Outcomes of left ventricular assist device implantation in hypercoagulable patients.

BACKGROUND: The aim of this study was to evaluate outcomes of left ventricular assist devices (LVADs) in patients who tested positive for hypercoagulable hematologic disorders. METHODS: Adults undergoing continuous-flow LVAD implantation with preoperative hypercoagulability testing between 2004 and 2018 at a single center were reviewed. Hypercoagulability was defined as testing positive for antiphospholipid antibody, anticardiolipin antibody, lupus anticoagulant, protein C, protein S, factor V Leiden, and/or heparin-induced thrombocytopenia. The primary outcome was survival on the original LVAD. Secondary outcomes included rates of thromboembolic complications and readmission for intravenous heparin treatment. RESULTS: A total of 270 LVAD patients with pre-implant hypercoagulability testing were included, and 157 (58%) tested positive for a hypercoagulable disorder. Of those testing positive, 10 (6.4%) had a clinical pre-LVAD history of thromboembolic events. Survival was comparable between hypercoagulable and non-hypercoagulable patients (1 year: 73.3% vs 78.9%, P = .2195, 2-year: 60.7% vs 62.8%, P = .3627). Rates of pump thrombosis (14.0% vs 13.3%, P = .8618), hemolysis (4.5% vs 3.5%, P = .3536), stroke (18.5% vs 14.2%, P = .3483) and readmission for IV heparin therapy (87.3% (n = 137) vs 77.9% (n = 88), P = .7560) were similar. Outcomes were comparable in patients with positive hypercoagulable tests when stratified by pre-implant clinical history of hypercoagulability as well as stratified by recent preoperative exposure to heparin or warfarin. CONCLUSIONS: In this series, positive laboratory tests for hypercoagulability were common amongst patients undergoing LVAD implantation although few had positive clinical histories. Survival and freedom from thromboembolic complications were comparable to non-hypercoagulable patients. Hypercoagulability alone should therefore not serve as a contraindication to LVAD implantation.

Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of undifferentiated myeloblasts, and agents that promote differentiation have been effective in this disease but are not curative. Dihydroorotate dehydrogenase inhibitors (DHODHi) have the ability to promote AML differentiation and target aberrant malignant myelopoiesis. We introduce HOSU-53, a DHODHi with significant monotherapy activity, which is further enhanced when combined with other standard-of-care therapeutics. We further discovered that DHODHi modulated surface expression of CD38 and CD47, prompting the evaluation of HOSU-53 combined with anti-CD38 and anti-CD47 therapies, where we identified a compelling curative potential in an aggressive AML model with CD47 targeting. Finally, we explored using plasma dihydroorotate (DHO) levels to monitor HOSU-53 safety and found that the level of DHO accumulation could predict HOSU-53 intolerability, suggesting the clinical use of plasma DHO to determine safe DHODHi doses. Collectively, our data support the clinical translation of HOSU-53 in AML, particularly to augment immune therapies. Potent DHODHi to date have been limited by their therapeutic index; however, we introduce pharmacodynamic monitoring to predict tolerability while preserving antitumor activity. We additionally suggest that DHODHi is effective at lower doses with select immune therapies, widening the therapeutic index.

Exercise reduces the protein abundance of TXNIP and its interacting partner REDD1 in skeletal muscle: potential role for a PKA-mediated mechanism.

Thioredoxin-interacting protein (TXNIP) negatively effects the redox state and growth signaling via its interactions with thioredoxin (TRX) and regulated in development and DNA damage response 1 (REDD1), respectively. TXNIP expression is downregulated by pathways activated during aerobic exercise (AE), via posttranslational modifications (PTMs; serine phosphorylation and ubiquitination). The purpose of this investigation was to determine the effects of acute AE on TXNIP expression, posttranslational modifications, and its interacting partners, REDD1 and TRX. Fifteen healthy adults performed 30 min of aerobic exercise (80% V̇o2max) with muscle biopsies taken before, immediately following, and 3 h following the exercise bout. To explore potential mechanisms underlying our in vivo findings, primary human myotubes were exposed to two models of exercise, electrical pulse stimulation (EPS) and palmitate-forskolin-ionomycin (PFI). Immediately following exercise, TXNIP protein decreased, but returned to preexercise levels 3 h after exercise. These results were replicated in our PFI exercise model only. Although not statistically significant, there was a trending main effect in serine-phosphorylation status of TXNIP (P = 0.07) immediately following exercise. REDD1 protein decreased 3 h after exercise. AE had no effect on TRX protein expression, gene expression, or the activity of its reducing enzyme, thioredoxin reductase. Consequently, AE had no effect on the TRX: TXNIP interaction. Our results indicate that AE leads to acute reductions in TXNIP and REDD1 protein expression. However, these changes did not result in alterations in the TRX: TXNIP interaction and could not be entirely explained by alterations in TXNIP PTMs or changes in TRX expression or activity.NEW & NOTEWORTHY Aerobic exercise is an effective tool in the prevention and treatment of several chronic metabolic diseases. However, the mechanisms through which these benefits are conferred have yet to be fully elucidated. Our data reveal a novel effect of aerobic exercise on reducing the protein expression of molecular targets that negatively impact redox and insulin/growth signaling in skeletal muscle. These findings contribute to the expanding repository of molecular signatures provoked by aerobic exercise.