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  • 1
    Language: English
    In: World Journal of Urology, 2016, Vol.34(2), pp.197-205
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s00345-015-1616-2 Byline: Jens Mani (1), Patrick Antonietti (2), Stefanie Rakel (2), Roman Blaheta (1), Georg Bartsch (1), Axel Haferkamp (1), Donat Kogel (2) Keywords: BAG3; ATG5; ABT-737; Bladder cancer Abstract: Purpose BAG3 is overexpressed in several malignancies and mediates a non-canonical, selective form of (macro)autophagy. By stabilizing pro-survival Bcl-2 proteins in complex with HSP70, BAG3 can also exert an apoptosis-antagonizing function. ABT-737 is a high affinity Bcl-2 inhibitor that fails to target Mcl-1. This failure may confer resistance in various cancers. Methods Urothelial cancer cells were treated with the BH3 mimetics ABT-737 and (-)-gossypol, a pan-Bcl-2 inhibitor which inhibits also Mcl-1. To clarify the importance of the core autophagy regulator ATG5 and BAG3 in ABT-737 treatment, cell lines carrying a stable lentiviral knockdown of ATG5 and BAG3 were created. The synergistic effect of ABT-737 and pharmaceutical inhibition of BAG3 with the HSF1 inhibitor KRIBB11 or sorafenib was also evaluated. Total cell death and apoptosis were quantified by FACS analysis of propidium iodide, annexin. Target protein analysis was conducted by Western blotting. Results Knockdown of BAG3 significantly downregulated Mcl-1 protein levels and sensitized urothelial cancer cells to apoptotic cell death induced by ABT-737, while inhibition of bulk autophagy through depletion of ATG5 had no discernible effect on cell death. Similar to knockdown of BAG3, pharmacological targeting of the BAG3/Mcl-1 pathway with KRIBB11 was capable to sensitize both cell lines to treatment with ABT-737. Conclusion Our results show that BAG3, but not bulk autophagy has a major role in the response of bladder cancer cells to BH3 mimetics. They also suggest that BAG3 is a suitable target for combined therapies aimed at synergistically inducing apoptosis in bladder cancer. Author Affiliation: (1) Department of Urology, Goethe University Hospital, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany (2) Experimental Neurosurgery, Neuroscience Center, Goethe University Hospital, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany Article History: Registration Date: 09/06/2015 Received Date: 08/01/2015 Accepted Date: 09/06/2015 Online Date: 23/06/2015
    Keywords: BAG3 ; ATG5 ; ABT-737 ; Bladder cancer
    ISSN: 0724-4983
    E-ISSN: 1433-8726
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  • 2
    Language: English
    In: PLoS ONE, 01 January 2012, Vol.7(12), p.e52420
    Description: The pathophysiologic mechanisms behind urologic disease are increasingly being elucidated. The object of this investigation was to evaluate the publication policies of urologic journals during a period of progressively better understanding and management of urologic disease. Based on the ISI Web of Knowledge Journal Citation Reports and the PubMed database, the number and percentage of original experimental, original clinical, review or commentarial articles published between 2002-2010 in six leading urologic journals were analyzed. "British Journal of Urology International", "European Urology", "Urologic Oncology-Seminars and Original Investigations" ("Urologic Oncology"), "Urology", "The Journal of Urology", and "World Journal of Urology" were chosen, because these journals publish articles in all four categories. The publication policies of the six journals were very heterogeneous during the time period from 2002 to 2010. The percentage of original experimental and original clinical articles, related to all categories, remained the same in "British Journal of Urology International", "Urologic Oncology", "Urology" and "The Journal of Urology". The percentage of experimental reports in "World Journal of Urology" between 2002-2010 significantly increased from 10 to 20%. A distinct elevation in the percentage of commentarial articles accompanied by a reduction of clinical articles became evident in "European Urology" which significantly correlated with a large increase in the journal's impact factor. No clearly superior policy could be identified with regard to a general increase in the impact factors from all the journals. The publication policy of urologic journals does not expressly reflect the increase in scientific knowledge, which has occurred over the period 2002-2010. One way of increasing the exposure of urologists to research and expand the interface between experimental and clinical research, would be to enlarge the percentage of experimental articles published. There is no indication that such policy would be detrimental to a journal's impact factor.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    In: PLoS ONE, 2013, Vol.8(12)
    Description: Scientists who are members of an editorial board have been accused of preferentially publishing their scientific work in the journal where they serve as editor. Reputation and academic standing do depend on an uninterrupted flow of published scientific work and the question does arise as to whether publication mainly occurs in the self-edited journal. This investigation was designed to determine whether editorial board members of five urological journals were more likely to publish their research reports in their own rather than in other journals. A retrospective analysis was conducted for all original reports published from 2001–2010 by 65 editorial board members nominated to the boards of five impact leading urologic journals in 2006. Publications before editorial board membership, 2001–2005, and publications within the period of time as an editorial board member, 2006–2010, were identified. The impact factors of the journals were also recorded over the time period 2001–2010 to see whether a change in impact factor correlated with publication locality. In the five journals as a whole, scientific work was not preferentially published in the journal in which the scientists served as editor. However, significant heterogeneity among the journals was evident. One journal showed a significant increase in the amount of published papers in the ‘own’ journal after assumption of editorship, three journals showed no change and one journal showed a highly significant decrease in publishing in the ‘own’ journal after assumption of editorship.
    Keywords: Research Article ; Science Policy
    E-ISSN: 1932-6203
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  • 4
    In: Journal of Cellular and Molecular Medicine, July 2014, Vol.18(7), pp.1460-1466
    Description: Molecular tumour targeting has significantly improved anti‐cancer protocols. Still, the addition of molecular targeting to the treatment regime has not led to a curative breakthrough. Combined mammalian target of apamycin (m) and histone deacetylase () inhibition has been shown not only to enhance anti‐tumour potential, but also to prevent resistance development seen under mono‐drug therapy. This investigation was designed to evaluate whether cross‐communication exists between m signalling and epigenetic events regulated by . ‐145 prostate cancer cells were treated with insulin‐like growth factor () to activate the Akt‐m cascade or with the ‐inhibitor valproic acid () to induce histone H3 and H4 acetylation (aH3, aH4). Subsequently, m, Rictor, Raptor, p70s6k, Akt (all: total and phosphorylated), H3 and H4 (total and acetylated) were analysed by western blotting. Both techniques revealed a link between m and the epigenetic machinery. activated m, Rictor, Raptor, p70s6k and Akt, but also enhanced aH3 and aH4. Inversely, r blockade and knock‐down blocked the Akt‐m axis, but simultaneously diminished aH3 and aH4. treatment up‐regulated histone acetylation, but also activated m‐Akt signalling. 1 and 2 knock‐down revealed that the interaction with the m system is initiated by histone H3 acetylation. ‐m communication, therefore, is apparent whereby tumour‐promoting (Akt/m, aH3/aH4) and tumour‐suppressing signals (Akt/m, aH3/aH4) are activated in parallel. Combined use of an ‐ and m inhibitor might then diminish pro‐tumour effects triggered by the ‐ (Akt/m) or m inhibitor (aH3/aH4) alone.
    Keywords: M ; Hdac ; Cross‐Communication ; Prostate Cancer Cells
    ISSN: 1582-1838
    E-ISSN: 1582-4934
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  • 5
    Language: English
    In: BMC cancer, 07 April 2015, Vol.15, pp.224
    Description: Acquired resistance to standard chemotherapy causes treatment failure in patients with metastatic bladder cancer. Overexpression of pro-survival Bcl-2 family proteins has been associated with a poor chemotherapeutic response, suggesting that Bcl-2-targeted therapy may be a feasible strategy in patients with these tumors. The small-molecule pan-Bcl-2 inhibitor (-)-gossypol (AT-101) is known to induce apoptotic cell death, but can also induce autophagy through release of the pro-autophagic BH3 only protein Beclin-1 from Bcl-2. The potential therapeutic effects of (-)-gossypol in chemoresistant bladder cancer and the role of autophagy in this context are hitherto unknown. Cisplatin (5637(r)CDDP(1000), RT4(r)CDDP(1000)) and gemcitabine (5637(r)GEMCI(20), RT4(r)GEMCI(20)) chemoresistant sub-lines of the chemo-sensitive bladder cancer cell lines 5637 and RT4 were established for the investigation of acquired resistance mechanisms. Cell lines carrying a stable lentiviral knockdown of the core autophagy regulator ATG5 were created from chemosensitive 5637 and chemoresistant 5637(r)GEMCI(20) and 5637(r)CDDP(1000) cell lines. Cell death and autophagy were quantified by FACS analysis of propidium iodide, Annexin and Lysotracker staining, as well as LC3 translocation. Here we demonstrate that (-)-gossypol induces an apoptotic type of cell death in 5637 and RT4 cells which is partially inhibited by the pan-caspase inhibitor z-VAD. Cisplatin- and gemcitabine-resistant bladder cancer cells exhibit enhanced basal and drug-induced autophagosome formation and lysosomal activity which is accompanied by an attenuated apoptotic cell death after treatment with both (-)-gossypol and ABT-737, a Bcl-2 inhibitor which spares Mcl-1, in comparison to parental cells. Knockdown of ATG5 and inhibition of autophagy by 3-MA had no discernible effect on apoptotic cell death induced by (-)-gossypol and ABT-737 in parental 5637 cells, but evoked a significant increase in early apoptosis and overall cell death in BH3 mimetic-treated 5637(r)GEMCI(20) and 5637(r)CDDP(1000) cells. Our findings show for the first time that (-)-gossypol concomitantly triggers apoptosis and a cytoprotective type of autophagy in bladder cancer and support the notion that enhanced autophagy may underlie the chemoresistant phenotype of these tumors. Simultaneous targeting of Bcl-2 proteins and the autophagy pathway may be an efficient new strategy to overcome their "autophagy addiction" and acquired resistance to current therapy.
    Keywords: Gossypol -- Analogs & Derivatives ; Proto-Oncogene Proteins C-Bcl-2 -- Genetics ; Urinary Bladder Neoplasms -- Drug Therapy
    E-ISSN: 1471-2407
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  • 6
    Language: English
    In: Journal of negative results in biomedicine, 08 November 2014, Vol.13, pp.17
    Description: In an earlier study we demonstrated the feasibility to create tissue engineered venous scaffolds in vitro and in vivo. In this study we investigated the use of tissue engineered constructs for ureteral replacement in a long term orthotopic minipig model. In many different projects well functional ureretal tissue was established using tissue engineering in animals with short-time follow up (12 weeks). Therefore urothelial cells were harvested from the bladder, cultured, expanded in vitro, labelled with fluorescence and seeded onto the autologous veins, which were harvested from animals during a second surgery. Three days after cell seeding the right ureter was replaced with the cell-seeded matrices in six animals, while further 6 animals received an unseeded vein for ureteral replacement. The animals were sacrificed 12, 24, and 48 weeks after implantation. Gross examination, intravenous pyelogram (IVP), H&E staining, Trichrome Masson's Staining, and immunohistochemistry with pancytokeratin AE1/AE3, smooth muscle alpha actin, and von Willebrand factor were performed in retrieved specimens. The IVP and gross examination demonstrated that no animals with tissue engineered ureters and all animals of the control group presented with hydronephrosis after 12 weeks. In the 24-week group, one tissue engineered and one unseeded vein revealed hydronephrosis. After 48 weeks all tissue engineered animals and none of the control group showed hydronephrosis on the treated side. Histochemistry and immunohistochemistry revealed a multilayer of urothelial cells attached to the seeded venous grafts. Venous grafts may be a potential source for ureteral reconstruction. The results of so far published ureteral tissue engineering projects reveal data up to 12 weeks after implantation. Even if the animal numbers of this study are small, there is an increasing rate of hydronephrosis revealing failure of ureteral tissue engineering with autologous matrices in time points longer than 3 months after implantation. Further investigations have to prove adequate clinical outcome and appropriate functional long-term results.
    Keywords: Models, Animal ; Tissue Engineering
    E-ISSN: 1477-5751
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  • 7
    In: Journal of Cellular and Molecular Medicine, August 2015, Vol.19(8), pp.1795-1804
    Description: A significant proportion of men diagnosed with prostate cancer (a) eventually develop metastatic disease, which progresses to castration resistance, despite initial response to androgen deprivation. As anticancer therapy has become increasingly effective, acquired drug resistance has emerged, limiting efficacy. Combination treatment, utilizing different drug classes, exemplifies a possible strategy to foil resistance development. The effects of the triple application of the histone deacetylase () inhibitor valproic acid (), the mammalian target of rapamycin inhibitor everolimus and low dosed interferon alpha (α) on a cell growth and dissemination capacity were investigated. For that purpose, the human a cell lines, ‐3, ‐145 and aP were treated with the combined regimen or separate single agents. Cell growth was investigated by the dye reduction assay. Flow cytometry served to analyse cell cycle progression. Adhesion to vascular endothelium or immobilized collagen, fibronectin and laminin was quantified. Migration and invasion characteristics were determined by the modified Boyden chamber assay. Integrin α and β subtypes were investigated by flow cytometry, western blotting and ‐. Integrin related signalling, Epidermal Growth Factor Receptor (EGFr), Akt, p70S6kinase and extracellular signal‐regulated kinases (ERK)1/2 activation were also assessed. The triple application of , everolimus and low dosed α blocked tumour cell growth and dissemination significantly better than any agent alone. Antitumour effects were associated with pronounced alteration in the cell cycle machinery, intracellular signalling and integrin expression profile. Combining , everolimus and low dosed α might be a promising option to counteract resistance development and improve outcome in a patients.
    Keywords: Prostate Cancer ; Combination Therapy ; Valproic Acid ; Everolimus ; Interferon Alpha
    ISSN: 1582-1838
    E-ISSN: 1582-4934
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  • 8
    Language: English
    In: Molecular cancer, 16 June 2014, Vol.13, pp.152
    Description: Targeted therapies have improved therapeutic options of treating renal cell carcinoma (RCC). However, drug response is temporary due to resistance development. Functional and molecular changes in RCC Caki-1 cells, after acquired resistance to the mammalian target of rapamycin (mTOR)-inhibitor everolimus (Cakires), were investigated with and without additional application of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA). Cell growth was evaluated by MTT assay, cell cycle progression and apoptosis by flow cytometry. Target molecules of everolimus and VPA, apoptotic and cell cycle regulating proteins were investigated by western blotting. siRNA blockade was performed to evaluate the functional relevance of the proteins. Everolimus resistance was accompanied by significant increases in the percentage of G2/M-phase cells and in the IC50. Akt and p70S6K, targets of everolimus, were activated in Cakires compared to drug sensitive cells. The most prominent change in Cakires cells was an increase in the cell cycle activating proteins cdk2 and cyclin A. Knock-down of cdk2 and cyclin A caused significant growth inhibition in the Cakires cells. The HDAC-inhibitor, VPA, counteracted everolimus resistance in Cakires, evidenced by a significant decrease in tumor growth and cdk2/cyclin A. It is concluded that non-response to everolimus is characterized by increased cdk2/cyclin A, driving RCC cells into the G2/M-phase. VPA hinders everolimus non-response by diminishing cdk2/cyclin A. Therefore, treatment with HDAC-inhibitors might be an option for patients with advanced renal cell carcinoma and acquired everolimus resistance.
    Keywords: Carcinoma, Renal Cell -- Drug Therapy ; Cyclin A -- Metabolism ; Cyclin-Dependent Kinase 2 -- Metabolism ; Histone Deacetylases -- Genetics
    E-ISSN: 1476-4598
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  • 9
    Language: English
    In: Patient Preference and Adherence, 2016, Vol.10, p.2181(7)
    Description: PURPOSE: This study compares early complications after cystectomy and urinary diversion (UD) stratified by the surgical focus and case load of two different department chairpersons in a single institution in two time periods. Creating clear data about complications that can affect the quality of life is an important tool for patients to decide whether and where to perform this extensive surgery.HYPOTHESIS: A team of surgeons with a clear focus on pelvic surgery leads to lower complication rates in radical cystectomy.MATERIALS AND METHODS: Radical cystectomy was performed in two separate time periods under the patronage of two different chairmen in the same university hospital. The patient data were analyzed retrospectively and the complications 30 days after surgery were assessed using the Clavien-Dindo classification.RESULTS: Statistical analysis showed a significant difference in the severity of complications between the two time periods, A and B, in total (P〈0.001). When placing patients into subgroups, significantly more complications in period A were also seen concerning sex (male, P〈0.001; female, P=0.003), age (〈70 years, P〈0.001; 〉70 years, P≤50.001) tumor grade (low grade, P〈0.001; high grade, P≤0.001), and UD (ileal conduit, P〈0.001; neobladder, P〈0.001). In a multivariable analysis, age (P=0.031) and type of UD (P=0.028) were determined as independent predictors for complications in period A. When joining the two periods together, the type of UD (P=0.0417), age (P=0.041), and the time periods (A/B) (P〈0.001) show a significant association with the presence of complications.CONCLUSION: This study compares for the first time surgical complications in two time periods with different case load and surgical focus in one department. Categorization shows that patients should prefer radical cystectomy in centers of excellence or a high-volume hospital in order to keep complications at the lowest possible level and thus have the highest benefit for oncologic outcome and quality of life.
    Keywords: Medicine;
    ISSN: 1177-889X
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  • 10
    Language: English
    In: Oncology Reports, March, 2016, Vol.35(3), p.1629(7)
    Keywords: Testicular Cancer -- Genetic Aspects ; Testicular Cancer -- Development And Progression ; Cellular Proteins -- Health Aspects ; Autophagy (Cytology) -- Genetic Aspects ; Autophagy (Cytology) -- Health Aspects
    ISSN: 1021-335X
    Source: Cengage Learning, Inc.
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