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Background Transrectal prostate biopsy (pbx) is the most frequent outpatient procedure in the urological field. Septic complications are a major health issue. Objective To evaluate complication rates with or without an antimicrobial lubricant. Design, setting, and participants A total of 1000 patients received pbx between 2013 and 2015. Information about complications was collected by a 3-wk questionnaire. Return rate was 73.2% (n = 732). Intervention Randomization for pbx with the instillation of an antimicrobial lubricant (intervention group, n = 385) or the standard lubricant (control group, n = 347) was performed. Outcome measurements and statistical analysis Multivariable analyses assessed the association between infectious complications at biopsy and use of an antimicrobial lubricant, International Prostate Symptom Score (IPSS), history of urogenitourinary infections, and several other confounders. Results and limitations The use of an antimicrobial lubricant did not reduce infection rate. Overall complication rate was very low. Of all patients, 69.3% described the procedure as pain free. Fever ≥38.5 °C was reported in overall 1.9% of patients. Urinary retention with catheterization occurred in 3.1%. Most common complications were hematospermia (47.4%), macrohematuria (23.8%), and rectal bleeding (7.4%). Readmission rate was 1% (n = 7). In multivariable analyses, IPSS and previous infectious complications were associated with a higher risk of infectious complications. Our results stem from a large German single center and therefore are limited to this patient group. Conclusions No significant reduction was shown in infectious complications in the intervention group with the antimicrobial agent. Low incidence of those complications may be the underlying cause. Severe morbidity at pbx is uncommon. Specifically, the rate of infection was very low. Patient summary Severe complications at prostate biopsy are rare. Among participants, 69.3% had no pain. Fever was rare (1.9% of patients). Voiding issues with catheterization occurred in 3.1%. Most common complications were blood in the semen (47.4%), urine (23.8%), or stool (7.4%). Men with voiding issues or previous infectious complications had a higher risk of infectious complications.

Polymer–ceramic composite electrolytes are major contenders for applications in commercial Li-metal solid-state batteries. However, the cycling performance and energy density of such batteries are ...

The purpose of the study was to define clinical factors for successful treatment response and re-exposure to docetaxel in metastatic castration-resistant prostate cancer (mCRPC). An mCRPC database of patients receiving first-line docetaxel and rechallenge courses was established. Several clinical factors were evaluated for prediction of treatment response. Multivariate cox-regression analysis was used to define pre-treatment and treatment factors for survival. Between 2005 and 2013, 94 patients with mCRPC were treated with docetaxel. Full data set and follow-up were available for 62 patients. Median follow-up was 84 m [interquartile range (IQR) 64–104 m]. Median biochemical progression-free survival (bPFS) and overall survival under docetaxel were 9 m (IQR 5–16 m) and 20 m (IQR 16–26 m), respectively. Partial PSA-response at first docetaxel-sequence (n = 62), rechallenge (n = 32), and third-sequence (n = 22) docetaxel was 48.4%, 31.6%, and 34.8%, respectively. Time from start of primary androgen deprivation to CRPC > 47 m was the only independent pre-treatment parameter to predict improved overall survival (Hazard Ratio 0.48, p = 0.015). Interestingly, there was a strong trend for improved overall survival in patients with high Gleason Score (Hazard Ratio 0.58; p = 0.08). Partial PSA-response at docetaxel-rechallenge (Hazard Ratio 0.31; p = 0.008) and treatment-free interval > 3 m (Hazard Ratio 3.49; p = 0.014) were the only independent predictive factors under taxane treatment for overall survival. Despite novel hormonal drugs, docetaxel still plays an important role in the treatment of mCRPC. Patients with partial-PSA-response at rechallenge or a treatment-free interval > 3 m benefit most from docetaxel re-exposure.

Systemic treatment is necessary for one third of patients with renal cell carcinoma. No valid biomarker is currently available to tailor personalized therapy. In this study we established a representative panel of patient derived xenograft (PDX) mouse models from patients with renal cell carcinomas and determined serum levels of high mobility group B1 (HMGB1) protein under treatment with sunitinib, pazopanib, sorafenib, axitinib, temsirolimus and bevacizumab. Serum HMGB1 levels were significantly higher in a subset of the PDX collection, which exhibited slower tumor growth during subsequent passages than tumors with low HMGB1 serum levels. Pre-treatment PDX serum HMGB1 levels also correlated with response to systemic treatment: PDX models with high HMGB1 levels predicted response to bevacizumab. Taken together, we provide for the first time evidence that the damage associated molecular pattern biomarker HMGB1 can predict response to systemic treatment with bevacizumab. Our data support the future evaluation of HMGB1 as a predictive biomarker for bevacizumab sensitivity in patients with renal cell carcinoma.

The industrial development of Li metal solid state batteries will be boosted not only by providing highly Li+ conductive electrolyte materials, but also by demonstrating their technical viability in the actual device. For the first time, the electrochemical performances of two different electrolytes, a pure Li7La3Zr2O12 ceramic and a polymer–ceramic composite, are compared in a solid state battery with a Li metal anode and a LiFePO4 cathode. No liquid or gel additive was added to improve the interfacial contacts. The technological viability of these two systems was assessed under realistic cycling conditions with a competitive cathode loading of 1 mA h cm−2. Here, we show promising performances for both electrolytes at 70 °C under slow cycling rates; however, the composite stands out under fast cycling rates due to enhanced interfacial contacts. The energy density of the two systems is compared to the electric vehicle industry targets providing clear specifications for future system development.

Birt-Hogg-Dube (BHD) disease is an autosomal dominant cancer syndrome characterized by benign skin tumors, renal cancer and spontaneous pneumothorax and is caused by mutations in the Folliculin (FLCN) gene. Benign skin tumors and pneumothorax occur in the majority of patients affected by BHD syndrome, but only 30-45% of them develop renal cell carcinoma (RCC) with a median age of diagnosis at 48. The earliest onset of RCC in a BHD patient has been reported at age 20. Here we report a case of a 14 year-old patient with germline FLCN mutation leading to an early-onset bulky RCC that could not be classified strictly according to existing histological types. Germline genetic testing revealed a deletion at FLCN exon 5. The father of the patient was identified as the asymptomatic carrier. We report the youngest patient with BHD-related RCC. This early onset presentation supports genetic testing of at-risk patients and initiation of imaging surveillance for RCC in early adolescence. In addition, future studies are necessary to understand the determinants of reduced penetrance in BHD disease.

The preparation of hybrid ceramic-polymer electrolytes, consisting of 70 wt% of Li+ cation conducting Li7La3Zr2O12 (LLZO) and 30 wt% of P(EO)15LiTFSI polymer electrolyte, through a solvent-free procedure is reported. The LLZO-P(EO)15LiTFSI hybrid electrolytes exhibit remarkable improvement in terms of flexibility and processability with respect to pure LLZO ceramic electrolytes. The physicochemical and electrochemical investigation shows the effect of LLZO annealing, resulting in ion conduction gain. However, slow charge transfer at the ceramic-polymer interface is also observed especially at higher temperatures. Nevertheless, improved compatibility with lithium metal anodes and good Li stripping/plating behavior are exhibited by the LLZO-P(EO)15LiTFSI hybrid electrolytes with respect to P(EO)15LiTFSI. © 2017 Elsevier B.V.

Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate (αKG). Glutamine can also generate aspartate, the carbon source for pyrimidine biosynthesis, and glutathione for redox balance. Here we have shown that VHL-/- RCC cells rely on RC-derived aspartate to maintain de novo pyrimidine biosynthesis. Glutaminase 1 (GLS1) inhibitors depleted pyrimidines and increased ROS in VHL-/- cells but not in VHL+/+ cells, which utilized glucose oxidation for glutamate and aspartate production. GLS1 inhibitor-induced nucleoside depletion and ROS enhancement led to DNA replication stress and activation of an intra-S phase checkpoint, and suppressed the growth of VHL-/- RCC cells. These effects were rescued by administration of glutamate, αKG, or nucleobases with N-acetylcysteine. Further, we observed that the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib synergizes with GLS1 inhibitors to suppress the growth of VHL-/- cells in vitro and in vivo. This work describes a mechanism that explains the sensitivity of RCC tumor growth to GLS1 inhibitors and supports the development of therapeutic strategies for targeting VHL-deficient RCC.

As the ionic conductivity of solid-state lithium ion conductors rises, knowledge of the detailed conductivity mechanisms is harder to obtain due to the limited frequency resolution of the traditional impedance spectrometers. Moreover, the data is easily affected by the local microstructure (i.e. pores, grain-boundaries) and the preparation conditions. The aim of this work is to demonstrate the feasibility of the coaxial reflection technique as a reliable tool to study fast ionic conductors (i.e. σ > 10−4 S cm−1). Especially the relative permittivity can be determined more accurately at room temperature. For the first time the electrical performance of LATP and LLZO manufactured via a scalable top-down glass-ceramic route is evaluated. The density turns out to be a key parameter influencing both relative permittivity and resulting conductivities. For a 100% dense LATP sample the coaxial reflection technique reveals a high grain-core conductivity of 6 × 10−3 S cm−1 similar to the conductivity of ideal single crystals.

For the first time, glass-ceramic particles (LATP and LLZO) have been processed with both a tumbling-mixer and a kneader on semi-industrial scale. Although sintered LATP and LLZO discs reveal a statistically negligible ionic interface resistance to PEO with LiTFSI, the total conductivity of dispersed particles within a PEO-LiTFSI matrix is only slightly enhanced at 80 °C. However, for a tumbling mixing process, SEM investigations prove insufficient contact of particles within the matrix as well as agglomerates, cracks and voids. With the shear intensive kneader, dense and homogeneous samples were obtained. Compared to nanometer-sized SiO2 particles, the LATP filler enable an increase of the ionic conductivity of the hybrid PEO system by a factor of about two. These finding help to overcome solvent-based mixing processes that may cause uncontrolled decomposition and surface reactions of filler particles thereby changing microscopic conduction mechanisms in the hybrid electrolytes.

Despite the clinical success of cemented TKA, aseptic loosening of the tibial component remains a potential long-term complication. Considering the constantly growing revision burden, there is a need for clarification regarding controversial views on primary fixation techniques. In this retrospective analysis, surface (SC) or full cementation (FC) of tibial components was compared in a matched-pair and long-term setting.Matching pairs were identified in a patient series from 1989 to 1994. Hence, 25 primary TKA (SC) were compared to 42 TKA (FC). The study population included 34 patients with rheumatoid arthritis. Patients were matched in a 1:1.7 fashion according to age, gender and initial diagnosis. Outcome was assessed by multiple clinical parameters, detailed radiographic evaluation and survivorship analysis.Clinical follow-up (FU) was at 10.3 years (range 1.5-15.6) for the SC and 12 years (range 0.2-16.2) for the FC group. Survivorship at 10 years was 100 % for the surface cemented trays and 93.3 % (95 % CI 80.5-100) for the fully cemented implants considering aseptic loosening as endpoint (p = 0.3918). Improvement of the AKS Score was greater in the SC group (p = 0.044) and patients in this group were more satisfied (p = 0.013). For any other clinical parameter, no difference could be observed (p0.05).Results of this study showed no statistically significant difference regarding long-term survivorship for the two cementing techniques. This finding questions the claimed advantage of full cementation for tibial components. The presented data do not support the concern that surface cementation results in insufficient fixation in patients with rheumatoid arthritis.

Antibiotic resistance may lead to increasing infection rates at transrectal prostate biopsy. Local antimicrobial agents might help to reduce bacterial load. The aim of this study was to test the potency of antimicrobial lubricants to reduce local bacterial loads and specifically fluoroquinolone-resistant strains. Overall, 384 prostate biopsy (PBx) patients of a larger prospective randomized trial (n = 1000) were included. Patients were randomized for biopsy with pre-interventional instillation of an antimicrobial lubricant (intervention group n = 256) or with the standard lubricant (control group n = 128). Bacteria were recovered on pre- and post-biopsy rectal swab cultures from both patient groups. Bacterial colonization was semi-quantitatively recorded and analyzed for the presence of ciprofloxacin-resistant isolates. Within the intervention group, where antimicrobial lubricant was instilled for PBx, the post-biopsy bacterial count was statistically significantly lower compared to prior biopsy bacterial count (p

Objectives: Novel personalized therapeutic approaches are urgently needed for patients with metastatic clear cell renal cell carcinoma (ccRCC). Methods and materials: We combined the development of a primary patient-derived ccRCC cell line with a phenotypic drug screen consisting of 101 approved anticancer compounds. Results: We identified the MNNG HOS transforming gene (MET)-anaplastic lymphoma receptor tyrosine kinase (ALK) inhibitor crizotinib as the top hit of our drug screen, whereas compounds targeting the vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) pathway showed no or only minor in vitro activity. Among the known major crizotinib targets MET, ALK, and ROS-1, only MET was expressed in our ccRCC cell line. Subsequent sequence analysis revealed a heterozygous R988C mutation of the MET gene and a VHL deletion in both the primary tumor and the tumor-derived ccRCC cell line. However, we were unable to show an activation of MET and, further, MET knockdown did not result in increased apoptosis or cytotoxicity. Therefore, our results suggest that MET R988C does not function as a major oncogenic driver mutation but rather represents a sequence variant. However, we provide evidence that the cytotoxic effect of crizotinib in our cell line model correlates with its ability to inhibit P-glycoprotein (ABCB1)-associated transport functions. Conclusions: Our study shows that a phenotypic screen of a patient-derived tumor cell line can identify compounds with antitumor activity but with an unexpected mode of action. Our results underscore that target validation and phenotype-genotype correlations remain a major experimental challenge. The implications of our findings for a personalized management of patients with cancer are discussed. r 2014

Introduction Cadherin family proteins are involved in the tumorigenesis of several malignancies. However, their significance in renal cell carcinoma (RCC) has not been extensively investigated. The current study investigates the potential of several cadherins to perform as biomarkers for tumor detection and exert functional RCC activity. Methods Pre- and postoperative concentrations of sE-cadherin, cadherin-6, N-cadherin, cadherin-11, cadherin-17, and cadherin-5 were measured in serum of patients undergoing surgery for RCC and correlated to clinical and histopathological parameters. Control serum was obtained from healthy volunteers. A498 and Caki-1 cells were incubated with sE-cadherin and assessed for cell growth, adhesion, and chemotaxis. Results sE-cadherin was significantly upregulated in RCC patients, as compared to controls, and discriminated them with striking accuracy (area under the curve value 0.83). Serum levels remained stable several days after surgery. Treating A498 and Caki-1 cancer cells with various concentrations of sE-cadherin attenuated cell growth and adhesion, while chemotaxis was augmented. Conclusions sE-cadherin is overexpressed in serum of RCC patients and provides a functional cellular switch from sessility to aggressive dissemination. While sE-cadherin is not tumor-specific and thus inappropriate for population-based screening, further studies are warranted to investigate its role in monitoring RCC and employing it as a therapeutic target.

We report on the transport properties of lithium ion conducting glass ceramics represented by the general composition Li1+x–yAlx3+My5+M2–x–y4+(PO4)3 with NASICON-type structure and their stability in contact with lithium metal. In particular, solid electrolyte phases with M = Ge, M = Ti, Ge, and M = Ti, Ta were investigated. AC impedance spectroscopy and DC polarization measurements were applied to determine the conductivity as a function of temperature, and to extract the partial electronic conductivity. The maximum total conductivity at room temperature was found to be about 4 × 10–4 S/cm for the solely Ge containing sample. We demonstrate that the combination of vacuum-based lithium thin film deposition and X-ray photoelectron spectroscopy (XPS) is well suited to study the reactivity of the solid electrolyte membranes in contact with lithium. As a major result, we show that none of the materials investigated is stable in contact with lithium metal, and we discuss the reactive interaction between solid ...

Objective To describe a feasible surgical technique for patients with renal cell carcinoma associated with a supradiaphragmatic tumor thrombus that avoids cardiopulmonary bypass procedure. Materials and Methods From 2004 to 2009, 4 patients with a right kidney tumor and tumor thrombus above the diaphragm (pT3c) underwent manual repositioning of the tumor thrombus out of the right atrium into the inferior vena cava on the beating heart. These patients were aged 65.8 years and had a body mass index of 25.5 kg/m 2 . Median tumor size was 10.8 cm, and 3 patients had synchronous metastasis. Results Manual repositioning of the tumor thrombus was safe and feasible in all patients. Mean operating time was 561 minutes (range, 302-613 minutes), and no perioperative death occurred. Auxiliary cardiopulmonary bypass procedure was applied in 1 patient to remove a preoperatively diagnosed pulmonary embolus. Three patients subsequently underwent systemic therapy for metastatic disease. Median survival was 16 months (range, 1.7-26 months). Conclusion Manual repositioning of a vena cava tumor thrombus without cardiopulmonary bypass is a safe and feasible approach. The risk of tumor thrombembolization seems to be low, and cardiopulmonary bypass can be avoided or at least reduced to a minimum time of intervention.

Growing evidence supports the use of multimedia presentations for informing patients. Therefore, we supported preoperative education by adding a multimedia tool and examined the effects in a randomized controlled trial. We randomized German-speaking patients scheduled for radical prostatectomy at our center to receive either a multimedia-supported (MME) or a standard education (SE). Outcomes were measured in a structured interview. Primary outcome was patient satisfaction. In addition, we applied validated instruments to determine anxiety and measures of decision-making. Results were given by mean and standard deviation. For comparison of groups we used t test and chi-square test. For an explorative analysis we applied multivariate logistic regression. We randomized 203 patients to receive MME (n = 102) or SE (n = 101). Complete satisfaction with preoperative education was more frequent in the MME group (69 vs 52 %, p = .016) and patients after MME reported more questions (5.7 vs 4.2, p = .018). There was no difference concerning the duration of talks and the number of recalled risks. However, perceived knowledge was higher after MME (1.3 vs 1.6, p = .037). Anxiety and measures of decision-making were comparable. Patients judged the multimedia tool very positive, and 74 % of the MME group thought that their preoperative education had been superior to SE. Multimedia support should be considered worthwhile for improving the informed consent process before surgery ( www.germanctr.de ; DRKS00000096).

The discharging and charging of batteries require ion transfer across phase boundaries. In conventional lithium-ion batteries, Li(+) ions have to cross the liquid electrolyte and only need to pass the electrode interfaces. Future high-energy batteries may need to work as hybrids, and so serially combine a liquid electrolyte and a solid electrolyte to suppress unwanted redox shuttles. This adds new interfaces that might significantly decrease the cycling-rate capability. Here we show that the interface between a typical fast-ion-conducting solid electrolyte and a conventional liquid electrolyte is chemically unstable and forms a resistive solid-liquid electrolyte interphase (SLEI). Insights into the kinetics of this new type of interphase are obtained by impedance studies of a two-chamber cell. The chemistry of the SLEI, its growth with time and the influence of water impurities are examined by state-of-the-art surface analysis and depth profiling.

Novel personalized therapeutic approaches are urgently needed for patients with metastatic clear cell renal cell carcinoma (ccRCC).We combined the development of a primary patient-derived ccRCC cell line with a phenotypic drug screen consisting of 101 approved anticancer compounds.We identified the MNNG HOS transforming gene (MET)-anaplastic lymphoma receptor tyrosine kinase (ALK) inhibitor crizotinib as the top hit of our drug screen, whereas compounds targeting the vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) pathway showed no or only minor in vitro activity. Among the known major crizotinib targets MET, ALK, and ROS-1, only MET was expressed in our ccRCC cell line. Subsequent sequence analysis revealed a heterozygous R988C mutation of the MET gene and a VHL deletion in both the primary tumor and the tumor-derived ccRCC cell line. However, we were unable to show an activation of MET and, further, MET knockdown did not result in increased apoptosis or cytotoxicity. Therefore, our results suggest that MET R988C does not function as a major oncogenic driver mutation but rather represents a sequence variant. However, we provide evidence that the cytotoxic effect of crizotinib in our cell line model correlates with its ability to inhibit P-glycoprotein (ABCB1)-associated transport functions.Our study shows that a phenotypic screen of a patient-derived tumor cell line can identify compounds with antitumor activity but with an unexpected mode of action. Our results underscore that target validation and phenotype-genotype correlations remain a major experimental challenge. The implications of our findings for a personalized management of patients with cancer are discussed.

Novel therapeutic options beyond hormone ablation and chemotherapy are urgently needed for patients with advanced prostate cancer. Tyrosine kinase inhibitors (TKIs) are an attractive option as advanced prostate cancers show a highly altered phosphotyrosine proteome. However, despite favorable initial clinical results, the combination of the TKI dasatinib with docetaxel did not result in improved patient survival for reasons that are not known in detail.The National Cancer Institute-Approved Oncology Drug Set II was used in a phenotypic drug screen to identify novel compounds with antineoplastic activity in prostate cancer cells. Validation experiments were carried out in vitro and in vivo.We identified the TKI nilotinib as a novel compound with antineoplastic activity in hormone-refractory prostate cancer cells. However, further analyses revealed that treatment with nilotinib was associated with a significant up-regulation of the phospho-extracellular-signal-regulated kinases (ERK) survival signal. ERK blockade alone led to a significant antitumoral effect and enhanced the cytotoxicity of nilotinib when used in combination.Our findings underscore that TKIs, such as nilotinib, have antitumoral activity in prostate cancer cells but that survival signals, such as ERK up-regulation, may mitigate their effectiveness. ERK blockade alone or in combination with TKIs may represent a promising therapeutic strategy in advanced prostate cancer.

Background Isolation and characterization of tumourigenic colon cancer initiating cells may help to develop novel diagnostic and therapeutic procedures. Methods We characterized a panel of fourteen human colon carcinoma cell lines and their corresponding xenografts for the surface expression of potential stem cell markers CD133, CD24, CD44, CDCP1 and CXCR4. In five cell lines and nine xenografts, mRNA expression of these markers was determined. Tumour growth behaviour of CD133+, CD133- and unsorted SW620 cells was evaluated in vivo. Results All five putative stem cell markers showed distinct expression patterns in the tumours examined. Two patient-derived cell lines highly expressed CD133 (> 85% of positive cells) and three other cell lines had an expression level of about 50% whereas in long-term culture based models CD133 expression ranged only from 0 to 20%. In 8/14 cell lines, more than 80% of the cells were positive for CD24 and 11/14 were over 70% positive for CD44. 10/14 cell lines expressed CDCP1 on ≥ 83% of cells. CXCR4 expression was determined solely on 94 L and SW480. Analyses of the corresponding xenografts revealed a significant reduction of cell numbers expressing the investigated surface markers and showed single cell fractions expressing up to three markers simultaneously. Statistical analysis revealed that the CXCR4 mRNA level correlates negatively with the protein expression of CD133, CD44, CD24 and CDCP1 in cell lines and xenografts. A lower differentiation grade of donor material correlated with a higher CDCP1 mRNA expression level in the respective tumour model. In vivo growth behaviour studies of SW620 revealed significantly higher take rates and shorter doubling times in the tumour growth of CD133 positive subclones in comparison to the unsorted cell line or CD133 negative subclones. Conclusions Our data revealed correlations in the expression of surface markers CD44 and CD24 as well as CD44 and CDCP1 and strongly suggest that CD133 is a stem cell marker within our colon carcinoma panel. Further studies will elucidate its role as a potential therapeutic target.

The use of metallic lithium anodes enables higher energy density and higher specific capacity Li-based batteries. However, it is essential to suppress lithium dendrite growth during electrodeposition. Li-ion-conducting ceramics (LICC) can mechanically suppress dendritic growth but are too fragile and also have low Li-ion conductivity. Here, a simple, versatile, and scalable procedure for fabricating flexible Li-ion-conducting composite membranes composed of a single layer of LICC particles firmly embedded in a polymer matrix with their top and bottom surfaces exposed to allow for ionic transport is described. The membranes are thin (

Background: Novel therapeutic options beyond hormone ablation and chemotherapy are urgently needed for patients with advanced prostate cancer. Tyrosine kinase inhibitors (TKIs) are an attractive option as advanced prostate cancers show a highly altered phosphotyrosine proteome. However, despite favorable initial clinical results, the combination of the TKI dasatinib with docetaxel did not result in improved patient survival for reasons that are not known in detail. Methods: The National Cancer Institute–Approved Oncology Drug Set II was used in a phenotypic drug screen to identify novel compounds with antineoplastic activity in prostate cancer cells. Validation experiments were carried out in vitro and in vivo. Results: We identified the TKI nilotinib as a novel compound with antineoplastic activity in hormone-refractory prostate cancer cells. However, further analyses revealed that treatment with nilotinib was associated with a significant up-regulation of the phospho-extracellularsignal-regulated kinases (ERK) survival signal. ERK blockade alone led to a significant antitumoral effect and enhanced the cytotoxicity of nilotinib when used in combination. Conclusions: Our findings underscore that TKIs, such as nilotinib, have antitumoral activity in prostate cancer cells but that survival signals, such as ERK up-regulation, may mitigate their effectiveness. ERK blockade alone or in combination with TKIs may represent a promising therapeutic strategy in advanced prostate cancer. r 2014 Elsevier Inc. All rights reserved.

not Available.