Search

Abstract Clear cell renal carcinoma (ccRCC) is one of the most common cancers worldwide. In this study, a new model of immune-related genes was developed to predict the overall survival and immunotherapy efficacy in patients with ccRCC. Immune-related genes were obtained from the ImmPort database. Clinical data and transcriptomics of ccRCC samples were downloaded from GSE29609 and The Cancer Genome Atlas. An immune-related gene-based prognostic model (IRGPM) was developed using the least absolute shrinkage and selection operator regression algorithm and multivariate Cox regression. The reliability of the developed models was evaluated by Kaplan–Meier survival curves and time-dependent receiver operating characteristic curves. Furthermore, we constructed a nomogram based on the IRGPM and multiple clinicopathological factors, along with a calibration curve to examine the predictive power of the nomogram. Overall, this study investigated the association of IRGPM with immunotherapeutic efficacy, immune checkpoints, and immune cell infiltration. Eleven IRGs based on 528 ccRCC samples significantly associated with survival were used to construct the IRGPM. Remarkably, the IRGPM, which consists of 11 hub genes (SAA1, IL4, PLAUR, PLXNB3, ANGPTL3, AMH, KLRC2, NR3C2, KL, CSF2, and SEMA3G), was found to predict the survival of ccRCC patients accurately. The calibration curve revealed that the nomogram developed with the IRGPM showed high predictive performance for the survival probability of ccRCC patients. Moreover, the IRGPM subgroups showed different levels of immune checkpoints and immune cell infiltration in patients with ccRCC. IRGPM might be a promising biomarker of immunotherapeutic responses in patients with ccRCC. Overall, the established IRGPM was valuable for predicting survival, reflecting the immunotherapy response and immune microenvironment in patients with ccRCC.

Abstract A growing body of evidence suggests that the histone demethylase-lysine demethylase 5 (KDM5) family is associated with drug resistance in cancer cells. However, it is still not clear whether KDM5 family members promote chemotherapy resistance in pancreatic ductal adenocarcinomas (PDAC). Comprehensive bioinformatics analysis was performed to investigate the prognostic value, and functional mechanisms of KDM5 family members in PDAC. The effects of KDM5 family members on drug resistance in PDAC cells and the relationship with CD44, as a stem cell marker, were explored by gene knockout and overexpression strategies. Finally, our findings were validated by functional experiments such as cell viability, colony formation and invasion assays. We found that the expression of KDM5A/C was significantly higher in gemcitabine-resistant cells than in sensitive cells, consistent with the analysis of the GSCALite database. The knockdown of KDM5A/C in PDAC cells resulted in diminished drug resistance, less cell colonies and reduced invasiveness, while KDM5A/C overexpression showed the opposite effect. Of note, the expression of KDM5A/C changed accordingly with the knockdown of CD44. In addition, members of the KDM5 family function in a variety of oncogenic pathways, including PI3K/AKT and Epithelial-Mesenchymal Transition. In conclusion, KDM5 family members play an important role in drug resistance and may serve as new biomarkers or potential therapeutic targets in PDAC patients.

Abstract Background Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and histopathologic glomerular lesions are among the earliest structural alterations of DN. However, the signaling pathways that initiate these glomerular alterations are incompletely understood. Methods To delineate the cellular and molecular basis for DN initiation, we performed single-cell and bulk RNA sequencing of renal cells from type 2 diabetes mice (BTBR ob/ob) at the early stage of DN. Results Analysis of differentially expressed genes revealed glucose-independent responses in glomerular cell types. The gene regulatory network upstream of glomerular cell programs suggested the activation of mechanosensitive transcriptional pathway MRTF-SRF predominantly taking place in mesangial cells. Importantly, activation of MRTF-SRF transcriptional pathway was also identified in DN glomeruli in independent patient cohort datasets. Furthermore, ex vivo kidney perfusion suggested that the regulation of MRTF-SRF is a common mechanism in response to glomerular hyperfiltration. Conclusions Overall, our study presents a comprehensive single-cell transcriptomic landscape of early DN, highlighting mechanosensitive signaling pathways as novel targets of diabetic glomerulopathy.

ObjectiveClear cell renal cell carcinoma may affect patients of any age. To date, there are only a limited number of large data studies on renal clear cell carcinoma in different age groups. This study assessed CCRCC risk factors in different age groups using the Surveillance Epidemiology and End Results (SEER) database.MethodsWe selected 58372 cases from the SEER database. These patients were divided into seven different age groups. Cox regression models were used to find independent risk factors for the survival of CCRCC patients. Based on independent risk factors, a nomogram was drawn with R software. Kaplan-Meier method for survival analysis and X-tile software were used to find the optimal age group for diagnosis.ResultsUnivariate analysis revealed that patients’ age, sex, race, marital status, grade, TNM (tumor, node, metastasis) stage, surgery, WHO/ISUP grade were correlated with survival (P

Adeno-associated virus (AAV) is a promising in vivo gene delivery platform showing advantages in delivering therapeutic molecules to difficult or undruggable cells. However, natural AAV serotypes have insufficient transduction specificity and efficiency in kidney cells. Here, we developed an evolution-directed selection protocol for renal glomeruli and identified what we believe to be a new vector termed AAV2-GEC that specifically and efficiently targets the glomerular endothelial cells (GEC) after systemic administration and maintains robust GEC tropism in healthy and diseased rodents. AAV2-GEC-mediated delivery of IdeS, a bacterial antibody-cleaving proteinase, provided sustained clearance of kidney-bound antibodies and successfully treated antiglomerular basement membrane glomerulonephritis in mice. Taken together, this study showcases the potential of AAV as a gene delivery platform for challenging cell types. The development of AAV2-GEC and its successful application in the treatment of antibody-mediated kidney disease represents a significant step forward and opens up promising avenues for kidney medicine. [ABSTRACT FROM AUTHOR]