BackgroundClear cell renal cell carcinoma (ccRCC) is known for its high drug resistance. The tumor-immune crosstalk mediated by the epigenetic regulation of N6-methyladenosine (m6A) modification has been demonstrated in recent studies. Therefore, m6A modification-mediated immune cell infiltration characteristics may be helpful to guide immunotherapy for ccRCC.MethodsThis study comprehensively analyzed m6A modifications using the clinical parameters, single-cell RNA sequencing data, and bulk RNA sequencing data from the TCGA-ccRC cohort and 13 external validation cohorts. A series of bioinformatic approaches were applied to construct an m6A regulator prognostic risk score (MRPRS) to predict survival and immunotherapy response in ccRCC patients. Immunological characteristics, enriched pathways, and mutation were evaluated in high- and low-MRPRS groups.ResultsThe expressional alteration landscape of m6A regulators was profiled in ccRCC cell clusters and tissue. The 8 regulator genes with minimal lambda were integrated to build an MRPRS, and it was positively correlated with immunotherapeutic response in extent validation cohorts. The clinicopathological features and immune infiltration characteristics could be distinguished by the high- and low-MRPRS. Moreover, the MRPRS-mediated mutation pattern has an enhanced response to immune checkpoint blockade in the ccRCC and pan-cancer cohorts.ConclusionsThe proposed MRPRS is a promising biomarker to predict clinical outcomes and therapeutic responses in ccRCC patients.
Our previous investigations showed that retroviral gene transfer of tissue-type plasminogen activator (tPA) effectively targeted thrombolysis in vitro and in the model of inferior caval veins of rabbits. This study is to identify the target thrombolysis of retroviral vector recombinant pLEGFP-N1-tPA transferred into the tissue around the Dacron patch (the same materials making of the ring of mechanical valve) in left atriums of rabbits. 70 Dacron patches were transplanted into the left atriums of 70 New Zealand white rabbits. The rabbits were randomly divided into three groups according to the different handling methods, including local pLEGFP-N1-tPA transferred group (gene therapy group, 30 animals), pLEGFP-N1 transferred group (control group, 20 animals), medium DMEM + 10% neonate calf serum (NCS) injected group (blank control group, 20 animals). Samples of blood, Dacron pieces and left atriums (auricles) wall from half of above in each group were harvested on second day and another half were harvested on 75th day after surgery. The EGFP expression of harvested left atriums (auricles) wall were observed under the confocal. The thrombi on the surface of Dacron patches were detected by stereoscope and electron microscope. The tPA expression in left atriums (auricles) wall and in blood from left atriums were detected by Western blot and their thrombolysis and activities were observed and calculated in plasma plates. ELISA were used to identify the contents of tPA. No thrombus was seen on the surface of Dacron patches that were transplanted in left atriums by tPA locally transferring around them. Activity and content of tPA were high in local tissue of left atrium and in blood of left atrium. It demonstrated effectively thrombolysis by tPA rapidly, efficiently and long expressing. This puts the foundation of mechanical valve replacement model for tPA gene valve, next.
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