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  • Mani, Jens  (9)
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  • 1
    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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  • 2
    Language: English
    In: Cells, 01 September 2018, Vol.7(9), p.129
    Description: This study was designed to investigate whether epigenetic modulation by histone deacetylase (HDAC) inhibition might circumvent resistance towards the mechanistic target of rapamycin (mTOR) inhibitor temsirolimus in a prostate cancer cell model. Parental (par) and temsirolimus-resistant (res) PC3 prostate cancer cells were exposed to the HDAC inhibitor valproic acid (VPA), and tumor cell adhesion, chemotaxis, migration, and invasion were evaluated. Temsirolimus resistance was characterized by reduced binding of PC3res cells to endothelium, immobilized collagen, and fibronectin, but increased adhesion to laminin, as compared to the parental cells. Chemotaxis, migration, and invasion of PC3res cells were enhanced following temsirolimus re-treatment. Integrin α and β receptors were significantly altered in PC3res compared to PC3par cells. VPA significantly counteracted temsirolimus resistance by down-regulating tumor cell-matrix interaction, chemotaxis, and migration. Evaluation of integrin expression in the presence of VPA revealed a significant down-regulation of integrin α5 in PC3res cells. Blocking studies demonstrated a close association between α5 expression on PC3res and chemotaxis. In this in vitro model, temsirolimus resistance drove prostate cancer cells to become highly motile, while HDAC inhibition reversed the metastatic activity. The VPA-induced inhibition of metastatic activity was accompanied by a lowered integrin α5 surface level on the tumor cells.
    Keywords: Mtor ; Histone Deacetylase ; Prostate Cancer ; Integrins ; Adhesion ; Invasion ; Biology
    E-ISSN: 2073-4409
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  • 3
    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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  • 4
    Language: English
    In: Patient preference and adherence, 2016, Vol.10, pp.2181-2187
    Description: 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. A team of surgeons with a clear focus on pelvic surgery leads to lower complication rates in radical cystectomy. 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. Statistical analysis showed a significant difference in the severity of complications between the two time periods, A and B, in total (70 years, ≤0.001) tumor grade (low grade, 〈0.001; high grade, ≤0.001), and UD (ileal conduit, 〈0.001; neobladder, 〈0.001). In a multivariable analysis, age (=0.031) and type of UD (=0.028) were determined as independent predictors for complications in period A. When joining the two periods together, the type of UD (=0.0417), age (=0.041), and the time periods (A/B) (〈0.001) show a significant association with the presence of complications. 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: Clavien–Dindo Classification ; Ud ; Early Complications ; High-Volume Period ; Low-Volume Period ; Radical Cystectomy ; Urinary Diversion
    ISSN: 1177-889X
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 5
    Language: English
    In: Investigational New Drugs, 2013, Vol.31(2), pp.265-272
    Description: Pharmacologic options for patients with castration-resistant prostate cancer are limited. It has been suggested that targeting intracellular molecules, which have been altered during neoplastic development, may slow tumor growth. Therefore, the growth-blocking potential of the histone deacetylase-inhibitor LBH589 and the multiple tyrosine kinase-inhibitor TKI258, applied alone or in combination, was investigated in a panel of prostate cancer cell lines. PC-3, DU-145 or LNCaP cells were treated with various concentrations of LBH589 and/or TKI258. Tumor cell growth, cell cycle regulating proteins, HDAC3- and HDAC4-expression and histone H3 and H4 acetylation were then evaluated by MTT assay and Western blotting. LBH589 dose-dependently blocked prostate cancer cell growth. In contrast, TKI258 did not down-regulate tumor cell growth up to a 1,000 nM dosage. LBH589 elevated histone H3 and H4 acetylation. The cell cycle regulators cyclin B, cyclin D1, cdk1 and cdk4 were down-regulated in PC-3, whereas the suppressor proteins p21 and p27 were up-regulated in LNCaP by LBH589. TKI258 up-regulated p27 in PC-3 or p21 in LNCaP and additionally elevated cyclin B, cyclin D1, cdk1 and cdk4 in both cell lines. Presumably, the increase in cyclin and cdk caused by TKI258 counteracts the benefit of p21 or p27 up-regulation, resulting in TKI258 non-responsiveness. The LBH589/TKI258-combination was not superior to the LBH589 single-drug use in terms of growth reduction. Obviously, TKI258 did not enhance the sensitivity of prostate cancer cells towards an HDAC based regimen. Therefore, the LBH589/TKI258-combination probably does not provide an optimum strategy in fighting advanced prostate cancer.
    Keywords: Prostate cancer ; LBH589 ; TKI258 ; Molecular therapy ; Tumor growth
    ISSN: 0167-6997
    E-ISSN: 1573-0646
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  • 6
    Language: English
    In: Journal of Clinical Oncology, 03/2015, Vol.33(7_suppl), pp.348-348
    ISSN: 0732-183X
    E-ISSN: 1527-7755
    Source: CrossRef
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  • 7
    Language: English
    In: Cancer Epidemiology, February 2018, Vol.52, pp.63-69
    Description: Incidence rates for urothelial carcinoma (UC) have been reported to differ between countries within the European Union (EU). Besides occupational exposure to chemicals, other substances such as tobacco and nitrite in groundwater have been identified as risk factors for UC. We investigated if regional differences in UC incidence rates are associated with agricultural, industrial and residential land use. Newly diagnosed cases of UC between 2003 and 2010 were included. Information within 364 administrative districts of Germany from 2004 for land use factors were obtained and calculated as a proportion of the total area of the respective administrative district and as a smoothed proportion. Furthermore, information on smoking habits was included in our analysis. Kulldorff spatial clustering was used to detect different clusters. A negative binomial model was used to test the spatial association between UC incidence as a ratio of observed versus expected incidence rates, land use and smoking habits. We identified 437,847,834 person years with 171,086 cases of UC. Cluster analysis revealed areas with higher incidence of UC than others (p = 0.0002). Multivariate analysis including significant pairwise interactions showed that the environmental factors were independently associated with UC (p 〈 0.001). The RR was 1.066 (95% CI 1.052–1.080), 1.066 (95% CI 1.042–1.089) and 1.067 (95% CI 1.045–1.093) for agricultural, industrial and residential areas, respectively, and 0.996 (95% CI 0.869–0.999) for the proportion of never smokers. This study displays regional differences in incidence of UC in Germany. Additionally, results suggest that socioeconomic factors based on agricultural, industrial and residential land use may be associated with UC incidence rates.
    Keywords: Environmental Exposure ; Socioeconomic Factor ; Smoking ; Incidence Rates ; Urothelial Carcinoma ; Medicine ; Public Health
    ISSN: 1877-7821
    E-ISSN: 1877-783X
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  • 8
    Language: English
    In: Urologic Oncology: Seminars and Original Investigations, October 2016, Vol.34(10), pp.432.e1-432.e8
    Description: To evaluate the prognostic relevance of different prostatic invasion patterns in pT4a urothelial carcinoma of the bladder (UCB) after radical cystectomy. Our study comprised a total of 358 men with pT4a UCB. Patients were divided in 2 groups—group A with stromal infiltration of the prostate via the prostatic urethra with additional muscle-invasive UCB ( = 121, 33.8%) and group B with continuous infiltration of the prostate through the entire bladder wall ( = 237, 66.2%). The effect of age, tumor grade, carcinoma in situ, lymphovascular invasion, soft tissue surgical margin, lymph node metastases, administration of adjuvant chemotherapy, and prostatic invasion patterns on cancer-specific mortality (CSM) was evaluated using competing-risk regression analysis. Decision curve analysis was used to evaluate the net benefit of including the variable invasion pattern within our model. The estimated 5-year CSM-rates for group A and B were 50.1% and 66.0%, respectively. In multivariable competing-risk analysis, lymph node metastases (hazard ratio [HR] = 1.73, 〈0.001), lymphovascular invasion (HR = 1.62, = 0.0023), soft tissue surgical margin (HR = 1.49, = 0.026), absence of adjuvant chemotherapy (HR = 2.11, 〈0.001), and tumor infiltration of the prostate by continuous infiltration of the entire bladder wall (HR = 1.37, = 0.044) were significantly associated with a higher risk for CSM. Decision curve analysis showed a net benefit of our model including the variable invasion pattern. Continuous infiltration of the prostate through the entire bladder wall showed an adverse effect on CSM. Besides including these patients into clinical trials for an adjuvant therapy, we recommend including prostatic invasion patterns in predictive models in pT4a UCB in men.
    Keywords: Bladder Cancer ; Radical Cystectomy ; Mortality ; Outcome ; Prostatic Invasion Pattern ; Medicine
    ISSN: 1078-1439
    E-ISSN: 1873-2496
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  • 9
    Language: German
    Description: Einleitung: Es wurde bereits gezeigt, dass es bei der Behandlung von Tumoren mit dem Apoptose induzierenden Molekül TNFα-related apoptosis inducing ligand (TRAIL) gehäuft zu Therapieresistenzen kommen kann. Methoden: Um diese Resistenzen zu umgehen untersuchten wir den kombinierten[zum vollständigen Text gelangen Sie über die oben angegebene URL]...
    Keywords: Medical Sciences; Medicine
    Source: DataCite
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