Background. Despite the constant iteration of small-molecule inhibitors and immune checkpoint inhibitors, PRAD (prostate adenocarcinoma) patients with distant metastases and biochemical recurrence maintain a poor survival outcome along with an increasing morbidity in recent years. N7-Methylguanine, a new-found type of RNA modification, has demonstrated an essential role in tumor progression but has hardly been studied for its effect on prostate carcinoma. The current study aimed to seek m7G (N7-methylguanosine) related prognostic biomarkers and potential targets for PRAD treatment. Methods. 42 genes related to m7G were collected from former literatures and GSEA (Gene Set Enrichment Analysis) website. Then, RNA-seq (RNA sequencing) and clinical data from TCGA-PRAD (The Cancer Genome Atlas-Prostate) cohort were retrieved to screen the differentially expressed m7G genes to further construct a multivariate Cox prognostic model for PRAD. Next, GSE116918, a prostate cancer cohort acquired from GEO (Gene Expression Omnibus) database, was analyzed for the external validation group to assess the ability to predict BFFS (biochemical failure-free survival) of our m7G prognostic signature. Kaplan-Meier, ROC (receiver operator characteristic), AUC (areas under ROC curve), and calibration curves were adopted to display the performance of this prognostic signature. In addition, immune infiltration analysis was implemented to evaluate the effect of these m7G genes on immunoinfiltrating cells. Correlation with drug susceptibility of the m7G signature was also analyzed by matching drug information in CellMiner database. Results. The m7G-related prognostic signature, including three genes (EIF3D, EIF4A1, LARP1) illustrated superior prognostic ability for PRAD in both training and validation cohorts. The 5-year AUC were 0.768 for TCGA-PRAD and 0.608 for GSE116918. It can well distinguish patients into different risk groups of biochemical recurrence ( p =1e-04 for TCGA-PRAD and p =0.0186 for GSE116918). Immune infiltration analysis suggested potential regulation of m7G genes on neutrophils and dendritic cells in PRAD. Conclusions. A m7G-related prognostic signature was constructed and validated in the current study, giving new sights of m7G methylation in predicting the prognostic and improving the treatment of PRAD.
Despite advances in its treatment, patients diagnosed with clear cell renal cell carcinoma (ccRCC) have a poor prognosis. The mechanism of cuproptosis has been found to differ from other mechanisms that regulate cell death, including apoptosis, iron poisoning, pyrophosphate poisoning, and necrosis. Cuproptosis is an essential component in the regulation of a wide variety of biological processes, such as cell wall remodeling and oxidative stress responses. However, cuproptosis-related genes’ expression in ccRCC patients and their association with the patient’s prognosis remain ambiguous. Evaluation of The Cancer Genome Atlas (TCGA) identified 11 genes associated with cuproptosis that were differently expressed in ccRCC and nearby nontumor tissue. To construct a multigene prognostic model, the prognostic value of 11 genes was assessed and quantified. A signature was constructed by least absolute shrinkage and selection operator (LASSO) Cox regression analysis, and this signature was used to separate ccRCC patients into different risk clusters, with low-risk patients having a much better prognosis. This five-gene signature, when combined with patients’ clinical characteristics, might serve as one independent predictor of overall survival (OS) in ccRCC patients. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that cuproptosis-related genes were enriched in patients with ccRCC. Then, quantitative real-time PCR (qPCR) was employed to verify these genes’ expression. Generally, research has indicated that cuproptosis-related genes are important in tumor immunity and can predict OS of ccRCC patients.
Background: Sarcopenia is highly prevalent in elderly and has a significant adverse effect on their physical health and quality of life, but the mechanisms remain unclear. Studies have indicated that transcription factors (TFs) and immune microenvironment played a vital role in skeletal muscle atrophy. Methods: RNA-seq data of 40 muscle samples were downloaded from GEO database. Then differential expressed genes (DEGs), TFs, pathways, and immune gene sets were identified with edgeR package, Cistrome Database, GO, KEGG, ORA, GSVA, and ssGAES, respectively. In silico regulatory network was built by Cytoscape and the potential medicine was screened by Connectivity Map. Finally, regulatory mechanisms and RNA expression of DEGs and TFs were identified by multiple online databases and RT-qPCR. Results: We primary screened 808 DEGs (log2 fold change (FC) > 1or < −1, p < 0.05), 4 differential expressed transcription factors (DETFs) (log2FC > 0.7 or < −0.7, p < 0.05), 304 differential expressed pathways (DEPs) (enrichment scores (ES) > 1or < −1, p < 0.05 or), and 1208 differential expressed immune genes sets (p < 0.01). Based on the results of Pearson correlation analysis (Correlation coefficient (CC) > 0.4 or < -0.4, p < 0.01), we then structured immune related network with 4 DETFs, 9 key DEGs, 11 DEPs, 5 immune cells and 1 immune reaction. Combining the results of online databases and vitro experiments, we found that PAX5-SERPINA5-PI3K/Akt (CC≤0.444, p≤ 0.004) was a potential transcriptional regulation axis, and the B cells (R = 0.437, p = 0.005) may play a vital role in this signal transduction. Finally, the compound of Tanespimycin (enrichment = -0.403, p < 0.0001) might be a potential medicine for sarcopenia based on mechanism of actions database and the result of literature review. Conclusions: We firstly identified immune related transcriptional regulatory network with High-throughput RNA-seq data in sarcopenia. We supposed that PAX5-SERPIAN5-PI3K/Akt axis was a potential mechanism in sarcopenia, and the B cells may play a vital role in this signal transduction. Besides, Tanespimycin is a potential medicine for sarcopenia by targeting Akt degradation.
Background Anoctamin family (Transmembrane Protein 16), has gained growing attention for generating exosome and ectosome to mediate cancer cell communication in the process of phospholipid scrambling. However, former studies only focused on one narrow process in a single cancer. Instead, we designed a multidimensional study to comprehensively investigate the impact of ANO family on eight critical multi-omics cancer features in TCGA pan-cancer cohort. Methods TCGA pan-cancer cohorts were downloaded from UCSC xena. Differential analysis, survival analysis, and correlation analysis with tumor mutation burden, immune-phenotyping, stemness, cell proportion of tumor microenvironment, and drug sensitivity were conducted by R software. Alteration landscape was obtained from cBioportal with STRING database showing the protein-protein interaction network. Nanoparticle Tracking Analysis and Western Blot were employed to identify the ANO5 exosome. Results Extensive and profound associations were found between ANO family and eight crucial cancer features, including clinical prognosis, metastasis, drug resistance, tumor mutation burden, stemness, and tumor microenvironment. ANO1 possessed a high mutation frequency and is a driver gene in multiple cancers. ANO5 can exist in exosome to mediate cell-cell communication. Conclusions ANO family broadly participates in the proliferation, metastasis, and drug resistance in a barrage of cancers by generating extracellular vesicles to mediate cell-cell communication and interacting with TMB, stemness, stromal and immune cell proportions in tumor microenvironment. ANO members can serve as reliable biomarkers for prognosis of cancer, as well as promising targets for trans-cancer treatment.
Mitochondrial function impairment due to abnormal opening of the mitochondrial permeability transition pore (MPTP) is considered the central event in acute pancreatitis; however, therapeutic choices for this condition remain controversial. Mesenchymal stem cells (MSCs) are a family member of stem cells with immunomodulatory and anti‐inflammatory capabilities that can mitigate damage in experimental pancreatitis. Here, it is shown that MSCs deliver hypoxia‐treated functional mitochondria to damaged pancreatic acinar cells (PACs) via extracellular vesicles (EVs), which reverse the metabolic function of PACs, maintain ATP supply, and exhibit an excellent injury‐inhibiting effect. Mechanistically, hypoxia inhibits superoxide accumulation in the mitochondria of MSCs and upregulates the membrane potential, which is internalized into PACs via EVs, thus, remodeling the metabolic state. In addition, cargocytes constructed via stem cell denucleation as mitochondrial vectors are shown to exert similar therapeutic effects to MSCs. These findings reveal an important mechanism underlying the role of mitochondria in MSC therapy and offer the possibility of applying mitochondrial therapy to patients with severe acute pancreatitis.
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