Loss of DAB2IP in RCC cells enhances their growth and resistance to mTOR-targeted therapies.

Targeted therapies using small-molecule inhibitors (SMIs) are commonly used in metastatic renal cell cancer (mRCC) patients; patients often develop drug resistance and eventually succumb to disease. Currently, understanding of mechanisms leading to SMIs resistance and any identifiable predictive marker(s) are still lacking. We discovered that DAB2IP, a novel Ras-GTPase-activating protein, was frequently epigenetically silenced in RCC, and DAB2IP loss was correlated with the overall survival of RCC patients. Loss of DAB2IP in RCC cells enhances their sensitivities to growth factor stimulation and resistances to SMI (such as mammalian target of rapamycin (mTOR) inhibitors). Mechanistically, loss of DAB2IP results in the activation of extracellular signal-regulated kinase/RSK1 and phosphoinositide-3 kinase/mTOR pathway, which synergizes the induction of hypoxia-inducible factor (HIF)-2α expression. Consequently, elevated HIF-2α suppresses p21/WAF1 expression that is associated with resistance to mTOR inhibitors. Thus combinatorial targeting both pathways resulted in a synergistic tumor inhibition. DAB2IP appears to be a new prognostic/predictive marker for mRCC patients, and its function provides a new insight into the molecular mechanisms of drug resistance to mTOR inhibitors, which also can be used to develop new strategies to overcome drug-resistant mRCC.

Dietary resistant maltodextrin ameliorates testicular function and spermatogenesis in streptozotocin-nicotinamide-induced diabetic rats.

This study investigated the effect of resistant maltodextrin (RMD) on reproduction in streptozotocin (STZ)-nicotinamide-induced type 2 diabetic male rats. Forty male rats were induced with diabetes by a single intraperitoneal injection of STZ (50 mg kg(-1)) and nicotinamide (100 mg kg(-1)). Five groups were analysed in total: normal, diabetic rats without RMD, diabetic rats with RMD 1.2 g per 100 g diet (1×), with RMD 2.4 g per 100 g (2×), and with RMD 6.0 g per 100 g (5×). The groups of diabetic rats with the RMD supplement, compared to those without supplement, showed improved plasma glucose control, attenuated insulin resistance and recovery of testosterone level and spermatogenesis stage. The STZ-nicotinamide-induced diabetes mellitus (DM) caused a significant reduction in serum testosterone, testis androgen receptor (AR), steroidogenic acute regulatory protein (StAR) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) protein, but a statistical recovery in each of these was observed in the 5× group. TUNEL-positive cells were observed in the diabetic without RMD group, and RMD treatment reduced apoptotic germ cells. The expression of Bax/Bcl2 was induced in the diabetic group and also significantly reduced in the 5× group. Dietary RMD may improve metabolic control in STZ-nicotinamide-induced diabetic rats and attenuate hyperglycaemia-related impaired male reproduction and testicular function.

Exploration of the association between chronic periodontal disease and erectile dysfunction from a population-based view point.

Several cross-sectional studies have indicated an association between chronic periodontal disease (CPD) and cardiovascular disease and metabolic syndrome. Erectile dysfunction (ED) also shares pathological mechanisms with these diseases. Using a nationwide population-based data set, we examined the association between ED and CPD and assessed the effect of dental extraction (DE) on ED prevalence in different aged CPD populations in Taiwan. We identified 5105 patients with ED and randomly selected 10 210 patients as controls. Of these patients, 2617 (17.09%) were diagnosed with CPD according to the index data: 1196 (23.43%) in the ED group and 1421 (13.92%) in the control group. After adjusting for comorbid factors, patients with ED were more likely to have been diagnosed with prior CPD than controls (OR = 1.79, 95% CI = 1.64-1.96, P < 0.001). Moreover, the association was much stronger in the populations aged less than 30 years (OR = 2.13, 95% CI = 1.23-3.70, P < 0.001) and more than 59 years (OR = 2.27, 95% CI = 1.99-2.59, P < 0.001). Dental extraction seems to attenuate damage to the penile endothelial beds caused by CPD-related inflammation and overcame the process of ED in the middle-aged and older populations.

Short-term result of renal transplantation using extracorporeal membrane oxygenation-supported brain-dead donors.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is now widely used to maintain hemodynamic stability after traumatic events among medical centers. It remains unclear whether renal transplantation using ECMO-supported donors carries poorer outcomes. METHODS: From February 2010 to March 2013, we performed 9 renal transplantations (6 females and 3 males) from 5 ECMO-supported donors. Demographic data and clinical outcomes were retrospectively analyzed through medical chart review. RESULTS: The mean follow-up period was 15 ± 9 months (range: 8-37). Eight of the 9 grafts remained functioning within the follow-up period. One (11.1%) graft loss was noted after repeated acute rejection. Acute rejection occurred in 3/9 (33%) of cases. Delayed graft function was also observed in 3/9 (33%) of cases. CONCLUSION: Renal transplantation using ECMO-supported brain-dead donors was not associated with an unacceptably high rate of graft loss in this short-term follow-up. It might be an alternative way to expand donor pools.

Neuronal-derived nitric oxide modulates the activity of mouse detrusor smooth muscle.

AIMS: We investigated the roles of neuronal-derived nitric oxide (NO) in the modulation of spontaneous activity of mouse detrusor smooth muscle. METHODS: Detrusor smooth muscle strips were isolated from nNOS gene knock-out (nNOS(-/-) ) mice and their wild type siblings (nNOS(+/+) ). The properties of smooth muscle cells were assessed using intracellular electrophysiology and Ca(2+) imaging by laser-scanning confocal microscopy. The effects of an nNOS inhibitor, 7-nitro indazole (7-NI) on electrically evoked contractility were assessed using nNOS(+/+) mouse detrusor strips. RESULTS: In spontaneously active cells, the frequency of spontaneous action potentials (sAPs) and whole cell Ca(2+) flashes in nNOS(-/-) preparations was lower than that in the nNOS(+/+) preparations. The frequency of sAPs was enhanced by a nitric oxide donor, diethylamine NONOate sodium salt (NONOate; 100 µM), both when used alone and when the cGMP pathway was blocked by 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, 10 µM). 7-NI (100 µM) significantly suppressed the electrically evoked contraction of mouse detrusor strips. CONCLUSIONS: We suggest that neuronal-derived NO facilitates the generation of spontaneous activity via a cGMP-independent pathway, and consequently enhances the evoked contraction of detrusor. Dysregulation of nNOS containing nerves may underlie bladder pathologies.

Experience with intracavernous injection in the treatment of erectile dysfunction after radical prostatectomy: dose considerations.

We sought to identify factors influencing dose maintenance of intracavernous (IC) injection among patients with ED following radical prostatectomy. A total of 93 patients underwent prostatectomy and received IC treatment for ED, including PGE1 single therapy (n=53) and triple therapy (n=40). In the PGE1-only group, the maintenance dosage was significantly correlated with preoperative sexual function and nerve sparing (NS) (P<0.05). For example, the maintenance dose among patients with no, unilateral and bilateral NS was 10.8 ± 6.6 µg (0.54 ± 0.33 ml), 10.8 ± 3.8 µg (0.54 ± 0.19 ml) and 6.4 ± 4.6 µg (0.32 ± 0.23 ml), respectively. In terms of preoperative sexual function, the maintenance dose among non-ED versus ED patients was 0.38 ± 0.25 ml (7.6 ± 5.0 µg) and 0.59 ± 0.31 ml (11.8 ± 6.2 µg), respectively. No significant correlation was observed between the maintenance dose and NS or preoperative sexual function among the triple-therapy patients or between the maintenance dose and age, body mass index, systemic diseases and initiation of ED treatment among all patients (P>0.05). Thus, maintenance dose of PGE1 therapy could be partly determined by NS status and prior ED of patients.

Acute fulminant colon cancer metastasis after renal transplantation.

We report a 52-year-old male with no family history of colonic cancer, who was found to have advanced colonic cancer with metastases two months post renal transplantation. With this case, we highlight the possibility of acute fulminant cancer metastases within short period after renal transplantation and the importance of periodic colorectal cancer screening pre-transplant. To our knowledge, this case is not yet reported in the literature, especially with such presentation of acute fulminant colonic cancer metastases post renal transplantation.

Waldenström macroglobulinaemia presenting as a perirenal mass: a case report.

Perirenal masses are a rare manifestation of Waldenström macroglobulinaemia (WM). We report a 70-year-old male diagnosed with Waldenström macroglobulinaemia arising as a huge perirenal mass, which was discovered by abdominal ultrasound and computed tomography. The patient underwent ultrasound-guided aspiration biopsy and the histopathological examination showed a monoclonal lymphoplasmocitoid proliferation of B-cells arranged in a diffuse pattern. This case report shows not only the importance of image and biopsy studies, but also the good response to chemotherapy with the CHOP regimen.

Danish Prostatic Symptom Score is not associated with lower urinary tract symptom severity.

OBJECTIVES: Lower urinary tract symptoms (LUTS) are associated with sexual dysfunction; however, these can vary by population. Thus, the prevalence, severity, and predisposing factors for sexual dysfunction in Taiwanese men (> 40 y) who visited a urologic clinic for LUTS was determined. METHODS: During 2005 and 2006, a prospective survey was carried out which included 412 men with LUTS. Demographic data were collected during face-to-face interviews. Sexual dysfunction and LUTS were evaluated using the Danish Prostatic Symptom Score (DAN-PSS) and the International Prostate Symptom Score (IPSS) questionnaire, respectively. RESULTS: Mild, moderate, and severe LUTS were observed in 25.61%, 47.80%, and 26.59% of the patients, respectively. Reduced or absence of erection, reduced or no ejaculation, and pain upon ejaculation were found in 78.29%, 76.59%, and 6.11% of the patients, respectively. However, only 26.9%, 22.1%, and 4.4% of patients with erectile dysfunction (ED), ejaculatory dysfunction, and pain upon ejaculation were bothered by the sexual dysfunction, respectively. Age was significantly associated with ED, ejaculatory dysfunction (EjD), and pain with ejaculation (p < 0.001). The prevalence of sexual dysfunction increased with the severity of LUTS but was not significantly different. Patients with diabetes were 5.96 times more likely to have sexual dysfunction (95% CI = 1.39 to 25.60; p = 0.017). CONCLUSIONS: Over 70% of LUTS patients in this study suffered from sexual dysfunction. Although age and diabetes were associated with sexual dysfunction, LUTS severity was not.

Holmium: yttrium-aluminum-garnet laser endoureterotomy for benign ureteral strictures: a single-centre experience.

PURPOSE: This study aimed to report the results of endoureterotomy for benign ureteral strictures using the holmium: yttrium-aluminum-garnet laser. MATERIAL AND METHODS: Nineteen patients (8 men and 11 women, mean age 51.47 years) underwent holmium: yttrium-aluminum-garnet laser endoureterotomy for benign ureteral strictures (8 proximal, 3 middle, and 8 distal) using semi-rigid ureteroscopy and 360-microm fibre at 1.2 J/pulse and 10 Hz. After completion of the incision, a 7-Fr double-J ureteral stent was left for 6 weeks. Thereafter, the patients were followed-up by ultrasound and/or intravenous urography at 3-6 monthly intervals. RESULTS: Success was defined as the absence of symptoms plus radiographic resolution of obstructions as assessed by diuretic renography and/or intravenous urography. With a mean follow-up of 40.2 months, success was achieved in 10 (52.6%) of the 19 patients. Nine patients developed recurrent strictures and were considered treatment failures. The stricture length and severity of hydronephrosis correlated with successful outcome, but gender, aetiology, side and location of strictures did not predict outcome. CONCLUSIONS: Although endoureterotomy using a holmium : yttrium-aluminum-garnet laser has an equivocal outcome, the procedure is recommended as a safe, less invasive therapeutic option for the initial management of benign ureteral strictures.

Ejaculatory duct obstruction after transurethral resection of the prostate.

Transurethral resection of the prostate is currently the most commonly employed surgical procedure for benign prostatic hyperplasia. Although several complications after the procedure have been well documented, ejaculatory duct obstruction is a rare complication. We describe this unusual complication in a 77-year-old male who presented with severe pain and a feeling of fullness in the lower abdomen and with dry ejaculate on three occasions after undergoing post-transurethral resection of the prostate. The patient's post-ejaculatory urinalysis demonstrated no sperm. Transrectal ultrasonography also showed no dilatation of the bilateral seminal vesicles or ejaculatory ducts. However, ejaculatory duct obstruction was finally diagnosed on vasovesiculography. The patient was successfully treated with transurethral resection of the ejaculatory duct and remained asymptomatic 6 months postoperatively. Although transrectal ultrasonography is currently widely used to evaluate ejaculatory duct obstruction, we suggest that vasovesiculography is still a feasible and useful tool that provides detailed anatomic information for the advanced confirmation of ejaculatory duct obstruction in patients with a high suspicion of ejaculatory duct obstruction who have normal transrectal ultrasonography findings.

Association between lower urinary tract symptoms and sexual dysfunction in Taiwanese men.

The study investigated the association between lower urinary tract symptoms (LUTS) and sexual dysfunction in ageing men. It was a cross-sectional study in an unselected consecutive sample of 398 men aged >40 years attending a urology clinic. LUTS and sexual function were assessed by validated symptom scales, including the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function-5 (IIEF-5). Clinically the severity of total and obstructive IPSS showed no significant correlation with age, but irritative IPSS is statistically correlated with age (P < 0.05). The prevalence of moderate to severe ED (IIEF-5 < 12) was significantly associated with LUTS severity (P < 0.05) and the severity of IIEF-5 correlated significantly with age (P < 0.01). A consistent inverse correlation was found between IIEF-5 and IPSS severity across the age groups, with the strongest effect within aged 60 to 69 years (r = -0.286, P < 0.01). The irritative IPSS showed a significant correlation with IIEF-5 severity across all age groups. These results reveal a significant correlation between LUTS and the severity of ED, especially on the irritative domain.

The mechanisms and managements of hormone-therapy resistance in breast and prostate cancers.

Breast and prostate cancer are the most well-characterized cancers of the type that have their development and growth controlled by the endocrine system. These cancers are the leading causes of cancer death in women and men, respectively, in the United States. Being hormone-dependent tumors, antihormone therapies usually are effective in prevention and treatment. However, the emergence of resistance is common, especially for locally advanced tumors and metastatic tumors, in which case resistance is predictable. The phenotypes of these resistant tumors include receptor-positive, ligand-dependent; receptor-positive, ligand-independent; and receptor-negative, ligand-independent. The underlying mechanisms of these phenotypes are complicated, involving not only sex hormones and sex hormone receptors, but also several growth factors and growth factor receptors, with different signaling pathways existing alone or together, and with each pathway possibly linking to one another. In this review, we will discuss the potential mechanisms of antihormone-therapy resistance in breast and prostate cancers, especially focusing on the similarities and differences of these two cancers. We will also discuss novel agents that have been applied in clinical practice or with clinical potential in the future.

Conjugation of maturation-related wheat-germ-lectin-binding proteins to caput epididymal sperm in co-cultures with corpus epididymal epithelial cells of BALB/c mouse.

In BALB/c mice, two maturation-related wheat-germ-binding glycoproteins (GP-49 and GP-83) are synthesized and secreted by corpus and cauda epididymis. A co-culture technique was used to investigate these glycoproteins in principal cells of corpus epididymis and the conjugation of these molecules on caput sperm. The principal cells were recovered from corpus epididymides of 4-week-old mice and cultured in RPMI 1640 medium supplemented with 10% fetal calf serum. After culturing for 3-4 days, most cells revealed epithelial cell-specific keratins in immunofluorescent localization with monoclonal antibody. By electron microscopy, a prominent nucleolus with well-extended euchromatin was revealed in the nucleus and the cytoplasm contained multivesicular bodies, and a well-developed Golgi apparatus with endoplasmic reticulum. By SDS-PAGE, GP-83 and GP-49 were revealed in the cell extracts and cell culture supernatants after incubation with 35S-methionine. Radiolabeled binding sites were also found on the surface of caput sperm co-cultured with the principal cells for 4 h in the presence of 35S-methionine. WGA-binding glycoproteins may be synthesized and secreted by the principal cells of corpus epididymis and conjugated to caput sperm during the epididymal transit.