Long Non-coding RNA AFAP1-AS1 Facilitates Prostate Cancer Progression by Regulating miR-15b/IGF1R Axis.

BACKGROUND: Prostate cancer (PCa) is a commonly diagnosed malignant cancer and is the second- highest cause of cancer death in men worldwide. Enzalutamide is the second-generation inhibitor of androgen receptor signaling and is the fundamental drug for the treatment of advanced PCa. However, the disease will eventually progress to metastatic castration-resistant prostate cancer (CRPC) and aggressive neuroendocrine prostate cancer (NEPC) because of androgen-deprivation therapy (ADT) resistance. The aim of the study was to investigate the role of long non-coding RNA (lncRNA) AFAP1-AS1 in ADT resistance. METHODS: Quantitative real-time PCR analysis (qPCR) was used to assess the expression of AFAP1-AS1 in PCa cell lines and tissues. Cell proliferation and invasion were assessed after AFAP1-AS1 knockdown using Cell Counting Kit (CCK)-8 and Transwell assay, respectively. A dual-luciferase reporter gene assay was carried out to validate the regulatory relationship among AFAP1-AS1, microRNA (miR)-15b, and insulin-like growth factor1 receptor (IGF1R). RESULTS: AFAP1-AS1 level was markedly increased in castration-resistant C4-2 cells and NE-like cells (PC3, DU145, and NCI-H660), compared with androgen-sensitive LNCaP cells. Enzalutamide treatment increased the expression of AFAP1-AS1 in vitro and in vivo. Functionally, AFAP1-AS1 knockdown repressed tumor cell proliferation and invasion. Mechanistically, AFAP1-AS1 functioned as an oncogene in PCa through binding to miR-15b and destroying its tumor suppressor function. Finally, we identified that AFAP1-AS1 up-regulated IGF1R expression by competitively binding to miR-15b to de-repress IGF1R. CONCLUSION: AFAP1-AS1 facilitates PCa progression by regulating miR-15b/IGF1R axis, indicating that AFAP1-AS1 may serve as a diagnostic biomarker and therapeutic target for PCa.

KDM5C is transcriptionally regulated by BRD4 and promotes castration-resistance prostate cancer cell proliferation by repressing PTEN.

Prostate cancer (PCa) is one of the leading causes of cancer-related death worldwide, and it is almost incurable once it has developed into castration-resistance prostate cancer (CRPC). However, the mechanisms underlying the oncogenesis of PCa and CRPC remain elusive. Lysine-specific histone demethylase 5C (KDM5C) is an important member of lysine demethylase family and has recently been found highly expressed in multiple cancer types. In this study, we reported that KDM5C was highly expressed in PCa and CRPC specimens, and the high expression promoted CRPC cell proliferation through repressing phosphatase and tensin homolog (PTEN) gene epigenetically. Moreover, KDM5C was transcriptionally upregulated by bromodomain-containing protein 4 (BRD4), and knockdown KDM5C sensitized the therapeutic effects of CRPC cells to the bromodomain and extraterminal (BET) inhibitor. Taken together, our study uncovers that the BRD4-KDM5C-PTEN may be a new oncogenic pathway in CRPC development, and KDM5C is a critical protein and could be an ideal target for CRPC treatment in this oncogenic pathway.

Sumoylation Negatively Regulates CSR1-Dependent Prostate Cancer Cell Death.

BACKGROUND/AIMS: SUMOylation is a dynamic process and reversed by the activity of SUMO-specific proteases (SENPs) family. SENP1, a member of this family, is highly expressed and plays oncogenic roles in diverse cancers including prostate cancer. However, the SENP1-transgenic mice exhibit aberrant transformation of the mouse prostate gland but do not develop cancer. Cellular Stress Response 1 (CSR1) is a tumor suppressor gene and frequently deleted in prostate cancers. Overexpression of CSR1 in prostate cancer cells inhibits colony formation, anchorage-independent growth and induces cell death. METHODS: The relationship between CSR1 and SENP1 were determined by immunoprecipitation-based proteomics screen and verified by GST-pull down assay. In vivo SUMOylation assay was used to detect the direct effect of SENP1 in the regulation of CSR1. Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing was used to generate Senp1-/- and CSR1-/- PC3 cells. FACS assay was used to determine the apoptosis ratio of cells after transfection. RESULTS: CSR1 is SUMOylated at K582 and rapid ubiquitinated and degradated in prostate cancer cells. SENP1 interacts with and deSUMOylates CSR1 to prevent its degradation and enhances CSR1-dependent prostate cancer cell death. CONCLUSION: Thus, our data indicates that CSR1 is a critical SUMOylated substrate of SENP1 that might partially explain the controversial roles of SENP1 in prostate cancer development.

Intermediate-Term Outcomes and Complications of Long Segment Urethroplasty with Lingual Mucosa Grafts.

PURPOSE: We evaluated outcomes and donor site complications in male patients with complex urethral strictures who underwent urethroplasty using with long strip oral mucosal grafts. We also analyzed whether a lingual mucosa graft is a good substitute for repairing long segment urethral strictures. MATERIALS AND METHODS: This retrospective study was done in 81 male patients with complex urethral strictures who underwent oral mucosal graft urethroplasty. Patients with long segment (8 cm or greater) anterior urethral strictures who were considered candidates for long strip lingual mucosa graft urethroplasty were included in study. RESULTS: Oral mucosal graft urethroplasty was performed in 81 patients with complex urethral strictures between August 2006 and December 2014. Mean urethral stricture length was 12.1 cm (range 8 to 20). A single 9 to 12 cm long strip lingual mucosa graft was used in 52 patients, a lingual mucosa graft greater than 12 cm was placed in 17 and a lingual mucosa graft combined with a buccal mucosal graft was used in 12. Mean followup was 41 months (range 15 to 86) postoperatively. The overall urethroplasty success rate was 82.7%. Urethral complications developed in 14 patients (17.3%), including urethral strictures in 10 and urethrocutaneous fistulas in 4. At 12 months 5 patients (6.2%) reported minimal difficulty with fine motor movement of the tongue. CONCLUSIONS: Lingual mucosa harvested from the ventrolateral surface of the tongue can provide a wide and long graft that is an excellent urethral substitute. Donor site complications are primarily limited to postoperative year 1. Our study confirms that the lingual mucosa graft is a good substitute for urethral reconstruction and lingual mucosa graft urethroplasty is a valuable procedure to treat long anterior urethral strictures.

[Meatoplasty with pedicle flap for meatal stenosis secondary to chronic balanitis].

OBJECTIVE: To evaluate the effect of meatoplasty with the pedicle flap in the treatment of meatal stenosis secondary to chronic balanitis. METHODS: We retrospectively analyzed 32 cases of meatal stenosis secondary to chronic balanitis treated by meato- plasty with the pedicle flap. All the patients had a history of chronic balanitis and had received meatal dilatation or simple ventral mea- totomy without significant effect. Their mean maximum urinary flow rate (Qmax) was (4.3 ± 2.4) ml/s. During the operation, A "/\"-shaped incision was made in the healthy epidermis and a flap was harvested from the frenulum. After complete removal of the scar, the flap was placed into the urethral wall, followed by reconstruction of the external urethral orifice. RESULTS: The patients were fol- lowed up for 6 to 30 months, which revealed smooth urination in all the patients with Qmax of (26.7 ± 4.5) ml/s and normal erectile function and uresiesthesis. CONCLUSION: With little invasiveness and few complications, meatoplasty with the pedicle flap is an ideal surgical method for the treatment of meatal stenosis secondary to chronic balanitis. However, there might be some change in the normal appearance of the balanus postoperatively, and its long-term effect needs further observation.

[Prostate cancer stem cells: advances in current research].

Prostate cancer is one of the most common malignancies threatening men's health, and the mechanisms underlying its initiation and progression are poorly understood. Last decade has witnessed encouraging progress in the studies of prostate cancer stem cells (PCSCs), which are considered to play important roles in tumor initiation, recurrence and metastasis, castration resistance, and drug resistance. Therefore, a deeper insight into PCSCs is of great significance for the successful management of prostate cancer. This article presents an overview on the location, origin, and markers of PCSCs as well as their potential correlation with tumor metastasis and castration resistance.

[Diagnosis and treatment of yolk sac tumor of the testis with hydrocele in children: report of 7 cases].

OBJECTIVE: To study the clinical characteristics of yolk sac tumor of the testis with concomitant testicular hydrocele in children and the association between the two conditions in order to improve the diagnosis and treatment of the disease. METHODS: We retrospectively analyzed the clinical data of 7 cases of stage-I yolk sac tumor of the testis with concomitant testicular hydrocele. The patients ranged in age from 6 to 14 (mean 11) months. As treatment, we performed radical high spermatic cord orchiectomy after diagnosis established on intraoperative frozen sections, and conducted follow-up visits by medical examination, serum alpha-fetoprotein (AFP) detection, chest X-ray, ultrasonography and CT for 3-41 (mean 17) months, every month in the first year, every 3 months in the second year and every 6 months in the third year after surgery. RESULTS: Postoperative pathology confirmed yolk sac tumor in all the cases, with negative incisal margin. The level of serum AFP were decreased to normal in 6 cases within 1 month after surgery, all diagnosed as at stage I, and cured without chemotherapy. The other 1 case, with the serum AFP level of 116 microg/L at 1 month after operation, was diagnosed as at stage II and received PVC chemotherapy, but lost to follow-up at 3 months post-operatively. CONCLUSION: Yolk sac tumor of the testis with concomitant testicular hydrocele is easily misdiagnosed in children. Ultrasonography is necessitated as routine examination in its diagnosis. Radical high spermatic cord orchiectomy can be performed for patients in stage I, and chemotherapy should follow for those in stage II. Its prognosis is similar to that of other yolk sac tumors. Hitherto, there has been no evidence for a definitive correlation between yolk sac tumor of the testis and hydrocele in children.

[Penoplasty with scrotal flap for the treatment of buried penis in children].

OBJECTIVE: To investigate the therapeutic effect of penoplasty with scrotal skin flap for the treatment of buried penis in children. METHODS: The narrow ring was cut vertically at the ventral side of penis and the prepuce inner plate was circularly cut 0.5 cm from the coronary sulcus. The prepuce was degloved to the base of penis. The abnormal aponeurosis was removed completely. The prepuce was designed to cover the coronary sulcus. The scrotal flaps at both sides were formed and advanced to cover the penile base. Then the prepuce was sutured to reconstruct penile-scrotal angle and scrotum plasty was completed. RESULTS: From March 2009 to July 2011, 24 children with buried penis were treated with scrotal flaps. Adhesion at external orifice of urethra was happened in two cases which recovered after urethra expansion. There was one case of necrosis at the distal end of prepuce. All the cases were followed up for 6 months to 2 years with no penile shrinkage. The penile appearance was good without rotation or lateral curvature during erection. CONCLUSIONS: The buried penis can be best corrected with scrotal flap. It is an ideal method with less complication.

Evaluation of erectile function after urethral reconstruction: a prospective study.

We conducted a prospective study of erectile dysfunction (ED) after urethral reconstructive surgery, using the 5-item International Index of Erectile Function (IIEF-5), the Sexual Life Quality Questionnaire (SLQQ) and the Quality of Life Questionnaire (QoLQ). Between January 2003 and July 2007, 125 male patients with urethral strictures underwent urethroplasty, and pre- and post-surgery erectile function was assessed using these three questionnaires. A formula to predict the probability of ED after urethroplasty was derived. At 3 months post-operatively, there was a significant decrease in IIEF-5 (16.57 +/- 7.98) and SLQQ scores (28.71 +/- 14.84) compared with pre-operative scores (P < 0.05). However, the IIEF-5 scores rebounded at 6 months post-operatively (17.22 +/- 8.41). Logistical regression analysis showed that the location of the urethral stricture, the recurrence of strictures and the choice of surgical technique were predictive of the post-operative occurrence of ED. This study identified the clinical risk factors for ED after urethroplasty. Posterior urethral stricture and end-to-end anastomosis were found to have a strong relationship with erectile function. The logistical model derived in this study may be applied to clinical decision algorithms for patients with urethral strictures.

[Reconstructive surgery for male urethral stricture affects erectile function and sexual life quality].

OBJECTIVE: To evaluate the influence of reconstructive surgery for male urethral stricture on erectile function and sexual life quality. METHODS: We analyzed retrospectively the clinical data of 326 male patients who underwent urethroplasty for urethral stricture in our department and evaluated their erectile function and sexual life quality. RESULTS: A total of 172 groups of valid data were collected, with the mean follow-up of 28.5 months. The mean scores on IIEF-5 (P=0.002) and sexual life quality (P=0.026) were statistically significantly reduced after surgery. Erectile dysfunction was found in 88 (51.2%) of the patients after urethroplasty, as compared with 56 (32.6%) preoperatively. CONCLUSION: The location of urethral stricture, surgical method and urethral stricture recurrence may affect the erectile function and sexual life quality of the patient, but both can be gradually improved with the time after urethroplasty.

Ileal ureteric replacement with an ileo-psoas muscle tunnel antirefluxing technique for the treatment of long segment ureteric strictures.

OBJECTIVES: To develop and report our initial experience with a novel antirefluxing technique for segmental ileal ureteric replacement for the treatment of long ureteric strictures. PATIENTS AND METHODS: Between January 2000 and January 2007, 12 cases of ureteric strictures (nine bilateral and three unilateral) were treated using a novel surgical technique in which the ureter was replaced with a segment of ileum using an end-to-side anastomosis. An antireflux valve was constructed by fixing the distal part of upper ureter (4 cm) between the psoas muscle and ileal segment (the ileo-psoas tunnel technique). The distal ileum was connected to the urinary bladder with an end-to-side anastomosis. RESULTS: The 12 cases were followed-up for a mean (range) of 39.42 (12-64) months. There were no cases of pyelonephritis or signs of renal failure after surgery. There was dramatic improvement in hydronephrosis, as assessed by intravenous urography, in the 4-9 months after surgery. Cystography showed no evidence of ileo-ureteric reflux. Mild hyperchloraemic acidosis was detected in two patients and was successfully treated with oral alkalization. CONCLUSIONS: In our initial experience, ileal ureteric replacement combined with the ileo-psoas tunnel antirefluxing technique is a highly effective procedure for the treatment of ureteric strictures.

Proteomic evaluation of urine from renal cell carcinoma using SELDI-TOF-MS and tree analysis pattern.

There is no useful marker in screening and early diagnosis for renal cell carcinomas (RCCs), especially in the urine. To screen for specific markers in the urine of RCCs patients, surface enhanced laser desorption and ionization time of flight mass spectrometry (SELDI-TOF-MS) was used and coupled with a tree analysis pattern to develop SELDI protein profiling of urine. Urine samples from 58 RCC patients, 45 healthy volunteers, and 56 patients with other urogenital diseases were analyzed using IMAC-Cu ProteinChip capable of specifically binding metal interesting proteins. Proteomic spectra were generated by mass spectrometry. Bioinformatic calculations were performed with Biomarker Wizard software 3.0 (Ciphergen). Four differentially expressed potential biomarkers from urine were identified with the relative molecular weights of 4020, 4637, 5070, and 5500. The discriminatory classifier with a panel of the four biomarkers determined in the training set could precisely detect 24 of 30 (sensitivity, 80.0%) RCC and 52 of 58 (specificity, 89.6%) non-RCC samples. Furthermore, a sensitivity of 67.8% (19/28) and a specificity of 81.4% (35/43) for the blinded test were obtained when comparing the RCC vs. non-RCC. So SELDI-TOF combined with a tree analysis pattern could potentially serve as a useful tool for diagnosis of RCC by urine samples.

[Tree analysis pattern of mass spectral urine profiles in differential diagnosis of bladder transitional cell carcinoma].

OBJECTIVE: To develope a tree analysis pattern of mass spectral urine profiles to discriminate bladder transitional cell carcinoma (TCC) from non-cancer lesions using surface-enhanced laser desorption and ionization time-of-flight mass spectrometry (SELDI-TOF-MS) technology. METHODS: Urine samples from 61 bladder transitional cell carcinoma (TCCs) patients, 53 healthy volunteers and 42 patients with other urogenital diseases were analyzed using IMAC-Cu-3 ProteinChip. Proteomic spectra were generated by SELDI-TOF- MS. A preliminary "training" set of spectra derived from analysis of urine from 46 TCC patients, 32 patients with benign urogenital diseases (BUD), and 40 age-matched unaffected healthy men were used to train and develop a decision tree classification algorithm which identified a fine-protein mass pattern that discriminated cancers from non-cancers effectively. A blinded test set including 38 cases was used to determine the sensitivity and specificity of the classification system. RESULTS: The algorithm identified a cluster pattern that, in the training set, segregated cancer from non-cancer with a sensitivity of 84.8% and specificity of 91.7%. The discriminatory pattern was correctly identified. A sensitivity of 93.3% and a specificity of 87% for the blinded test were obtained when compared the TCC versus non-cancers. CONCLUSION: SELDI-TOF-MS technology is a rapid, convenient and high-throughput analyzing method. The urine tree analysis proteomic pattern as a screening tool is effective for differential diagnosis of bladder cancer. More detailed studies are needed to further evaluate the clinical value of this pattern.

Staged pendulous-prostatic anastomotic urethroplasty followed by reconstruction of the anterior urethra: an effective treatment for long-segment bulbar and membranous urethral stricture.

OBJECTIVES: To describe a novel surgical technique for male long-segment urethral stricture after pelvic trauma using the intact and pedicled pendulous urethra to replace the bulbar and membranous urethra, followed by reconstruction of the anterior urethra. METHODS: Two patients with long-segment post-traumatic bulbar and membranous urethral strictures with short left pendulous urethras who had undergone several failed previous surgeries were treated with staged pendulous-prostatic anastomotic urethroplasty followed by reconstruction of the anterior urethra. This procedure was divided into three stages. First-stage surgery was mobilization of the anterior urethra down to the coronary sulcus and then rerouted to the prostatic urethra followed by pendulous-prostatic anastomotic urethroplasty with transposition of the penis to the perineum. Second-stage surgery was transecting the anterior urethra at the revascularised coronary sulcus 6 mo later, followed by straightening of the penis and urethroperineostomy. Third-stage surgery was reconstruction of the anterior urethra 6 mo later. RESULTS: Postoperatively, the two patients reported satisfactory voiding. For patient 1, retrograde urethrography showed that the urethra was patent, and that the mean maximal flow rate (MFR) was 18.4 ml/s with no postvoiding residual urine after the third-stage surgery and at 3-yr follow-up. For patient 2, a 22F urethral catheter could pass smoothly through the urethra, and the MFR was 19.5 ml/s with no postvoiding residual urine at 2-yr follow-up. CONCLUSIONS: This procedure was an effective surgical option for men with complex long-segment post-traumatic bulbar and membranous urethral strictures, especially for those who had undergone failed previous surgical treatments.

[Clinical analysis of operative treatment of 191 patients with posterior urethral strictures].

OBJECTIVE: To evaluate the various operative details of strictures of the posterior urethra that are essential for a successful result. METHODS: The clinical data of 191 patients with posterior urethral strictures or distraction defects from January 1990 to January 2006 were analyzed retrospectively. All patients underwent a retrograde and voiding urethrogram, 62 patients had urethral ultrasonography, 48 patients had urethroscopy, 3 patients had MRI. Repair was performed with a simple anastomosis after urethral mobilization in 66 patients, separation of the corporeal bodies in 48 patients, separation of the corporeal bodies and inferior pubectomy in 30 patients, transpubic anastomosis in 18 patients, pull-through operation in 3 patients, and optical urethrotomy in 26 patients. Followup ranged from 6 to 48 months. RESULTS: The mean stricture length was 3.6 cm (range from 1.5 to 8.0 cm). Posterior urethral strictures is in 31 (16%), posterior distraction defects is in 160 (84%), of which the length of the distraction defects < 3 cm is in 102 (53.4%), and the the length of the distraction defects > 3 cm is in 58 (30.6%). The overall successful results (Qmax > 15 ml/s) after operation was 84.3%. Optical urethrotomy was 69%, the successful results with anastomotic urethroplasty were 97% with a simple anastomosis; 79% with separation of the corporeal bodies; 80% with separation of the corporeal bodies and inferior pubectomy; 83% with transpubic anastomosis; and 67% with pull-through operation. CONCLUSIONS: The anastomotic urethroplasty is better than the optical urethrotomy, the length of the strictures or distraction defect which is lower than 3 cm is much more successfully corrected.

[The treatment of complex urethral stricture greater than 8 cm long].

OBJECTIVE: To evaluate the selection of different procedures and the feasibility for the treatment of long segment urethral stricture. METHODS: Seventy-six patients with complex urethral stricture greater than 8 cm long underwent different procedures of urethroplasty. Of them various mucosa grafts urethral reconstruction were adopted in 42 cases (colonic mucosal graft, n = 26; buccal mucosal graft, n = 10; bladder mucosal graft, n = 6); One-stage pedicle flaps urethroplasty in 20; two-stage urethroplasty of Johanson procedure in 12; and penile urethra-prostatic urethra anastomosis, three-stage urethroplasty in 2. RESULTS: In early followed up (within 6 months postoperatively), 67 patients (88%) voided well and complications developed in 10. Among the 70 patients who lasted more than 1 year after operation, 51 cases were followed up. Forty-four patients voided well, and complications developed in 8. Of the 8 cases urethral restructure developed in 2 (18%) for pedicle flaps urethroplasty, 2 for colonic mucosal urethroplasty (9%), 1 for buccal mucosal graft (1/7), 1 for bladder mucosal graft (1/3); penile chordee in 2 (2/5), and one of them was accompanied by hair bearing neourethra for two-stage urethroplasty of Johanson procedure. CONCLUSIONS: Colonic mucosal and buccal mucosal grafts urethroplasty are feasible procedures for the treatment of long segment urethral stricture, and Colonic mucosal graft urethroplasty may be considered when more conventional procedures fail or complicated urethral strictures greater than 10 cm long.

An evaluation of surgical approaches for posterior urethral distraction defects in boys.

PURPOSE: We present our preliminary experience with operative approaches in the treatment of complex posterior urethral distraction defects in children. MATERIALS AND METHODS: A total of 24 boys 7 to 14 years old with obliterative complex posterior urethral distraction defects were treated with 1 of 3 surgical approaches between January 1998 and December 2002. A perineal approach was used in 5 cases, a transperineal-inferior pubic approach including distal urethral mobilization, corporeal body separation and inferior pubectomy in 10, and a combined transpubic-perineal approach in 9. RESULTS: Patients were followed 1 to 5 years postoperatively. A successful result of no recurrence of stricture was achieved in 19 of 24 patients (79.2%), including 3 of 5 (60%) treated with a perineal approach, 9 of 10 (90%) with a transperineal-inferior pubic approach and 7 of 9 (77.8%) with a transpubic-perineal approach. Complications included 1 combined false passage, which was resolved using a transperineal-inferior pubic approach, 2 urethrocutaneous fistulas, which were resolved using a perineal approach in 1 and a transpubic-perineal approach in 1, and 3 rectourethral fistulas, which were resolved using a transpubic-perineal approach in 1 and a transperineal-inferior pubic approach in 1. Of the 9 patients treated with the transpubic-perineal approach 3 walked with an abnormal gait postoperatively. CONCLUSIONS: The transperineal-inferior pubic approach fully exposes the space behind the pubis, does not damage pelvic stability and yields better results compared to the perineal and transpubic-perineal approaches. We recommend it as first line operative treatment for complex posterior urethral distraction defects in boys.

[Ultrasonographic assessment of urethral condyloma acuminatum in men].

OBJECTIVE: To evaluate the value of ultrasonography in diagnosing urethral condyloma acuminatum (CA) in men. METHODS: Twenty-two male patients, aged 36 +/- 19, diagnosed as with urethral CA based on history and clinical symptoms underwent ultrasonography and urethroscopy. The patients were asked to micturate to distend the urethra. The posterior urethra was detected by transrectum approach. Transperineal scans were performed to image the bulbar urethra, scrotal urethra and penile urethra. The sonographically positive results were compared with the pathological results. RESULTS: Eighty-three vegetations were found in the anterior urethra of seventeen patients, and eighty-one vegetations were diagnosed as CA by pathology, of which 1.2% were polyp shape, 38.3% papillary shape, and 60.5% cauliflower mass. Sonourethrography was an accurate predictor of papillary shape and cauliflower mass; however, it was difficult to differentiate between polyp shape vegetation and crystal. CONCLUSION: Sonourethrography is a sensitive and accurate tool not only for primary diagnosis of but also for follow-up of urethral CA in men.