Starving tumors with fat
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The hippocampus (HPC) has emerged as a critical player in the control of food intake, beyond its well-known role in memory. While previous studies have primarily associated the HPC with food intake inhibition, recent research suggests a role in appetitive processes. Here we identified spatially distinct neuronal populations within the dorsal HPC (dHPC) that respond to either fats or sugars, potent natural reinforcers that contribute to obesity development. Using activity-dependent genetic capture of nutrient-responsive dHPC neurons, we demonstrate a causal role of both populations in promoting nutrient-specific intake through different mechanisms. Sugar-responsive neurons encoded spatial memory for sugar location, whereas fat-responsive neurons selectively enhanced the preference and motivation for fat intake. Importantly, stimulation of either nutrient-responsive dHPC neurons increased food intake, while ablation differentially impacted obesogenic diet consumption and prevented diet-induced weight gain. Collectively, these findings uncover previously unknown orexigenic circuits underlying macronutrient-specific consumption and provide a foundation for developing potential obesity treatments.
High baseline levels of PD-L1 reduce the heterogeneity of immune checkpoint signature and sensitize anti-PD1 therapy in lung and colorectal cancers
Immune checkpoint blockade (ICB) therapy only induces durable responses in a subset of cancer patients. The underlying mechanisms of such selective efficacy remain largely unknown. By analyzing the expression profiles of immune checkpoint molecules in different statuses of murine tumors, we found that tumor progression generally randomly upregulated multiple immune checkpoints, thus increased the Heterogeneity of Immune checkpoint Signature (HIS) and resulted in immunotherapeutic resistance. Interestingly, overexpressing one pivotal immune checkpoint in a tumor hindered the upregulation of a majority of other immune checkpoint genes during tumor progression via suppressing interferon γ, resulting in HIS-low. Indeed, PD-L1 high-expression sensitized baseline large tumors to anti-PD1 therapy without altering the sensitivity of baseline small tumors. In line with these preclinical results, a retrospective analysis of a phase III study involving patients with non-small cell lung cancer (NSCLC) revealed that PD-L1 tumor proportion score (TPS) ≥ 50% more reliably predicted therapeutic response in NSCLC patients with baseline tumor volume (BTV)-large compared to patients with BTV-small. Notably, TPS combined with BTV significantly improved the predictive accuracy. Collectively, the data suggest that HIS reflects the dynamic features of tumor immune evasion and dictates the selective efficacy of ICB in a tumor size-dependent manner, providing a potential novel strategy to improve precision ICB. These findings highlight the application of ICB to earlier stages of cancer patients. The integration of PD-L1 with BTV may immediately improve patient stratification and prediction performance in the clinic.
The radiogenomic and spatiogenomic landscapes of glioblastoma and their relationship to oncogenic drivers
Glioblastoma is a highly heterogeneous brain tumor, posing challenges for precision therapies and patient stratification in clinical trials. Understanding how genetic mutations influence tumor imaging may improve patient management and treatment outcomes. This study investigates the relationship between imaging features, spatial patterns of tumor location, and genetic alterations in IDH-wildtype glioblastoma, as well as the likely sequence of mutational events.
Role of pancreatic lipase inhibition in obesity treatment: mechanisms and challenges towards current insights and future directions
The worldwide health emergency of obesity is closely connected to how dietary fats are metabolized, whereas the process is significantly influenced by pancreatic lipase (PL), an enzyme critical for lipid hydrolysis into fatty acids. This narrative review employs a methodological approach utilizing literature searches of PubMed data up to March 2024. The search term criteria encompasses keywords related to the role, mechanism, challenges, and current and future treatments of pancreatic lipase in obesity with an overall references is 106. This paper offers a comprehensive explanation of the role of PL, underlining its significance in the digestive process and lipid imbalances that contribute to obesity and by extension, its impact on obesity development and progression. Additionally, it delves into the dual functionality of the pancreas, emphasizing its impact on metabolism and energy utilization which, when dysregulated, promotes obesity. A focal point of this review is the investigation into the efficacy, challenges, and adverse effects of current pancreatic lipase inhibitors, with orlistat being highlighted as a primary current drug delivery. By discussing advanced obesity treatments, including the exploration of novel anti-obesity medications that target specific biological pathways, this review underscores the complexity of obesity treatment and the necessity for a multifaceted approach. In conclusion, this paper emphasizing the importance of understanding the role of enzymes like pancreatic lipase mechanistic and adopting a multidisciplinary approach to treatment and side effects of current obesity drugs and explore new emerging therapeutic strategies for more effective obesity management.
Implantation of engineered adipocytes suppresses tumor progression in cancer models
Tumors exhibit an increased ability to obtain and metabolize nutrients. Here, we implant engineered adipocytes that outcompete tumors for nutrients and show that they can substantially reduce cancer progression, a technology termed adipose manipulation transplantation (AMT). Adipocytes engineered to use increased amounts of glucose and fatty acids by upregulating UCP1 were placed alongside cancer cells or xenografts, leading to significant cancer suppression. Transplanting modulated adipose organoids in pancreatic or breast cancer genetic mouse models suppressed their growth and decreased angiogenesis and hypoxia. Co-culturing patient-derived engineered adipocytes with tumor organoids from dissected human breast cancers significantly suppressed cancer progression and proliferation. In addition, cancer growth was impaired by inducing engineered adipose organoids to outcompete tumors using tetracycline or placing them in an integrated cell-scaffold delivery platform and implanting them next to the tumor. Finally, we show that upregulating UPP1 in adipose organoids can outcompete a uridine-dependent pancreatic ductal adenocarcinoma for uridine and suppress its growth, demonstrating the potential customization of AMT.
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