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  • 1
    Keywords: CANCER ; IRRADIATION ; radiotherapy ; Germany ; LUNG ; MODEL ; CT ; DENSITY ; FOLLOW-UP ; DISEASE ; MORTALITY ; computed tomography ; MICE ; MOUSE ; NO ; MOBILITY ; PARAMETERS ; tomography ; leukocyte ; MOUSE MODEL ; COMPUTED-TOMOGRAPHY ; THIN-SECTION CT ; HIGH-RESOLUTION ; WEIGHT ; lung function ; AMIFOSTINE ; INDUCED PULMONARY FIBROSIS ; lung fibrosis ; MOUSE LUNG ; STRAIN-DEPENDENT DIFFERENCES
    Abstract: Rationale and Objectives: To identify characteristics of lung fibrosis in a mouse model after radiotherapy (RT) using thin-section computed tomography (CT), histology and clinical parameters. Materials and Methods: Using a multislice CT-scanner, follow-up chest CT scans of 10 out of 72 included mice (C57BL/6J, 36 control mice, 36 mice (20Gy)) were performed every 2 weeks until week 26 after RT. Hounsfield units (HU) and cardiothoracic ratio (CTR) were measured, and a multireader analysis on characteristic lung changes was performed and correlated with histology and clinical parameters. Results: From weeks 4 to 8 after RT changes in histology (leukocyte count, extraalveolar edema, P 〈 0.01) and from week 12 changes in CT were detected (increase in HU, intralobular opacity and fibrotic strandings, P 〈 0.05). From week 14 clinical manifestations occurred (loss of weight, mobility, breathing, increased mortality, P 〈 0.01). CTR showed no significant changes. Three readers showed excellent interobserver agreement (kappa 〉 0.84). Conclusion: Thin-section CT in a mouse model is capable of detecting the development of lung fibrosis after RT prior to the onset of clinical deterioration
    Type of Publication: Journal article published
    PubMed ID: 15377939
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  • 2
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; IRRADIATION ; radiotherapy ; SURVIVAL ; FACTOR RECEPTOR ; Germany ; KINASE ; LUNG ; TYROSINE KINASE ; DISEASE ; MICE ; radiation ; PHOSPHORYLATION ; TYROSINE KINASE INHIBITOR ; MOUSE ; EFFICACY ; chemotherapy ; COMPUTED-TOMOGRAPHY ; imatinib ; inflammation ; FACTOR-BETA ; TGF-BETA ; lung fibrosis ; MOUSE LUNG ; STRAIN-DEPENDENT DIFFERENCES ; IMATINIB MESYLATE ; KINASE INHIBITORS ; PDGF
    Abstract: Pulmonary fibrosis is the consequence of a variety of diseases with no satisfying treatment option. Therapy-induced fibrosis also limits the efficacy of chemotherapy and radiotherapy in numerous cancers. Here, we studied the potential of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors (RTKIs) to attenuate radiation-induced pulmonary fibrosis. Thoraces of C57BL/6 mice were irradiated (20 Gy), and mice were treated with three distinct PDGF RTKIs (SU9518, SU11657, or Imatinib). Irradiation was found to induce severe lung fibrosis resulting in dramatically reduced mouse survival. Treatment with PDGF RTKIs markedly attenuated the development of pulmonary fibrosis in excellent correlation with clinical, histological, and computed tomography results. Importantly, RTKIs also prolonged the life span of irradiated mice. We found that radiation up-regulated expression of PDGF (A-D) isoforms leading to phosphorylation of PDGF receptor, which was strongly inhibited by RTKIs. Our findings suggest a pivotal role of PDGF signaling in the pathogenesis of pulmonary fibrosis and indicate that inhibition of fibrogenesis, rather than inflammation, is critical to antifibrotic treatment. This study points the way to a potential new approach for treating idiopathic or therapy-related forms of lung fibrosis
    Type of Publication: Journal article published
    PubMed ID: 15781583
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  • 3
    Keywords: RECEPTOR ; SPECTRA ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; proliferation ; radiotherapy ; SURVIVAL ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; LUNG ; MODEL ; MODELS ; THERAPY ; VITRO ; VIVO ; PROTEIN ; radiation ; TIME ; ACTIVATION ; MESSENGER-RNA ; fibroblasts ; PHOSPHORYLATION ; MOUSE ; TRIAL ; ASSAY ; chemotherapy ; MOUSE MODEL ; signaling ; RE ; cell proliferation ; LEVEL ; ASSAYS ; in vivo ; AA ; KINASE INHIBITOR ; receptor tyrosine kinase ; CHRYSOTILE ASBESTOS ; INDUCED LUNG FIBROSIS ; PDGF RECEPTOR ; PDGFR inhibitor ; PULMONARY-FIBROSIS ; RAT LUNG ; VEGFR inhibitor
    Abstract: Background: Several small receptor tyrosine kinase inhibitors (RTKI) have entered clinical cancer trials alone and in combination with radiotherapy or chemotherapy. The inhibitory spectrum of these compounds is often not restricted to a single target. For example Imatinib/Gleevec (primarily a bcr/abl kinase inhibitor) or SU11248 (mainly a VEGFR inhibitor) are also potent inhibitors of PDGFR and other kinases. We showed previously that PDGF signaling inhibition attenuates radiation-induced lung fibrosis in a mouse model. Here we investigate effects of SU9518, a PDGFR inhibitor combined with ionizing radiation in human primary fibroblasts and endothelial cells in vitro, with a view on utilizing RTKI for antifibrotic therapy. Methods: Protein levels of PDGFR-alpha/-beta and phosphorylated PDGFR in fibroblasts were analyzed using western and immunocytochemistry assays. Functional proliferation and clonogenic assays were performed (i) to assess PDGFR-mediated survival and proliferation in fibroblasts and endothelial cells after SU9518 (small molecule inhibitor of PDGF receptor tyrosine kinase); (ii) to test the potency und selectivity of the PDGF RTK inhibitor after stimulation with PDGF isoforms (-AB, -AA, -BB) and VEGF+bFGF. In order to simulate in vivo conditions and to understand the role of radiation-induced paracrine PDGF secretion, co-culture models consisting of fibroblasts and endothelial cells were employed. Results: In fibroblasts, radiation markedly activated PDGF signaling as detected by enhanced PDGFR phosphorylation which was potently inhibited by SU9518. In fibroblast clonogenic assay, SU9518 reduced PDGF stimulated fibroblast survival by 57%. Likewise, SU9518 potently inhibited fibroblast and endothelial cell proliferation. In the co-culture model, radiation of endothelial cells and fibroblast cells substantially stimulated proliferation of non irradiated fibroblasts and vice versa. Importantly, the RTK inhibitor significantly inhibited this paracrine radiation-induced fibroblast and endothelial cell activation. Conclusion: Radiation-induced autocrine and paracrine PDGF signaling plays an important role in fibroblast and endothelial cell proliferation. SU9518, a PDGFR tyrosine kinase inhibitor, reduces radiation-induced fibroblast and endothelial cell activation. This may explain therapeutic anticancer effects of Imatinib/Gleevec, and at the same time it could open a way of attenuating radiation-induced fibrosis
    Type of Publication: Journal article published
    PubMed ID: 16556328
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  • 4
    Keywords: CANCER ; EXPRESSION ; COMBINATION ; LUNG ; MODEL ; MODELS ; TOXICITY ; CLASSIFICATION ; liver ; GENE ; GENE-EXPRESSION ; microarray ; validation ; QUALITY ; BREAST ; breast cancer ; BREAST-CANCER ; PERFORMANCE ; gene expression ; MICROARRAY DATA ; HUMANS ; microarrays ; PREDICTION ; PROJECT ; FOLLICULAR LYMPHOMA ; MULTIPLE-MYELOMA ; rodent ; neuroblastoma ; development ; methods ; GENE-EXPRESSION DATA ; DNA MICROARRAYS ; rodents ; RECOMMENDATIONS ; EXPRESSION DATA ; CONTROL MAQC PROJECT ; PUBLISHED MICROARRAY ; RISK-STRATIFICATION
    Abstract: Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, 〉30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis
    Type of Publication: Journal article published
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  • 5
    ISSN: 0014-4827
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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