Targeting dysregulated phago-/auto-lysosomes in Sertoli cells to ameliorate late-onset hypogonadism.

Age-related changes in testicular function can impact health and well-being. The mechanisms underlying age-related testicular dysfunction, such as late-onset hypogonadism (LOH), remain incompletely understood. Using single-cell RNA sequencing on human testes with LOH, we delineated Sertoli cells (SCs) as pivotal metabolic coordinators within the testicular microenvironment. In particular, lysosomal acidity probing revealed compromised degradative capacity in aged SCs, hindering autophagy and phagocytic flux. Consequently, SCs accumulated metabolites, including cholesterol, and have increased inflammatory gene expression; thus, we termed these cells as phago-/auto-lysosomal deregulated SCs. Exposure to a high-fat diet-induced phago-/auto-lysosomal dysregulated-like SCs, recapitulating LOH features in mice. Notably, efferent ductular injection and systemic TRPML1 agonist administration restored lysosomal function, normalizing testosterone deficiency and associated abnormalities in high-fat diet-induced LOH mice. Our findings underscore the central role of SCs in testis aging, presenting a promising therapeutic avenue for LOH.

Artificial cavernosa-like tissue based on multibubble Matrigel and a human corpus cavernous fibroblast scaffold.

Ex vivo tissue culture of the human corpus cavernosum (CC) can be used to explore the tissue structural changes and complex signaling networks. At present, artificial CC-like tissues based on acellular or three-dimensional (3D)-printed scaffolds are used to solve the scarcity of primary penis tissue samples. However, inconvenience and high costs limit the wide application of such methods. Here, we describe a simple, fast, and economical method of constructing artificial CC-like tissue. Human CC fibroblasts (FBs), endothelial cells (ECs), and smooth muscle cells (SMCs) were expanded in vitro and mixed with Matrigel in specific proportions. A large number of bubbles were formed in the mixture by vortexing combined with pipette blowing, creating a porous, spongy, and spatial structure. The CC FBs produced a variety of signaling factors, showed multidirectional differentiation potential, and grew in a 3D grid in Matrigel, which is necessary for CC-like tissue to maintain a porous structure as a cell scaffold. Within the CC-like tissue, ECs covered the surface of the lumen, and SMCs were located inside the trabeculae, similar to the structure of the primary CC. Various cell components remained stable for 3 days in vitro, but the EC content decreased on the 7th day. Wingless/integrated (WNT) signaling activation led to lumen atrophy and increased tissue fibrosis in CC-like tissue, inducing the same changes in characteristics as in the primary CC. This study describes a preparation method for human artificial CC-like tissue that may provide an improved experimental platform for exploring the function and structure of the CC and conducting drug screening for erectile dysfunction therapy.

Association between platelet­to­lymphocyte ratio and serum prostate specific antigen.

There is evidence that the systemic inflammatory response may have an impact on prostate-specific antigen (PSA) levels. However, the relationship between the platelet-to-lymphocyte ratio (PLR) and PSA remains unclear. As a result, the relationship between PLR and PSA using the National Health and Nutrition Examination Survey (NHANES) database was examined. After the screening, 6,638 participants out of 52,186 in the NHANES survey conducted between 2001 to 2010 were suitable for the present study. The PLR was the independent variable in the present study, and PSA was the dependent variable. The selected subjects in the present study had an average age of 58.563±11.848 years. After controlling for covariates, the results showed that with every increase in PLR, the PSA concentration increased by 0.004 ng/ml (0.001, 0.007). This difference was statistically significant. Furthermore, a smoothing curve based on a fully adjusted model was created to investigate the possibility of a linear relationship between PLR and PSA concentration in men from USA. In men from USA, an independent and positive correlation between PLR and PSA was identified, which could potentially result in overdiagnosis of asymptomatic prostate cancer in populations with higher PLR levels.

Can Double J stent encrustation be predicted by risk analysis and nomogram?: A retrospective case-control study.

To explore the risk factors and develop a nomogram to predict Double J stent encrustation incidence. The general demographic characteristics and underlying risk factors of 248 patients with upper urinary tract calculus who underwent endoscopic lithotripsy and Double J stenting at the Fifth Affiliated Hospital of Sun Yat-Sen University between January 1st, 2018 and January 1st, 2023 were retrospectively analyzed. Among them,173 patients were randomly selected to form the development cohort. A multivariate logistic regression model was employed to identify the independent risk factors associated with Double J stent encrustation, and a nomogram was developed for predicting its occurrence. Additionally, 75 patients were randomly selected to form the validation cohort to validate the nomogram. Multivariate logistic regression analysis revealed that several factors were significantly associated with Double J stent encrustation: indwelling time (odds ratio [OR]1.051; 95% confidence interval [CI] 1.030-1.073, P < .001), urine PH (OR 2.198; 95% CI 1.061-4.539, P = .033), fasting blood glucose (OR 1.590; 95% CI 1.300-1.943, P < .001), and total cholesterol (OR 2.676; 95% CI 1.551-4618, P < .001).Based on these findings, A nomogram was developed to predict the occurrence of Double J stent encrustation. The nomogram demonstrated good performance with an area under the curve of 0.870 and 0.862 in the development and validation cohorts, respectively. Furthermore, the calibration curve indicated a well-fitted model. We constructed and validated an accessible nomogram to assist urologists in evaluating the risk factors associated with Double J stent encrustation and predicting its likelihood.

Effect of a Single Light-intensity Walking Session on Sleep Quality of Patients with Bladder Cancer: A Randomized Cross-Over Study.

OBJECTIVES: Exercise has been recommended to enhance sleep. However, there is a paucity of studies investigating the relationships between exercise and sleep problems in patients with bladder cancer. The authors explored the effects of a single bout of light-intensity walking on the sleep quality of patients with bladder cancer who have sleep disorders. DATA SOURCES: A total of 14 patients with bladder cancer with sleep disorders were recruited for this trial. The participants were randomly assigned to the walking or control condition in a cross-over design to explore the effects of a single light-intensity walking session on objectively measured sleep quality. A two-way repeated measures analysis of variance and a nonparametric permutation test were used to examine intervention effects. Twelve participants (85.7%) completed the trial. A significant group × time interaction for sleep latency (P = .023) was identified. The pairwise comparison showed significant results (P = .012) for the difference between the post-test sleep latency and the pre-test. No significant group × time interactions were observed for the remaining seven sleep parameters. Additionally, only the main effects of time on length of awakening and time in bed were significant (P < .001). CONCLUSION: A single bout of light-intensity walking has a positive effect on shortening the sleep latency of patients with bladder cancer who have sleep disorders. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses can encourage patients with bladder cancer to exercise, even light-intensity walking, which may improve sleep quality.

Knockdown of NR3C1 inhibits the proliferation and migration of clear cell renal cell carcinoma through activating endoplasmic reticulum stress-mitophagy.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is closely associated with steroid hormones and their receptors affected by lipid metabolism. Recently, there has been growing interest in the carcinogenic role of NR3C1, the sole gene responsible for encoding glucocorticoid receptor. However, the specific role of NR3C1 in ccRCC remains unclear. The present study was thus developed to explore the underlying mechanism of NR3C1's carcinogenic effects in ccRCC. METHODS: Expression of NR3C1 was verified by various tumor databases and assessed using RT-qPCR and western blot. Stable transfected cell lines of ccRCC with NR3C1 knockdown were constructed, and a range of in vitro and in vivo experiments were performed to examine the effects of NR3C1 on ccRCC proliferation and migration. Transcriptomics and lipidomics sequencing were then conducted on ACHN cells, which were divided into control and sh-NR3C1 group. Finally, the sequencing results were validated using transmission electron microscopy, mitochondrial membrane potential assay, immunofluorescence co-localization, cell immunofluorescent staining, and Western blot. The rescue experiments were designed to investigate the relationship between endoplasmic reticulum stress (ER stress) and mitophagy in ccRCC cells after NR3C1 knockdown, as well as the regulation of their intrinsic signaling pathways. RESULTS: The expression of NR3C1 in ccRCC cells and tissues was significantly elevated. The sh-NR3C1 group, which had lower levels of NR3C1, exhibited a lower proliferation and migration capacity of ccRCC than that of the control group (P < 0.05). Then, lipidomic and transcriptomic sequencing showed that lipid metabolism disorders, ER stress, and mitophagy genes were enriched in the sh-NR3C1 group. Finally, compared to the control group, ER stress and mitophagy were observed in the sh-NR3C1 group, while the expression of ATF6, CHOP, PINK1, and BNIP3 was also up-regulated (P < 0.05). Furthermore, Ceapin-A7, an inhibitor of ATF6, significantly down-regulated the expression of PINK1 and BNIP3 (P < 0.05), and significantly increased the proliferation and migration of ccRCC cells (P < 0.05). CONCLUSIONS: This study confirms that knockdown of NR3C1 activates ER stress and induces mitophagy through the ATF6-PINK1/BNIP3 pathway, resulting in reduced proliferation and migration of ccRCC. These findings indicate potential novel targets for clinical treatment of ccRCC.

Identifying ureteral stent encrustation using machine learning based on CT radiomics features: a bicentric study.

Obstructive: To develop and validate radiomics and machine learning models for identifying encrusted stents and compare their recognition performance with multiple metrics. Methods: A total of 354 patients with ureteral stent placement were enrolled from two medical institutions and divided into the training cohort (n = 189), internal validation cohort (n = 81) and external validation cohort (n = 84). Based on features selected by Wilcoxon test, Spearman Correlation Analysis and least absolute shrinkage and selection operator (LASSO) regression algorithm, six machine learning models based on radiomics features were established with six classifiers (LR, DT, SVM, RF, XGBoost, KNN). After comparison with those models, the most robust model was selected. Considering its feature importance as radscore, the combined model and a nomogram were constructed by incorporating indwelling time. Accuracy, sensitivity, specificity, area under the curve (AUC), decision curve analysis (DCA) and calibration curve were used to evaluate the recognition performance of models. Results: 1,409 radiomics features were extracted from 641 volumes of interest (VOIs) and 20 significant radiomics features were selected. Considering the superior performance (AUC 0.810, 95%CI, 0.722-0.888) in the external validation cohort, feature importance of XGBoost was used as a radscore, constructing a combined model and a nomogram with indwelling time. The accuracy, sensitivity, specificity and AUC of the combined model were 98, 100, 97.3% and 0.999 for the training cohort, 83.3, 80, 84.5% and 0.867 for the internal cohort and 78.2, 76.3, 78.8% and 0.820 for the external cohort, respectively. DCA indicates the favorable clinical utility of models. Conclusion: Machine learning model based on radiomics features enables to identify ureteral stent encrustation with high accuracy.

Ammonium tetrathiomolybdate relieves oxidative stress in cisplatin-induced acute kidney injury via NRF2 signaling pathway.

Cisplatin is an efficient chemotherapeutic agent for various solid tumors, but its usage is restricted by nephrotoxicity. A single dose of cisplatin can cause acute kidney injury (AKI), which is characterized by rapid reduction in kidney function. However, the current therapies, such as hydration, are limited. It is vital to develop novel therapeutic reagents that have both anticancer and renoprotective properties. The objective of this study was to determine whether ammonium tetrathiomolybdate (TM), a copper chelator used to treat cancer and disorders of copper metabolism, may offer protection against cisplatin-induced AKI. In this study, we demonstrated that TM treatment had antioxidative effects and mitigated cisplatin-induced AKI both in vivo and in vitro. Mechanically, TM inhibited NRF2 ubiquitination, which activated the NRF2 pathway in HK-2 cells and promoted the expression of target genes. It should be noted that the protective effect conferred by TM against cisplatin was compromised by the knockdown of the NRF2 gene. Furthermore, TM selectively activated the NRF2 pathways in the liver and kidney. The current study provided evidence for additional clinical applications of TM by showing that it activates NRF2 and has a favorable therapeutic impact on cisplatin-induced AKI.

Analysis of Risk Factors for Early Progression of Prostate Cancer After Initial Endocrine Therapy.

Background: Prolonged androgen deprivation therapy (ADT) in patients with prostate cancer can eventually lead to the development of castration-resistant prostate cancer (CRPC). Once CRPC occurs, the patient's prognosis will be inferior. However, the risk factors for progression to CRPC in a short period of time are unclear. Methods: We retrospectively analyzed prostate cancer patients who received their first ADT between January 1, 2015 and January 1, 2021. The main statistical methods used were a logistic regression model and Kaplan-Meier survival analysis. Results: Among 159 prostate cancer patients initially treated with ADT, 90 were screened for inclusion. Patients who progressed to CRPC after ADT were included in group B and others were included in group A. Group B was divided into group B1 and B2 according to whether CRPC progressed within 18 months. Multi-factor logistic regression analysis showed that the time to PSA nadir (TTN) (p = 0.031) and serum lactate dehydrogenase (LDH) (p = 0.013) were significantly different between Group A and B. TTN (p < 0.001), LDH (p = 0.001) and platelet to lymphocyte ratio (PLR) (p = 0.005) were significantly different between Group B1 and B2. Kaplan-Meier survival analysis and log-rank tests showed that TTN, LDH, and PLR statistically differed in CRPC patients' progression-free survival. The ROC curve showed the AUC value of TTN combined with PLR and LDH increased to 0.958 (95% CI 0.911-0.997, p < 0.001). The Chi-square test showed that the expression of p63 in group A was higher than that in groups B1 (p = 0.002) and B2 (p = 0.001). Conclusion: Lower TTN, higher LDH and PLR were associated with early CRPC occurrence after ADT in hormone-sensitive prostate cancer patients. p63 expression was associated with favorable prognosis in prostate cancer patients.

Multiomics analysis of ferroptosis-related molecular subtypes in muscle-invasive bladder cancer immunotherapy.

Background: The purpose of this study was to identify the ferroptosis-related molecular subtypes in muscle invasive bladder cancer (MIBC) associated with the tumor microenvironment (TME) and immunotherapy. Methods: Expression profiles and corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA) dataset and the Gene Expression Omnibus (GEO) dataset. Nonnegative matrix factorization (NMF) analysis was performed to identify two molecular subtypes based on 41 ferroptosis-related prognostic genes. The differences between the two subtypes were compared in terms of prognosis, somatic mutations, gene ontology (GO), cytokines, pathways, immune cell infiltrations, stromal/immune scores, tumor purity and response to immunotherapy. We also constructed a risk prediction model using multivariate Cox regression analysis to analyze survival data based on differentially expressed genes (DEGs) between subtypes. In combination with clinicopathological features, a nomogram was constructed to provide a more accurate prediction for overall survival (OS). Results: Two molecular subtypes (C1 and C2) of MIBC were identified according to the expression of ferroptosis-related genes. The C2 subtype manifested poor prognosis, high enrichment in the cytokine-cytokine receptor interaction pathway, high abundance of immune cell infiltration, immune/stromal scores and low tumor purity. Additionally, C2 is less sensitive to immunotherapy. The risk prediction model based on five pivotal genes (SLC1A6, UPK3A, SLC19A3, CCL17 and UGT2B4) effectively predicted the prognosis of MIBC patients. Conclusions: A novel MIBC classification approach based on ferroptosis-related gene expression profiles was established to provide guidance for patients who are more sensitive to immunotherapy. A nomogram with a five-gene signature was built to predict the prognosis of MIBC patients, which would be more accurate when combined with clinical factors.

High expression of CD73 contributes to poor prognosis of clear-cell renal cell carcinoma by promoting cell proliferation and migration.

Background: Accumulating data have shown that high expression of CD73 is associated with poor prognosis in various cancers, however the role and significance of CD73 in clear-cell renal cell carcinoma (ccRCC) still remain unclear. The present study aims to evaluate the prognostic significance of CD73 in ccRCC and explore the potential function in vitro and in vivo. Methods: Firstly, the expression of CD73 in ccRCC was detected using clinical tissues and verified using TCGA and GEO data. Immunohistochemistry and Kaplan-Meier test were performed for survival analysis. Furthermore, knockdown or overexpression of CD73 was conducted by lentivirus transfection in ccRCC cells. MTT assay, colony formation assay, wound healing assay, transwell assay and xenograft assay were performed in vitro or in vivo. Results: Our results showed that CD73 was highly expressed in ccRCC, and high expression of CD73 was negatively correlated with prognosis. In addition, CD73 promoted cell proliferation and migration in vitro and in vivo. Our data also showed that CD73 played both enzymatic and non-enzymatic functions in the regulation of cell proliferation and migration in ccRCC. Conclusions: These findings suggested that CD73 might promote the growth of ccRCC and contribute to poor prognosis. Taken together, CD73 may be a potential therapeutic target in ccRCC.

Novel sequential therapy with metformin enhances the effects of cisplatin in testicular germ cell tumours via YAP1 signalling.

BACKGROUND: Testicular germ cell tumours (TGCTs) are the most commonly diagnosed malignancy in young men. Although cisplatin has been shown to be effective to treat TGCT patients, long-term follow-up has shown that TGCT survivors who accepted cisplatin treatment suffered from a greater number of adverse reactions than patients who underwent orchiectomy alone. As metformin has shown an anticancer effect in various cancers, we investigated whether metformin could enhance the effects of cisplatin to treat TGCTs. METHODS: The anticancer effects of different treatment strategies consisting of metformin and cisplatin in TCam-2 and NTERA-2 cells were assessed in vitro and in vivo. First, we used a colony formation assay, CCK-8 and MTT assays to explore the viability of TGCT cells. Flow cytometry was used to assess the cell cycle and apoptosis of TGCTs. Then, Western blotting was used to detect the protein expression of TGCTs cells after different treatments. In addition, a xenograft model was used to investigate the effects of the different treatments on the proliferation of TGCT cells. Immunohistochemistry assays were performed to analyse the expression of related proteins in the tissues from the xenograft model. RESULTS: Metformin inhibited the proliferation of TCam-2 and NTERA-2 cells by arresting them in G1 phase, while metformin did not induce apoptosis in TGCT cells. Compared with cisplatin monotherapy, the CCK-8, MTT assay and colony formation assay showed that sequential treatment with metformin and cisplatin produced enhanced anticancer effects. Further study showed that metformin blocked the cells in G1 phase by inducing phosphorylated YAP1 and reducing the expression of cyclin D1, CDK6, CDK4 and RB, which enhanced the chemosensitivity of cisplatin and activated the expression of cleaved caspase 3 in TGCTs. CONCLUSIONS: Our study discovers the important role of YAP1 in TGCTs and reports a new treatment strategy that employs the sequential administration of metformin and cisplatin, which can reduce the required cisplatin dose and enhance the sensitivity of TGCT cells to cisplatin. Therefore, this sequential treatment strategy may facilitate the development of basic and clinical research for anticancer therapies to treat TGCTs.

A combination of laparoscopic ureteroplasty and flexible uteroscopic lithotripsy in the treatment of circumcaval ureter and right renal calculi: A case report.

Patients with circumcaval ureter and right renal calculi are not often seen in the clinical practice and require special approach. Hereby we report a case of a 34-year-old male that was diagnosed with circumcaval ureter complicated by right kidney stones. Laparoscopic ureteroplasty and flexible ureteroscopic lithotripsy were implemented in the treatment of both of these entities. A combination of these approaches allowed us to perform the surgery effectively, efficiently and safely without having to do the second one.

Development and validation of prognostic nomograms in patients with adrenocortical carcinoma: a population-based study.

BACKGROUND: Predicting the prognosis of patients with adrenocortical carcinoma (ACC) is difficult, due to its unpredictable behavior. The aim of this study is to develop and validate a nomogram to predict survival outcomes in patients with ACC. METHODS: Nomograms were established using the data collected from the Surveillance, Epidemiology, and End Results (SEER) database. Based on univariate and multivariate Cox regression analyses, we identified independent risk factors for overall survival (OS) and cancer-specific survival (CSS). Concordance indexes (c-indexes), the area under the receiver operating characteristics curve (AUC) and calibration curve were used to evaluate predictive performance of these models. The clinical use of nomogram was measured by decision curve analysis (DCA) and clinical impact curves. RESULTS: A total of 855 eligible patients, randomly divided into training (n = 600) and validation cohorts (n = 255), were included in this study. Based on the independent predictors, the nomograms were established and demonstrated good discriminative abilities, with C-indexes for OS and CSS were 0.762 and 0.765 in training cohorts and 0.738 and 0.758 in validation cohorts, respectively. The AUC and calibration plots also demonstrated a good performance for both nomograms. DCA indicated that the two nomograms provide clinical net benefits. CONCLUSION: We unveiled the prognostic factors of ACC and developed novel nomograms that predict OS and CSS more accurately and comprehensively, which can help clinicians improve individual treatment, making proper clinical decisions and adjusting follow-up management strategies.

Clinical analysis of retroperitoneoscopic nephroureterectomy for renal tuberculosis.

OBJECTIVES: To explore the feasibility and safety of retroperitoneoscopic nephroureterectomy for kidney tuberculosis. METHODS: Forty-eight retroperitoneoscopic nephroureterectomies and thirty-five nephroureterectomies for kidney tuberculosis procedures were performed from June 2008 to December 2014. The patients consisted of 53 males and 30 females with a mean age of 36 years (range: 26-51 years). The patients' data were reviewed and analyzed. RESULTS: The retroperitoneoscopic nephroureterectomy procedures were completed successfully in 48 cases with no conversions to open surgery. The mean operating time was 170 minutes (range: 121-258 minutes), the mean blood loss was 110 ml (range: 70-250 ml), and the mean hospital stay was 5.70 days (range: 5-14 days); these were all much less than nephroureterectomy procedures (P < 0.05). A total of five minor complications (10.4%) occurred, injury to the peritoneum was observed in three patients, and infection at the incision site was observed in two patients, there were no obvious difference between the two surgical methods (P > 0.05). Seventy-five patients were followed up, and the average follow-up time was 12.5 months (range: 6-20 months). All the patients recovered without any lesions remaining. CONCLUSIONS: The results of this study indicate that retroperitoneoscopic nephroureterectomy is a feasible, safe, effective, and less invasive treatment modality for treating renal tuberculosis.