Background: To explore the prediction value of PI-RADS v2 in high-grade prostate cancer and establish a prediction model combined with related variables of prostate cancer.

5-hydroxymethylcytosine (5hmC) is converted from DNA methylation of cytosine (5mC) by the catalysis of TET proteins, and proposed to be involved in tumorigenesis. However, the prognostic value of 5hmC in renal cell carcinoma (RCC) is still unclear. This study aimed to define the clinical significance of 5hmC in RCC. We performed dot blot assays to measure the relative expression of 5hmC in RCC. We reviewed the clinical records of 310 RCC patients and performed immunohistochemical (IHC) staining of 5hmC. The overall survival (OS) and cancer specific survival (CSS) of all patients were recorded over a 10-year follow-up period. Effective prognostic nomograms which contained 5hmC were established to provide individualized OS and CSS in RCC. 5hmC expression level was significantly decreased in RCC tissues compared with those in the normal counterparts. Kaplan-Meier curves revealed that high 5hmC expression had a good prognostic impact on RCC patients. Cox multivariate survival analyses further indicated 5hmC was an independent prognostic factor for RCC survival. Nomograms constructed based on cox regression analysis were available to calculate the survival probability directly. Calibration curves displayed good agreements. The findings were validated with an independent external cohort included 77 RCC cases. Thus, we believe we have found a significative prognostic factor for RCC.

The purpose of our study was to explore the effect and intrinsic mechanism of wild-type IDH1 and its substrate α-KG on renal cell carcinoma (RCC). IDH1 was observed lower expression in RCC cell lines. Phenotype experiment was carried out in the wild-type IDH1 and mutant IDH1^R132H plasmid treated cell line. The results showed that the wild-type IDH1 could significantly inhibit the proliferation, migration and promote the apoptosis of RCC cell lines, which were consistent with the IDH1's substrate α-KG. The mutant IDH1^R132H was found to lose this biological function of IDH1. Moreover, we verified the proliferation inhibition of IDH1 in vivo. In addition, we verified the correlation between IDH1 and hypoxia signal-related proteins in vitro and in vivo, specifically, IDH1 overexpression could significantly reduce the expression of HIF-1α and HIF-2α proteins and its downstream proteins (VEGF, TGF-α). Furthermore, we preliminarily verified the possibility of α-KG in the RCC's treatment by injecting α-KG into the xenograft model. α-KG significantly reduced tumor size and weight in tumor-bearing mice. This study provided a new therapeutic target and small molecule for the study of the treatment and mechanism of RCC.

AJA publishes new findings in basic and clinical (including modern, traditional and epidemiological) research on Andrology.

Apalutamide, a novel endocrine therapy agent, has been shown to significantly improve the prognosis of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, resistance to apalutamide has also been reported, and the underlying mechanism for this response has yet to be clearly elucidated. First, this study established apalutamide-resistant prostate cancer (PCa) cells, and confirmed that apalutamide activated the release of calcium ions (Ca²⁺) and endoplasmic reticulum stress (ERS) to enhance autophagy. Second, RNA sequencing, western blotting, and immunohistochemistry revealed significantly decreased Calpain 2 (CAPN2) expression in the apalutamide-resistant PCa cells and tissues. Furthermore, immunofluorescence and transmission electron microscopy (TEM) showed that CAPN2 promoted apalutamide resistance by activating protective autophagy. CAPN2 promoted autophagy by reducing Forkhead Box O1 (FOXO1) degradation while increasing nuclear translocation via nucleoplasmic protein isolation and immunofluorescence. In addition, FOXO1 promoted protective autophagy through the transcriptional regulation of autophagy-related gene 5 (ATG5). Furthermore, a dual-fluorescence assay confirmed that transcription factor 3 (ATF3) stimulation promoted CAPN2-mediated autophagy activation via transcriptional regulation. In summary, CAPN2 activated protective autophagy by inhibiting FOXO1 degradation and promoting its nuclear translocation via transcriptional ATG5 regulation. ATF3 activation and transcriptional CAPN2 regulation jointly promoted this bioeffect. Thus, our findings have not only revealed the mechanism underlying apalutamide resistance, but also provided a promising new target for the treatment of metastatic PCa.