Sphingolipid metabolism controls mammalian heart regeneration.

Utilization of lipids as energy substrates after birth causes cardiomyocyte (CM) cell-cycle arrest and loss of regenerative capacity in mammalian hearts. Beyond energy provision, proper management of lipid composition is crucial for cellular and organismal health, but its role in heart regeneration remains unclear. Here, we demonstrate widespread sphingolipid metabolism remodeling in neonatal hearts after injury and find that SphK1 and SphK2, isoenzymes producing the same sphingolipid metabolite sphingosine-1-phosphate (S1P), differently regulate cardiac regeneration. SphK2 is downregulated during heart development and determines CM proliferation via nuclear S1P-dependent modulation of histone acetylation. Reactivation of SphK2 induces adult CM cell-cycle re-entry and cytokinesis, thereby enhancing regeneration. Conversely, SphK1 is upregulated during development and promotes fibrosis through an S1P autocrine mechanism in cardiac fibroblasts. By fine-tuning the activity of each SphK isoform, we develop a therapy that simultaneously promotes myocardial repair and restricts fibrotic scarring to regenerate the infarcted adult hearts.

PD-1/L1 inhibitors can improve but not replace chemotherapy for advanced urothelial carcinoma: A systematic review and network meta-analysis.

Background: Programmed cell death-1/ligand 1 inhibitors are a new treatment strategy for advanced urothelial carcinoma. Therefore, a comparative evaluation of their efficacy and toxicity compared with chemotherapy is necessary. Methods: We comprehensively searched PubMed, Web of Science, Embase, and Cochrane Library databases and performed a meta-analysis of randomized controlled trials up to July 2021. We considered overall survival as the primary outcome, and progression-free survival, objective response rate, and treatment-related adverse events as secondary outcomes. Results: Overall, 3584 patients from five studies were evaluated. Compared with first-line chemotherapy, programmed cell death-1/ligand 1 inhibitors were significantly associated with worse progression-free survival (p < 0.001) and adverse objective response rates (p < 0.001). However, the treatments were not significantly different in terms of overall survival (p = 0.33). Compared with second-line chemotherapy, programmed cell death-1/ligand 1 inhibitors significantly improved overall survival (p < 0.001), and there was no statistically significant difference in progression-free survival (p = 0.89) or objective response rate (p = 0.34). Compared with chemotherapy, programmed cell death-1/ligand 1 inhibitors were well tolerated (first-line chemotherapy: p < 0.001; second-line chemotherapy: p < 0.001). Conclusions: The efficacy of programmed cell death-1/ligand 1 inhibitors in patients with advanced urothelial carcinoma is not superior to that of first-line platinum-based chemotherapy but is better than second-line chemotherapy; however, programmed cell death-1/ligand 1 inhibitors are safer than first- and second-line chemotherapy and have a broader prospect for use in combination therapy.