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Asthenozoospermia (ASZ) is a condition characterized by reduced forward motility of spermatozoa affecting approximately 19% of infertile men. A kinase anchor protein 4 (AKAP4) is an X-linked testis-specific gene and plays a major role in sperm motility and flagella formation. However, few studies have reported its association with ASZ. Here, we sequenced for exonic mutations of human AKAP4 gene by high-fidelity PCR/Sanger sequencing in peripheral blood samples from 150 ASZ patients and 150 fertile men. We reported the identification of three novel hemizygous mutations unique to four ASZ patients, including one patient carrying missense mutation c.454T>C (p.S152P), two patient carrying synonymous mutation c.1173T>C (p.H391H), and one patient carrying synonymous mutation c.2007 A>G (p.R669R). The p.S152P mutation was located in a precursor pro-polypeptide domain of AKAP4 protein, which was predicted to be damaging by SIFT and PolyPhen-2 and could cause the protein accumulation in the cytoplasm of COS-7 cells. The mature protein of AKAP4 was absent in spermatozoa of ASZ patient harboring AKAP4 p.S152P mutation. Further in vitro cellular assays showed that reactive oxygen species (ROS), malondialdehyde (MDA), myeloperoxidase (MPO) levels, and apoptotic cells were increased in GC2-spd cells by AKAP4 p.S152P mutant protein, whereas superoxide dismutase (SOD) level was decreased. AKAP4 p.H391H and p.R669R mutant proteins were coimmunoprecipitated with ribonuclease T2 (RNASET2) protein in GC2-spd cells, whereas no interaction between the AKAP4 p.S152P mutant protein and RNASET2 protein was observed. In addition, AKAP4 p.S152P mutant protein could decrease the activity of PKA/PI3K signaling. Overall, our study identifies a novel AKAP4 p.S152P mutation is associated with ASZ probably through affecting oxidative stress and cell apoptosis by regulating the interaction with RNASET2 and the activity of the PKA/PI3K signaling pathway.

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.

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.

Background The role of adrenal venous sampling (AVS) has been challenged by some recent evidence. This study aimed to compare the role of AVS and computed tomography (CT) in the management of primary aldosteronism. Methods Patients who underwent unilateral adrenalectomy for primary aldosteronism at a single center between January 2015 and December 2018 were included, and postoperative outcomes of the patients who underwent surgery based on CT (n = 195) or AVS (n = 40) were compared. The data of all the patients who underwent AVS successfully (n = 75) during this period were also collected and analyzed. Results There were no significant differences between the CT-guided and AVS-guided adrenalectomies in most of the postoperative outcomes, and the proportion of patients achieving cure of hypokalemia (CT vs. AVS, 98.3 vs. 96.4%) and alleviation of hypertension (89.2 vs. 92.9%) were similar between the two groups. However, since the baseline characteristics of the two groups were not identical, the AVS-guided group showed greater improvement in postoperative hypokalemia and greater reduction in the number of antihypertensive medications than the CT-guided group. In addition, for the 75 patients who underwent AVS successfully, the concordance rate between CT abnormalities and AVS lateralization was 60.0% in total, and 22.7% patients changed treatment plans according to the AVS results. Conclusion Although the clinical outcomes were not significantly different between the CT-guided and AVS-guided group, the AVS-guided group seemed to benefit more from the surgery, and a considerable number of patients with primary aldosteronism would have received inappropriate treatment if they did not undergo AVS.

Primary thyroid lymphoma (PTL) is an exceptionally rare and highly aggressive potentially curable malignant disease. We report three typical cases of PTL referred to our hospital. All three cases had long history of Hashimoto's thyroiditis, and presented with progressively enlarging neck mass. The first two cases were confirmed by surgical biopsy to be diffuse large B cell lymphoma, and received radiotherapy combined with chemotherapy, or received only chemotherapy. The third case was confirmed by core needle biopsy to be mucosa-associated lymphoid tissue lymphoma, and received radiotherapy. In summary, confirmation of PTL diagnosis is essential for further clinical decisions. Core biopsy should be one of the most important methods to make the diagnosis of PTL, while the use of fine needle aspiration cytology alone is still limited in diagnosing PTL.

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.

Iatrogenic injury to the vas deferens is an indication for vasovasostomy (VV). Various surgical approaches, including pure microsurgical VV (MVV), pelviscrotal laparoscopic-assisted VV (LAVV), and intra-abdominal robot-assisted VV (RAVV), have been reported to restore vasal patency. MVV is often faced a formidable challenge to provide tension-free VV due to an inadequate vas deferens length. Alternatively, pelviscrotal LAVV is much more effective for the identification and retrieval of the pelvic vas deferens prior to performing MVV. However, vasal laparoscopic mobilization could still be limited by insufficient vasal length for extracorporeal transfer in some cases. The addition of robotic assistance, on the other hand, allows the performance of "in-situ" vasal anastomoses and offers unique features compared with pure MVV/LAVV. However, few such approaches have been described in the literature. This study presents the initial results and validation of robot-assisted VV in an Asian population who had undergone triple herniorrhaphy. Briefly, Intra-operative findings demonstrated a large defect of the vas deferens, and a two-layer bilateral tension-free RAVV was performed to pursue the possibility of naturally achieved pregnancy. With our promising results, intra-abdominal RAVV may be described as a practical approach for cases with iatrogenic large defects of the vas deferens within the inguinal canal.

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.

AIMS Low-intensity extracorporeal shock wave therapy (Li-ESWT) has been applied in urolithiasis and some chronic diseases. We performed a systematic review and meta-analysis to assess the efficacy of Li-ESWT for the treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS A comprehensive search of MEDLINE, Web of Science, EMBASE, and the Cochrane Library to January 6, 2019 was performed for randomized controlled trials (RCTs) reporting on patients with CP/CPPS treated with Li-ESWT compared with the sham group. Outcomes were evaluated based on the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI). The quality assessment of included studies was performed by the Cochrane System. RESULTS Six publications involving five RCTs with 280 patients were assessed in this review. NIH-CPSI total score, pain domain and quality of life (QOL) were significantly better in the Li-ESWT group than those in the control group at the endpoint (P

Traumatic penis amputation is a urological emergency. Although repair techniques have been well described in literature, failure of replantation and its causes are poorly understood and reported. The aim of this study is to evaluate the treatment and prognosis of microsurgical replantation of penile amputation with a relative long-term ischemia, and review related literatures to summarize relevant clinical experiences. We report two cases of penile amputation and microsurgical replantation performed in our hospital in August 2016. In the first case, the patient was injured by sharp scissors due to family conflict, while in the second case, it was a mechanical injury. For both cases, microsurgical approaches were adopted. After the microsurgical replantation, both the patients recovered well and showed normal urination, erectile function, return of sensations and satisfactory cosmetic appearance. With the development of microsurgical techniques, the successful re-anastomosis of blood vessel and nerve can increase the survival and functional recovery of the penis even in cases exceeding 10 hours of ischemia. This provides greater possibility of graft survival with minimum complication.

Phosphorylation of serine 81 (pS81) in the N-terminal transactivation domain of the androgen receptor (AR) has been linked to its transcriptional activation in prostate cancer (PCa) cell lines, but in vivo studies have been limited. Moreover, the role of pS81 in the reactivation of AR when tumors relapse after androgen deprivation therapy (castration-resistant prostate cancer, CRPC) has not been determined. In this study we validate a pS81 antibody for immunohistochemistry (IHC) and show it yields strong nuclear staining in primary PCa clinical samples and in the VCaP PCa xenograft model. Moreover, this staining was decreased at 7 days post-castration in VCaP xenografts, coinciding with markedly decreased AR transcriptional activity. Staining with the pS81 antibody then was restored when the VCaP xenografts relapsed, which was associated with restoration of AR transcriptional activity. Significantly, analysis of CRPC clinical samples, including tumors that had progressed during treatment with abiraterone, showed strong nuclear staining with the pS81 antibody. Together these findings indicate that AR reactivation in CRPC is associated with S81 phosphorylation, and suggest that IHC for pS81 may be useful as a biomarker of AR activity in CRPC.

Background: An association between lower urinary tract symptoms (LUTS) and risk of sexual dysfunction in male remains controversial in recent decades.Materials and Methods: PubMed and Web of Science were searched up to October 28, 2020, for articles reporting the prevalence of sexual dysfunction in men with LUTS. The main outcomes were results from sexual dysfunction assessments. Pooled odds ratio (OR) and weighted mean difference (WMD) with 95% confidence interval (CI) were calculated. The quality assessment of the included studies was performed by using The Newcastle-Ottawa Scale (NOS) or JBI Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI).Results: A total of 24 full-manuscript papers met the inclusion criteria. The pooled OR for 21 studies suggested that patients with severer LUTS had a higher risk of sexual dysfunction (OR = 3.31, 95% CI: 2.43 to 4.49, p < 0.001, I2 = 90%). A significant decrease in scores of assessment tools for sexual dysfunction was observed in the patients with higher severity of LUTS compared with those patients with lower severity (WMD = −5.49, 95%CI: −7.25 to −3.27, P < 0.001, I2 = 96%). Similar outcomes were also found in subgroup analyses. In a detailed analysis of specific sexual function domains, the severity of LUTS was associated with erectile dysfunction, intercourse satisfaction, and overall satisfaction, except for sexual desire.Conclusion: The study demonstrates an association between exposure of lower urinary tract symptoms and risk of sexual dysfunction in male. Assessment of sexual function is necessary for patients with lower urinary tract symptoms.Systematic Review Registration:http://www.crd.york.ac.uk/prospero, identifier: CRD42020208747.

Background Janus kinase 2 (JAK2) is activated in diabetic mellitus (DM) conditions and may enhance oxidative stress, apoptosis and fibrosis in many tissues. Whether JAK2 activation is involved in the occurrence of diabetic erectile dysfunction (ED) is unknown. Objectives We performed this study to investigate the effect of JAK2 deficiency on diabetic ED. Materials and methods Conditional JAK2 gene knockout mice (Cre+/+ -JAK2fl/fl ) were used, in which JAK2 gene knockout could be induced by tamoxifen. Mice fell into four groups: control, JAK2 knockout (JAK2-/- ), DM, and DM with JAK2-/- . DM was induced by intraperitoneal injection of streptozotocin. Two months later, JAK2 gene knockout was induced with tamoxifen in Cre+/+ -JAK2fl/fl mice. After another 2 months, erectile function was measured by electrical stimulation of the cavernous nerve, and penile tissues were harvested. Ratio of maximal intracavernosal pressure (MIP) to mean arterial blood pressure (MAP), expression and phosphorylation of JAK2, oxidative stress level, NO/Cyclic Guanosine Monophosphate (cGMP) pathway, apoptosis, fibrosis, and transforming growth factor beta 1 (TGF-β1)/Smad/Collagen IV pathway in corpus cavernosum, were measured. Results JAK2 expression was remarkably decreased after induction with tamoxifen. JAK2 was activated in penile tissues of diabetic mice, and JAK2 deficiency could improve the impaired erectile function caused by DM. However, in mice without DM, JAK2 deficiency had no apparent influence on erectile function. Levels of oxidative stress, apoptosis, fibrosis, and TGF-β1/Smad/Collagen IV pathway were all elevated by DM, whereas JAK2 deficiency lessened these alterations in diabetic mice. Moreover, JAK2 deficiency improved the expression of the down-regulated NO/cGMP pathway in diabetic mice. In non-diabetic mice, no apparent changes were found in aforementioned parameters after JAK2 gene knockout. Discussion and conclusion Our study showed that JAK2 deficiency could improve erectile function in diabetic mice, which might be mediated by reduction in oxidative stress, apoptosis, and fibrosis in corpus cavernosum.

Background To evaluate the predictive value of AR-V7 expression detected by immunohistochemical (IHC) in the prognosis of prostate cancer patients receiving adjuvant hormonal therapy (AHT) following radical prostatectomy (RP). Methods We retrospectively collected data of 110 patients with prostate cancer receiving RP, followed by AHT, from Tongji hospital. IHC analysis of AR-V7 expression was performed in a retrospective cohort. Results In total, 110 patients were enrolled, of whom 21 patients (19.1%) were AR-V7-positive and 89 patients (80.9%) were AR-V7-negative. No significant differences in baseline characteristics were found between the two groups. AR-V7-positive patients had shorter progression-free survival (PFS) (HR: 4.26; 95% CI, 1.55 to 11.68; P = 0.003), shorter cancer-special survival (CSS) (HR: 22.47; 95% CI, 2.912 to 173.4; P = 0.003) and shorter overall survival (OS) (HR: 6.61; 95% CI, 1.40 to 31.20; P = 0.017) compared to AR-V7-negative patients. In multivariate analysis, AR-V7 is an independent risk factor for shorter PFS (HR, 3.76; 95% CI, 1.63 to 8.70; P = 0.002), shorter CSS (HR: 9.17; 95% CI, 1.48 to 55.56; P = 0.017) and shorter OS (HR: 4.81; 95% CI, 1.28 to 17.86; P = 0.020). Conclusion The presence of AR-V7 in prostate cancer tissue is independently associated with an unfavorable prognosis for PFS, OS and CSS in patients who received AHT.

Androgen receptor (AR) is the principal molecule in prostate cancer (PCa) etiology and therapy. AR re‐activation still remains a major challenge during treatment of castration‐resistant prostate cancer (CRPC) tumors that relapse after castration therapies. Recent reports have indicated the enrichment of Ser81‐phosphorylated AR (pS81) in the nucleus of CRPC cells, and CDK1 and CDK9 as the kinases phosphorylating AR at S81. In the current study we showed that pS81 is preferentially localized in the nucleus in both rapid biopsy metastatic CRPC samples and PCa xenografts, and nuclear pS81 localization is correlated with AR transactivation in tumor xenografts. Chromatin immunoprecipitation (ChIP) analysis demonstrated an alignment of S81 phosphorylation and AR‐mediated transactivation with the chromatin locus openness. Moreover, pS81‐specific ChIP‐Seq showed a disproportional occupancy of pS81 on AR‐activated promoters, while 3C‐ChIP assays further indicated an enrichment of pS81 at the PSA enhancer‐promoter loop, a known AR activating hub. In the latter, CDK9 was shown to modulate the transactivation of the AR and RNA Pol II. Indeed, ChIP and re‐ChIP assays also confirmed that AR‐dependent activation of the PSA enhancer and promoter mediated by pS81 was coupled with activation of Pol II and the pTEFb complex. Mechanistically, we determined that CDK1 and CDK9 sustained the pS81 AR modification in the soluble and chromatin‐bound fractions of PCa cells, respectively. Finally, we demonstrated that CDK1 activity was maintained throughout the cell cycle, and that CDK1 inhibitors restored androgen sensitivity in CRPC tumor cells. Based on these findings, CDK1 and CDK9 could be targeted as pS81 kinases in patients with CRPC, either alone or in conjunction with direct AR antagonists., Androgen receptor (AR) is phosphorylated at Ser81 (pS81) in prostate cancer. By using chromatin immunoprecipitation analyses (ChIP, ChIP‐seq, reChIP and 3C‐ChIP), we demonstrated that pS81 is coupled to AR transactivation and enriched at AR‐activated enhancer‐promoter loops. pS81 is co‐stimulated by CDK1 and CDK9, both representing potential therapeutic targets in castration‐resistant prostate cancer patients, either alone or in conjunction with direct AR antagonists.

BACKGROUND: Erectile dysfunction (ED) is common but usually underdiagnosed in diabetics. The correlation between different vascular lesions and ED in diabetics without clinical cardiovascular symptoms is unknown. The aim was to explore the association between cardiovascular risks and ED in Chinese type 2 diabetic men lacking clinical performance. METHODS: Erectile function of patients with type 2 diabetes was assessed by the 5-item International Index of Erectile Function (IIEF-5) questionnaire. The data of clinical characteristics and vascular lesions at carotid and lower limb sites assessed by the Doppler ultrasound were collected to evaluate diabetes- metabolic indices. Univariate and multivariate analyses were conducted to find statistical correlation between cardiovascular risks and diabetic ED. RESULTS: A total of 71.21% reported suffering from ED. Lower limb plaques were more common (45.38%) than carotid district (35.62%) in diabetes. Men with ED had higher carotid intima-media thickness (IMT) (P

RNA binding proteins (RBPs) play a key role in post-transcriptional gene regulation. They have been shown to be dysfunctional in a variety of cancers and are closely related to the occurrence and progression of cancers. However, the biological function and clinical significance of RBPs in clear cell renal carcinoma (ccRCC) are unclear. In our current study, we downloaded the transcriptome data of ccRCC patients from The Cancer Genome Atlas (TCGA) database and identified differential expression of RBPs between tumor tissue and normal kidney tissue. Then the biological function and clinical value of these RBPs were explored by using a variety of bioinformatics techniques. We identified a total of 40 differentially expressed RBPs, including 10 down-regulated RBPs and 30 up-regulated RBPs. Eight RBPs (APOBEC3G, AUH, DAZL, EIF4A1, IGF2BP3, NR0B1, RPL36A, and TRMT1) and nine RBPs (APOBEC3G, AUH, DDX47, IGF2BP3, MOV10L1, NANOS1, PIH1D3, TDRD9, and TRMT1) were identified as prognostic related to overall survival (OS) and disease-free survival (DFS), respectively, and prognostic models for OS and DFS were constructed based on these RBPs. Further analysis showed that OS and DFS were worse in high-risk group than in the low-risk group. The area under the receiver operator characteristic curve of the model for OS was 0.702 at 3 years and 0.726 at 5 years in TCGA cohort and 0.783 at 3 years and 0.795 at 5 years in E-MTAB-1980 cohort, showing good predictive performance. Both models have been shown to independently predict the prognosis of ccRCC patients. We also established a nomogram based on these prognostic RBPs for OS and performed internal validation in the TCGA cohort, showing an accurate prediction of ccRCC prognosis. Stratified analysis showed a significant correlation between the prognostic model for OS and ccRCC progression.

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.

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.

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.

BackgroundThe prognostic value of androgen receptor splice variant 7 (AR-V7) for the treatment response of metastatic castration-resistant prostate cancer (mCRPC) remains unclear. In this study, we aimed to synthesize relevant studies that assessed the prognostic value of AR-V7 status for the treatment response of mCRPC patients treated with androgen receptor signalling inhibitors (ARSis) and chemotherapy.MethodsWe searched the PubMed, Embase, and MEDLINE databases by using the keywords AR-V7 and prostate cancer to identify relevant studies published before 25 September 2019. The main outcomes were prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS). Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. The quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale.ResultsA total of 1,545 patients from 21 studies were included. For the mCRPC patients treated with ARSis, AR-V7-positive patients had a lower PSA response rate (OR 6.01, 95% CI 2.88–12.51; P < 0.001), shorter PFS (HR 2.56, 95% CI 1.80–3.64; P < 0.001) and shorter OS (HR 4.28, 95% CI 2.92–6.27; P < 0.001) than AR-V7-negative patients. Although AR-V7-positive patients treated with chemotherapy also had a lower PSA response rate (OR 2.23, 95% CI 1.38–3.62; P = 0.001) and shorter OS than AR-V7-negative patients (HR 1.60, 95% CI 1.02–2.53; P = 0.043), there was no significant difference in PFS (HR 1.05, 95% CI 0.74–1.49; P = 0.796) between these groups. Furthermore, AR-V7-positive patients receiving ARSis had a shorter median OS than those receiving chemotherapy (HR 3.50, 95% CI 1.98–6.20; P < 0.001); There was no significant difference among AR-V7-negative patients (HR 1.30, 95% CI 0.64–2.62; P = 0.47).ConclusionsAR-V7 is a potential biomarker of treatment resistance in mCRPC patients. AR-V7-positive mCRPC patients had poorer treatment outcomes than AR-V7-nagetive patients when treated with ARSis. AR-V7-positive patients have better outcomes when treated with taxane than ARSis. Furthermore, the ability of AR-V7 status to predict treatment outcomes varies from different detection methods. The detection of AR-V7 before treatment is important for the selection of treatment modalities for mCRPC patients.

Background Erectile dysfunction (ED) occurs more frequently and causes a worse response to the first-line therapies in diabetics compared with nondiabetic men. Corpus cavernosum vascular dysfunction plays a pivotal role in the occurrence of diabetes mellitus ED (DMED). The aim of this study was to investigate the protective effects of glucagon-like peptide-1 (GLP-1) analog liraglutide on ED and explore the underlying mechanisms in vivo and in vitro. Methods Type 1 diabetes was induced in rats by streptozotocin, and the apomorphine test was for screening the DMED model in diabetic rats. Then they were randomly treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Erectile function was assessed by cavernous nerve electrostimulation. The corpus cavernosum was used for further study. In vitro, effects of liraglutide were evaluated by primary corpus cavernosum smooth muscle cells (CCSMCs) exposed to low or high glucose (HG)-containing medium with or without liraglutide and GLP-1 receptor (GLP-1R) inhibitor. Western blotting, fluorescent probe, immunohistochemistry, and relevant assay kits were performed to measure the levels of target proteins. Results Administration of liraglutide did not significantly affect plasma glucose and body weights in diabetic rats, but improved erectile function, reduced levels of NADPH oxidases and ROS production, downregulated expression of Ras homolog gene family (RhoA) and Rho-associated protein kinase (ROCK) 2 in the DMED group dramatically. The liraglutide treatment promoted autophagy further and restored expression of GLP-1R in the DMED group. Besides, cultured CCSMCs with liraglutide exhibited a lower level of oxidative stress accompanied by inhibition of the RhoA/ROCK pathway and a higher level of autophagy compared with HG treatment. These beneficial effects of liraglutide effectively reversed by GLP-1R inhibitor. Conclusion Liraglutide exerts protective effects on ED associated with the regulation of smooth muscle dysfunction, oxidative stress and autophagy, independently of a glucose- lowering effect. It provides new insight into the extrapancreatic actions of liraglutide and preclinical evidence for a potential treatment for DMED.

INTRODUCTION AND OBJECTIVE:As one of diabetic complications, erectile dysfunction (ED) is more frequent and causes worse response to PDE5 inhibitors compared with non-diabetic men. Corpus cavernosu...

Objective: To compare outcomes and postoperative quality of life (QoL) among patients with kidney stone who received mini-percutaneous nephrolithotomy (mPCNL), partial tubeless mPCNL or mPCNL with ureter catheter in a prospective randomized clinical trial. Methods: From May 2017 to December 2017, 60 patients with kidney stone who underwent mPCNL were randomized into 3 groups: Group I (mPCNL), Group II (partial tubeless mPCNL), Group III (mPCNL with ureter catheter). We evaluated perioperative characteristics, stone clearance, analgesic requirements and QoL by using the Wisconsin Stone QOL questionnaire. Results: The age, gender, stone diameter, body mass index, length of operation, drop in hemoglobin and stone-free rates for the 3 groups were similar among these groups. However, the postoperative visual analog scale and the analgesic requirement in Group II were significantly the lowest (p < 0.05). According to Wisconsin Stone QOL questionnaire, compared to Group I, statistical significant difference in the QoL was seen in Group II and III, indicating a meaningful and immediate improvement in the postoperative QoL following mPCNL. Conclusion: Compared with standard and partial tubeless mPCNL, mPCNL with ureter catheter is a safe and useful form of mPCNL, which can offer better QoL and is more cost effective.

Background The growth and function of seminal vesicle are dependent on androgen. This study was conducted to investigate the role of oxidative stress in castration-induced seminal vesicle atrophy and to explore the effects of curcumin, an antioxidant extracted from rhizome of turmeric, on seminal vesicle of castrated mice. Methods C57BL/6J mice were randomly divided into three groups: control, castration, and castration with curcumin (n = 10 for each group). After surgical castration, mice in the curcumin treatment group received intragastric administration of curcumin at 100 mg/kg body weight for 4 weeks, whereas mice in the other two groups were treated with olive oil. After that, the body weight, seminal vesicle weight and serum testosterone of mice were measured. Apoptosis and oxidative stress levels in seminal vesicle were also determined. Results After castration, both the weight and size of seminal vesicle decreased dramatically. The expression of three NADPH oxidase (NOX) subtypes: NOX1, NOX2 and NOX4, increased in seminal vesicle of castrated mice, resulting in high level oxidative stress. The ratio of Bax to Bcl-2 was also elevated after castration, accompanied by enhanced caspase3 activity. Additionally, castration increased the number of apoptotic cells in seminal vesicle. Curcumin treatment could inhibit the expression of NOX1, NOX2 and NOX4, decreasing oxidative stress and apoptosis. The atrophy of seminal vesicle caused by castration was ameliorated by curcumin. Conclusion Castration could cause atrophy of seminal vesicle probably via inducing oxidative stress. Curcumin treatment could reduce the oxidative stress in seminal vesicle by decreasing the expression of NOX1, NOX2 and NOX4, thereby ameliorating apoptosis and atrophy of seminal vesicle. Oxidative stress might play a role in castration-induced seminal vesicle atrophy.

We aimed to confirm the predictive ability of the presence of intraductal carcinoma of the prostate (IDC-P) for prognosis and the associations between IDC-P and clinicopathological parameters. Studies were identified in PubMed, Cochrane Library, EMBASE, Web of Science, and SCOPUS up to December 1, 2019. Hazard ratios (HRs) for survival data and odds ratios for clinicopathological data with 95% confidence intervals (CIs) were extracted. Heterogeneity was evaluated by the I[2] value, and quality was assessed by the Newcastle–Ottawa Scale criteria. A total of 4179 patients from 13 studies were included. The results showed that IDC-P presence was significantly associated with poor progression-free survival (PFS; HR = 2.31; 95% CI: 1.96–2.73), cancer-specific survival (HR = 1.89; 95% CI: 1.28–2.77), and overall survival (HR = 2.14; 95% CI: 1.53–3.01). In the subgroup analysis, IDC-P presence was significantly associated with poor PFS in prostate cancer treated by radical prostatectomy (HR = 2.48; 95% CI: 2.05–3.00) and treated by radiotherapy (HR = 2.83; 95% CI: 1.65–4.85). Regarding clinicopathological characteristics, patients with IDC-P presence had significantly higher tumor clinical stages, Gleason scores, probabilities of lymph node invasion, positive surgical margins, and positive extraprostatic extension. Our meta-analysis indicates that the presence of IDC-P is closely associated with poor prognosis and adverse clinicopathological characteristics. Our data support the value and clinical utility of the routine detection of IDC-P by pathological examination. These conclusions need further validation, and prospective studies are needed to find better treatment modalities other than traditional first-line therapy for patients with IDC-P.

Purpose Pulsatile gonadotropin-releasing hormone (GnRH) therapy and gonadotropin therapy (GT) were widely used for male patients with congenital hypogonadotropic hypogonadism (CHH), but their efficacy was not well compared before. We conducted this meta-analysis to compare the efficacy of restoring fertility using these two therapies. Materials and methods PubMed, Web of Science, and Scopus were systematically searched for comparative studies evaluating the efficiency of GnRH therapy and GT for male patients with CHH. For continuous outcomes, the weighted mean difference (WMD) was used to measure the difference, whereas the risk ratio with 95% confidence interval was calculated for binary variables. Results Overall, eight articles from seven studies with 420 patients enrolled were included in the analysis. Patients from the two different groups were determined to be comparable in age, proportion with Kallmann syndrome, percentage of cryptorchidism and pretreatment hormones (follicular-stimulating hormone, luteinizing hormone, and testosterone). GnRH therapy was related to a larger testicular volume (standardized mean difference=-1.43; p=0.01) and earlier spermatogenesis (WMD=-5.30 months; p=0.004) compared to GT. However, the difference in the rate of positive sperm detection (p=0.08), sperm concentration (p=0.37), and pregnancy rate (p=0.11) were not significant. Allergic reactions mostly occurred during GnRH therapy, while GT was related to a higher incidence of gynecomastia and acne. Conclusions Compared to GT, GnRH was related to earlier spermatogenesis and less estradiol-related adverse reactions, although there were no significant differences in spermatogenesis rate, sperm concentration, and pregnancy rate. High-quality randomized controlled trials are needed for future research.

BACKGROUND Previous reports have documented protein phosphatase 1 (PP1) as an essential androgen receptor (AR) activator. However, more systemic studies are needed to further define PP1 effects on AR, particularly in the settings of prostate cancer cells and under conditions mimicking androgen ablation. METHODS PP1 effects on AR protein expression, degradation, ubiquitination, and stabilization were examined in non-prostate cancer cells, followed by validation on exogenous settings in androgen-sensitive (LNCaP and VCaP) and castration-resistant (C4-2) prostate cancer cells. Effects of PP1 on AR protein expression, on AR-mediated transcription of exogenous reporter and endogenous gene, and on LNCaP and C4-2 cell proliferation were monitored under androgen-containing versus androgen-depleted conditions to assess the effects of PP1 on AR responsiveness to androgen. RESULTS In this report, we determined that PP1 functions to stabilize AR proteins that exclusively undergo the proteasome-dependent degradation, and the stimulatory effects of PP1 were predominantly mediated by the AR ligand-binding domain (LBD). Consistently, PP1 enhances AR protein stability by disrupting the LBD-mediated and K48-linked ubiquitination cascade. We further validated the above findings in the prostate cancer cells by showing that PP1 inhibition can increase ubiquitin- and proteasome-dependent degradation of endogenous AR under androgen deprivation. Significantly, we found that PP1 could markedly activate AR transcriptional activities under conditions mimicking androgen ablation and that androgen sensitivity was substantially evoked by PP1 inhibition in the prostate cancer cell lines. CONCLUSIONS As summarized in a simplified model, our studies defined an essential PP1-mediated pathway for AR protein stabilization that can compensate the loss of androgen and established a mechanistic link between PP1 and androgen responsiveness. The amplified PP1-dependence for AR activation under the androgen ablated conditions provides a rationale to therapeutically target the PP1-AR module in the castration–resistant prostate cancer (CRPC). Our findings also suggested an alternative AR-targeting compounds screening strategy that aims to circumvent PP1-AR interaction. Prostate © 2016 Wiley Periodicals, Inc.

The purpose of this study is to compare the efficacy and safety of transurethral enucleation and resection of prostate for treatment of benign prostatic hyperplasia (BPH). This meta-analysis was conducted through a systematic search before 1 September 2018. All included publications were randomized controlled trials (RCTs). Efficacy was evaluated based on International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax), and quality of life (QoL). Perioperative data and complications postoperatively were also assessed. The quality assessment of included studies and results was performed by using the Cochrane System and GRADE (grading of recommendation assessment, development, and evaluation) System. Thirty-one publications involving 26 RCTs with 3283 patients were assessed in this review. The differences between enucleation and resection in IPSS, Qmax, and QoL at 1, 3, and 6 months postoperative were not significant. At 12 months postoperatively, IPSS and Qmax in the enucleation group were significantly better than those in the resection group. The results also suggested a benefit of enucleation over resection in hospital stay, hemoglobin loss, serum sodium decrease, blood transfusion rate, grade II, grade III complications, and early complications. However, resection exhibited a better operative time. Compared with resection, enucleation showed better efficacy and safety postoperatively with less hematological changes and severe complications, except for longer operative time.

Percutaneous nephrolithotomy (PCNL) is generally accepted as the gold standard treatment for the treatment of large kidney stones (> 2 cm). For nearly 40 years, with the continuous progress of technology and the constant updating of ideas, PCNL has made great progress. In this review, we discuss the current research progress, recent advancement and hot spot of the whole process of PCNL including anesthesia, position, puncture, dilation, lithotripsy approaches, perfusate, tube placement, hospitalization time, drug, treatment of residual stones, prognosis judgment and operation evaluation by summarizing the related research in this article.

The phosphoprotein phosphatases are emerging as important androgen receptor (AR) regulators in prostate cancer (PCa). We reported previously that the protein phosphatase 1 catalytic subunit (PP1α) can enhance AR activity by dephosphorylating a site in the AR hinge region (Ser650) and thereby decrease AR nuclear export. In this study we show that PP1α increases the expression of wildtype as well as an S650A mutant AR, indicating that it is acting through one or more additional mechanisms. We next show that PP1α binds primarily to the AR ligand binding domain and decreases its ubiquitylation and degradation. Moreover, we find that the PP1α inhibitor tautomycin increases phosphorylation of AR ubiquitin ligases including SKP2 and MDM2 at sites that enhance their activity, providing a mechanism by which PP1α may suppress AR degradation. Significantly, the tautomycin mediated decrease in AR expression was most pronounced at low androgen levels or in the presence of the AR antagonist enzalutamide. Consistent with this finding, the sensitivity of LNCaP and C4–2 PCa cells to tautomycin, as assessed by PSA synthesis and proliferation, was enhanced at low androgen levels or by treatment with enzalutamide. Together these results indicate that PP1α may contribute to stabilizing AR protein after androgen deprivation therapies, and that targeting PP1α or the AR-PP1α interaction may be effective in castration-resistant prostate cancer (CRPC).

Metabolic syndrome (MetS) is a risk factor for erectile dysfunction (ED), but the underlying mechanisms are unclear. The aims of this study were to determine the underlying mechanisms of metabolic syndrome-related ED (MED). Sprague Dawley (SD) rats were fed a high-fat diet for 6 months, and metabolic parameters were then assessed. An apomorphine test was conducted to confirm MED. Only rats with MED were administered an intracavernosal injection of either epidermal growth factor (EGF) or vehicle for 4 weeks. Erectile responses were evaluated by determining the mean arterial blood pressure (MAP) and intracavernosal pressure (ICP). Levels of protein expression were examined by western blotting and immunohistochemistry. Body weight, fasting blood glucose, plasma insulin and plasma total cholesterol were increased in the MetS rats compared with those in control rats (each p

Castration resistance is a major obstacle to hormonal therapy for prostate cancer patients. Although androgen independence of prostate cancer growth is a known contributing factor to endocrine resistance, the mechanism of androgen receptor deregulation in endocrine resistance is still poorly understood. Herein, the CAMK2N1 was shown to contribute to the human prostate cancer cell growth and survival through AR-dependent signaling. Reduced expression of CAMK2N1 was correlated to recurrence-free survival of prostate cancer patients with high levels of AR expression in their tumor. CAMK2N1 and AR signaling form an auto-regulatory negative feedback loop: CAMK2N1 expression was down-regulated by AR activation; while CAMK2N1 inhibited AR expression and transactivation through CAMKII and AKT pathways. Knockdown of CAMK2N1 in prostate cancer cells alleviated Casodex inhibition of cell growth, while re-expression of CAMK2N1 in castration-resistant cells sensitized the cells to Casodex treatment. Taken together, our findings suggest that CAMK2N1 plays a tumor suppressive role and serves as a crucial determinant of the resistance of prostate cancer to endocrine therapies.

Objective To present our experience with nine patients with small cell carcinoma of the bladder (SCCB) who were treated with different modalities and review the literature for patients with SCCB who have been reported in 56 literatures. SCCB is a rare, highly aggressive tumor that presents in an advanced stage and has a propensity for early metastasis. Hematuria is the main clinical manifestations. Surgery, chemotherapy, and radiotherapy, either alone or as part of combined therapy have been used for treatment. Methods We retrospectively evaluated nine patients with SCCB by medical record review between February 1980 and January 2014 at Tongji Hospital of Huazhong University of Science and Technology. In order to better understand the clinical features of SCCB, 56 literatures were concerned (from January 1979 to March 2014). The general characteristics, clinical manifestation, the pathological and immunohistochemical characteristics, treatment options and prognostication in those eligible manuscripts are analyzed, a retrospective analysis is performed. Results All the nine cases in Tongji hospital were successfully operated and tissue samples were carried on pathological examination. All the tumor tissue contained small cell carcinoma components, there were four cases coexisting with other histologic types of bladder cancers, and 2 of the 9 cases have three different cell components. All patients had muscle-invasive disease at presentation, 4 cases showed lymph nodes metastasis, 3 cases showed invasion of the surrounding seminal vesicle or uterus, and 1 case greatly suspected the liver metastasis. Specimens of all cases underwent immunohistochemistry examination showed that NSE, PCK, Syn, and CD56 were all positive, but LCA was negative. After operation, 3 patients underwent chemotherapy and only one patient received post operational radiotherapy. Patients were followed up range between 3 to 84 months and the median survival time was 33 months. The main reasons of the patients die are tumor recurrence and metastasis, but two patients are still alive. Conclusions SCCB is different from transitional cell carcinoma (TCC) of the bladder. It has its unique cytology, immunohistochemistry and ultrastructural features. Diagnosis depends on pathological examination and immunohistochemistry. Surgery followed by chemotherapy is the main treatment method currently. In view of the disease is easily early metastasis, the overall prognosis for this cancer is poor. Further research is required to understand the molecular pathogenesis so that novel targeted therapies can be developed for this rare cancer.

CX43 plays a critical role in tumor progression. Previous studies imply that AR pathway may be involved in regulation of CX43. This study was focused on determining the relationship between AR pathway and CX43. The result showed that the expression of CX43 in malignant cells was higher than that in normal cells, and in nonmalignant and malignant cells, not only is the expression level of CX43 different, but the localization of CX43 can also be changed. After androgen stimulation and inhibition of AR pathway, expression of CX43 can also be changed. Thus, AR pathway plays an important role in regulation of CX43 expression in prostate cancer cells. AR may be the upstream signal of CX43.

In the U.S., prostate cancer (PCa) ranked second for cancer related deaths for men. It has been well established that androgen receptor (AR) plays an essential role in the development of primary PCa and its activity is restored in castration resistant prostate cancers (CRPC). While AR has been extensively characterized as a transcriptional activator, it can also function by direct or indirect mechanisms to suppress gene expression. Despite the critical role AR plays in PCa, mechanisms by which it functions as a transcriptional repressor are poorly understood. Using VCaP and VCaP derived CRPC cell lines, we have reported that androgen-repressed genes were functionally enriched for DNA synthesis and repair, while AR stimulated genes were associated with lipid/sterol synthesis and other aspects of cellular metabolism. Significantly, a subset of the genes that were androgen-repressed in VCaP cells were consistently increased in CRPC clinical samples, and this 53-gene subset was also highly enriched for genes mediating DNA synthesis and repair. Using AR ChIP-seq and transcriptome profiling in VCaP cells, we found that the majority of this AR-suppressed gene subset (39/53) have one or more AR binding sites within the gene locus. The expression level of these direct AR-suppressed genes is associated with poor survival of disease in clinical cohorts. Interestingly, although the suppression activity of AR on this subset of genes is direct, in other PCa cell lines such as LNCaP, there is a secondary mechanism that allows AR to indirectly stimulate the expression of these genes. Importantly, the direct AR mediated repression of these genes is enhanced in PCa cells expressing higher levels of AR, and overexpression of AR in LNCaP cells resulted in increased and more persistent AR binding to these genes, and also enhanced the direct AR repression of this gene subset. Mechanistically, we found that the indirect activation of these DNA synthesis genes by AR is mediated through transcriptionally stimulating lipid synthesis, which could subsequently drive the G1/S cell cycle progression and RB1 phosphorylation. Indeed, this indirect stimulatory effect of AR on these genes could be suppressed by cyclin dependent kinase inhibition or by preventing the AR stimulation of mTOR (rapamycin) or sterol synthesis (statins). Taken together, these findings indicate that the ability of AR to repress this gene set mediating DNA synthesis may persist in CRPC, and may be exploited therapeutically by combination therapies that stimulate AR while repressing its metabolic functions. Citation Format: Yanfei Gao, Shuai Gao, Housheng He, Xiaming Liu, Sen Chen, Fen Ma, X. Shirley Liu, Myles Brown, Steven P. Balk, Shaoyong Chen, Changmeng Cai. Androgen receptor transcriptionally represses genes mediating DNA synthesis and repair in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1849. doi:10.1158/1538-7445.AM2015-1849