Dynamic changes of quality of life in muscle-invasive bladder cancer survivors.

BACKGROUND: To explore the dynamic changes and effects of radical cystectomy on quality of life in muscle-invasive bladder cancer survivors. METHODS: Patients with muscle-invasive bladder cancer were randomly recruited in this study. We used the World Health Organization Quality of Life-Brief questionnaire to assess consecutive patients' quality of life. We applied kernel smoothing to illustrate the dynamic changes of the domain and item scores after treatment. Mixed-effects models were constructed to determine the effects of radical cystectomy on the scores of each item and domain of the World Health Organization Quality of Life-Brief questionnaire after controlling demographic and clinical factors. RESULTS: We collected 397 repeated measurements of the World Health Organization Quality of Life-Brief questionnaire from 109 muscle-invasive bladder cancer patients. Forty-two of them received radical cystectomy. Patients with radical cystectomy exhibited higher levels of education, less co-morbidities (i.e., diabetes and heart diseases), but were associated with more malignancies. Construction of mixed-effects models showed patients with radical cystectomy and those with bladder sparing had similar scores in the three main domains and their items, except that of certain items of physical domain. By applying kernel smoothing method, we found that stage III-IV patients consistently showed higher scores on sleep and rest after radical cystectomy for more than 5 years. In contrast, stage II patients receiving radical cystectomy did not show a higher score on the "sleep and rest" item compared with those with bladder sparing operation. CONCLUSIONS: Radical cystectomy may result in sound sleep and rest, especially in those with stage III-IV bladder cancer.

The DeltaN p63 Promotes EMT and Metastasis in Bladder Cancer by the PTEN/AKT Signalling Pathway.

Bladder cancer is a common tumour of the urinary system, and more than 90% is urothelial carcinoma. Therefore, it is important for discovering the key target genes and molecules of bladder tumour cell metastasis and invasion. Our research initially explored the regulation of deltaN p63 on the progression and metastasis of bladder cancer and found that deltaN p63 can influence the occurrence of EMT through PTEN and ultimately regulate the growth and metastasis of bladder cancer. In summary, this study identified a new EMT regulator, deltaN p63, further revealed the mechanism of the invasion and metastasis of bladder cancer cells, and provided a theoretical basis for finding new target molecules and drugs to treat bladder cancer. In conclusion, this study will further reveal the mechanism of tumour cell invasion and metastasis and provide a theoretical basis for cancer treatment to find new target molecules and drugs.

Simvastatin delays castration­resistant prostate cancer metastasis and androgen receptor antagonist resistance by regulating the expression of caveolin­1.

The failure of androgen deprivation therapy in prostate cancer treatment mainly results from drug resistance to androgen receptor antagonists. Although an aberrant caveolin­1 (Cav­1) expression has been reported in multiple tumor cell lines, it is unknown whether it is responsible for the progression of castration­resistant prostate cancer (CRPC). Thus, the aim of the present study was to determine whether Cav­1 can be used as a key molecule for the prevention and treatment of CRPC, and to explore its mechanism of action in CRPC. For this purpose, tissue and serum samples from patients with primary prostate cancer and CRPC were analyzed using immunohistochemistry and enzyme­linked immunosorbent assay, which revealed that Cav­1 was overexpressed in CRPC. Furthermore, Kaplan­Meier survival analysis and univariate Cox proportional hazards regression analysis demonstrated that Cav­1 expression in tumors was an independent risk factor for the occurrence of CRPC and was associated with a shorter recurrence­free survival time in patients with CRPC. Receiver operating characteristic curves suggested that serum Cav­1 could be used as a diagnostic biomarker for CRPC (area under the curve, 0.876) using a cut­off value of 0.68 ng/ml (with a sensitivity of 82.1% and specificity of 80%). In addition, it was determined that Cav­1 induced the invasion and migration of CRPC cells by the activation of the H­Ras/phosphoinositide­specific phospholipase Cε signaling cascade in the cell membrane caveolae. Importantly, simvastatin was able to augment the anticancer effects of androgen receptor antagonists by downregulating the expression of Cav­1. Collectively, the findings of this study provide evidence that Cav­1 is a promising predictive biomarker for CRPC and that lowering cholesterol levels with simvastatin or interfering with the expression of Cav­1 may prove to be a useful strategy with which to prevent and/or treat CRPC.

Incorporating Simplified Fournier's Gangrene Severity Index with early surgical intervention can maximize survival in high-risk Fournier's gangrene patients.

OBJECTIVES: To determine the optimal surgical timing in high-risk patients with Fournier's gangrene by the Simplified Fournier's Gangrene Severity Index. METHODS: From 1989 to 2018, 118 male patients diagnosed with Fournier's gangrene with complete medical records were retrospectively reviewed. Patients' demographics, laboratory parameters at initial diagnosis, Fournier's Gangrene Severity Index and Simplified Fournier's Gangrene Severity Index, and the time interval from emergency room arrival to surgical intervention were collected. The Fournier's gangrene patients were categorized into low-risk (Simplified Fournier's Gangrene Severity Index ≤2) and high-risk groups (Simplified Fournier's Gangrene Severity Index >2). Differences between the variables within the two groups were analyzed. The optimal surgical timing was analyzed with the receiver operating characteristic curve in high-risk Fournier's gangrene patients. RESULTS: The overall mortality of 118 Fournier's gangrene patients was 14.4%. After risk stratification with the Simplified Fournier's Gangrene Severity Index scoring system, the mortality of low-risk and high-risk Fournier's gangrene patients was 1.3% and 41.0%, respectively. In the high-risk group, the time interval from emergency room arrival to surgical intervention was the only variable with a significant difference between survivors and non-survivors (P = 0.039). The optimal surgical timing was determined at 14.35 h, which allowed the highest sensitivity (0.688) and specificity (0.762) to affect mortality. The mortality was significantly lower in high-risk Fournier's gangrene patients with early surgical intervention compared with late intervention (23.8% vs 68.8%, P = 0.007). CONCLUSIONS: The Simplified Fournier's Gangrene Severity Index is a quick and reliable screening tool for first-line physicians to identify high-risk patients with Fournier's gangrene (Simplified Fournier's Gangrene Severity Index >2) who have poor survival outcomes. We recommended early surgical intervention within 14.35 h to maximize the survival of high-risk Fournier's gangrene patients.

Management of nocturnal enuresis in Taiwan: Consensus statements of the Taiwan enuresis expert committee.

Nocturnal enuresis causes significant psychological distress to affected children and their family and requires appropriate management. A 12-member expert committee of pediatric urologists and pediatric nephrologists in Taiwan with extensive experience in treating enuresis was established to develop consensus statements and a recommended treatment algorithm for the management of patients with nocturnal enuresis in Taiwan after careful consideration of current evidence, existing guidelines, and expert opinion as well as local practice and culture. The finalized consensus statements were reviewed by and have received endorsement from the Taiwan Urological Association and the Taiwan Pediatric Association. Patients with suspected enuresis should undergo a thorough initial assessment to fully evaluate urinary signs and symptoms and to rule out underlying causes of diurnal and nocturnal incontinence. Behavioral therapy is recommended throughout the course of management. Desmopressin in the fast-melting formulation is the recommended first-line pharmacological treatment. Combination therapy may be effective in patients who have failed first-line treatment. These consensus statements and a recommended treatment algorithm were created by the expert committee to provide practical support for clinical decision making by physicians in Taiwan.

Long-term outcomes of total ureterectomy with ileal-ureteral substitution treatment for ureteral cancer: a single-center experience.

BACKGROUND: To explore the feasibility and long-term outcomes of renal preservation in a retrospective cohort of patients with ureteral urothelial carcinoma undergoing total ureterectomy with ileal-ureteral substitution. METHODS: A retrospective review of the data from patients treated with total ureterectomy with ileal-ureteral substitution from 1988 to 2016 was performed. The pre-operative oncological status, long-term oncological outcome, long-term renal functional outcome, early and late complications were analyzed. RESULTS: A total of eight patients with a median age of 70 years were included. The median follow-up time was 109 months. Six patients had multi-focal tumor involvement over the target ureter, and six patients had bilateral upper tract involvement. Only one patient encountered the upper-tract recurrence. The 2 and 5-year cancer-specific survival rates were 87.5 and 75.0%, respectively. The renal function was well-preserved in most patients, with only one patient needed life-long postoperative hemodialysis. Five patients experienced early complications and four patients experienced late complications. No perioperative mortality happened. CONCLUSIONS: A total ureterectomy with an ileal-ureteral substitution is feasible for treating ureteral urothelial carcinoma when a renal-sparing procedure is indicated. It provides good long-term oncological outcomes over the upper tract, and it also preserves the renal function.

Detecting miRNA biomarkers from extracellular vesicles for cardiovascular disease with a microfluidic system.

According to World Health Organization reports, cardiovascular diseases (CVDs) are amongst the major causes of death globally and are responsible for over 18 million deaths every year. Traditional detection methods for CVDs include cardiac computerized tomography scans, electrocardiography, and myocardial perfusion imaging scans. Although diagnosis of CVDs through such bio-imaging techniques is common, these methods are relatively costly and cannot detect CVDs in their earliest stages. In contrast, the levels of certain micro RNA (miRNA) biomarkers extracted from extracellular vesicles (EVs) in the bloodstream have been recognized as promising indicators for early CVD detection. However, detection and quantification of miRNA using existing methods are relatively labor-intensive and time-consuming. In this study, a new integrated microfluidic system equipped with highly sensitive field-effect transistors (FETs) was capable of performing EV extraction, EV lysis, target miRNA isolation and miRNA detection within 5 h. The limit of detection was within the physiological range (femtomolar) for two targeted miRNAs, miR-21 and miR-126, meaning that this integrated microfluidic system has the potential to be used as a tool for early detection of CVDs.

Associations between arsenic in drinking water and occurrence of end-stage renal disease with modifications by comorbidities: A nationwide population-based study in Taiwan.

Arsenic may affect the function of proximal convoluted tubules and glomeruli, but epidemiological data on the association between arsenic ingestion and end-stage renal disease (ESRD) are limited. Therefore, we conducted a nationwide population-based study in Taiwan, where the incidence of ESRD is the highest in the world, to study the potential association. Using the National Health Insurance Database in Taiwan, we constructed a cohort of 362,505 members with age≥40years in 1998. We identified patients of ESRD newly diagnosed between January 1, 1998 and December 31, 2010 and performed Cox proportional hazard regressions to identify risk factors for ESRD and evaluate their effects. Arsenic levels in drinking water were assessed on the basis of a nationwide census survey conducted by the government, of which measurement reports were available for 311 townships. We identified 5442 new patient of ESRD during the study period and found that residents of areas with arsenic levels≥50µg/L in the drinking water had a hazard ratio (HR) of 1.14 (95% confidence interval [CI]: 1.08-1.21) for ESRD. After adjusting for sex, age, income, and comorbidities, we found an adjusted HR of 1.12 (95% CI: 1.06-1.19), which was still statistically significant. Furthermore, the effect was modified by comorbidities, with more prominent effects on patients with less than three comorbidities (adjusted HR=1.51; 95% CI: 1.22-1.86 for low comorbidity score). In conclusion, a high arsenic level in drinking water was a risk factor for ESRD, independent of other documented risk factors. Reducing high-risk comorbidities in patients with early-stage renal dysfunction is important for slowing the progression of the disease to ESRD, even in the endemic area of arsenic exposure.

The role of Lutheran/basal cell adhesion molecule in human bladder carcinogenesis.

BACKGROUND: Lutheran/basal cell adhesion molecule (Lu/BCAM) is a membrane bound glycoprotein. This study was performed to investigate the role and downstream signaling pathway of Lu/BCAM in human bladder tumorigenesis. METHODS: Five human bladder cancer (E6, RT4, TSGH8301, TCCSUP and J82), one stable mouse fibroblast cell line (NIH-Lu) expressing Lu/BCAM transgene and sixty human uroepithelial carcinoma specimens were analyzed by real-time PCR, immunohistochemistry (IHC), immunofluorescence (IFA) staining, Western blotting and promoter luciferase assay for Lu/BCAM, respectively. The tumorigenicity of Lu/BCAM was demonstrated by focus formation, colony-forming ability, tumour formation, cell adhesion and migration. RESULTS: H-ras V12 was revealed to up-regulate Lu/BCAM at both transcriptional and translation levels. Lu/BCAM expression was detected on the membrane of primary human bladder cancer cells. Over-expression of Lu/BCAM in NIH-Lu stable cells increased focus number, colony formation and cell adhesion accompanied with F-actin rearrangement and decreased cell migration compared with parental NIH3T3 fibroblasts. In the presence of laminin ligand, Lu/BCAM overexpression further suppressed cell migration accompanied with increased cell adhesion. We further revealed that laminin-Lu/BCAM-induced cell adhesion and F-actin rearrangement were through increased Erk phosphorylation with an increase of RhoA and a decrease of Rac1 activity. Similarly, high Lu/BCAM expression was detected in the tumors of human renal pelvis, ureter and bladder, and was significantly associated with advanced tumor stage (p = 0.02). Patients with high Lu/BCAM expression showed a trend toward larger tumor size (p = 0.07) and lower disease-specific survival (p = 0.08), although not reaching statistical significance. CONCLUSION: This is the first report showing that Lu/BCAM, in the presence of its ligand laminin, is oncogenic in human urothelial cancers and may have potential as a novel therapeutic target.

Antiangiogenesis as the novel mechanism for justicidin A in the anticancer effect on human bladder cancer.

Justicidin A (JA) is one of the methanol extracts of Justicia procumbens and was reported to induce apoptosis and inhibit the proliferation of human colon cancer cells. Using bladder cancer as a paradigm, this study was designed to identify the novel molecular basis underlying the antiangiogenic activities of JA and its potential in cancer therapy. Human bladder cancer cell lines (TSGH8301 and RT4) and immortalized uroepithelial cell lines (E6 and E7) were chosen to investigate the efficacy of JA in cell proliferation, apoptosis, and angiogenesis in vitro. The biological effects of JA treatment in vivo were examined using a xenograft tumor model in SCID mice. JA showed a dose-dependent and time-dependent inhibition of cell proliferation on TSGH8301 cancer cells, with IC50 values determined to be 0.44 µmol/l. Of interest, TSGH8301 cancer cells were more sensitive to JA than E7 immortalized uroepithelial cells, especially at lower concentrations. We further showed that JA inhibited the autocrine production of angiogenic factors and matrix-degrading enzymes in vitro and microvessel density in SCID mice in vivo (P< 0.01). Both differential cytotoxicity and angiogenesis inhibition of JA were confirmed by SCID mice experiments. Together, JA showed antiangiogenesis in vitro and in vivo through pleiotropic positive and negative regulators of angiogenesis molecules. The current investigation supports the potential of JA as an alternative chemoprevention agent for human bladder cancer.

Validation and simplification of Fournier's gangrene severity index.

OBJECTIVES: 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 clinically-documented 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.

Epithelial membrane protein 2 is a prognostic indictor for patients with urothelial carcinoma of the upper urinary tract.

Upper urinary tract urothelial carcinoma is a relatively uncommon disease and is diagnosed more frequently at advanced stages. The prognosis of these patients mainly has been related to tumor stage and grade. As a result, the definition of prognostic indicators enabling precise patient selection is mandatory for neoadjuvant or adjuvant therapies. The epithelial membrane protein (EMP2) was identified as one of the up-regulated genes by isoflavones. EMP2 overexpression suppressed foci formation, anchorage-independent growth in vitro, and tumorigenicity in severe combined immunodeficiency mice (all P < 0.05). In addition, a cross-talk between EMP2 and integrins αV and ß3 was shown in the regulation of cell adhesion and migration. Higher EMP2 expression was associated with a better progression-free survival (P = 0.008) and cancer-related death (P < 0.001). EMP2 was identified as a tumor-suppressor gene in urinary tract urothelial carcinoma and may be an innovative co-targeting candidate for designing integrin-based cancer therapy.

Risk factors for renal scarring and deterioration of renal function in primary vesico-ureteral reflux children: a long-term follow-up retrospective cohort study.

BACKGROUND AND PURPOSE: The aim was to identify the risk factors for renal scarring and deteriorating renal function in children with primary vesico-ureteral reflux (VUR). MATERIALS AND METHODS: Patients with primary VUR admitted to the National Cheng Kung University Hospital were retrospectively analyzed. The outcomes were renal scarring, assessed by technetium-99 m dimercaptosuccinic acid scanning, and renal function, assessed by estimated glomerular filtration rate. Univariate and multivariate models were applied to identify the corresponding independent predictors. RESULTS: A total of 173 patients with primary VUR were recruited. The median age of VUR diagnosis was 10.0 months (IQR: 4.0-43.0 months). After adjusting for confounding factors, it was found that older age of VUR diagnosis (≥5 years vs. <1 year, adjusted OR = 2.78, 95% CI = 1.00-7.70, p = 0.049), higher grade of VUR (high grade [IV-V] vs. none, adjusted OR = 15.17, 95% CI = 5.33-43.19, p<0.0001; low grade [I-III] vs. none, adjusted OR = 5.72, 95% CI = 2.43-13.45, p<0.0001), and higher number of UTI (≥2 vs. 0, adjusted OR = 3.21, 95% CI = 1.06-9.76, p = 0.039) were risk factors for renal scarring, whereas a younger age of VUR diagnosis (≥5 years vs. <1 year, adjusted HR = 0.16, 95% CI: 0.05-0.51, p = 0.002), renal scarring (yes vs. no, adjusted HR = 3.66, 95% CI: 1.32-10.16, p = 0.013), and APN (yes vs. no, adjusted HR = 3.10, 95% CI: 1.05-9.14, p = 0.041) were risk factors for developing chronic kidney disease stage 2 or higher. CONCLUSIONS: Our findings expand on the current knowledge of risk factors for renal scarring and deteriorating renal function, and this information can be used to modify the management and treatment of VUR.

Clinical Significance of ErbB Receptor Family in Urothelial Carcinoma of the Bladder: A Systematic Review and Meta-Analysis.

The prognostic importance of examining ErbB receptor family expression in human bladder cancer remains uncertain. Using published evidence, we examined the clinical value and the updated results of clinical trials targeting ErbB receptor family members. Twenty-seven articles from 65 references related to ErbB receptor expression assessment in bladder cancer were reviewed. The estimates included the association significance, hazard ratios, and 95% confidence intervals (CIs) from actuarial curves and survival analyses. A meta-analysis was done on those reports using univariate log-rank tests or a Cox-regression model. The methods of analysis and study subjects chosen varied widely among studies. The overall risks of disease progression for patients with EGFR or ErbB2 overexpression were 4.5 (95% CI: 2.5-8.4) and 1.1 (95% CI: 0.6-1.9), and the risks of mortality were 3.0 (95% CI: 1.6-5.9) and 1.1 (95% CI: 1.0-1.2), respectively. However, the significance of coexpression patterns of the ErbB receptor family remains controversial. None of six clinical trials yielded convincing results for blockading ErbB receptor signaling in urothelial carcinoma. The results of this analysis suggest that assessing co-expression patterns of the ErbB family may provide better prognostic information for bladder cancer patients.

Non-inferiority of silodosin to tamsulosin in treating patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

UNLABELLED: 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.

Urinary CD14 as a potential biomarker for benign prostatic hyperplasia - discovery by combining MALDI-TOF-based biostatistics and ESI-MS/MS-based stable-isotope labeling.

PURPOSE: Quest for specific urinary biomarkers for benign prostatic hyperplasia (BPH). EXPERIMENTAL DESIGN: Proteomics studies were conducted with urines of the training set to discovering marker candidates that could differentiate BPH from normal subjects by matching results deduced from MALDI-TOF of individual samples and results deduced from nanoLC-ESI-MS/MS-based stable isotope dimethyl labeling of two pooled samples (BPH and normal). Samples were digested before analysis and such an approach takes into account the subject-to-subject variation and differential amount, as well as protein identification. Selected markers were validated by ELISA conducted on the training set and the test set as well as another set of urines collected from prostate cancer patients. RESULTS: Nine marker candidates were identified from proteomics studies; CD14, prostate-specific antigen and pancreatic α-amylase precursor were further selected for ELISA validation. Urinary CD14 is among the best match with high specificity (>81%) for both training and test sets. In addition, from the study of prostate cancer patients, CD14 also allows the distinction of BPH from cancer with high specificity (84-100%) when combined with urinary prostate-specific antigen. CONCLUSIONS AND CLINICAL RELEVANCE: Urinary CD14 is suggested to have a high specificity in the diagnosis of BPH in distinction from normal as well as cancer subjects.

An unusual function of RON receptor tyrosine kinase as a transcriptional regulator in cooperation with EGFR in human cancer cells.

Homodimerization of RON (MST1R), a receptor tyrosine kinase, usually occurs in cells stimulated by a ligand and leads to the downstream activation of signaling pathways. Here we report that bladder cancer cells, in response to physiological stress, use an alternative mechanism for signaling activation. Time-course studies indicated that RON migrated directly from the membrane to the nucleus of bladder cancer cells in response to serum starvation. Biochemical and genetic studies implied that this nuclear internalization was complexed with epidermal growth factor receptor (EGFR) and required the docking of importins. In vivo analysis confirmed that nuclear RON was present in 38.4% (28/73) of primary bladder tumors. Chromatin immunoprecipitation (ChIP) on microarray analysis further revealed that this internalized complex bound to at least 134 target genes known to participate in three stress-responsive networks: p53, stress-activated protein kinase/c-jun N-terminal kinase and phosphatidylinositol 3-kinase/Akt. These findings suggest that RON, in a complex with EGFR, acts as a transcriptional regulator in response to acute disturbances (e.g. serum starvation) imposed on cancer cells. In an attempt to re-establish homeostasis, these cells bypass regular mechanisms required by ligand stimulation and trigger the RON-directed transcriptional response, which confers a survival advantage.

[Effects of silencing transforming growth factor-beta1 by RNAi upon transdifferentiation of renal allograft tubular epithelial cells in rats].

OBJECTIVE: To investigate the effects of shRNA-transforming growth factor (TGF)-beta1 plasmid upon epithelial-myofibroblast transdifferentiation of renal allograft in rats. METHODS: Divided the Wistar rats into 4 groups: Group J (sham-operated group), T (plasmid group), H (vacant plasmid group) and Y (simply transplantation group). The SD to Wistar rat transplant kidney-sclerosis accelerated model was constructed and transfected with the plasmid based on hydromechanics. Transplanted kidneys were collected at Months 1, 2 and 3 post-transplantation. The gene transcriptional levels of TGF-beta1 and E-cadherin were detected by RT-PCR and the protein variation of E-cadherin was examined by Western blotting. The pathological changes and infiltrated inflammatory cells were assessed by HE staining and the immunohistochemical staining of E-cadherin and alpha-SMA used to label epithelial cells and fibroblast in order to exhibit cell transdifferentiation. RESULTS: Compared with Group H and Y, the mRNA transcription of TGF-beta1 was obviously inhibited in the Group T: at Month 3, the TGF-beta1 mRNA of Group T is 0.73 +/- 0.08, significantly lower than Group H and Y (0.92 +/- 0.07 and 0.95 +/- 0.04, both P < 0.01); the expression of E-cadherin was maintained at a high level: at the Month 3, the E-cadherin mRNA of Group T is 0.39 +/- 0.11, significantly higher than Group H and Y (0.15 +/- 0.07, and 0.17 +/- 0.06, both P < 0.01); the E-cadherin protein of Group T is 0.38 +/- 0.08, significantly higher than group H and Y (0.15 +/- 0.07 and 0.15 +/- 0.07, both P < 0.01); epithelial cells were much more and fibroblast was much less than that of Group H and Y; there were also less infiltrated chronic inflammatory cells and extracellular matrix deposition in the Group T. CONCLUSION: The shRNA-TGF-beta1 plasmid can inhibit the epithelial-myofibroblast transdifferentiation of renal allograft in rats. The mechanisms may be associated with its effects of down-regulating TGF-beta1 and up-regulating E-cadherin.

The molecular signature for urothelial carcinoma of the upper urinary tract.

PURPOSE: Frequent loss of heterozygosity of microsatellites on a specific chromosomal region has been reported in various types of human cancer. The same loss of heterozygosity has also been identified in matched serum or urine DNA. We determined a urine microsatellite marker profile specific to urothelial carcinoma of the upper urinary tract. MATERIALS AND METHODS: We analyzed the loss of heterozygosity of primary tumors and their matched urine DNA samples from 30 patients with urothelial carcinoma of the upper urinary tract. We investigated a total of 77 markers from 25 chromosomal regions and a total of 53 from 23 chromosomal regions for their preferential loss in urothelial carcinoma and renal cell carcinoma of the kidney, respectively. Specificity was then confirmed in a cohort of 22 renal cell carcinoma cases. RESULTS: Of 30 patients with urothelial carcinoma 25 (83.3%) were detected using the molecular urine test. Of 48 markers detected as loss of heterozygosity in urine 20 (41.7%) were localized at the chromosomal loci reported for renal cell carcinoma. The diagnostic specificity of the remaining 31 markers was cross-validated in a renal cell carcinoma cohort. With the cutoff set at 100% specificity urothelial carcinoma was accurately diagnosed in 24 of 30 patients (80.0%) using 13 markers, including D9S195, D18S67, GSN, D1S162, D8S261, D3S1300, D21S1436, D16S310, D3S1307, FABP2, D11S907, D15S1007 and D13S133. CONCLUSIONS: The marker panel may permit a high throughput differential diagnosis of urothelial carcinoma of the upper urinary tract from that of renal cell carcinoma at an early stage of disease. The accurate diagnosis of renal cancer may help determine appropriate treatment planning and minimizing intraoperative frozen consultation.

Immunohistochemical detection of prostate-specific antigen expression in primary urothelial carcinoma of the urinary bladder.

BACKGROUND: Prostate-specific antigen (PSA) is a 33-kDa serine protease that is secreted by prostatic epithelium and non-prostate tissues. Ectopic expression of PSA has also been reported in a variety of non-prostatic epithelial tumors. PATIENTS AND METHODS: Expression of PSA and its clinical implication were examined in a total of 422 cases of primary urothelial carcinoma of the bladder. RESULTS: Cytoplasmic reactivity to PSA was observed in 6 cases (1.4%), with the staining being to a low degree in 3 and a high degree in the remaining 3 cases. Expression of PSA was positively related to multiplicity, large tumors (> or = 3 cm) and muscle invasion (> or = pT2) (p = 0.0008, 0.004 and 0.03, respectively). Patients with tumors of low PSA expression had a better survival than those with tumors of high PSA expression (p = 0.03). CONCLUSION: Focal expression of PSA can occasionally be detected in some large, invasive urothelial cancer cells. This phenotypic change should be considered in the differential diagnosis of poorly differentiated carcinoma of the lower urinary tract.