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Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma.

J Clin Invest

January 2025

Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Metabolic reprogramming shapes tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. "Immune cold" PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of pro-tumor macrophages, and reduced cytotoxic T cell in the TME.

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Organisms adapt to predictable environmental changes via a biological mechanism called priming. Phototropin (phot) is a plant-specific blue light photoreceptor that mediates daily light-induced responses, such as chloroplast relocation, stomatal opening, and phototropism, to optimize photosynthesis. Phot also functions as a thermosensor for chloroplast relocation that may sense daily temperature decreases at night, thereby modulating light-induced responses at dawn; however, this hypothesis has not yet been fully explored.

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The formation of histamine in food is influenced by temperature, and histamine growth can be inhibited by maintaining a cold chain. However, simply relying on temperature control is insufficient, as certain bacteria can produce the enzyme histidine decarboxylase even at temperatures below 5°C. To address this issue, various methods, such as modified atmosphere packaging, high hydrostatic pressure, and irradiation, have been developed to control histamine in fishery products.

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It has been well documented that cold is an enhancer of lipid metabolism in peripheral tissues, yet its effect on central nervous system lipid dynamics is underexplored. It is well recognized that cold acclimations enhance adipocyte functions, including white adipose tissue lipid lipolysis and beiging, and brown adipose tissue thermogenesis in mammals. However, it remains unclear whether and how lipid metabolism in the brain is also under the control of ambient temperature.

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Socioeconomic conditions remain an important factor in determining health outcomes in Northern Europe. In this commentary, we argue for evidence-based temperature-related climate adaptation policies in Northern Europe that account for disparities in socioeconomic conditions and aim at universal health coverage. We highlight the role of spatial and occupational disparities in urban areas that can be important factors in increased physical and mental health impacts related to heat and cold.

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