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Treatment for metastatic clear cell renal cell carcinoma (ccRCC) has dramatically advanced with tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) administration. However, most patients eventually succumb to their disease, and toxicities associated with individual treatment modalities are significant. Multiple single-modality transcriptomic signatures have been developed to predict treatment response, yielding insightful yet inconsistent results when applied to independent cohorts. By unifying transcriptomic data from 14 cohorts (total n = 3,621), we present harmonized immune tumor microenvironment (HiTME) ccRCC subtypes validated with spatial proteomics. This AI-based multimodal approach integrates genomic, transcriptomic, and tumor microenvironment (TME) features for ICI and TKI therapy response prediction.
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http://dx.doi.org/10.1016/j.xcrm.2025.102299 | DOI Listing |
EMBO J
September 2025
Department of Bacterial Infection and Host Response, Graduate School of Medical and Dental Sciences, Institute of SCIENCE TOKYO, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Many enteric bacterial pathogens deliver virulence effectors to counteract host innate immune responses, such as inflammation and cell death, and colonize the intestinal epithelium. However, host cells recognize the disruption of their innate immune signaling by bacterial effectors and induce alternative immune responses, collectively termed "effector-triggered immunity", to clear bacterial pathogens. Here, we describe a mechanism of cell death induction via effector-triggered immunity and the bacterial countermeasures of the pathogen Shigella flexneri.
View Article and Find Full Text PDFNature
September 2025
The Randall Centre for Cell & Molecular Biophysics, School of Basic & Medical Biosciences, King's College London, London, UK.
Epithelial cells work collectively to provide a protective barrier, yet they turn over rapidly through cell division and death. If the numbers of dividing and dying cells do not match, the barrier can vanish, or tumours can form. Mechanical forces through the stretch-activated ion channel Piezo1 link both of the processes; stretch promotes cell division, whereas crowding triggers live cells to extrude and then die.
View Article and Find Full Text PDFNucleic Acids Res
September 2025
State Key Laboratory of Vaccines for Infectious Diseases, School of Public Health, Xiamen University, Xiamen 361102, Fujian, China.
The abnormal expansion of GGGGCC (G4C2) repeats in the noncoding region of the C9orf72 gene is a major genetic cause of two devastating neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These G4C2 repeats are known to form G-quadruplex (G4) structures, which are hypothesized to contribute to disease pathogenesis. Here, we demonstrated that four DNA G4C2 repeats can fold into two structurally distinct G4 conformations: a parallel and an antiparallel topology.
View Article and Find Full Text PDFPharmacol Res
September 2025
National Key Laboratory of Immunology & Inflammation, Institute of Immunology, Naval Medical University, Shanghai 200433, China. Electronic address:
Nonapoptotic programmed cell death (PCD) has been recognized as potential alternative target for increasing chemosensitivity and augmenting antitumor efficacy. Among various types of nonapoptotic PCD, methuosis has gotten increasing attention recently, largely due to its unique morphological features and potential implications for apoptosis-resistant tumor therapy with negligible side effects. Methuosis is characterized by cytoplasmic vacuolization initiated by sustained macropinocytosis, concomitantly, the other cytotoxic agents from extracellular fluid can be delivered into cytoplasm of tumor cell via macropinocytosis, which can profoundly strengthen the combined antitumor efficacy.
View Article and Find Full Text PDFJ Biol Chem
September 2025
Department of Oral Disease Research, National Center for Geriatrics and Gerontology, 7-430 Moriokacho, Obu, Aichi, 474-8511, Japan; Department of dental hygiene, Ogaki women's college, 109-1 Nishinokawa-cho, Ogaki-city, Gifu, 503-8554, Japan. Electronic address:
Phagocytosis is mediated mainly by immune cells, such as macrophages, monocytes and neutrophils, that clear large pathogens including bacteria. The small GTP-binding protein Rab5 is crucial for both clathrin-dependent endocytosis and phagocytosis, but the role and mechanism of Rab5 activation during phagocytosis are poorly understood. Here we report that nitric oxide (NO), a novel regulator of Rab5, regulates phagocytosis through S-nitrosylation of Rab5.
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