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2025
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- Page : pp.100938-100938
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2025
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- Pub. Date : 2025
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2025
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2025
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2025
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2025
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2025
Chondrosarcomas are common bone sarcomas frequently resistant to radiation and chemotherapy, with high recurrence rates, development of metastatic disease, and death. Fibrosarcomas are soft tissue sarcomas associated with poor outcomes. Translocase of outer mitochondrial membrane receptor 20 (TOMM20) is a mitochondrial receptor protein associated with cancer aggressiveness in many cancer subtypes, but the mechanisms remain poorly understood. Here, we studied the effects of TOMM20 overexpression and downregulation on the redox state, mitochondrial oxidative phosphorylation (OXPHOS), and tumor growth using fibrosarcoma and chondrosarcoma models. TOMM20 overexpression increased OXPHOS, NADH, and NADPH with reduced cellular reactive oxygen species (ROS). TOMM20 induced resistance to apoptosis, including with BCL‐2 and OXPHOS complex IV inhibitors, but with increased sensitivity to an OXPHOS complex I inhibitor. Also, TOMM20 induced cell growth and migration in vitro and promoted tumor growth in vivo. Conversely, knocking down TOMM20 using CRISPR‐Cas9 reduced cancer aggressiveness in vivo in both chondrosarcoma and fibrosarcoma mouse models. In conclusion, TOMM20 is a driver of cancer aggressiveness by OXPHOS, apoptosis resistance, and the maintenance of a reduced state.- Book : ()
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2025
AbstractThe magnitude of Type I interferon (IFN) mediated innate immune response within the tumor microenvironment (TME) critically influences the effectiveness of radiotherapy. Unfortunately, due to a myriad of resistance mechanisms, the double‐stranded DNA (dsDNA) signals produced by tumor cells postradiotherapy often induce a diminished response from immune cells. Through chemical screening targeting deubiquitinating enzymes, we identified USP1 (Ubiquitin Specific Peptidase 1) inhibitor as an enhancer of post‐radiotherapy dsDNA responses. Mechanistically, within the context of immune‐stimulatory cells in TME, USP1 serves as a suppressor in the stress‐mediated stages of the cGAS (Cyclic GMP‐AMP synthase) ‐STING (Stimulator of interferon genes protein) signaling pathway, specifically affecting the trafficking of STING from endoplasmic reticulum to Golgi apparatus. It is elucidated that SAR1A (Secretion associated Ras related GTPase 1A) requires K27‐linked oligo‐ubiquitination to assemble the STING‐COP‐II (Coat protein II) transport complex for STING trafficking. USP1 counteracts this activation by removing SAR1A ubiquitination, thereby blocking STING trafficking and activation. Consequently, pharmacological USP1 inhibition using ML323 sustains SAR1A ubiquitination and COP‐II complex formation, significantly enhancing STING trafficking and subsequent Type I IFN production. This intervention substantially amplifies radiotherapy‐induced immune activation in the TME, providing a strategic approach to overcome therapeutic resistance and synergize radiotherapy with immunotherapies.- Book : ()
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2025
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2025
The gut microbiome can be shaped by both intrinsic host factors and extrinsic environmental factors. However, the relative importance of intrinsic and extrinsic factors in gut microbial composition has rarely been investigated, particularly for a single host across its natural range. Here, we characterise the gut microbiome of an endemic, endangered antelope, the blackbuck or Antilope cervicapra. We evaluated the influence of seven predictor variables, which were classified into intrinsic and extrinsic factors, on the gut microbiome. The intrinsic factors are nucleotide diversity (mitochondrial and nuclear) and blackbuck population density, whereas extrinsic factors are temperature, precipitation, distance to human settlement and anthropogenic land‐use. We determined which of these seven variables explains greater variation in the microbiome within (α‐diversity) and between (β‐diversity) the blackbuck hosts. We analysed the microbiome of n = 60 blackbuck hosts from ten different populations across India. We recorded 11 800 unique OTUs across 30 known phyla and 2.9 million reads. We find an average of 2056 OTUs per individual, with Bacillota and Bacteroidota being the most dominant phyla. Overall, we also show that the genetic diversity (intrinsic) of the host is more important than their environment (extrinsic) for both within‐ and between‐host variation in the microbiome of blackbuck. Our results suggest that an increase in genetic relatedness between blackbuck hosts can lead to a decrease in the variation of their gut microbial composition. Therefore, conservation efforts should be directed to not only preserve natural habitats but also increase the genetic pool of the blackbuck populations, which will positively impact their survival through diverse gut microbiomes.- Book : ()
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