Yuxin Tang

Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A2B adenosine receptor signaling

Priapism is a condition of persistent penile erection in the absence of sexual excitation. Of men with sickle cell disease (SCD), 40% display priapism. The disorder is a dangerous and urgent condition, given its association with penile fibrosis and eventual erectile dysfunction. Current strategies to prevent its progression are poor because of a lack of fundamental understanding of the molecular mechanisms for penile fibrosis in priapism. Here we demonstrate that increased adenosine is a novel causative factor contributing to penile fibrosis in two independent animal models of priapism, adenosine deaminase (ADA)‐deficient mice and SCD transgenic mice. An important finding is that chronic reduction of adenosine by ADA enzyme therapy successfully attenuated penile fibrosis in both mouse models, indicating an essential role of increased adenosine in penile fibrosis and a novel therapeutic possibility for this serious complication. Subsequently, we identified that both mice models share a similar fibrotic gene expression profile in penile tissue (including procollagen I, TGF‐ß1, and plasminogen activator inhibitor‐1 mRNA), suggesting that they share similar signaling pathways for progression to penile fibrosis. Thus, in an effort to decipher specific cell types and underlying mechanism responsible for adenosine‐mediated penile fibrosis, we purified corpus cavernosal fibroblast cells (CCFCs), the major cell type involved in this process, from wild‐type mice. Quantitative RT‐PCR showed that the major receptor expressed in these cells is the adenosine receptor A2BR Based on this fact, we further purified CCFCs from A2BR‐deficient mice and demonstrated that A2BR is essential for excess adenosine‐mediated penile fibrosis. Finally, we revealed that TGF‐ß functions downstream of the A2BR to increase CCFC collagen secretion and proliferation. Overall, our studies identify an essential role of increased adenosine in the pathogenesis of penile fibrosis via A2BR signaling and offer a potential target for prevention and treatment of penile fibrosis, a dangerous complication seen in priapism.—Wen, J., Jiang, X., Dai, Y., Zhang, Y., Tang, Y., Sun, H., Mi, T., Phatarpekar, P. V., Kellems, R E., Blackburn, M. R, Xia, Y. Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A2B adenosine receptor signaling. FASEB J. 24, 740–749 (2010). www.fasebj.org

Adenosine deaminase enzyme therapy prevents and reverses the heightened cavernosal relaxation in priapism.

INTRODUCTION Priapism featured with painful prolonged penile erection is dangerous and commonly seen in sickle cell disease (SCD). The preventive approaches or effective treatment options for the disorder are limited because of poor understanding of its pathogenesis. Recent studies have revealed a novel role of excess adenosine in priapism caused by heightened cavernosal relaxation, and therefore present an intriguing mechanism-based therapeutic possibility. AIM The aim of this study was to determine the therapeutic effects of adenosine deaminase (ADA) enzyme therapy to lower adenosine in priapism. METHODS Both ADA-deficient mice and SCD transgenic (Tg) mice display priapism caused by excessive adenosine. Thus, we used these two distinct lines of mouse models of priapism as our investigative tools. Specifically, we treated both of these mice with different dosages of polyethylene glycol-modified ADA (PEG-ADA) to reduce adenosine levels in vivo. At the end points of the experiments, we evaluated the therapeutic effects of PEG-ADA treatment by measuring adenosine levels and monitoring the cavernosal relaxation. MAIN OUTCOME MEASURES Adenosine levels in penile tissues were measured by high-performance liquid chromatography, and cavernosal relaxation was quantified by electrical field stimulation (EFS)-induced corporal cavernosal strip (CCS) assays. RESULTS We found that lowering adenosine levels in penile tissues by PEG-ADA treatment from birth in ADA-deficient mice prevented the increased EFS-induced CCS relaxation associated with priapism. Intriguingly, in both ADA-deficient mice and SCD Tg mice with established priapism, we found that normalization of adenosine levels in penile tissues by PEG-ADA treatment relieved the heightened EFS-induced cavernosal relaxation in priapism. CONCLUSIONS Our studies have identified that PEG-ADA is a novel, safe, and mechanism-based drug to prevent and correct excess adenosine-mediated increased cavernosal relaxation seen in two independent priapic animal models, and suggested its therapeutic possibility in men suffering from priapism.

Peripheral Blood Mitochondrial DNA Copy Number Is Associated with Prostate Cancer Risk and Tumor Burden

Alterations of mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between mtDNA copy number in peripheral blood leukocytes (PBLs) and the risk of prostate cancer (PCa) has not been investigated. In a case-control study of 196 PCa patients and 196 age-paired healthy controls in a Chinese Han population, the association between mtDNA copy number in PBLs and PCa risk was evaluated. The relative mtDNA copy number was measured using quantitative real-time PCR; samples from three cases and two controls could not be assayed, leaving 193 cases and 194 controls for analysis. PCa patients had significantly higher mtDNA copy numbers than controls (medians 0.91 and 0.82, respectively; P<0.001). Dichotomized at the median value of mtDNA copy number in the controls, high mtDNA copy number was significantly associated with an increased risk of PCa (adjusted odds ratio  = 1.85, 95% confidence interval: 1.21–2.83). A significant dose-response relationship was observed between mtDNA copy number and risk of PCa in quartile analysis (P trend = 0.011). Clinicopathological analysis showed that high mtDNA copy numbers in PCa patients were significantly associated with high Gleason score and advanced tumor stage, but not serum prostate-specific antigen level (P = 0.002, 0.012 and 0.544, respectively). These findings of the present study indicate that increased mtDNA copy number in PBLs is significantly associated with an increased risk of PCa and may be a reflection of tumor burden.

The prognostic role of preoperative serum albumin/globulin ratio in patients with bladder urothelial carcinoma undergoing radical cystectomy

OBJECTIVE To date, only a few studies have demonstrated the prognostic value of pretreatment serum albumin in bladder urothelial carcinoma (BUC). The aim of this study was to evaluate the association between the pretreatment albumin/globulin ratio (AGR) and the survival of patients with BUC treated with radical cystectomy (RC). MATERIALS AND METHODS Data from 296 patients with BUC who underwent RC between June 2000 and June 2013 were analyzed. The AGR was calculated as follows: albumin/(total protein-albumin). The AGR was divided into 2 groups for receiver operating characteristics curve analysis. Survival was estimated using Kaplan-Meier analysis and compared using the log rank test. Cox proportional hazards models were used for univariate and multivariate survival analyses. RESULTS Patients in the high AGR group (AGR≥1.60) had a lower 5-year recurrence-free mortality rate compared with those in the low AGR group (AGR<1.60) (87.0% vs. 48.0%, P<0.001). The median cancer-specific survival (CSS) time was 71.1 months for low AGR patients and 156.0 months for the high AGR patients (P<0.001). After adjusting for confounding variables, the AGR remained an independent predictor of recurrence-free survival (RFS) (hazard rate = 0.356; 95% CI: 0.170-0.748; P = 0.006) and CSS (hazard rate = 0.280; 95% CI: 0.115-0.683; P = 0.005). Moreover, in the subset of 167 patients with normal serum albumin (albumin of≥40.0g/l), serum AGR continues to be an independent predictor of RFS (P = 0.012) and CSS (P = 0.008). CONCLUSIONS High AGR is a strong independent predictor of long-term RFS and CSS in patients with BUC undergoing RC. Additionally, among patients with normal albumin (≥40g/l) levels, patients with higher globulin, but lower AGR have worse survival. The pretreatment AGR is an easily accessible and cheap to use for predicting mortality in patients with BUC treated by RC.

The adenosine A2b receptor promotes tumor progression of bladder urothelial carcinoma by enhancing MAPK signaling pathway

The adenosine A2b receptor (A2bR) was considered to play an oncogenic role in many human malignancies. However, the expression and molecular function of A2bR in bladder urothelial carcinoma (BUC) have not been well elucidated. Herein, we found that the expression of A2bR was higher than other adenosine receptors in BUC tissues and cells, and it was upregulated in BUC tissues compared with matched normal bladder tissues. Furthermore, high expression of A2bR was associated with poor prognosis of patients with BUC. In addition, suppression of A2bR inhibited the proliferation, migration and invasion of BUC cells and arrested the cell cycle at the G1 phase. Finally, we demonstrated that downregulation of A2bR inhibited the proliferation, migration and invasion of BUC in part via the MAPK signaling pathway, increasing the levels of P21 but decreasing the levels of cyclin B1, D, E1, MMP-2 and MMP-9. Overexpression of MMP-2 could rescue BUC cells migration and invasion. Thus, the present study indicates that A2bR may play a potential oncogenic role in BUC progression and act as a potential biomarker to identify BUC patients with poor clinical outcomes.

The effect of immediate surgical bipolar plasmakinetic transurethral resection of the prostate on prostatic hyperplasia with acute urinary retention

In the present study, we evaluated the safety and efficacy of immediate surgical bipolar plasmakinetic transurethral resection of the prostate (PK-TURP) for patients with benign prostatic hyperplasia (BPH) with acute urinary retention (AUR). We conducted a retrospective analysis of clinical data of BPH patients who received PK-TURP. A total of 1126 BPH patients were divided into AUR (n = 348) and non-AUR groups (n = 778). After the urethral catheters were removed, the urine white blood cell (WBC) count in the AUR group significantly increased compared with the non-AUR group (P < 0.01). However, there was no significant difference in international prostate symptom score, painful urination, and maximal urinary flow rate. The duration of hospitalization of the AUR group was longer than that of the non-AUR group (P < 0.001). A total of 87.1% (303/348) patients in the AUR group and 84.1% (654/778) patients in the non-AUR group completed all of the postoperative follow-up visits. The incidence of urinary tract infection in the AUR group within 3 months after surgery was significantly higher than that in the non-AUR group (P < 0.01). The incidence of temporary urinary incontinence in the AUR group did not exhibit significant difference. During 3-12 months after surgery, there were no significant differences in major complications between the two groups. Multivariate regression analyses showed that age, postvoid residual, maximal urinary flow rate, diabetes, and hypertension, but not the presence of AUR, were independent predictors of IPSS post-PK-TURP. In conclusion, immediate PK-TURP surgery on patients accompanied by AUR was safe and effective.

Knockdown of HMGN5 suppresses the viability and invasion of human urothelial bladder cancer 5637 cells in vitro and in vivo.

The high-mobility group nucleosome-binding domain 5 (HMGN5) is a new and typical member of HMGN protein family. Numerous studies confirmed that HMGN5 was highly expressed in several kinds of malignant tumors, but its role in cancer progression of urothelial bladder cancer (UBC) has not been fully clarified. This study aimed to further investigate the oncogenic role of HMGN5 in UBC 5637 cells employing in vitro and in vivo models and explored the mechanism. RNA interference was used to down-regulate HMGN5 expression in 5637 cells by a shRNA expression lentiviral vector. Then cell viability, apoptosis and cell cycle distribution, invasion were detected by MTT assay, flow cytometry and transwell assay, respectively. Tumor growth was also evaluated in nude mice. As a result, successful transfection was confirmed using fluorescence microscopy and HMGN5 was efficiently inhibited. HMGN5 knockdown suppressed invasion induced G1/S cell cycle arrest but not apoptosis and thus contributed to decreased cell viability in UBC 5637 cells. Consistent with the cell cycle arrest, the protein expression levels of cyclin D1 were decreased. In vivo study further showed that HMGN5 knockdown affected the tumorigenesis of 5637 cells in nude mice. Western blot also demonstrated that the expression of E-cadherin and VEGF-C was decreased in 5637 cells depleted of HMGN5. In conclusion, we provide both in vivo and in vitro evidence that HMGN5 contribute to the growth and invasion of UBC 5637 cell line and HMGN5 could be exploited as a target for therapy in UBC.

Progression of penile cutaneous horn to squamous cell carcinoma: A case report

The current report presents the case of a 43-year-old male suffering from a penile cutaneous horn. A surgical excision of the lesion was performed and histopathology demonstrated hyperkeratosis, dyskeratosis and epithelial hyperplasia. The cutaneous horn progressed to squamous cell carcinoma <1.5 months following surgery and a partial penectomy was conducted. The International Index of Erectile Function 5 questionnaire was used to assess the patient and the score had decreased in the one-month postoperative follow-up compared with that of the preoperative period. These findings indicate that undergoing a partial penectomy on initial diagnosis of a penile cutaneous horn should be considered in order to conserve a greater quantity of the penile tissue and improve the postoperative quality of life.

The use of intracavernous injection and audiovisual sexual stimulation during real-time pharmacopenile doppler ultrasonography in vasculogenic erectile dysfunction.

Introduction: The objective of this study was to explore the role of intracavernous injection (ICI) and audiovisual sexual stimulation (AVSS) during real-time pharmacopenile Doppler ultrasonography (PDDU) in vasculogenic subtypes of erectile dysfunction. Materials and Methods: A total of 200 consecutive men with erectile dysfunction (ED) were enrolled. Each patient received 2 sessions of real-time PDDU. Session A was performed under ICI alone. Session B was performed under ICI plus AVSS. The interval between sessions was 7 days. Penile vascular parameters, including peak systolic velocity (PSV), end diastolic velocity (EDV) and resistive index, were monitored 5, 10 and 20 min after the start of the test. Patients were asked to describe the level of sexual arousal generated by choosing one of the pre-set answers. Results: In veno-occlusive ED, during session A, EDV at 10 min was significantly greater than at 5 and 20 min (p < 0.05). During session B, there was a significant difference regarding PSV in arteriogenic ED (p < 0.05). Mixed vasculogenic ED showed significant differences in PSV levels during session B, and EDV at 5 min was greater than at 10 and 20 min (p < 0.05). PDDU under ICI alone diagnosed 34 (17%), 35 (17.5%), 31 (15.5%) and 100 (50%) cases of arteriogenic, veno-occlusive, mixed vasculogenic and nonvasculogenic ED, respectively. The combination of ICI plus AVSS diagnosed 27 (13.5%), 44 (22%), 7 (3.5%) and 122 (60.7%) cases, respectively. Conclusions: Adding AVSS during PDDU improves the recording of physiologic erectile response and may help the physician to accurately evaluate the cause of ED.

Long‐term efficacy and safety of self‐intracavernous injection of prostaglandin E1 for treatment of erectile dysfunction in China

The study evaluated the long‐term efficacy and safety profiles of self‐intracavernous injection of prostaglandin E1 (PGE1) for erectile dysfunction (ED). Four hundred and sixteen ED patients were treated with self‐intracavernous injection of PGE1 from January 1998 to December 2007 in our outpatient service. Follow‐up was made to investigate the efficacy and side effects of this treatment. It was found that 261 patients (62.7%) felt satisfied and kept using this treatment due to its advantages of satisfactory efficacy and reasonable expense. Twenty‐seven of them (6.5%) got rid of PGE1 treatment after five times injections and did not need any other drugs to maintain satisfactory sexual lives. Two hundred and fourteen (51.4%) patients kept using this treatment for over 1 year, 26 (6.2%) over 5 years, 12 (2.9%) over 8 years and 7 (1.7%) over 10 years. The major complications of self‐intracavernous injection of PGE1 include fibrosis of corpus cavernosum (three cases), ecchymosis associated with vascular injury due to injection (23 cases) and pain associated with injection (295 cases). There were no patients displaying priapism. It is concluded that self‐intracavernous injection of PGE1 is a safe and effective treatment for ED with various aetiologies and a broad range of severity, and no serious complications were observed after long‐term application.