In silico research of coagulation- and fibrinolysis-related genes for predicting prognosis of clear cell renal cell carcinomaDeng, Yang, Zhou
et alTransl Androl Urol (2025) 14 (2), 307-324
Abstract: Coagulation- and fibrinolysis-related genes (CFRGs) are involved in tumor progression. However, their regulatory mechanisms in clear cell renal cell carcinoma (ccRCC) remain unclear. The aim of this study was to search for genes related to coagulation and fibrinolytic systems in ccRCC and to investigate their potential role in tumor pathogenesis and progression.Differentially expressed genes (DEGs) between ccRCC and control samples, as well as key module genes associated with ccRCC, were extracted from The Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) dataset. Differentially expressed CFRGs (DE-CFRGs) were identified by intersecting these DEGs with CFRGs. Prognostic genes were identified through univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox analyses of DE-CFRGs. Additional independent prognostic and enrichment analyses were conducted, and potential therapeutic drugs were predicted. In addition, quantitative real-time polymerase chain reaction (RT-qPCR) was performed to validate the expression of prognostic genes.Sixteen DE-CFRGs were identified by intersecting 3,311 DEGs, 1,719 key module genes, and CFRGs. Four prognostic genes-TIMP1, RUNX1, BMP6, and PROS1-were found to be involved in complement and coagulation cascades and other functional pathways. The prognostic model demonstrated strong predictive power for ccRCC, with stage, risk score, and grade all correlating with prognosis. Additionally, 14 potential drugs, such as tamoxifen citrate and cytarabine, were predicted for therapeutic targeting of the identified prognostic genes. RT-qPCR confirmed that the expression levels of TIMP1, and RUNX1 were significantly upregulated in ccRCC samples, consistent with bioinformatics analysis.A prognostic model incorporating TIMP1, RUNX1, BMP6, and PROS1 was constructed, offering new insights for prognostic evaluation and therapeutic strategies in ccRCC.Copyright © 2025 AME Publishing Company. All rights reserved.
Single-cell and spatial transcriptomics analysis reveals that Pros1+ oligodendrocytes are involved in endogenous neuroprotection after brainstem strokeLi, Zeng, Pang
et alNeurobiol Dis (2025) 208, 106855
Abstract: Brainstem stroke accounts only 7-10 % of all ischemic stroke while it had more morbidity and mortality. As the predominant cellular component of nerve tracts, oligodendrocytes might provide some neuroprotection against ischemic injury in the context of brainstem stroke, but the underlying mechanism remains unclear.A mouse model of brainstem stroke was established, and single-cell RNA sequencing and spatial transcriptomic sequencing analysis were performed to elucidate the phenotype of oligodendrocytes within this context.Loss of oligodendrocytes led to neurological impairment following brainstem stroke, and subsequent proliferation of oligodendrocytes was observed. We identified a subcluster of Pros1+ oligodendrocytes, designated OLG8 cells. These cells increased in number after brainstem stroke and were enriched around the peri-infarct zone. OLG8 cells were derived from oligodendrocyte progenitor cells, and this process was found to be regulated by Myo1e. We found that OLG8 cells protected interneurons. Notably, the overexpression of Myo1e within OLG8 cells led to a marked reduction in infarct volume while simultaneously improving the recovery of neurological function.In conclusion, we identified a novel cell subcluster, OLG8 cells, in the context of brainstem stroke, and found that overexpression of Myo1e alleviated ischemic injury by facilitating the differentiation of OLG8 cells. Our study provided insight into the mechanism of brainstem stroke.Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.
Population-Scale Studies of Protein S Abnormalities and ThrombosisChaudhry, Haj, Ryu
et alJAMA (2025)
Abstract: Clinical decision-making in thrombotic disorders is impeded by long-standing uncertainty regarding the magnitude of venous and arterial thrombosis risk associated with low protein S. Population-scale multiomic datasets offer an unprecedented opportunity to answer questions regarding the epidemiology and clinical impacts of protein S deficiency.To evaluate the risk associated with protein S deficiency across multiple thrombosis phenotypes.Cross-sectional study using longitudinal population cohorts derived from the UK Biobank (n = 426 436) and the US National Institutes of Health All of Us (n = 204 006) biorepositories. UK Biobank participants were enrolled in 2006-2010 (last follow-up, May 19, 2020) and underwent whole exome sequencing, with a subset (n = 44 431) having protein S levels measured by high-throughput plasma proteomics. Recruitment for All of Us began in 2017 and is ongoing, with participants receiving germline whole genome sequencing. Both cohorts include individual-level data on demographics, laboratory measurements, and clinical outcomes.Presence of rare germline genetic variants in PROS1, segmented by functional impact score (FIS), an in silico prediction of the probability that a genetic variant will disrupt protein activity.Firth logistic regression and linear regression modeling were used to evaluate the thrombosis risk associated with low plasma protein S levels and PROS1 variants across a range of FIS ratings.The UK Biobank cohort was 54.3% female, with a median age of 58.3 (IQR, 50.5-63.7) years at enrollment. Most participants (95.6%) were of European ancestry, and 18 011 had experienced a venous thromboembolism (VTE). In this population cohort, heterozygosity for the highest-risk PROS1 variants with an FIS of 1.0 (nonsense, frameshift, and essential splice site disruptions) was rare (adjusted prevalence, 0.0091% in the UK and 0.0178% in the US) and associated with markedly increased risk of VTE (odds ratio [OR], 14.01; 95% CI, 6.98-27.14; P = 9.09 × 10-11). Plasma proteomics (n = 44 431) demonstrated that carriers of these variants had total protein S levels that were 48.0% of normal (P = .02 compared with noncarriers). In contrast, less damaging missense variants (FIS ≥0.7) occurred more commonly (adjusted prevalence, 0.22% in the UK and 0.20% in the US) and were associated with marginally reduced plasma protein S concentrations and a smaller point estimate for VTE risk (OR, 1.977; 95% CI, 1.552-2.483; P = 1.95 × 10-7). Associations between PROS1 and VTE at both FIS cutoffs were independently validated in the All of Us cohort with similar effect sizes. No association was detected between the presence of coding PROS1 variants and 3 forms of arterial thrombosis: myocardial infarction, peripheral artery disease, and noncardioembolic ischemic stroke. The presence of PROS1 variants correlated poorly with low plasma protein S levels, and protein S deficiency was significantly associated with VTE and peripheral artery disease regardless of PROS1 variant carrier status. The elevated risk of VTE associated with germline loss of function in PROS1 was evident in Kaplan-Meier survival analysis and appeared to persist throughout life (log-rank P = .0005).True inherited loss of function in PROS1 is rare but represents a stronger risk factor for VTE in the general population than previously understood. Acquired, environmental, or trans-acting genetic factors are more likely to cause circulating protein S deficiency than coding variation in PROS1, and low plasma protein S is associated with VTE.
PTP inhibition improves the macrophage anti-tumor immune response and the efficacy of chemo- and radiotherapyPrieto-Dominguez, Goel, Ojo
et alCancer Immunol Res (2025)
Abstract: Traditional anti-cancer therapies induce tumor cell death and subsequent release of Damage Associated Molecular Patterns (DAMPs) that activate the innate inflammatory response. Paradoxically, after treatment, macrophages often adopt a pro-wound healing, rather than pro-inflammatory, phenotype and contribute to cancer progression. We found that in areas proximal to DAMP release, tumor cells upregulate the expression of Pros1. Tumor-secreted Pros1 binds to the macrophage Mer receptor, consequently limiting responsiveness to DAMPs by preventing Toll Like Receptor (TLR) signal transduction. Pharmacological inhibition of PTP1b signaling downstream of Mer rescued the pro-inflammatory response, even in the presence of Pros1. Combining PTP inhibition with traditional therapeutics, like chemo- or radiotherapy, rescued the innate immune response to DAMPs, increased immune infiltration, and resulted in a 40-90% reduction in tumor growth in multiple treatment refractory preclinical models. Our findings suggest using PTP1b inhibitors may be a tumor agnostic means of improving the efficacy of some of the most widely used anti-cancer therapeutic agents.
膜杰作
Star Staining
