI resistant cells as a single agent. Furthermore, we found that CB-839 synergistically enhanced the activity of multiple PIs with the most dramatic synergy being observed with carfilzomib (Crflz), which was confirmed in a panel of genetically diverse PI sensitive and resistant MM cells. Mechanistically, CB-839 enhanced Crflz-induced ER stress and apoptosis, characterized by a robust induction of ATF4 and CHOP and the activation of caspases. Our findings suggest that the acquisition of PI resistance involves adaptations in cellular bioenergetics, supporting the combination of CB-839 with Crflz for the treatment of refractory MM.

The introduction of a pre-hospital education program has led to an improvement in attendance rates and early weight loss post-bariatric surgery.

Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.

Training and assessment methods for knot tying by medical students or residents have traditionally been subjective. Objective methods for evaluating creation of a tied knot should include assessing the strength and quality of the knotted suture. The purpose of this study was to evaluate the use of a tensiometer as a feedback device for improving knot-tying performance. Twelve medical students with no knot-tying experience were selected to perform three-throw instrument ties with 00 silk suture. Students were randomly assigned to perform between 10 and 20 baseline knots and then received one of four feedback training conditions followed by 10 completion knots. Subjects were timed, and all knots were pulled in the tensiometer to assess for strength and slippage. Differences between baseline and completed knots for each subject were analyzed with an unpaired t test. Subjects receiving both subjective and tensiometer feedback demonstrated the greatest improvements in knot quality score (KQS) and slip percentage (Subject 1: 0.15 ± 0.9 vs 0.21 ± 0.05, P < 0.04, 75% vs 60%, P = NS; Subject 2: 0.22 ± 0.10 vs 0.29 ± 0.05, P < 0.02, 33% vs 0%, P < 0.05; Subject 3: 0.10 ± 0.07 vs 0.25 ± 0.07, P < 0.0001, 60% vs 10%, P < 0.01). Objective assessment of knot-tying performance is possible using the tensiometer device. Introduction of the tensiometer during the learning phase produced improved KQS and slip percentage in most students regardless of the number of baseline knots tied. Greatest improvements in performance were seen when the tensiometer was used in combination with subjective instruction.

No abstract