Ruipeng Jia

EIF2AK2, also known as PKR, is a stress‐responsive kinase that regulates multiple cellular processes, including autophagy, apoptosis, and tumor progression. However, the mechanisms underlying EIF2AK2 stability and function in bladder cancer (BLCA) remain underexplored. In this study, we investigated the mechanisms governing post‐translational EIF2AK2 expression and its impact on BLCA progression. Through a luciferase‐based screening of candidate E3 ubiquitin ligases, we identified CNOT4 as a potential regulator of EIF2AK2. Bioinformatics analysis of public BLCA transcriptomic datasets showed that CNOT4 expression is significantly decreased in BLCA tissues relative to that in normal bladder tissues, and reduced CNOT4 levels are associated with unfavorable clinical outcomes. Functional assays demonstrated that CNOT4 overexpression suppresses viability and motility, while promoting apoptosis in BLCA cells. Moreover, CNOT4 inhibited autophagy and related signaling pathways. Mechanistic analyses revealed that CNOT4 interacted with EIF2AK2 and promoted its K48‐linked ubiquitination and proteasomal degradation. Restoration of EIF2AK2 expression largely reversed the tumor‐suppressive effects of CNOT4, indicating that EIF2AK2 acts as a key downstream effector. Consistent with these findings, CNOT4 overexpression significantly suppressed tumor growth in a BLCA xenograft model. Collectively, our observations identify CNOT4 as a previously unrecognized EIF2AK2 stability regulator and reveal that CNOT4 suppresses BLCA progression by promoting EIF2AK2 degradation and thereby suppressing autophagy. These results reveal a novel mechanism for the post‐translational modulation of EIF2AK2 and suggest a potential therapeutic target for BLCA.

Erectile dysfunction (ED) is widespread among individuals with high blood pressure and negatively affects quality of life. The effect of stromal vascular fraction (SVF) on hypertension‐related ED remains unexplored. We used a hypertensive rat model to explore the relative efficacy of adipose tissue stromal vascular fraction (tSVF) and cellular SVF (cSVF). We then investigated the possible mechanisms of these treatments. Hypertensive rats were divided into three groups according to different treatments. Their intracavernous pressure (ICP) during erection and condition of cavernous tissue were compared to those of the controlled group. Endothelial‐mesenchymal transformation (EndMT) markers as well as related inflammatory factors were also measured. cSVF and tSVF were labeled with CM‐Dil before injection in order to determine whether cSVF and tSVF survived, proliferated, and transdifferentiated in vivo. The increased ICP during erection demonstrated that tSVF treatment significantly improved hypertension‐related ED. tSVF increased the smooth muscle‐to‐collagen ratio and inhibiting the expression of fibrosis‐related proteins in hypertensive rats while rescuing the expression of vWF and eNOS, which indicated the preserving of endothelial tissue of the penis. Immunofluorescence staining and western blotting of penile tissue clearly suggest the inhibitory effect of tSVF on the overoccurring EndMT. Immunofluorescence staining and Western blot analysis of endothelial cells in vitro corroborate the whole‐tissue findings. The experiments in N‐nitro‐L‐arginine methyl ester hydrochloride (L‐NAME)–induced human umbilical vein endothelial cells (HUVECs) revealed tSVF suppresses EndMT via inhibiting the TGF‐ β 2–Smad2/Smad3 pathway. In vivo tSVF and cSVF tracing suggested that tSVF showed better longevity and transdifferentiation capacity than cSVF, thus exerting a more significant therapeutic effect. Treatment with tSVF significantly reserved erectile function in a hypertensive rat model. The mechanism appears to be inhibition of pathological EndMT through self‐differentiation. We conclude that tSVF is a promising therapeutic candidate for treating hypertensive ED.

Objective: The purpose of this study is to further investigate the diagnostic value and precise localization of ⁶⁸ Gallium prostate-specific membrane antigen positron emission tomography/computed tomography ( ⁶⁸ Ga-PSMA PET/CT) for preoperative pelvic invasion in prostate cancer (PCa) patients in comparison with multiparametric MRI (mpMRI), in order to explore the better clinical diagnostic recommendations. Patients and methods: The clinical data of 118 PCa patients who underwent ⁶⁸ Ga-PSMA PET/CT and mpMRI, including the patients with Pelvic invasion (n = 46) and No pelvic invasion (n = 72), was collected from May 2019 to June 2024. The correlation between the maximum standardized uptake value (SUVmax) of ⁶⁸ Ga-PSMA-11 PET/CT, Prostate Imaging Reporting and Data System (PI-RADS) of mpMRI and serum prostate-specific antigen (PSA) levels, and Gleason score was analyzed and explored. Thereafter, both modalities were directly compared for every patient and PCa lesion in the terms of pelvic invasion by all collected and analyzed data. In addition, the sensitivity and specificity of ⁶⁸ Ga-PSMA PET/CT and mpMRI were verified by postoperative hematoxylin-eosin staining and PSMA immunohistochemistry of intraoperative localized microcarcinoma. Results: Analyzing the clinical and imaging data of PCa patients, it was found that the SUVmax of ⁶⁸ Ga-PSMA-11 PET/CT and PI-RADS of mpMRI had a positive correlation with the PCa patients’ serum PSA and Gleason score. In addition, SUVmax, PI-RADS and PSA, Gleason score of PCa patients with pelvic invasion were significantly higher than those without pelvic invasion. After further data analysis, ⁶⁸ Ga-PSMA-11 PET/CT presented the sensitivity and specificity of 95.56% and 95.89%, respectively. Moreover, mpMRI demonstrated the sensitivity and specificity of 93.18% and 93.24%, respectively. There was no significant statistical difference between them. Meanwhile, the comparison between ⁶⁸ Ga-PSMA PET/CT and mpMRI in the diagnosis of lymph node metastasis was similar. Conclusions: Both ⁶⁸ Ga-PSMA PET/CT and mpMRI have high sensitivity and specificity in the detection of primary PCa lesions with pelvic invasion. Despite the excellent performance of ⁶⁸ Ga-PSMA PET/CT in the diagnosis of small PCa lesions, it cannot replace the diagnostic value of mpMRI in localization and staging of PCa.

Background: The optimal timing of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) remains a subject of debate, particularly in the immunotherapy era. This study compares survival outcomes between deferred CN (dCN) and upfront CN (uCN) in mRCC patients receiving modern immunotherapy regimens in the real-world setting. Methods: We retrospectively analyzed the SEER database for mRCC patients diagnosed between 2016 and 2021 who underwent dCN or uCN. The primary endpoint was overall survival (OS), while the secondary endpoints were disease-specific survival (DSS) and other-cause specific survival (OCSS). Statistical analyses included propensity score matching (PSM), Kaplan–Meier survival curves, Cox proportional hazards modeling, as well as sensitivity, subgroup, and landmark analyses. Results: A total of 1892 mRCC patients were included, with 346 patients (18.3%) undergoing dCN and 1546 patients (81.7%) receiving uCN. Patients in the uCN group were characterized with lower T stage (p < 0.001), while those in the dCN group exhibited a higher incidence of lymph node involvement (p = 0.02) and sarcomatoid dedifferentiation (p = 0.002). Following 1:2 PSM, dCN demonstrated significantly better OS and DSS, but comparable OCSS to uCN. The sensitivity and subgroup analyses suggested that dCN may substantially improve the prognosis of mRCC patients across conditions. The landmark analysis showed that the survival advantage of dCN diminished after two years of follow-up. Conclusions: dCN may be associated with improved survival outcomes compared to uCN in selected mRCC patients receiving immunotherapy, and careful patient selection for dCN or uCN is essential.

Repairing tissue, especially in chronic wounds, is a major clinical challenge. Traditional treatments often lead to slow recovery and poor biocompatibility. Adipose-derived stem cell exosomes (ADSC-exo) offer a promising solution for tissue regeneration due to their anti-inflammatory and immunomodulatory effects. However, directly injecting stem cells results in a low survival and function loss. This study introduces a Janus G-Avs patch that promotes tissue repair by releasing ADSC-exo and prevents postoperative tissue adhesion. The patch's top layer, created via coaxial electrospinning, acts as an ADSC-exo delivery system with a core-shell structure by incorporating ADSC-exo and hyaluronic acid (HA) into methacrylate gelatin (GelMA) to prolong exosome release. The bottom layer consists of a 4arm-PLGA(4aPLGA)-Glu/PCL electrospun membrane, offering a lubricated antifouling surface that prevents protein adsorption and provides mechanical support. In rat models, the G-Avs patch has demonstrated its ability to enhance cell proliferation, promote angiogenesis, and encourage macrophage polarization toward the M2 phenotype, thereby mitigating inflammatory responses and promoting tissue repair. Transcriptomic analysis indicates that the G-Avs patch augments cellular energy metabolism by upregulating metabolic pathways and downregulating immune-inflammatory pathways, collectively supporting tissue repair. In summary, the Janus G-Avs patch has a strong clinical potential.

The role of sphingolipid metabolism (SM) dysregulation in promoting bladder cancer (BLCA) progression and influencing patient prognosis has been well documented. To enhance therapeutic strategies, we aimed to identify key sphingolipid metabolism–related genes (SMGs) and develop a prognostic signature for personalized BLCA management. In this study, 430 BLCA samples from The Cancer Genome Atlas (TCGA) were analyzed via univariate Cox regression to screen critical SMGs involved in tumor progression. A LASSO regression model was applied to minimize overfitting, followed by multivariable Cox regression to construct and validate a SMG‐based prognostic signature in an independent cohort. Key findings revealed that SM dysregulation correlated with poor clinical outcomes and eight pivotal prognostic genes (ATP13A2, PCSK2, NR2F1, GSDMB, NFASC, NTF3, LGALS4, and SREBF1) were identified. The resulting risk model demonstrated robust prognostic performance with AUC values of 0.772 (training cohort) and 0.725 (validation cohort). Notably, high‐risk patients exhibited a highly active immunological profile characterized by elevated immune scores and enhanced functionality across 26 immune components, including increased infiltration of NK cells, CD8 ⁺ T cells, and elevated cytolytic activity. These results suggest that SM dysregulation may drive immunomodulatory changes in BLCA microenvironments, offering mechanistic insights into tumor immune evasion. This study provides a novel biomarker tool for risk stratification and highlights SM pathways as potential therapeutic targets for BLCA patients with immune microenvironment dysregulation.

The prevalence of urological malignancies continues to pose a significant global health challenge, particularly due to the poor prognosis associated with advanced stages of these diseases. Consequently, there is an urgent need to deepen our understanding of the molecular mechanisms governing the development of urological malignancies to facilitate breakthroughs in diagnosis and treatment. Pyroptosis, a novel and specific form of programmed cell death, plays a crucial role in regulating inflammatory responses, cell development, tissue homeostasis, and stress responses. Recent research has revealed a close association between pyroptosis and urological malignancies. In this paper, we review the pathogenesis and recent advancements in the understanding of pyroptosis in urological malignancies, elucidate the molecular mechanisms involved in its regulation, and aim to provide new directions for the clinical management of these diseases.