Recepteur d'Origine Nantais (RON) is a distinct receptor tyrosine kinase in the c-met proto-oncogene family. We examined the mutational and expression patterns of RON in eight human uroepithelial cell lines. Biological effects of RON overexpression on cancer cells were investigated in vitro, and the prognostic significance of RON and/or c-met protein (MET) expression was analysed in a bladder cancer cohort (n ¼ 183). There was no evidence of mutation in the kinase domain of RON. Overexpression of RON using an inducible Tet-off system induced increased cell proliferation, motility, and antiapoptosis. Immunohistochemical analysis showed that RON was overexpressed in 60 cases (32.8%) of primary tumours, with 14 (23.3%) showing a high level of expression. Recepteur d'Origine Nantais expression was positively associated with histological grading, larger size, nonpapillary contour, and tumour stage (all Po0.01). In addition, MET was overexpressed in 82 cases (44.8%). Co-expressed RON and MET was significantly associated with decreased overall survival (P ¼ 0.005) or metastasis-free survival (P ¼ 0.01) in 35 cases (19.1%). Recepteur d'Origine Nantaisassociated signalling may play an important role in the progression of human bladder cancer. Evaluation of RON and MET expression status may identify a subset of bladder-cancer patients who require more intensive treatment.

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) has been reported to induce keratinocyte apoptosis in vitro by engaging its sole receptor of fibroblast growth factor-inducible 14 (Fn14). In this study, we explored the role of TWEAK/Fn14 pathway in the growth of psoriatic keratinocytes that is, however, characterized by suppressed apoptotic cell death. Skin tissues from the patients with psoriasis or healthy donors were determined for TWEAK and Fn14 expression, and primary keratinocytes were evaluated under the stimulation of psoriatic proinflammatory cytokines or plus TWEAK. The results showed that both TWEAK and Fn14 were highly expressed in psoriatic skins. Moreover, the stimulation of psoriatic cytokines enhanced Fn14 expression by keratinocytes in vitro, which expressed TNF receptor 2 predominantly and proliferated increasingly with the addition of TWEAK. Furthermore, TWEAK stimulation enhanced the synthesis of survivin, inhibitor of apoptosis protein 2 and cellular FLICE-inhibitory protein in lesional keratinocytes. Therefore, TWEAK/Fn14 interaction prefers to enhance proliferation but not apoptosis of keratinocytes under psoriatic inflammation. The activation of nuclear factor-κB signalling-dependent anti-apoptotic proteins and biased expression of TNF receptors may be responsible for such a novel principle in keratinocytes under psoriatic inflammation.

Abbreviations & AcronymsObjectives: To validate the predictive value of Fournier's Gangrene Severity Index in patients with Fournier gangrene and to facilitate patient mortality risk-stratification by simplifying the Fournier's Gangrene Severity Index. Methods: From January 1989 to December 2011, 85 male patients with clinicallydocumented Fournier's gangrene undergoing intensive treatment and with complete medical records were recruited. The demographic information and nine parameters of Fournier's Gangrene Severity Index were compared between survivors and non-survivors. The parameters that showed a significant difference between the two groups were selected to generate a simplified scoring index. Results: Of the 85 patients recruited, 16 patients died of the disease with mortality rate of 18.8%. The Fournier's Gangrene Severity Index score at initial diagnosis was significantly higher in non-survivors than in survivors. Of the nine parameters of Fournier's Gangrene Severity Index, the scores of serum creatinine level, hematocrit level and serum potassium level were significantly different between the two groups. However, the mean body temperatures, heart rate, respiration rate, white blood cell count, serum sodium and bicarbonate levels were non-significantly different. Of the 12 patients with chronic kidney disease or end-stage renal disease, 10 died of severe sepsis. A simplified scoring index including parameters of creatinine, hematocrit and potassium was generated, which provided sensitivity and specificity of 87% and 77% in predicting patient mortality, respectively. The predictive values of this simplified Fournier's Gangrene Severity Index were shown to be non-inferior to Fournier's Gangrene Severity Index in our patients. Conclusions:The simplified Fournier's Gangrene Severity Index is easy to use at initial diagnosis, and offers a way to compare outcomes in different clinical populations.

Previously, tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) had been known to be an inducer of apoptosis of keratinocytes by engaging the Fn14 receptor. However, the high-risk human papillomavirus (HPV) infection confers a proliferation advantage on keratinocytes that may consequently harbor tumorigenicity. This study was designed to investigate the cross-talk in keratinocytes between TWEAK/Fn14 signaling and HPV type 16 infection, which may cooperate in regulating cell-cycle progression. TWEAK and Fn14 expression was determined in anogenital warts and normal skin. Both primary keratinocytes and HaCaT cells were transfected with HPV16 E6/E7 genes. The results showed that Fn14 is highly expressed upon HPV16 transfection and accompanied by an increase in Ras GTPase activity and TNF-receptor-associated factor 2 (TRAF2) expression. Moreover, the E6/E7-transfected keratinocytes exhibit a shift of TNF receptor profile from type 1 to type 2 and weakened apoptotic response to TNF-α stimuli, when compared with the normal control. Surprisingly, significant increase in proliferation but not apoptosis was seen in E6/E7-positive keratinocytes, as TWEAK was additionally supplemented. In conclusion, the HPV16 infection in keratinocytes causes a switch of apoptotic to proliferative fate under TWEAK/Fn14 interaction, possibly by favoring Ras and TRAF2 activation and modulating TNF receptor expression.

What's known on the subject? and What does the study add?Silodosin administered by 4 mg twice daily is as effective as tamsulosin 0.2 mg daily in treating patients with LUTS associated with BPH.Relative to tamsulosin, silodosin has less cardiovascular side effects as judged by the minimal changes of blood pressure and pulse rats after treatment. OBJECTIVE• To test the hypothesis that the efficacy of silodosin would not be inferior to tamsulosin in treating patients with lower urinary tract symptoms associated with benign prostate hyperplasia (BPH). PATIENTS AND METHODS• At nine medical centres, 209 patients with an International Prostate Symptom Score (IPSS) of ≥ 13 were randomized to silodosin (4 mg twice daily) or tamsulosin (0.2 mg once daily) for 12 weeks.• The primary efficacy measure was the mean change from baseline to endpoint in IPSS.• The non-inferiority margin of the IPSS change was set at 1.0.• Secondary efficacy measures included change in maximal urinary flow rate (Q max ) and health-related quality of life (HRQL) score. RESULTS• Of the 170 (81.3%) patients who completed the study, 86.2% in the silodosin group vs 81.9% in the tamsulosin group achieved a ≥ 25% decrease in IPSS ( P = 0.53).• The mean difference (silodosin minus tamsulosin) in IPSS change from baseline was − 0.60 (95% confidence interval − 2.15, 0.95), inferring the non-inferiority of silodosin to tamsulosin.• The mean changes in the Q max and HRQL score from baseline were comparable between the groups (both, P > 0.05). Although patients receiving silodosin had a significantly higher incidence of abnormal ejaculation (9.7% vs tamsulosin 1.0%, P = 0.009), only 1.9% discontinued treatment.• Tamsulosin treatment resulted in a significant reduction in mean systolic blood pressure ( − 4.2 mmHg, within-group P = 0.004) relative to the negligible change of silodosin ( − 0.1 mmHg, within-group P = 0.96) CONCLUSION• The trial shows the non-inferiority of silodosin 4 mg twice daily to tamsulosin 0.2 mg once daily in patients with symptoms of BPH.

The c-met proto-oncogene plays a more important role in the progression of bladder carcinogenesis than p53. Evaluation of Met expression could identify a subset of bladder cancer patients who may require a more intensive treatment strategy.

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