Malonyl-CoA Accumulation as a Compensatory Cytoprotective Mechanism in Cardiac Cells in Response to 7-Ketocholesterol-Induced Growth Retardation.

The major oxidized product of cholesterol, 7-Ketocholesterol (7KCh), causes cellular oxidative damage. In the present study, we investigated the physiological responses of cardiomyocytes to 7KCh. A 7KCh treatment inhibited the growth of cardiac cells and their mitochondrial oxygen consumption. It was accompanied by a compensatory increase in mitochondrial mass and adaptive metabolic remodeling. The application of [U-13C] glucose labeling revealed an increased production of malonyl-CoA but a decreased formation of hydroxymethylglutaryl-coenzyme A (HMG-CoA) in the 7KCh-treated cells. The flux of the tricarboxylic acid (TCA) cycle decreased, while that of anaplerotic reaction increased, suggesting a net conversion of pyruvate to malonyl-CoA. The accumulation of malonyl-CoA inhibited the carnitine palmitoyltransferase-1 (CPT-1) activity, probably accounting for the 7-KCh-induced suppression of ß-oxidation. We further examined the physiological roles of malonyl-CoA accumulation. Treatment with the inhibitor of malonyl-CoA decarboxylase, which increased the intracellular malonyl-CoA level, mitigated the growth inhibitory effect of 7KCh, whereas the treatment with the inhibitor of acetyl-CoA carboxylase, which reduced malonyl-CoA content, aggravated such a growth inhibitory effect. Knockout of malonyl-CoA decarboxylase gene (Mlycd-/-) alleviated the growth inhibitory effect of 7KCh. It was accompanied by improvement of the mitochondrial functions. These findings suggest that the formation of malonyl-CoA may represent a compensatory cytoprotective mechanism to sustain the growth of 7KCh-treated cells.

Vaccine-induced immune thrombotic thrombocytopenia presenting with normal platelet count.

Adenoviral-vector based vaccines for coronavirus disease 2019 (COVID-19) have been linked with a thrombotic syndrome, vaccine-induced thrombotic thrombocytopenia (VITT). A key clinical question is whether VITT can be reliably ruled out by the absence of thrombocytopenia. We report on three patients who presented to our institute with this syndrome. Noteworthy in our presentations are two patients who presented for medical assessment of thrombotic symptoms with a normal platelet count, one preceding and one following a period of thrombocytopenia. Prompt diagnosis of VITT is critical to prevent rapid patient decline. We provide herein a new diagnostic algorithm that we believe will help optimally capture case presentations of VITT. These cases broaden and refine our understanding of the disease process and highlight to practitioners that VITT cannot be adequately ruled out by thrombocytopenia alone.

A strategy of Day14 bone marrows and early intervention is not superior to a strategy of noDay14 bone marrows and delayed intervention in patients with acute myeloid leukemia.

We conducted a retrospective study of 364 acute myeloid leukemia patients treated using a Day14 or a noDay14 strategy. Under the Day14 strategy, patients received an interim marrow at 7-10 days following chemotherapy and, in case of residual disease, received immediate reinduction chemotherapy. Under the noDay14 strategy patients were only evaluated at end-of-induction (EOI). Overall induction mortality was higher in the Day14 cohort (8.3 vs. 3.6%, p = .12) but rates of remission (75.4 vs. 83%, p = .13) and refractory disease (14.3 vs. 13.4%, p = .87) at EOI were similar in the Day14 and noDay14 cohorts as were relapse rates (37.9% vs. 34.3%, p = .616), median relapse-free survival (14.8 vs. 15 months, p = .658) and median overall survival (25.3 vs. 37.2 months, p = .264). In multivariate analysis, the use of a Day14 strategy did not impact outcomes suggesting that a Day14 strategy is not superior to a noDay14 strategy.