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1.  Stilbene Induced Inhibition of Androgen Receptor Dimerization: Implications for AR and ARΔLBD-Signalling in Human Prostate Cancer Cells 
PLoS ONE  2014;9(6):e98566.
Background
Advanced castration resistant prostate cancer (CRPC) is often characterized by an increase of C-terminally truncated, constitutively active androgen receptor (AR) variants. Due to the absence of a ligand binding domain located in the AR-C-terminus, these receptor variants (also termed ARΔLBD) are unable to respond to all classical forms of endocrine treatments like surgical/chemical castration and/or application of anti-androgens.
Methodology
In this study we tested the effects of the naturally occurring stilbene resveratrol (RSV) and (E)-4-(2, 6-Difluorostyryl)-N, N-dimethylaniline, a fluorinated dialkylaminostilbene (FIDAS) on AR- and ARΔLBD in prostate cancer cells. The ability of the compounds to modulate transcriptional activity of AR and the ARΔLBD-variant Q640X was shown by reporter gene assays. Expression of endogenous AR and ARΔLBD mRNA and protein levels were determined by qRT-PCR and Western Blot. Nuclear translocation of AR-molecules was analyzed by fluorescence microscopy. AR and ARΔLBD/Q640X homo-/heterodimer formation was assessed by mammalian two hybrid assays. Biological activity of both compounds in vivo was demonstrated using a chick chorioallantoic membrane xenograft assay.
Results
The stilbenes RSV and FIDAS were able to significantly diminish AR and Q640X-signalling. Successful inhibition of the Q640X suggests that RSV and FIDAS are not interfering with the AR-ligand binding domain like all currently available anti-hormonal drugs. Repression of AR and Q640X-signalling by RSV and FIDAS in prostate cancer cells was caused by an inhibition of the AR and/or Q640X-dimerization. Although systemic bioavailability of both stilbenes is very low, both compounds were also able to downregulate tumor growth and AR-signalling in vivo.
Conclusion
RSV and FIDAS are able to inhibit the dimerization of AR and ARΔLBD molecules suggesting that stilbenes might serve as lead compounds for a novel generation of AR-inhibitors.
doi:10.1371/journal.pone.0098566
PMCID: PMC4041728  PMID: 24887556
2.  Survival advantage of partial over radical nephrectomy in patients presenting with localized renal cell carcinoma 
BMC Cancer  2014;14:372.
Background
Partial nephrectomy (PN) preserves renal function and has become the standard approach for T1a renal cell carcinoma (RCC). However, there is still an ongoing debate as to which patients will actually derive greater benefit from partial than from radical nephrectomy (RN). The aim of this study was to retrospectively evaluate the impact of the type of surgery on overall survival (OS) in patients with localized RCC.
Methods
Renal surgery was performed in 4326 patients with localized RCC (pT ≤ 3a N/M0) at six German tertiary care centers from 1980 to 2010: RN in 2955 cases (68.3%), elective (ePN) in 1108 (25.6%), and imperative partial nephrectomy (iPN) in 263 (6.1%) cases. The median follow-up for all patients was 63 months. Kaplan-Meier and Cox regression analyses were carried out to identify prognosticators for OS.
Results
PN was performed significantly more often than RN in patients presenting with lower tumor stages, higher RCC differentiation, and non-clear cell histology. Accordingly, the calculated 5 (10)-year OS rates were 90.0 (74.6)% for ePN, 83.9 (57.5)% for iPN, and 81.2 (64.7)% for RN (p < 0.001). However, multivariate analysis including age, sex, tumor diameter and differentiation, histological subtype, and the year of surgery showed that ePN compared to RN still qualified as an independent factor for improved OS (HR 0.79, 95% CI 0.66-0.94, p = 0.008).
Conclusion
Even allowing for the weaknesses of this retrospective analysis, our multicenter study indicates that in patients with localized RCC, PN appears to be associated with better OS than RN irrespective of age or tumor size.
doi:10.1186/1471-2407-14-372
PMCID: PMC4038042  PMID: 24885955
3.  German second-opinion network for testicular cancer: Sealing the leaky pipe between evidence and clinical practice 
Oncology Reports  2014;31(6):2477-2481.
In 2006, the German Testicular Cancer Study Group initiated an extensive evidence-based national second-opinion network to improve the care of testicular cancer patients. The primary aims were to reflect the current state of testicular cancer treatment in Germany and to analyze the project’s effect on the quality of care delivered to testicular cancer patients. A freely available internet-based platform was developed for the exchange of data between the urologists seeking advice and the 31 second-opinion givers. After providing all data relevant to the primary treatment decision, urologists received a second opinion on their therapy plan within <48 h. Endpoints were congruence between the first and second opinion, conformity of applied therapy with the corresponding recommendation and progression-free survival rate of the introduced patients. Significance was determined by two-sided Pearson’s χ2 test. A total of 1,284 second-opinion requests were submitted from November 2006 to October 2011, and 926 of these cases were eligible for further analysis. A discrepancy was found between first and second opinion in 39.5% of the cases. Discrepant second opinions led to less extensive treatment in 28.1% and to more extensive treatment in 15.6%. Patients treated within the framework of the second-opinion project had an overall 2-year progression-free survival rate of 90.4%. Approximately every 6th second opinion led to a relevant change in therapy. Despite the lack of financial incentives, data from every 8th testicular cancer patient in Germany were submitted to second-opinion centers. Second-opinion centers can help to improve the implementation of evidence into clinical practice.
doi:10.3892/or.2014.3153
PMCID: PMC4055348  PMID: 24788853
second-opinion network; testicular cancer; quality of care; treatment scope
4.  Comparison of surgical technique (Open vs. Laparoscopic) on pathological and long term functional outcomes following radical prostatectomy 
BMC Urology  2014;14:18.
Background
Few studies to date have directly compared outcomes of retropubic (RRP) and laparoscopic (LRP) radical prostatectomy. We investigated a single institution experience with RRP and LRP with respect to functional and pathological outcomes.
Methods
168 patients who underwent RRP were compared to 171 patients who underwent LRP at our institution. Pathological and functional outcomes including postoperative urinary incontinence and erectile dysfunction (ED) of the two cohorts were examined.
Results
Patients had bilateral, unilateral and no nerve sparing technique performed in 83.3%, 1.8% and 14.9% of cases for RRP and 23.4%, 22.8% and 53.8% of cases for LRP, respectively (p < 0.001). Overall positive surgical margin rates were 22.2% among patients who underwent RRP compared to 26.5% of patients who underwent LRP (p = 0.435). Based upon pads/day, urinary continence postoperatively was achieved in 83.2% and 82.8% for RRP and LRP, respectively (p = 0.872). Analysis on postoperative ED was limited due to lack of information on the preoperative erectile status. However, postoperatively there were no differences with respect to ED between the two cohorts (p = 0.151). Based on ICIQ-scores, surgeons with more experience had lower rates of postoperative incontinence irrespective of surgical technique (p = 0.001 and p < 0.001 for continuous and stratified data, respectively).
Conclusions
RRP and LRP represent effective surgical approaches for the treatment of clinically localized prostate cancer. Pathological outcomes are excellent for both surgical techniques. Functional outcomes including postoperative urinary incontinence and ED are comparable between the cohorts. Surgeon experience is more relevant than surgical technique applied.
doi:10.1186/1471-2490-14-18
PMCID: PMC3922887  PMID: 24506815
Prostate cancer; Erectile dysfunction; Incontinence; Radical prostatectomy; Laparoscopic prostatectomy
5.  Elevated C-reactive protein values predict nodal metastasis in patients with penile cancer 
BMC Urology  2013;13:53.
Background
The nodal status is a strong predictor for cancer specific death in patients with penile carcinoma, and the C-reactive protein (CRP) level at diagnosis has recently been shown to be associated with poor clinical outcome in various solid malignancies. Therefore, this retrospective study was performed to evaluate the association between preoperative CRP levels and the incidence of nodal metastasis in patients with squamous cell carcinoma (SCC) of the penis.
Methods
The analysis included 51 penile cancer patients who underwent either radical or partial penectomy for pT1-4 penile cancer between 1990 and 2010. The nodal status was correlated with patient and tumor specific characteristics.
Results
Sixteen (31%) patients had lymph node metastasis at the time of penile cancer surgery. Nodal status was associated with tumor stage but did not correlate significantly with tumor grade. In contrast, high presurgical CRP levels were significantly associated with the diagnosis of nodal involvement (p = 0.04). The optimal CRP cut-off value to predict lymph node metastasis was set at 20 mg/l based on ROC analysis.
Conclusions
Since a high preoperative serum CRP level was closely correlated with nodal disease, it could be used as an additional marker to help identify patients with penile cancer who may benefit from inguinal lymph node dissection.
doi:10.1186/1471-2490-13-53
PMCID: PMC4016472  PMID: 24148787
Penile cancer; Biomarker; C-reactive protein; Nodal disease; Prognosis; Survival
6.  Interdisciplinary decision making in prostate cancer therapy – 5-years’ time trends at the Interdisciplinary Prostate Cancer Center (IPC) of the Charité Berlin 
Background
Patients with prostate cancer face the difficult decision between a wide range of therapeutic options. These men require elaborate information about their individual risk profile and the therapeutic strategies´ risks and benefits to choose the best possible option. In order to detect time trends and quality improvements between an early patient population (2003/2004) and a later reference group (2007/2008) data was analysed with regards to epidemiologic parameters, differences in diagnostics and the type and ranking of the recommended therapies taking into account changes to Gleason Grading System and implementation of new therapeutic strategies, particularly Active surveillance, in 2005.
Methods
Data from all 496 consecutive patients who received consultation in 2003/2004 (n = 280) and 2007/2008 (n = 216) was retrospectively evaluated. Categorical variables were compared using the Chi-square test. Dependent variables were analysed using the unpaired Students´ t-test and the Mann–Whitney U-test.
Results
The cohorts were comparable concerning clinical stage, initial PSA, prostate volume, comorbidities and organ confined disease. Patients in Cohort I were younger (66.44 vs. 69.31y; p < .001) and had a longer life expectancy (17.22 vs. 14.75y; p < .001). 50.9%, 28.2% and 20.9% in Cohort I and 37.2%, 39.6% and 23.2% in Cohort II showed low-, intermediate- and high-risk disease (D´Amico) with a trend towards an increased risk profile in Cohort II (p = .066). The risk-adapted therapy recommended as first option was radical prostatectomy for 91.5% in Cohort I and 69.7% in Cohort II, radiation therapy for 83.7% in Cohort I and 50.7% in Cohort II, and other therapies (brachytherapy, Active surveillance, Watchful waiting, high-intensity focused ultrasound) for 6.5% in Cohort I and 6.9% in Cohort II (p < .001). Radiation therapy was predominant in both cohorts as second treatment option (p < .001). Time trends showing quality improvement involved an increase in biopsy cores (9.95 ± 2.38 vs. 8.43 ± 2.29; p < .001) and an increased recommendation for bilateral nerve sparing (p < .001).
Conclusion
In the earlier years, younger patients with a more favourable risk profile presented for interdisciplinary consultation. A unilateral recommendation for radical prostatectomy and radiation therapy was predominant. In the later years, the patient population was considerably older. However, this group may have benefitted from optimised diagnostic possibilities and a wider range of treatment options.
doi:10.1186/1472-6947-13-83
PMCID: PMC3751298  PMID: 23915212
Prostate cancer; Interdisciplinary consultation; Medical decision making; Time trends
7.  Overexpression of p16INK4a in Urothelial Carcinoma In Situ Is a Marker for MAPK-Mediated Epithelial-Mesenchymal Transition but Is Not Related to Human Papillomavirus Infection 
PLoS ONE  2013;8(5):e65189.
Background
The role of human papillomavirus (HPV) in bladder carcinogenesis remains controversial. Overexpression of p16INK4a, a surrogate marker for infection with oncogenic HPV in other tumours, has been described for urothelial carcinoma in situ (UCIS). Our goal was therefore to evaluate whether overexpression of p16INK4a is associated with HPV infection and to identify mechanisms of p16INK4a upregulation in UCIS.
Materials and Methods
In 60 tissue specimens from a total of 45 patients (UCIS and controls), we performed p16INK4a immunohistochemistry followed by detection and subclassification of HPV DNA. In a subset of samples, we tested for gene amplification of p16INK4a applying fluorescence in situ hybridization (FISH). RAS/MAPK signalling and epithelial-mesenchymal transition (EMT) was assessed using immunohistochemistry. Finally, we transfected urothelial carcinoma cells with KRAS and examined the expression of p16INK4a as well as markers of EMT.
Results
We found overexpression of p16INK4a in 92.6% of UCIS and in all cervical intraepithelial neoplasia (CIN) controls. In contrast, we detected high-risk HPV DNA in 80% of CIN, but none in UCIS. There was no gene amplification of p16INK4a. High levels of phosphorylated kinases and urokinase plasminogen activator (uPA) and loss of membraneous E-cadherin were detected in UCIS. KRAS transfection of urothelial carcinoma cells led to upregulation of p16INK4a and uPA accompanied by loss of E-cadherin that could be inhibited by application of the kinase-inhibitor Sorafenib.
Conclusions
Our results show that overexpression of p16INK4a in UCIS is neither associated with HPV infection nor p16INK4a gene amplification but is a consequence of enhanced RAS/MAPK signalling that promotes EMT, possibly due to Sorafenib-sensitive paracrine secretion of the EMT activator uPA. These findings might open a novel therapeutic option for localized but aggressive urothelial cancer.
doi:10.1371/journal.pone.0065189
PMCID: PMC3665800  PMID: 23724131
8.  High CRP values predict poor survival in patients with penile cancer 
BMC Cancer  2013;13:223.
Background
High levels of circulating C-reactive protein (CRP) have recently been linked to poor clinical outcome in various malignancies. The aim of this study was to evaluate the prognostic significance of the preoperative serum CRP level in patients with squamous cell carcinoma (SCC) of the penis.
Methods
This retrospective analysis included 79 penile cancer patients with information about their serum CRP value prior to surgery who underwent either radical or partial penectomy at two German high-volume centers (Ulm University Medical Center and Hannover Medical School) between 1990 and 2010. They had a median (mean) follow-up of 23 (32) months.
Results
A significantly elevated CRP level (>15 vs. ≤ 15 mg/l) was found more often in patients with an advanced tumor stage (≥pT2) (38.9 vs. 11.6%, p=0.007) and in those with nodal disease at diagnosis (50.0 vs. 14.6%, p=0.007). However, high CRP levels were not associated with tumor differentiation (p=0.53). The Kaplan-Meier 5-year cancer-specific survival (CSS) rate was 38.9% for patients with preoperative CRP levels above 15 mg/l and 84.3% for those with lower levels (p=0.001). Applying multivariate analysis and focusing on the subgroup of patients without metastasis at the time of penile surgery, both advanced local tumor stage (≥pT2; HR 8.8, p=0.041) and an elevated CRP value (>15 mg/l; HR 3.3, p=0.043) were identified as independent predictors of poor clinical outcome in patients with penile cancer.
Conclusions
A high preoperative serum CRP level was associated with poor survival in patients with penile cancer. If larger patient populations confirm its prognostic value, its routine use could enable better risk stratification and risk-adjusted follow-up of patients with SCC of the penis.
doi:10.1186/1471-2407-13-223
PMCID: PMC3649950  PMID: 23642165
SCC; Penis; Penile cancer; Biomarker; C-reactive protein; Prognosis; Survival
9.  Does Obesity Influence the Prognosis of Metastatic Renal Cell Carcinoma in Patients Treated with Vascular Endothelial Growth Factor–Targeted Therapy? 
The Oncologist  2011;16(11):1565-1571.
Whether or not obesity (measured in terms of body mass index, body surface area, visceral fat area, and s.c. fat area) can predict the long-term prognosis of renal cell cancer patients treated with vascular endothelial growth factor–targeted therapy is examined.
Background.
Obesity increases the risk for renal cell carcinoma (RCC). However, it has only recently been identified as an independent positive prognostic factor for localized RCC.
Objective.
To determine whether obesity influences long-term prognosis in metastatic RCC patients receiving vascular endothelial growth factor–targeted therapy.
Design, Setting, and Participants.
In 116 patients with metastatic RCC who received antiangiogenic agents (sunitinib, sorafenib, axitinib, bevacizumab) in 2005–2010, we evaluated whether body mass index (BMI), a body surface area (BSA) above the European average, the visceral fat area (VFA), or s.c. fat area (SFA) were of predictive relevance.
Measurements.
BMI was categorized based on current World Health Organization definitions. BSA was stratified according to the European average for men (1.98 m2) and women (1.74 m2). VFA and SFA were dichotomized using the median of the observed distribution as the cutoff. The primary endpoints of this study were time to progression and overall survival time.
Results and Limitations.
The whole population had median progression-free and overall survival times of 8.3 months and 20.5 months, respectively. In contrast to BMI and BSA, higher than average VFA and SFA levels were significant predictors of longer progression-free and overall survival times. The major limitations of this study are its retrospective design and its heterogeneous patient population.
Conclusion.
This is the first study to identify high VFA and SFA levels as positive predictive biomarkers for patients who receive first-line antiangiogenic agents for metastatic RCC.
doi:10.1634/theoncologist.2011-0213
PMCID: PMC3233291  PMID: 22020210
Metastatic kidney cancer; Prognosis; Body mass index; BMI; Body surface area; BSA; Visceral fat; Subcutaneous fat; Obesity; Overweight
10.  Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33 
HSP90 inhibition depletes STK33 in KRAS mutant tumors.
Previous efforts to develop drugs that directly inhibit the activity of mutant KRAS, the most commonly mutated human oncogene, have not been successful. Cancer cells driven by mutant KRAS require expression of the serine/threonine kinase STK33 for their viability and proliferation, identifying STK33 as a context-dependent therapeutic target. However, specific strategies for interfering with the critical functions of STK33 are not yet available. Here, using a mass spectrometry-based screen for STK33 protein interaction partners, we report that the HSP90/CDC37 chaperone complex binds to and stabilizes STK33 in human cancer cells. Pharmacologic inhibition of HSP90, using structurally divergent small molecules currently in clinical development, induced proteasome-mediated degradation of STK33 in human cancer cells of various tissue origin in vitro and in vivo, and triggered apoptosis preferentially in KRAS mutant cells in an STK33-dependent manner. Furthermore, HSP90 inhibitor treatment impaired sphere formation and viability of primary human colon tumor-initiating cells harboring mutant KRAS. These findings provide mechanistic insight into the activity of HSP90 inhibitors in KRAS mutant cancer cells, indicate that the enhanced requirement for STK33 can be exploited to target mutant KRAS-driven tumors, and identify STK33 depletion through HSP90 inhibition as a biomarker-guided therapeutic strategy with immediate translational potential.
doi:10.1084/jem.20111910
PMCID: PMC3328372  PMID: 22451720
11.  Validation of CRP as prognostic marker for renal cell carcinoma in a large series of patients 
BMC Cancer  2012;12:399.
Background
To evaluate the prognostic significance of the pre-operative C-reactive protein (CRP) serum level in patients with renal cell cancer (RCC).
Methods
We evaluated 1,161 RCC patients with complete patient and tumour specific characteristics as well as information about their pre-operative CRP-level, who had undergone either radical nephrectomy or nephron-sparing surgery at two German high-volume centres (University Hospitals of Hannover and Ulm). The mean follow-up was 54 months.
Results
The CRP-level, stratified to three subgroups (CRP ≤ 4, 4–10, and >10 mg/l), correlated significantly with tumour stage (p < 0.001), the risk of presenting nodal disease (2.1, 3.1, and 16.4%) and distant metastasis (2.9, 8.6, and 30.0%; p < 0.001). The Kaplan-Meier 5-year cancer specific survival (CSS) rates were 89.4, 77.9, and 49.5%, respectively (p < 0.001). Multivariate analysis identified CRP as an independent prognosticator for CSS as well as overall survival (p < 0.001). Patients with a CRP of 4–10 and >10 mg/l had a 1.67 and 2.48 fold higher risk of dying due to their RCC compared to those with a pre-operative CRP ≤4 mg/l, respectively.
Conclusions
A high preoperative serum CRP level is an independent predictor of poor survival in patients with RCC. Its routine use could allow better risk stratification and risk-adjusted follow-up of RCC patients.
doi:10.1186/1471-2407-12-399
PMCID: PMC3502607  PMID: 22958305
Renal cell cancer; Biomarker; C-reactive protein; Prognosis; Survival
12.  Laparoscopic and open postchemotherapy retroperitoneal lymph node dissection in patients with advanced testicular cancer – a single center analysis 
BMC Urology  2012;12:15.
Background
The open approach represents the gold standard for postchemotherapy retroperitoneal lymph node dissection (O-PCLND) in patients with residual testicular cancer. We analyzed laparoscopic postchemotherapy retroperitoneal lymph node dissection (L-PCLND) and O-PCLND at our institution.
Methods
Patients underwent either L-PCLND (n = 43) or O-PCLND (n = 24). Categorical and continuous variables were compared using the Fisher exact test and Mann–Whitney U test respectively. Overall survival was evaluated with the log-rank test.
Results
Primary histology was embryonal cell carcinomas (18 patients), pure seminoma (2 cases) and mixed NSGCTs (47 patients). According to the IGCCCG patients were categorized into “good”, “intermediate” and “poor prognosis” disease in 55.2%, 14.9% and 20.8%, respectively. Median operative time for L-PCLND was 212 min and 232 min for O-PCLND (p = 0.256). Median postoperative duration of drainage and hospital stay was shorter after L-PCLND (0.0 vs. 3.5 days; p < 0.001 and 6.0 vs. 11.5 days; p = 0.002). Intraoperative complications occurred in 21.7% (L-PCLND) and 38.0% (O-PCLND) of cases with 19.5% and 28.5% of Clavien Grade III complications for L-PCLND and O-PCLND, respectively (p = 0.224). Significant blood loss (>500 ml) was almost equally distributed (8.6% vs. 14.2%: p = 0.076). No significant differences were observed for injuries of major vessels and postoperative complications (p = 0.758; p = 0.370). Tumor recurrence occurred in 8.6% following L-PCLND and in 14.2% following O-PCLND with a mean disease-free survival of 76.6 and 89.2 months, respectively. Overall survival was 83.3 and 95.0 months for L-PCNLD and O-PCLND, respectively (p = 0.447).
Conclusions
L-PCLND represents a safe surgical option for well selected patients at an experienced center.
doi:10.1186/1471-2490-12-15
PMCID: PMC3431976  PMID: 22651395
Advanced testicular cancer; Postchemotherapy; Retroperitoneal lymph node dissection; Laparoscopy; Metastasis
13.  The Retrourethral Transobturator Sling Suspension in the Treatment of Male Urinary Stress Incontinence: Results of a Single Institution Experience 
ISRN Urology  2012;2012:304205.
Objective. To evaluate functional outcome of the retrourethral transobturator sling suspension (RTS) in the treatment of stress urinary incontinence (SUI) caused by prior prostate surgery. Methods. The RTS (AdVance male sling) was implanted in 32 patients who suffered from mild to severe postsurgical-treatment incontinence at the University Hospital Ulm from September 2010 to September 2011 including 10 patients with prior radiation therapy. Functional data (uroflowmetry, daily pad use, and postvoid residual urine) as well as quality of life with impact of urinary problems (ICIQ-UI SF) were prospectively assessed at baseline and during followup. Results. After a median followup of 9 months (range, 3–14) the incontinence cure rate (no pad usage) was 56.2% and the improvement rate (1-2 pads/day or ≥50% reduction) was 21.9%. No improvement was observed in 21.9%. Daily pad use and ICIQ-UI SF score improved significantly. No major perioperative complications occurred. Postoperatively, 15.6% of the patients exhibited transient acute urinary retention which resolved without further treatment after a maximum of 3 weeks. One patient underwent sling explantation due to dislocation and persistent perineal pain. Conclusions. The implantation of the RTS is a safe and effective procedure in selected patients with SUI resulting from prostate surgery.
doi:10.5402/2012/304205
PMCID: PMC3362920  PMID: 22675643
14.  JS-K, a glutathione/glutathione S-transferase-activated nitric oxide releasing prodrug inhibits androgen receptor and WNT-signaling in prostate cancer cells 
BMC Cancer  2012;12:130.
Background
Nitric oxide (NO) and its oxidative reaction products have been repeatedly shown to block steroid receptor function via nitrosation of zinc finger structures in the DNA-binding domain (DBD). In consequence NO-donors could be of special interest for the treatment of deregulated androgen receptor(AR)-signaling in castration resistant prostate cancer (CRPC).
Methods
Prostate cancer (PCa) cells were treated with JS-K, a diazeniumdiolate derivate capable of generating large amounts of intracellular NO following activation by glutathione S-transferase. Generation of NO was determined indirectly by the detection of nitrate in tissue culture medium or by immunodetection of nitrotyrosine in the cytoplasm. Effects of JS-K on intracellular AR-levels were determined by western blotting. AR-dimerization was analyzed by mammalian two hybrid assay, nuclear translocation of the AR was visualized in PCa cells transfected with a green fluorescent AR-Eos fusion protein using fluorescence microscopy. Modulation of AR- and WNT-signalling by JS-K was investigated using reporter gene assays. Tumor cell proliferation following JS-K treatment was measured by MTT-Assay.
Results
The NO-releasing compound JS-K was shown to inhibit AR-mediated reporter gene activity in 22Rv1 CRPC cells. Inhibition of AR signaling was neither due to an inhibition of nuclear import nor to a reduction in AR-dimerization. In contrast to previously tested NO-donors, JS-K was able to reduce the intracellular concentration of functional AR. This could be attributed to the generation of extremely high intracellular levels of the free radical NO as demonstrated indirectly by high levels of nitrotyrosine in JS-K treated cells. Moreover, JS-K diminished WNT-signaling in AR-positive 22Rv1 cells. In line with these observations, castration resistant 22Rv1 cells were found to be more susceptible to the growth inhibitory effects of JS-K than the androgen dependent LNCaP which do not exhibit an active WNT-signaling pathway.
Conclusions
Our results suggest that small molecules able to inhibit WNT- and AR-signaling via NO-release represent a promising platform for the development of new compounds for the treatment of CRPC.
doi:10.1186/1471-2407-12-130
PMCID: PMC3376035  PMID: 22462810
15.  Prostate Cancer Risk Is not Altered by TP53AIP1 Germline Mutations in a German Case-Control Series 
PLoS ONE  2012;7(3):e34128.
Prostate cancer susceptibility has previously been associated with truncating germline variants in the gene TP53AIP1 (tumor protein p53 regulated apoptosis inducing protein 1). For two apparently recurrent mutations (p.Q22fs and p.S32X) a remarkable OR of 5.1 was reported for prostate cancer risk. Since these findings have not been validated so far, we genotyped p.Q22fs and p.S32X in two German series with a total of 1,207 prostate cancer cases and 1,495 controls. The truncating variants were not significantly associated with prostate cancer in none of the two cohorts, nor in the combined analysis [odds ratio (OR) = 1.16; 95% confidence interval (CI 95%) = 0.62–2.15; p = 0.66]. Carriers showed no significant differences in family history of prostate cancer, age at diagnosis, Gleason score or PSA at diagnosis when compared to non-carrier prostate cancer cases. The large sample size of the combined cohort rejects a high-risk effect greater than 2.2 and indicates a limited role of TP53AIP1 in prostate cancer predisposition.
doi:10.1371/journal.pone.0034128
PMCID: PMC3311578  PMID: 22457820
16.  Morbidity and Quality of Life in Bladder Cancer Patients following Cystectomy and Urinary Diversion: A Single-Institution Comparison of Ileal Conduit versus Orthotopic Neobladder 
ISRN Urology  2012;2012:342796.
Objective. To evaluate and compare noncontinent and continent urinary diversion after radical cystectomy in patients with bladder cancer. Methods. A total of 301 patients submitted to radical cystectomy at the Charité-University Hospital Berlin from 1993 to 2007 including 146 with an ileal conduit and 115 with an ileal neobladder. Clinical and pathological data as well as oncological outcome were retrospectively analyzed and compared. Quality of life was analyzed using the EORTC QLQ-C30 and BLM30 questionnaires. Results. 69.1% and 69.6% of all patients who received an ileal conduit and ileal neobladder, respectively, developed early complications. The two groups differed significantly concerning the occurrence of postoperative ileus (P = 0.02) favoring patients who received an ileal conduit but not with regard to any other early-onset complication evaluated. Patients with ileal neobladder had a significantly better global health status and quality of life (P = 0.02), better physical functioning (P = 0.02), but also a higher rate of diarrhoea (P = 0.004). Conclusion. Cystectomy with any type of diversion remains a complication-prone surgery. Even if the patient groups are not homogeneous in all respects, there are many arguments in favor of the ileal neobladder as the urinary diversion of choice.
doi:10.5402/2012/342796
PMCID: PMC3302022  PMID: 22523713
17.  Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells 
Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa) is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR). A putative mechanism allowing prostate cancer (PCa) cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD). Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.
doi:10.3390/ijms130911530
PMCID: PMC3472761  PMID: 23109869
sorafenib; truncated androgen receptor variants; castration resistant prostate cancer
18.  Partial nephrectomy using porcine small intestinal submucosa 
Background
Whenever technically feasible and oncologically justified, nephron-sparing surgery is the current standard of care for localized renal cell carcinomas (RCC). The main complications of partial nephrectomy, especially for large and centrally located tumors, are urinary leakage and parenchymal bleeding. We prospectively evaluated the pros and cons of using porcine small intestinal submucosa (SIS, Surgisis®) to close the renal defect after nephron-sparing surgery.
Methods
We used Surgisis® (Cook medical, Bloomington, IN, USA) to secure and compress the capsular defect after tumor resection in 123 patients submitted to 129 partial nephrectomies between August 2003 and February 2011.
Results
The median tumor size was 3.7 cm (range 1.1-13.0 cm). Procedures were performed with cold ischemia in 24 cases (18.2%), with warm ischemia in 46 (35.6%), and without ischemia in 59 cases (44.8%). In the total group of patients, 4 (3.1%) developed urinary fistula, and only 2 (1.6%) required postoperative transfusions due to hemorrhage after the application of the small intestinal submucosa membrane.
Conclusion
Small intestinal submucosa is an easy-to-use biomaterial for preventing complications such as postoperative bleeding and urinary fistula in nephron-sparing surgery, especially in cases where tumor excision causes significant renal capsular and/or renal pelvic defects.
doi:10.1186/1477-7819-9-126
PMCID: PMC3233505  PMID: 21992771
renal cell carcinoma; nephron-sparing surgery; urinoma; postoperative hemorrhage; complications
19.  Inhibition of Glycogen Synthase Kinase-3β Counteracts Ligand-Independent Activity of the Androgen Receptor in Castration Resistant Prostate Cancer 
PLoS ONE  2011;6(9):e25341.
In order to generate genomic signals, the androgen receptor (AR) has to be transported into the nucleus upon androgenic stimuli. However, there is evidence from in vitro experiments that in castration-resistant prostate cancer (CRPC) cells the AR is able to translocate into the nucleus in a ligand-independent manner. The recent finding that inhibition of the glycogen-synthase-kinase 3β (GSK-3β) induces a rapid nuclear export of the AR in androgen-stimulated prostate cancer cells prompted us to analyze the effects of a GSK-3β inhibition in the castration-resistant LNCaP sublines C4-2 and LNCaP-SSR. Both cell lines exhibit high levels of nuclear AR in the absence of androgenic stimuli. Exposure of these cells to the maleimide SB216763, a potent GSK-3β inhibitor, resulted in a rapid nuclear export of the AR even under androgen-deprived conditions. Moreover, the ability of C4-2 and LNCaP-SSR cells to grow in the absence of androgens was diminished after pharmacological inhibition of GSK-3β in vitro. The ability of SB216763 to modulate AR signalling and function in CRPC in vivo was additionally demonstrated in a modified chick chorioallantoic membrane xenograft assay after systemic delivery of SB216763. Our data suggest that inhibition of GSK-3β helps target the AR for export from the nucleus thereby diminishing the effects of mislocated AR in CRPC cells. Therefore, inhibition of GSK-3β could be an interesting new strategy for the treatment of CRPC.
doi:10.1371/journal.pone.0025341
PMCID: PMC3183056  PMID: 21980429
20.  Matrix-Dependent Regulation of AKT in Hepsin-Overexpressing PC3 Prostate Cancer Cells12 
Neoplasia (New York, N.Y.)  2011;13(7):579-589.
The serine-protease hepsin is one of the most prominently overexpressed genes in human prostate carcinoma. Forced expression of the enzyme in mice prostates is associated with matrix degradation, invasive growth, and prostate cancer progression. Conversely, hepsin overexpression in metastatic prostate cancer cell lines was reported to induce cell cycle arrest and reduction of invasive growth in vitro. We used a system for doxycycline (dox)-inducible target gene expression in metastasis-derived PC3 cells to analyze the effects of hepsin in a quantitative manner. Loss of viability and adhesion correlated with hepsin expression levels during anchorage-dependent but not anchorage-independent growth. Full expression of hepsin led to cell death and detachment and was specifically associated with reduced phosphorylation of AKT at Ser473, which was restored by growth on matrix derived from RWPE1 normal prostatic epithelial cells. In the chorioallantoic membrane xenograft model, hepsin overexpression in PC3 cells reduced the viability of tumors but did not suppress invasive growth. The data presented here provide evidence that elevated levels of hepsin interfere with cell adhesion and viability in the background of prostate cancer as well as other tissue types, the details of which depend on the microenvironment provided. Our findings suggest that overexpression of the enzyme in prostate carcinogenesis must be spatially and temporally restricted for the efficient development of tumors and metastases.
PMCID: PMC3132844  PMID: 21750652
21.  Impact of hormonal therapy on the detection of promoter hypermethylation of the detoxifying glutathione-S-transferase P1 gene (GSTP1) in prostate cancer 
BMC Urology  2006;6:15.
Background
In spite of excellent cure rates for prostate cancer patients with favorable tumor characteristics, patients with unfavorable characteristics after radical prostatectomy are still at a significantly increased risk of tumor progression. Early adjuvant hormonal therapy (AHT) has been shown to be of prognostic benefit in these patients. Unfortunately initiation and duration of early AHT in the individual patient is based on statistic data. PSA, as the standard prostate marker is neither able to reliably indicate minimal residual tumor disease in the early postoperative phase, nor can it be used for therapy monitoring due to the suppressive effect of hormonal therapy on PSA production. Promoter hypermethylation of the detoxifying glutathione-S-transferase P1 gene (GSTP1-HM) has been shown to be the most common DNA alteration of primary prostatic carcinoma which, when used as a marker, is supposed to be able to overcome some of the disadvantages of PSA. However until now information on the impact of hormonal therapy on the detection of GSTP1-HM is lacking. The purpose of our study was to assess the impact of endocrine therapy on the detection of GSTP1-HM by methylation-specific PCR (MSP) in prostate cancer.
Methods
Paraffin embedded tumor samples from the radical prostatectomy (RP) specimens from 15 patients after hormonal therapy (HT) (mean 8 months) were assessed by MSP. In 8 of the patients the GSTP-1 status of the tumors before HT was assessed on the corresponding initial diagnostic biopsies.
Results
Following HT MSP showed GSTP1-HM in 13/15 of the RP specimens. In two patients analysis of the RP specimens failed to show GSTP1-HM. All initial tumor samples (8/8 biopsy specimens) showed GSTP1-HM, including both patients negative for GSTP1 HM in the corresponding RP specimen.
Conclusion
In most cases hormonal therapy appears to not alter GSTP1 HM detection. However the change from a positive to a negative GSTP1 HM status in a subset of the patients may point to an, at least partial androgen dependency. Further studies on a larger cohort of patients are necessary to assess its frequency and the exact hormonal interactions.
doi:10.1186/1471-2490-6-15
PMCID: PMC1540432  PMID: 16803634
22.  The differentiation status of primary gonadal germ cell tumors correlates inversely with telomerase activity and the expression level of the gene encoding the catalytic subunit of telomerase 
BMC Cancer  2002;2:32.
Background
The activity of the ribonucleoprotein enzyme telomerase is detectable in germ, stem and tumor cells. One major component of telomerase is human telomerase reverse transcriptase (hTERT), which encodes the catalytic subunit of telomerase. Here we investigate the correlation of telomerase activity and hTERT gene expression and the differentiation status of primary testicular germ cell tumors (TGCT).
Methods
Telomerase activity (TA) was detected by a quantitative telomerase PCR ELISA, and hTERT mRNA expression was quantified by online RT-PCR in 42 primary testicular germ cell tumors. The control group consisted of benign testicular biopsies from infertile patients.
Results
High levels of telomerase activity and hTERT expression were detected in all examined undifferentiated TGCTs and in the benign testicular tissue specimens with germ cell content. In contrast, differentiated teratomas and testicular control tissue without germ cells (Sertoli-cell-only syndrome) showed no telomerase activity and only minimal hTERT expression.
Conclusions
These findings demonstrate an inverse relationship between the level of telomerase activity and hTERT mRNA expression and the differentiation state of germ cell tumors. Quantification of telomerase activity and hTERT mRNA expression enables a new molecular-diagnostic subclassification of germ cell tumors that describes their proliferation potential and differentiation status.
doi:10.1186/1471-2407-2-32
PMCID: PMC139987  PMID: 12459049
Telomerase activity; human telomerase reverse transcriptase; testicular germ cell tumors
23.  A Data Base System to Analyze the Epidemiology of Chlamydia Trachomatis Infections 
Infections due to Chlamydia trachomatis and their sequelae pose a major public health problem. An estimated three to four million Americans acquire chlamydial infections each year, and thus are victimized by the most common, and possibly the most costly to the nation's health, of all of the sexually transmitted conditions. Women of reproductive age are particularly menaced, since infection may lead to pelvic inflammatory disease, ectopic pregnancy and involuntary infertility.
The Centers for Disease Control (CDC) is cooperating with several communities in studies designed to acquire a more detailed description of the epidemiology of Chlamydia trachomatis infections. These studies should advance the formulation and evaluation of community-based strategies for the control of this disease.
To support three of these studies, a data entry system, utilizing commercially available data base software, was developed for implementation on personal computers. It enables systematic entry of study data from medical, patient interview, and diagnostic laboratory records, and provides for the data base linkages between records required for epidemiologic analyses. Systems of this design offer cost-effective solutions to common data management problems that are shared by many public health-based programs that seek to study or control infectious diseases.
PMCID: PMC2578147

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