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Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury, but how metabolism controls their regenerative potential is poorly understood. We describe that primary metabolic changes can determine murine MuSC fate decisions. We found that glutamine anaplerosis into the tricarboxylic acid (TCA) cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and fusion, combined with loss of self-renewal in vitro and in vivo. Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation and inhibited the malate-aspartate shuttle (MAS). The resulting defect in transporting NADH-reducing equivalents into the mitochondria induced compartment-specific NAD + /NADH ratio shifts. MAS activity restoration or directly altering NAD + /NADH ratios normalized myogenesis. In conclusion, GLUD1 prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS in proliferating MuSCs. It thereby acts as a compartment-specific metabolic brake on MuSC differentiation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors (ICI) therapy with or without chemotherapy has been established as the first-line treatment for patients with non-oncogene addicted advanced Non-Small Cell Lung Cancer (NSCLC). Yet some clinical settings, such as the treatment sequence in patients with brain metastases, have barely been evidenced. Although ICIs cannot directly cross the blood-brain barrier (BBB), evidence suggests that BBB damage could allow ICIs into the central nervous system, or that they can have an indirect effect on the tumor immune microenvironment (TIME) and cause an anti-tumor response. Pivotal phase III trials have included a highly selected population but offer few data on these patients. Here we first review how ICIs can indirectly shape the brain metastases microenvironment through different mechanisms, and some possible causes of ICIs resistance. We also analyze the evidence reported in pivotal phase III trials and phase II trials focused on NSCLC brain metastases for first-line treatment, and the evidence for upfront or delayed local brain therapy. Finally, we discuss the best evidence-based approach to treat NSCLC patients with brain metastases and propose future research., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Suay G has received travel grants to attend oncology meetings from Janssen and Roche. Aparisi F has served in a consultant or advisory role for Pzifer and Boheringher Inghelheim. He has received speaker fees from Astra-Zeneca, Takeda and Sanofi, and travel expenses from Janssen, Gallecto, Pfizer, Roche, MSD and Takeda. Juan-Vidal O has received honoraria or advisory role fees from Bristol-Myers Squibb, Roche/Genentech, AstraZeneca, Pfizer, Eli Lilly, Takeda and Janssen. He has received travel and accommodation grants from Takeda, Astra-Zeneca, Roche/Genentech, Pfizer and MSD., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Non-small cell lung cancer (NSCLC) is one of the world's leading causes of morbidity and mortality. ICIs alone or combined with chemotherapy have become the standard first-line treatment of metastatic NSCLC. The impressive results obtained have stimulated our interest in applying these therapies in early disease stage treatments, as neoadjuvant immunotherapy has shown promising results. Among many of the factors that may influence responses, the role played by sex is attracting increased interest and needs to be addressed. Here, we aim to first review the state of the art regarding neoadjuvant ICIs, whether they are administered in monotherapy or in combination with chemotherapy at stages IB-IIIA, particularly at stage IIIA, before analyzing whether sex may influence responses. To this end, a meta-analysis of publicly available data comparing male and female major pathological responses (MPR) and pathological complete responses (pCR) was performed. In our meta-analysis, MPR was found to be significantly higher in females than in males, with an odds ratio (OR) of 1.82 (95% CI 1.13-2.93; p = 0.01), while pCR showed a trend to be more favorable in females than in males, but the OR of 1.62 was not statistically significant (95% CI 0.97-2.75; p = 0.08). Overall, our results showed that sex should be systematically considered in future clinical trials settings in order to establish the optimal treatment sequence.