Dimethyl fumarate ameliorates erectile dysfunction in bilateral cavernous nerve injury rats by inhibiting oxidative stress and NLRP3 inflammasome-mediated pyroptosis of nerve via activation of Nrf2/HO-1 signaling pathway.

OBJECTIVE: To investigate the therapeutic potential of dimethyl fumarate (DMF) in improving erectile function of bilateral cavernous nerve injury (BCNI) rats, along with elucidating its underlying mechanisms. METHODS: A BCNI rat model was established by clamping bilateral cavernous nerve (CN). DMF was given by gavage at low (20 mg/kg/day) and high (40 mg/kg/day) dosages for a duration of 4 weeks. Erectile function was assessed by electrical stimulation of CN. Penis and CN tissues were collected for subsequent analysis. Additionally, PC-12 cell line was used to verify the mechanism of DMF in vitro. Nfe2l2 or Ho-1 gene knockdown PC-12 cell lines were constructed by lentiviral transfection, respectively. A damaged cell model was induced using H2O2. And then molecular biological methods were employed to analyze cellular molecules and proteins. RESULTS: DMF administration for 4 weeks led to improvements in erectile function, reduced fibrosis of penis corpus cavernosum in BCNI rats. The morphology of CN was improved and the number of nerve fibers increased. Furthermore, the levels of nNOS, NO, and cGMP were increased, while Ca2+ was decreased in penis corpus cavernosum. Notably, the levels of ROS, 3-NT and NLRP3 inflammasomes production were reduced, alongside increased expression of Nrf2 and HO-1 proteins in the dorsal penile nerve (DPN) and CN. In vitro, DMF increased cell viability, reduced ROS level, promoted SOD, diminished 3-NT, MDA and DNA damage markers, and inhibited the activation of NLRP3 inflammasomes in H2O2 induced PC-12 cells. Nfe2l2 knockdown and Ho-1 knockdown significantly attenuated the protective effect of DMF, respectively. Furthermore, inhibition of ROS production by N-acetylcysteine led to a reduction in NLRP3 inflammasome activation in H2O2 induced PC-12 cells. CONCLUSIONS: DMF improved erectile function of BCNI rats by protecting nerves through inhibiting oxidative stress and the activation of NLRP3 inflammasome-mediated pyroptosis via activation of Nrf2/HO-1 pathway.

A novel cuproptosis pattern and tumor immune microenvironment characterization in urothelial carcinoma of the bladder.

Background: Urothelial carcinoma of the bladder (UCB) is the most prevalent malignant tumor of the urinary system worldwide, which has a significant recurrence rate despite multiple treatment options available. As a unique and novel copper-dependent programmed cell death mechanism, the comprehensive impact of cuproptosis on the tumor immune microenvironment, clinicopathological characteristics and the prognosis of patients remains largely unclear. Methods: A total of 568 UCB samples were thoroughly examined for cuproptosis patterns using data downloaded from TCGA and GEO, based on 10 cuproptosis-related genes reported previously. Then, the univariate COX regression analysis was performed on the genes that differed across the various patterns. To measure individual cuproptosis pattern, a cuproptosis score system was constructed using a principal component analysis algorithm. To validate the scoring system, immunohistochemical staining was performed on tumor tissues with different pathological grades, and experiments in vitro were conducted about the differentially expressed genes related to prognosis. Finally, the capacity of scoring system to predict the response to immunotherapy was verified by using data from IMvigor 210 cohort. Results: Four unique cuproptosis clusters and two gene clusters were finally found by the investigation. The clinical features and prognosis of patients, as well as the mRNA transcriptome, pathway enrichment, and immune cell infiltration in TME, varied dramatically between various cuproptosis clusters and gene clusters. To identify individual cuproptosis patterns in UCB patients, we also established a cuproptosis scoring system. After validation with multiple methods, it was indicated that the score system could predict the prognosis of UCB patients and was significantly connected to clinical features such TNM category, tumor grade, molecular type and ultimate survival status. The clinical outcomes of UCB patients were predicted effectively according to the tumor mutation burden in conjunction with the scoring system. Furthermore, we found that the cuproptosis score had a significant correlation with the response to immunotherapy and the sensitivity to chemotherapy. Conclusion: This study revealed the potential impact of cuproptosis on the UCB tumor immune microenvironment and clinical pathological characteristics. The cuproptosis score system could effectively predict the prognosis of patients and the response to chemotherapy and immunotherapy.

Inhibition of MicroRNA-92a Improved Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats via Suppressing Oxidative Stress and Endothelial Dysfunction.

PURPOSE: To determine whether microRNA could be a therapy target of erectile dysfunction (ED) and the underlying mechanisms. MATERIALS AND METHODS: Eight-week-old fasting male SD rats were intraperitoneally injected with streptozotocin to construct diabetic rat models. Diabetic ED rats were treated with miRNA-92a inhibitor. The cavernous nerves were electrically stimulated to measure the intracavernous pressure and mean arterial pressure of rats in each group. After the detection, the penile cavernous tissues are properly stored for subsequent experiments. Rat aortic endothelial cells were used in in vitro studies. RESULTS: The expression of miR-92a was significantly increased in the corpus cavernosum of Streptozocin (STZ)-induced diabetic rats and injection of miR-92a antagomir into the corpus cavernosum of diabetic rats significantly increased eNOS/NO/cGMP signaling pathway activities, cavernous endothelial cell proliferation, endothelial cell-cell junction protein expression and decreased the levels of oxidative stress. These changes restored erectile function in STZ-induced diabetic rats. Moreover, in vitro study demonstrated that the miR-92a expression increased significantly in endothelial cells treated with high glucose, inhibiting AMPK/eNOS and AMPK/Nrf2/HO-1 signaling pathways in rat aortic endothelial cells via targeting Prkaa2, causing endothelial dysfunction and overactive oxidative stress, miR-92a inhibitor can improve the above parameters. CONCLUSIONS: miRNA-92a inhibitor could exert an inhibition role on oxidative stress and endothelial dysfunction to improve diabetic ED effectively.

Relaxin-2 Prevents Erectile Dysfunction by Cavernous Nerve, Endothelial and Histopathological Protection Effects in Rats with Bilateral Cavernous Nerve Injury.

PURPOSE: Cavernous nerve injury induced erectile dysfunction (ED) is a refractory complication with high incidence in person under radical prostatectomy. Studies have shown that relaxin-2 (RLX-2) plays a vital role of endothelial protection, vasodilation, anti-fibrosis and neuroprotection in a variety of diseases. However, whether penile cavernous erection can benefit from RLX-2 remains unknown. The purpose of the experiment was to explore the effects of RLX-2 on ED in the rat suffering with bilateral cavernous nerve injury (BCNI). MATERIALS AND METHODS: The rats were divided into three groups: Sham group was underwent sham operation, BCNI+RLX group or BCNI group was underwent bilateral cavernous nerve crush and then randomly treated with RLX-2 (0.4 mg/kg/d) or saline by continuous administration using a subcutaneously implanted micro pump for 4 weeks respectively. Then, erectile function was evaluated by electrical stimulation of cavernous nerves. Cavernous nerves and penile tissues and were collected for histological evaluation. RESULTS: Erectile function of rats with BCNI was partially improved after RLX-2 treatment. The BCNI group had lower expression of relaxin family peptide receptor (RXFP) 1, p-AKT/AKT, p-eNOS/eNOS ratios than sham operation rats, but RLX-2 could partially reversed these changes. Histologically, the BCNI+RLX group had a significant effect on preservation of neurofilament, neuronal glial antigen 2 of penile tissue and nNOS of cavernous nerves when compared with BCNI group. RLX-2 could inhibited the lever of BCNI induced corporal fibrosis and apoptosis via regulating TGFß1-Smad2/3-CTGF pathway and the expression of Bax/Bcl-2 ratio, caspase3. CONCLUSIONS: RLX-2 could improve erectile function of BCNI rats by protecting cavernous nerve and endothelial function and suppressing corporal fibrosis and apoptosis via RXFP1 and AKT/eNOS pathway. Our findings may provide a promising treatment for refractory BCNI induced ED.

Molecular pathogenesis and treatment of cavernous nerve injury-induced erectile dysfunction: A narrative review.

Introduction: Erectile dysfunction (ED) is a common complication after radical prostatectomy (RP), and it seriously affects the quality of life in patients and their partners. The primary trigger of postoperative ED is surgical injury to the cavernous nerves that control penile erection and run along the anterolateral aspect of the prostate. Despite the introduction and ongoing innovation of nerve-sparing techniques, a significant number of patients still suffer from moderate cavernous nerve injury (CNI), which is thought to be transient and reversible. Therefore, early postoperative penile rehabilitation therapy may salvage patients' erectile function by promoting cavernous nerve regeneration and preventing penile structural alterations. Aims: To present a comprehensive overview of the current molecular pathogenesis of CNI-induced ED, as well as novel therapeutic strategies and their potential mechanisms. Methods: A literature search was performed using PubMed. Search terms included erectile dysfunction, cavernous nerve injury, pathogenesis, pathway, and treatment. Results: The NOS/NO pathway, oxidative stress-related pathway, RhoA/ROCK pathway, transforming growth factor-ß (TGF-ß), sonic hedgehog (Shh), and hydrogen sulfide (H2S) are involved in the molecular pathogenesis of CNI-induced ED. Multiple neurotrophins, including brain-derived nerve growth factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and neurturin (NTN), were found to promote cavernous nerve regeneration. Emerging therapeutic approaches can be roughly summarized into four categories, namely small molecule and drug, stem cell-based therapy (SCT), micro-energy therapy and platelet-rich plasma (PRP) therapy. Conclusion: These pathways collectively lead to the irreversible damage to the penile structure after CNI. The combined early rehabilitation strategies of promoting upstream nerve regeneration and recovering abnormal molecular signals of downstream penis are presumed to save patients' erectile function after RP. In future studies, the cross-talk between these molecular pathways needs to be further clarified, and the questions of how denervation injury induces the molecular alterations in the penis also need to be addressed.

Comprehensive analysis to identify the RP11-478C19.2/ E2F7 axis as a novel biomarker for treatment decisions in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC), accounting for 70-80% of all renal cell carcinomas, is a common malignancy. Survival rates decrease significantly in patients with advanced and metastatic ccRCC. Furthermore, ccRCC is less responsive to radiation and chemotherapy than other cancers. Therefore, targeted therapy and immunotherapy are particularly important for ccRCC management. A growing body of literature recognizes that competitive endogenous RNA (ceRNA) regulatory networks play a crucial role in various cancers. However, the biological functions of the ceRNA network in ccRCC require further investigation. In this study, we built the ceRNA network for ccRCC using the "GDCRNATools" package. After survival analysis, the RP11-478C19.2/hsa-miR-181b-5p, hsa-miR-181a-5p, and hsa-miR-181c-5p/E2F7 axes were obtained for further analysis. Unsupervised clustering was conducted basing on this ceRNA network. The results indicated that the prognosis and immune infiltration levels differed between the two clusters. Furthermore, we conducted correlation analysis, immune infiltration analysis, tumor mutation burden analysis, GSEA analysis, drug sensitivity analysis and pan-cancer analysis of E2F7 to explore its potential role in oncogenesis. Experiments in vitro were performed to confirm the pro-oncogenic impact of E2F7. The results suggest that the RP11-478C19.2/E2F7 axis might be a biomarker for the inclusion of cabozantinib, pazopanib, sunitinib, and immunotherapy in the therapeutic regimen. In summary, we found that the ceRNA-based RP11-478C19.2/E2F7 axis is involved in ccRCC and that it could be a novel biomarker for treatment decisions and a possible therapeutic target to increase the success of targeted therapy and immunotherapy in ccRCC.

Acetyl-L-carnitine improves erectile function in bilateral cavernous nerve injury rats via promoting cavernous nerve regeneration.

BACKGROUND: Neurogenic erectile dysfunction (NED) caused by cavernous nerve (CN) injury is a typical complication after pelvic surgery, which lacks efficient treatments. Acetyl-L-carnitine (ALCAR) has been proven to promote nerve repair. OBJECTIVES: To investigate the effect and potential mechanism of ALCAR in the treatment of NED. MATERIALS AND METHODS: Thirty-two rats were randomly divided into bilateral CN injury (BCNI) group, BCNI + lower-dose ALCAR (50 mg/kg/day) group, BCNI + higher-dose (100 mg/kg/day) group, and sham-operated group. Erectile function was assessed 14 days after daily intraperitoneal injection of ALCAR or placebo. The penile tissues were gathered for subsequent histological and molecular biological analysis. Rat Schwann cell (SC) line S16 was used to verify the mechanism of ALCAR in vitro. RESULTS: We found that the erectile function of the rats in the BCNI group was severely impaired, which was improved considerably in both BCNI+ALCAR-LD and BCNI+ALCAR-HD groups. Also, we observed decreased smooth muscle and increased collagen content in the corpus cavernosum in the BCNI group. The expressions of fibrosis markers transforming growth factor-beta (TGF-ß), connective tissue growth factor (CTGF), and Smad 2/3 were significantly up-regulated in the BCNI group. The above changes were alleviated after the administration of lower and higher-dose ALCAR. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate pathway (cGMP) was promoted and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was inhibited in the corpus cavernosum of BCNI rats after ALCAR treatment, accompanied by increased neuronal nitric oxide synthase (nNOS) and down-regulated tyrosine hydroxylase (TH). In vitro, ALCAR promoted the migration and proliferation of SC and increased the expression of 22-kD peripheral myelin protein and nerve growth factor (NGF). Further, rats treated with ALCAR had high expression of ATF3 and S100 in the distal nerve tissues of the CN extrusion site. DISCUSSION AND CONCLUSION: ALCAR could promote nerve repair and regeneration, inhibit penile fibrosis, and improve penile erection by promoting the proliferation and migration of SC and the secretion of NGF. Our study confirms that ALCAR may be a potential treatment strategy for NED.

Evaluation of mid- and long-term impact of COVID-19 on male fertility through evaluating semen parameters.

Background: The coronavirus disease 2019 (COVID-19) has spread worldwide with alarming levels of spread and severity. The distribution of angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) from bioinformatics evidence, the autopsy report for COVID-19 and the published study on sperm quality indicated COVID-19 could have a negative impact on male fertility. However, whether the negative impact of COVID-19 on male fertility is persistent remains unknown, which requires long-term follow-up investigation. Methods: Semen samples were collected from 36 male COVID-19 patients with a median recovery time of 177.5 days and 45 control subjects. Then, analysis of sperm quality and alterations of total sperm number with recovery time were performed. Results: There was no significant difference in semen parameters between male recovered patients and control subjects. And the comparisons of semen parameters between first follow-up and second follow-up revealed no significant difference. In addition, we explored the alterations of sperm count with recovery time. It showed that the group with recovery time of ≥120 and <150 days had a significantly lower total sperm number than controls while the other two groups with recovery time of ≥150 days displayed no significance with controls, and total sperm number showed a significant decline after a recovery time of 90 days and an improving trend after a recovery time of about 150 days. Conclusions: The sperm quality of COVID-19 recovered patients improved after a recovery time of nearly half a year, while the total sperm number showed an improvement after a recovery time of about 150 days. COVID-19 patients should pay close attention to the quality of semen, and might be considered to be given medical interventions if necessary within about two months after recovery, in order to improve the fertility of male patients as soon as possible.

Berberine ameliorates erectile dysfunction in rats with streptozotocin-induced diabetes mellitus through the attenuation of apoptosis by inhibiting the SPHK1/S1P/S1PR2 and MAPK pathways.

BACKGROUND: The population with diabetes mellitus-induced erectile dysfunction is increasing rapidly, but current drugs are not effective in treating erectile dysfunction. Studies of the traditional Chinese medicine extract berberine on diabetes and its complications provide us with new ideas. OBJECTIVES: To evaluate the therapeutic effect and potential mechanism of berberine on the erectile function of diabetic rats. MATERIALS AND METHODS: Fifty male Sprague-Dawley rats were randomly grouped, and 42 rats were injected intraperitoneally with streptozotocin to establish a diabetes model. Erectile dysfunction rats were screened out through the apomorphine test and randomly divided into the diabetes mellitus and berberine groups, and these animals were administered berberine (200 mg/kg/day) and normal saline by gavage for 4 weeks. Primary corpus cavernous smooth muscle cells from healthy rats were cultured and treated with berberine. RESULTS: Fasting blood glucose in the diabetes mellitus group was significantly increased, while berberine showed no significant effect on glucose. Erectile function was obviously impaired in the diabetes mellitus group, and berberine administration partially rescued this impairment. The expression of sphingosine kinase 1, S1PR2, and sphingosine-1-phosphate in the diabetes mellitus group was increased. Berberine partially inhibited the expression of sphingosine kinase 1 and S1PR2, but the decrease in sphingosine-1-phosphate was not significant. Moreover, mitogen-activated protein kinase pathway factor expression was upregulated and eNOS activity was decreased in the diabetes mellitus group. Berberine treatment could partially reverse these alterations. Severe fibrosis and apoptosis were detected in diabetic rats, accompanied by higher expression of TGFß1, collagen I/IV, Bax/Bcl-2, and caspase 3 than in the other groups. However, supplementation with berberine inhibited the expression of these proteins and attenuated fibrosis and apoptosis. CONCLUSIONS: Berberine ameliorated erectile dysfunction in rats with diabetes mellitus, possibly by improving endothelial function and inhibiting apoptosis and fibrosis by suppressing the sphingosine kinase 1/sphingosine-1-phosphate/S1PR2 and mitogen-activated protein kinase pathways.

A Mitochondrial Dysfunction and Oxidative Stress Pathway-Based Prognostic Signature for Clear Cell Renal Cell Carcinoma.

Mitochondria not only are the main source of ATP synthesis but also regulate cellular redox balance and calcium homeostasis. Its dysfunction can lead to a variety of diseases and promote cancer and metastasis. In this study, we aimed to explore the molecular characteristics and prognostic significance of mitochondrial genes (MTGs) related to oxidative stress in clear cell renal cell carcinoma (ccRCC). A total of 75 differentially expressed MTGs were analyzed from The Cancer Genome Atlas (TCGA) database, including 46 upregulated and 29 downregulated MTGs. Further analysis screened 6 prognostic-related MTGs (ACAD11, ACADSB, BID, PYCR1, SLC25A27, and STAR) and was used to develop a signature. Kaplan-Meier survival and receiver operating characteristic (ROC) curve analyses showed that the signature could accurately distinguish patients with poor prognosis and had good individual risk stratification and prognostic potential. Stratified analysis based on different clinical variables indicated that the signature could be used to evaluate tumor progression in ccRCC. Moreover, we found that there were significant differences in immune cell infiltration between the low- and high-risk groups based on the signature and that ccRCC patients in the low-risk group responded better to immunotherapy than those in the high-risk group (46.59% vs 35.34%, P = 0.008). We also found that the expression levels of these prognostic MTGs were significantly associated with drug sensitivity in multiple ccRCC cell lines. Our study for the first time elucidates the biological function and prognostic significance of mitochondrial molecules associated with oxidative stress and provides a new protocol for evaluating treatment strategies targeting mitochondria in ccRCC patients.

Exploration of Redox-Related Molecular Patterns and the Redox Score for Prostate Cancer.

Redox homeostasis is the key to cell survival, and its imbalance can promote the occurrence and progression of tumors. However, it remains unclear whether these redox-related genes (RRGs) have potential roles in the tumor microenvironment, immunotherapy, and drug sensitivity. Here, we performed a systematic and comprehensive analysis of 489 prostate cancer (PC) samples from The Cancer Genome Atlas database and 214 PC samples from 8 datasets in the Gene Expression Omnibus database to determine redox modification patterns and the redox scoring system for PC. We identified two modification patterns (Redox_A and Redox_B) in PC using unsupervised consensus clustering based on 1410 differential expression RRGs. We then compared the prognostic value, tumor microenvironment characteristics, immune cell infiltration, and molecular characteristics of the two patterns. The Redox_A pattern was significantly enriched in the carcinogenic activation signaling pathways and had a poor prognosis, while the Redox_B pattern was mainly enriched in a variety of metabolic and redox pathways and had a good prognosis. Next, redox-related characteristic genes were extracted from these two patterns, and a scoring system (Redox_score) was constructed to evaluate PC patients. Further analysis indicated that lower Redox_score patients had a better prognosis, while higher Redox_score patients had a higher tumor mutation burden, driver gene mutation rate, and immune checkpoint inhibitor gene expression. We also found that higher Redox_score patients were more responsive to anti-PD-1 immunotherapy. Moreover, Redox_score was determined to be significantly correlated with anticancer drug sensitivity and resistance. Our study provides a comprehensive analysis of redox modifications in PC and reveals new patterns of PC based on RRGs, which will provide insights into the complex mechanisms of PC and develop more effective individualized therapeutic strategies.

A Mid-to-Long Term Comprehensive Evaluation of Psychological Distress and Erectile Function in COVID-19 Recovered Patients.

BACKGROUND: The psychological and sexual health of different populations are negatively affected during the coronavirus disease 2019 (COVID-19) pandemic. However, little is known about psychological distress and erectile function of male recovered patients with COVID-19 in the long term. AIM: We aimed to evaluate psychological distress and erectile function of male recovered patients with COVID-19 in the mid-to-long terms. METHODS: We recruited 67 eligible male recovered patients with COVID-19 and followed them up twice within approximately 6 months of recovery time. The psychological distress and erectile function were assessed by validated Chinese version of paper questionnaires. OUTCOMES: The primary outcomes were Symptom Checklist 90 questionnaire for psychological distress and International Index of Erectile Function-5 for erectile function. RESULTS: In the first visit, COVID-19 patients with a median recovery time of 80 days mainly presented the following positive symptoms: Obsessive-Compulsive, additional items (ADD), Hostility, Interpersonal Sensitivity, Depression, and Somatization; while the dimension scores in Somatization, Anxiety, ADD, and Phobia were higher than Chinese male norms. Besides, the prevalence of erectile dysfunction (ED) in the first-visit patients was significantly higher than Chinese controls. In the second visit, the primary psychological symptoms of COVID-19 patients with a median recovery time of 174 days were Obsessive-Compulsive, ADD, Interpersonal Sensitivity, and Hostility, while all dimensions scores of Symptom Checklist 90 were lower than Chinese male norms. Moreover, second-visit patients had no significant difference with Chinese controls in ED prevalence. In addition, it suggested that GSI was the independent risk factor for ED in the regression analysis for the first-visit patients. CLINICAL IMPLICATIONS: The study showed the changes of psychological symptoms and erectile function in COVID-19 recovered patients, and provided reference on whether psychological and sexual supports are needed after a period of recovery. STRENGTHS AND LIMITATIONS: To our knowledge, it is the first study to comprehensively evaluate the psychological distress and erectile function of COVID-19 recovered patients in the mid-to-long terms. The main limitations were the low number of analyzed participants, and the psychological distress and erectile function of healthy Chinese men over the same period were not evaluated, and the psychological and sexual related data of participants prior to COVID-19 were not available. Additionally, there was a selection bias in comparing COVID-19 patients with healthy controls. CONCLUSION: With less impact of COVID-19 event, the impaired erectile function and psychological distress improved in COVID-19 recovered patients with a recovery time of nearly half a year. Hu B, Ruan Y, Liu K, et al. A Mid-to-Long Term Comprehensive Evaluation of Psychological Distress and Erectile Function in COVID-19 Recovered Patients. J Sex Med 2021;18:1863-1871.

Identification of the Functions and Prognostic Values of RNA Binding Proteins in Bladder Cancer.

Post-transcriptional regulation plays a leading role in gene regulation and RNA binding proteins (RBPs) are the most important posttranscriptional regulatory protein. RBPs had been found to be abnormally expressed in a variety of tumors and is closely related to its occurrence and progression. However, the exact mechanism of RBPs in bladder cancer (BC) is unknown. We downloaded transcriptomic data of BC from the Cancer Genome Atlas (TCGA) database and used bioinformatics techniques for subsequent analysis. A total of 116 differentially expressed RBPs were selected, among which 61 were up-regulated and 55 were down-regulated. We then identified 12 prognostic RBPs including CTIF, CTU1, DARS2, ENOX1, IGF2BP2, LIN28A, MTG1, NOVA1, PPARGC1B, RBMS3, TDRD1, and ZNF106, and constructed a prognostic risk score model. Based on this model we found that patients in the high-risk group had poorer overall survival (P < 0.001), and the area under the receiver operator characteristic curve for this model was 0.677 for 1 year, 0.697 for 3 years, and 0.709 for 5 years. Next, we drew a nomogram based on the risk score and other clinical variables, which showed better predictive performance. Our findings contribute to a better understanding of the pathogenesis, progression and metastasis of BC. The model of these 12 genes has good predictive value and may have good prospects for improving clinical treatment regimens and patient prognosis.

Development of an Individualized Ubiquitin Prognostic Signature for Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a common tumor type in genitourinary system and has a poor prognosis. Ubiquitin dependent modification systems have been reported in a variety of malignancies and have influenced tumor genesis and progression. However, the molecular characteristics and prognostic value of ubiquitin in ccRCC have not been systematically reported. In our study, 204 differentially expressed ubiquitin related genes (URGs) were identified from The Cancer Genome Atlas (TCGA) cohort, including 141 up-regulated and 63 down-regulated URGs. A total of seven prognostic related URGs (CDCA3, CHFR, CORO6, RNF175, TRIM72, VAV3, and WDR72) were identified by Cox regression analysis of differential URGs and used to construct a prognostic signature. Kaplan-Meier analysis confirmed that high-risk patients had a worse prognosis (P = 1.11e-16), and the predicted area under the receiver operating characteristic (ROC) curves were 0.735 at 1 year, 0.702 at 3 years, and 0.744 at 5 years, showing good prediction accuracy. Stratified analysis showed that the URGs-based prognostic signature could be used to evaluate tumor progression in ccRCC. Further analysis confirmed that the signature is an independent prognostic factor related to the prognosis of ccRCC patients, which may help to reveal the molecular mechanism of ccRCC and provide potential diagnostic and prognostic markers for ccRCC.

Integrated Analysis to Identify a Redox-Related Prognostic Signature for Clear Cell Renal Cell Carcinoma.

The imbalance of the redox system has been shown to be closely related to the occurrence and progression of many cancers. However, the biological function and clinical significance of redox-related genes (RRGs) in clear cell renal cell carcinoma (ccRCC) are unclear. In our current study, we downloaded transcriptome data from The Cancer Genome Atlas (TCGA) database of ccRCC patients and identified the differential expression of RRGs in tumor and normal kidney tissues. Then, we identified a total of 344 differentially expressed RRGs, including 234 upregulated and 110 downregulated RRGs. Fourteen prognosis-related RRGs (ADAM8, CGN, EIF4EBP1, FOXM1, G6PC, HAMP, HTR2C, ITIH4, LTB4R, MMP3, PLG, PRKCG, SAA1, and VWF) were selected out, and a prognosis-related signature was constructed based on these RRGs. Survival analysis showed that overall survival was lower in the high-risk group than in the low-risk group. The area under the receiver operating characteristic curve of the risk score signature was 0.728 at three years and 0.759 at five years in the TCGA cohort and 0.804 at three years and 0.829 at five years in the E-MTAB-1980 cohort, showing good predictive performance. In addition, we explored the regulatory relationships of these RRGs with upstream miRNA, their biological functions and molecular mechanisms, and their relationship with immune cell infiltration. We also established a nomogram based on these prognostic RRGs and performed internal and external validation in the TCGA and E-MTAB-1980 cohorts, respectively, showing an accurate prediction of ccRCC prognosis. Moreover, a stratified analysis showed a significant correlation between the prognostic signature and ccRCC progression.

Optimizing Management to Reduce the Mortality of COVID-19: Experience From a Designated Hospital for Severely and Critically Ill Patients in China.

Background: The coronavirus disease 2019 (COVID-19) has swept through the world at a tremendous speed, and there is still limited data available on the treatment for COVID-19. The mortality of severely and critically ill COVID-19 patients in the Optical Valley Branch of Tongji Hospital was low. We aimed to analyze the available treatment strategies to reduce mortality. Methods: In this retrospective, single-center study, we included 1,106 COVID-19 patients admitted to the Optical Valley Branch of Tongji Hospital from February 9 to March 9, 2020. Cases were analyzed for demographic and clinical features, laboratory data, and treatment methods. Outcomes were followed up until March 29, 2020. Results: Inflammation-related indices (hs-CRP, ESR, serum ferritin, and procalcitonin) were significantly higher in severe and critically ill patients than those in moderate patients. The levels of cytokines, including IL-6, IL2R, IL-8, and TNF-α, were also higher in the critical patients. Incidence of acute respiratory distress syndrome (ARDS) in the severely and critically ill group was 23.0% (99/431). Sixty-one patients underwent invasive mechanical ventilation. The correlation between SpO2/FiO2 and PaO2/FiO2 was confirmed, and the cut-off value of SpO2/FiO2 related to survival was 134.43. The mortality of patients with low SpO2/FiO2 (<134.43) at intubation was higher than that of patients with high SpO2/FiO2 (>134.43) (72.7 vs. 33.3%). Among critical patients, the application rates of glucocorticoid therapy, continuous renal replacement therapy (CRRT), and anticoagulation treatment reached 55.2% (238/431), 7.2% (31/431), and 37.1% (160/431), respectively. Among the intubated patients, the application rates of glucocorticoid therapy, CRRT, and anticoagulation treatment were respectively 77.0% (47/61), 54.1% (33/61), and 98.4% (60/61). Conclusion: No vaccines or specific antiviral drugs for COVID-19 have been shown to be sufficiently safe and effective to date. Comprehensive treatment including ventilatory support, multiple organ function preservation, glucocorticoid use, renal replacement therapy, anticoagulation, and restrictive fluid management was the main treatment strategy. Early recognition and intervention, multidisciplinary collaboration, multi-organ function support, and personalized treatment might be the key for reducing mortality.

Optimize the management of urological tube-related emergencies during the coronavirus disease 2019 (COVID-19) pandemic.

BACKGROUND: To introduce and determine the value of optimized strategies for the management of urological tube-related emergencies with increased incidence, complexity and operational risk during the global spread of coronavirus disease 2019 (COVID-19). METHODS: All emergent urological patients at Tongji Hospital, Wuhan, during the period of January 23 (the beginning of lockdown in Wuhan) to March 23, 2020, and the corresponding period in 2019 were recruited to form this study's COVID-19 group and control group, respectively. Tongji Hospital has the most concentrated and strongest Chinese medical teams to treat the largest number of severe COVID-19 patients. Patients in the control group were routinely treated, while patients in the COVID-19 group were managed following the optimized principles and strategies. The case incidence for each type of tube-related emergency was recorded. Baseline characteristics and management outcomes (surgery time, secondary complex operation rate, readmission rate, COVID-19 infection rate) were analyzed and compared across the control and COVID-19 periods. RESULTS: The total emergent urological patients during the COVID-19 period was 42, whereas during the control period, it was 124. The incidence of tube-related emergencies increased from 53% to 88% (P<0.001) during the COVID-19 period. In particular, the incidence of nephrostomy tube-related (31% vs. 15%, P=0.027) and single-J stent-related problems (19% vs. 6%, P=0.009) increased significantly. The mean surgery times across the two periods were comparable. The number of secondary complex operations increased from 12 (18%) to 14 (38%) (P=0.028) during the COVID 19-period. The number of 2-week postoperative readmission decreased from 10 (15%) to 1 (3%) (P=0.049). No participants contracted during the COVID-19 period. CONCLUSIONS: Urological tube-related emergencies have been found to have a higher incidence and require more complicated and dangerous operations during the COVID-19 pandemic. However, the optimized management strategies introduced in this study are efficient, and safe for both urologists and patients.

No detection of SARS-CoV-2 from urine, expressed prostatic secretions, and semen in 74 recovered COVID-19 male patients: A perspective and urogenital evaluation.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has been spreading all over the world since December 2019. However, medical information regarding the urogenital involvement in recovered COVID-19 patients is limited or unknown. OBJECTIVES: To comprehensively evaluate urogenital involvement in recovered COVID-19 patients. MATERIALS AND METHODS: Men aged between 20 years and 50 years who were diagnosed with SARS-CoV-2 infection and recovered when the study was conducted were enrolled in our study. Demographic and clinical characteristics, and history of hospitalization were collected and analyzed. Urine, expressed prostatic secretions (EPSs), and semen samples were collected for SARS-CoV-2 RNA detection. Semen quality and hormonal profiles were analyzed. RESULTS: Among 74 male recovered COVID-19 patients, 11 (14.9%) were asymptomatic, classified into mild type, and 31 (41.9%) were classified into moderate type. The remaining patients (32/74, 43.2%) had severe pneumonia. No critically ill recovered COVID-19 patient was recruited in our cohort. The median interval between last positive pharyngeal swab RT-PCR test and semen samples collection was 80 days (IQR, 64-93). The median age was 31 years (IQR, 27-36; range, 21-49), and the median body mass index (BMI) was 24.40 (IQR, 22.55-27.30). Forty-five (61.6%) men were married, and 28 (38.4%) were unmarried. Fifty-three (72.6%) patients denied cigarette smoking, 18 (24.7%) were active smokers, and 2 of them were past smokers. The majority of our participants (53/74, 72.6%) did not consume alcohol. Fever occurred in most of the patients (75.3%), and 63 of them had abnormal chest CT images. Only one patient complained of scrotal discomfort during the course of COVID-19, which was ruled out orchitis by MRI (data not shown). A total of 205 samples were collected for SARS-CoV-2 detection (74 urine samples, 70 semen samples, and 61 EPS samples). However, viral nucleic acid was not detected in body fluids from the urogenital system. In terms of hormonal profiles, the levels of FSH, LH, testosterone, and estradiol were 5.20 [4.23] mIU/mL, 3.95 [1.63] mIU/mL, 3.65 [1.19] ng/mL, and 39.48 [12.51] pg/mL, respectively. And these values were within the normal limits. The overall semen quality of recovered COVID-19 patients was above the lower reference limit released by the WHO. While compared with healthy control, sperm concentration, total sperm count, and total motility were significantly declined. In addition, different clinical types of COVID-19 have no significant difference in semen parameters, but total sperm count showed a descending trend. Interestingly, subjects with a longer recovery time showed worse data for sperm quality. Small sample size and lacking semen parameters before the infection are the major limitations of our study. DISCUSSION AND CONCLUSIONS: To the best of our knowledge, it is the largest cohort study with longest follow-up for urogenital evaluation comprehensively so far. Direct urogenital involvement was not found in the recovered COVID-19 male patients. SARS-CoV-2 RNA was undetectable in the urogenital secretions, and semen quality declined slightly, while hormonal profiles remained normal. Moreover, patients with a long time (≥90 days) since recovery had lower total sperm count. Great attention and further study should be conducted and follow-up on the reproductive function in the following months.

Regenerating Urethral Striated Muscle by CRISPRi/dCas9-KRAB-Mediated Myostatin Silencing for Obesity-Associated Stress Urinary Incontinence.

Overweight females are prone to obesity-associated stress urinary incontinence (OA-SUI), and there are no definitive medical therapies for this common urologic condition. This study was designed to test the hypothesis that regenerative therapy to restore urethral striated muscle (stM) and pelvic floor muscles might represent a valuable therapeutic approach. For the in vitro experiment, single-guide RNAs targeting myostatin (MSTN) were used for CRISPRi/dCas9-Kruppel associated box (KRAB)-mediated gene silencing. For the in vivo experiment, a total of 14 female lean ZUC-Leprfa 186 and 14 fatty ZUC-Leprfa 185 rats were used as control and CRISPRi-MSTN treated groups, respectively. The results indicated that lentivirus-mediated expression of MSTN CRISPRi/dCas9-KRAB caused sustained downregulation of MSTN in rat L6 myoblast cells and significantly enhanced myogenesis in vitro. In vivo, the urethral sphincter injection of lentiviral-MSTN sgRNA and lentiviral-dCas9-KRAB significantly increased the leak point pressure, the thickness of the stM layer, the ratio of stM to smooth muscle, and the number of neuromuscular junctions. Downregulation of MSTN with CRISPRi/dCas9-KRAB-mediated gene silencing significantly enhanced myogenesis in vitro and in vivo. It also improved urethral continence in the OA-SUI rat model.

An eleven metabolic gene signature-based prognostic model for clear cell renal cell carcinoma.

In this study, we performed bioinformatics and statistical analyses to investigate the prognostic significance of metabolic genes in clear cell renal cell carcinoma (ccRCC) using the transcriptome data of 539 ccRCC and 72 normal renal tissues from TCGA database. We identified 79 upregulated and 45 downregulated (n=124) metabolic genes in ccRCC tissues. Eleven prognostic metabolic genes (NOS1, ALAD, ALDH3B2, ACADM, ITPKA, IMPDH1, SCD5, FADS2, ACHE, CA4, and HK3) were identified by further analysis. We then constructed an 11-metabolic gene signature-based prognostic risk score model and classified ccRCC patients into high- and low-risk groups. Overall survival (OS) among the high-risk ccRCC patients was significantly shorter than among the low-risk ccRCC patients. Receiver operating characteristic (ROC) curve analysis of the prognostic risk score model showed that the areas under the ROC curve for the 1-, 3-, and 5-year OS were 0.810, 0.738, and 0.771, respectively. Thus, our prognostic model showed favorable predictive power in the TCGA and E-MTAB-1980 ccRCC patient cohorts. We also established a nomogram based on these eleven metabolic genes and validated internally in the TCGA cohort, showing an accurate prediction for prognosis in ccRCC.