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  • 1
    Keywords: brain ; RECEPTOR ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; IN-VIVO ; VIVO ; DISEASE ; RISK ; GENOME ; HYBRIDIZATION ; PROTEIN ; SAMPLE ; TISSUE ; TUMORS ; MICE ; PATIENT ; DOMAIN ; GENETIC POLYMORPHISMS ; TISSUES ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; DELETION ; IN-SITU ; prevention ; immunohistochemistry ; UP-REGULATION ; NUMBER ; PATHOGENESIS ; DISPLAY ; HUMAN GENOME ; SURFACE ; EPITHELIAL-CELLS ; genetic polymorphism ; NORMAL TISSUE ; CHAIN-REACTION ; SMALL-INTESTINE ; ULCERATIVE-COLITIS ; TERMINAL DIFFERENTIATION ; inflammation ; SALIVARY AGGLUTININ ; SURFACTANT PROTEIN-D ; INFLAMMATORY-BOWEL-DISEASE ; MALIGNANT BRAIN-TUMORS ; SCAVENGER RECEPTOR ; in situ hybridization ; CHAIN ; BRAIN-TUMORS ; pathogen ; VARIANT ; ALLELE ; inflammatory bowel disease ; LEVEL ; methods ; SUBTYPES ; SULFATE ; USA ; function ; INCREASED RISK ; odds ratio ; in vivo ; case control ; quantitative ; MUCOSAL ; EXONS ; CRP-DUCTIN ; DEXTRAN SULFATE SODIUM
    Abstract: Background & Aims: Impaired mucosal. defense plays an important role in the pathogenesis of Crohn's disease (CD), one of the main subtypes of inflammatory bowel disease (IBD). Deleted in malignant brain tumors 1(DMBT1) is a secreted scavenger receptor cysteine-rich protein with predominant expression in. the intestine and has been proposed to exert possible functions in regenerative processes and pathogen defense. Here, we aimed at analyzing the role of DMBT1 in IBD. Methods: We studied DMBT1 expression in IBD and normal tissues by quantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and mRNA in situ hybridization. Genetic polymorphisms within DMBT1 were analyzed in an Italian IBD case-control sample. Dmbt1(-/-) mice were generated, characterized, and analyzed for their susceptibility to dextran sulfate sodium-induced colitis. Results: DMBT1 levels correlate with disease activity in inflamed IBD tissues. A highly significant fraction of the patients with IBD displayed up-regulation of DMBT1 specifically in the intestinal epithelial surface cells and Paneth cells. A deletion allele of DMBT1 with a reduced: number of scavenger receptor cysteine-rich domain coding exons is associated with an increased risk of CD (P =.00056; odds ratio, 1.75) but not for ulcerative colitis. Dmbt1(-/-) mice display enhanced susceptibility to dextran sulfate sodium-induced colitis and elevated Tnf, Il6, and Nod2 expression levels during inflammation. Conclusions: DMBT1 may play a role in intestinal mucosal protection and prevention of inflammation. Impaired DMBT1 function may contribute to the pathogenesis of CD
    Type of Publication: Journal article published
    PubMed ID: 17983803
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  • 2
    Publication Date: 2018-08-02
    Description: Purpose: Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor type with limited treatment options and poor prognosis. The angiokinase inhibitor nintedanib has shown promising activity in the LUME-Meso phase II MPM trial and thus is currently being evaluated in the confirmatory LUME-Meso phase III trial. However, the anti-MPM potential of nintedanib has not been studied in the preclinical setting. Experimental Design: We have examined the antineoplastic activity of nintedanib in various in vitro and in vivo models of human MPM. Results: Nintedanib's target receptors were (co)expressed in all the 20 investigated human MPM cell lines. Nintedanib inhibited MPM cell growth in both short- and long-term viability assays. Reduced MPM cell proliferation and migration and the inhibition of Erk1/2 phosphorylation were also observed upon nintedanib treatment in vitro . Additive effects on cell viability were detected when nintedanib was combined with cisplatin, a drug routinely used for systemic MPM therapy. In an orthotopic mouse model of human MPM, survival of animals receiving nintedanib per os showed a favorable trend, but no significant benefit. Nintedanib significantly reduced tumor burden and vascularization and prolonged the survival of mice when it was administered intraperitoneally. Importantly, unlike bevacizumab, nintedanib demonstrated significant in vivo antivascular and antitumor potential independently of baseline VEGF-A levels. Conclusions: Nintedanib exerts significant antitumor activity in MPM both in vitro and in vivo . These data provide preclinical support for the concept of LUME-Meso trials evaluating nintedanib in patients with unresectable MPM. Clin Cancer Res; 24(15); 3729–40. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 3
    Publication Date: 2018-02-13
    Description: The triple-angiokinase inhibitor nintedanib is an orally available, potent, and selective inhibitor of tumor angiogenesis by blocking the tyrosine kinase activities of vascular endothelial growth factor receptor (VEGFR) 1–3, platelet-derived growth factor receptor (PDGFR)- α and - β , and fibroblast growth factor receptor (FGFR) 1–3. Nintedanib has received regulatory approval as second-line treatment of adenocarcinoma non–small cell lung cancer (NSCLC), in combination with docetaxel. In addition, nintedanib has been approved for the treatment of idiopathic lung fibrosis. Here we report the results from a broad kinase screen that identified additional kinases as targets for nintedanib in the low nanomolar range. Several of these kinases are known to be mutated or overexpressed and are involved in tumor development (discoidin domain receptor family, member 1 and 2, tropomyosin receptor kinase A (TRKA) and C, rearranged during transfection proto-oncogene [RET proto oncogene]), as well as in fibrotic diseases (e.g., DDRs). In tumor cell lines displaying molecular alterations in potential nintedanib targets, the inhibitor demonstrates direct antiproliferative effects: in the NSCLC cell line NCI-H1703 carrying a PDGFR α amplification (ampl.); the gastric cancer cell line KatoIII and the breast cancer cell line MFM223, both driven by a FGFR2 amplification; AN3CA (endometrial carcinoma) bearing a mutated FGFR2; the acute myeloid leukemia cell lines MOLM-13 and MV-4-11-B with FLT3 mutations; and the NSCLC adenocarcinoma LC-2/ad harboring a CCDC6-RET fusion. Potent kinase inhibition does not, however, strictly translate into antiproliferative activity, as demonstrated in the TRKA-dependent cell lines CUTO-3 and KM-12. Importantly, nintedanib treatment of NCI-H1703 tumor xenografts triggered effective tumor shrinkage, indicating a direct effect on the tumor cells in addition to the antiangiogenic effect on the tumor stroma. These findings will be instructive in guiding future genome-based clinical trials of nintedanib.
    Print ISSN: 0022-3565
    Electronic ISSN: 1521-0103
    Topics: Medicine
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