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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  62. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS); 20170917-20170921; Oldenburg; DOCAbstr. 177 /20170829/
    Publication Date: 2017-08-29
    Keywords: Biometrie ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  HEC 2016: Health - Exploring Complexity; Joint Conference of GMDS, DGEpi, IEA-EEF, EFMI; 20160828-20160902; München; DOCAbstr. 840 /20160808/
    Publication Date: 2016-08-11
    Keywords: Statistical methods for health services research ; ddc: 610
    Language: German
    Type: conferenceObject
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  • 3
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMDS 2014; 59. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS); 20140907-20140910; Göttingen; DOCAbstr. 14 /20140904/
    Publication Date: 2014-09-05
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 4
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMDS 2013; 58. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS); 20130901-20130905; Lübeck; DOCAbstr.352 /20130827/
    Publication Date: 2013-08-28
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 5
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Mainz//2011; 56. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds), 6. Jahrestagung der Deutschen Gesellschaft für Epidemiologie (DGEpi); 20110926-20110929; Mainz; DOC11gmds050 /20110920/
    Publication Date: 2011-09-20
    Keywords: rare diseases ; literature review ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 6
    Keywords: IN-VIVO ; PATHWAY ; PROTEIN ; GROWTH-FACTOR RECEPTOR ; COLORECTAL-CANCER ; gene amplification ; TRANSCRIPTION 3 ; TYROSINE-PHOSPHORYLATED STAT3 ; ACTIVATED SIGNAL TRANSDUCER ; MULTIPOLAR MITOSES
    Abstract: Signal transducer and activator of transcription 3 (STAT3) is altered in several epithelial cancers and represents a potential therapeutic target. Here, STAT3 expression, activity and cellular functions were examined in two main histotypes of esophageal carcinomas. In situ, immunohistochemistry for STAT3 and STAT3-Tyr705 phosphorylation (P-STAT3) in esophageal squamous cell carcinomas (ESCC, n=49) and Barrett's adenocarcinomas (BAC, n=61) revealed similar STAT3 expression in ESCCs and BACs (P=0.109), but preferentially activated P-STAT3 in ESCCs (P=0.013). In vitro, strong STAT3 activation was seen by epidermal growth factor (EGF) stimulation in OE21 (ESCC) cells, whereas OE33 (BAC) cells showed constitutive weak STAT3 activation. STAT3 knockdown significantly reduced cell proliferation of OE21 (P=0.0148) and OE33 (P=0.0243) cells. Importantly, STAT3 knockdown reduced cell migration of OE33 cells by 2.5-fold in two types of migration assays (P=0.073, P=0.015), but not in OE21 cells (P=0.1079, P=0.386). Investigation of transcriptome analysis of STAT3 knockdown revealed a reduced STAT3 level associated with significant downregulation of cell cycle genes in both OE21 (P〈0.0001) and OE33 (P=0.01) cells. In contrast, genes promoting cell migration (CTHRC1) were markedly upregulated in OE21 cells, whereas a gene linked to tight-junction stabilization and restricted cell motility (SHROOM2) was downregulated in OE21 but upregulated in OE33 cells. This study shows frequent, but distinct, patterns of STAT3 expression and activation in ESCCs and BACs. STAT3 knockdown reduces cell proliferation in ESCC and BAC cells, inhibits migration of BAC cells and may support cell migration of ESCC cells. Thereby, novel STAT3-regulated genes involved in ESCC and BAC cell proliferation and cell migration were identified. Thus, STAT3 may be further exploited as a potential novel therapeutic target, however, by careful distinction between the two histotypes of esophageal cancers.
    Type of Publication: Journal article published
    PubMed ID: 23912451
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  • 7
    Keywords: GROWTH-FACTOR RECEPTOR ; SQUAMOUS-CELL CARCINOMA ; GASTRIC-CANCER ; BARRETTS-ESOPHAGUS ; ARBEITSGEMEINSCHAFT INTERNISTISCHE ONKOLOGIE ; HER-2/NEU GENE AMPLIFICATION ; LABEL PHASE-3 TRIAL ; ESOPHAGOGASTRIC CANCER ; JUNCTION CANCER ; II TRIAL
    Abstract: Receptor tyrosine kinases (RTKs) are in the focus of targeted therapy for epithelial tumors. Our study addressed the role of EGFR, HER2 and HER3 expression and dimerization in esophageal cancers in situ and in vitro in the context of therapeutic EGFR and HER2 inhibitors. In archival pretreatment biopsies of esophageal carcinomas (n = 110), EGFR was preferentially expressed in esophageal squamous cell carcinomas (ESCCs) (22.4%; p = 0.088) and HER2 (34.4%; p 〈 0.001) with HER3 (91.5%; p 〈 0.001) in esophageal (Barrett's) adenocarcinomas (EACs). In situ proximity ligation assays revealed mainly EGFR and HER2 homodimers in ESCC and EAC cases, respectively. However, EAC cases also exhibited HER2/HER3 heterodimers. In vitro ESCC (OE21) cells displayed a significant response to erlotinib, gefitinib and lapatinib, with loss of AKT phosphorylation, G0/G1 cell cycle arrest and induction of apoptosis. In EAC cells (OE19, OE33 and SK-GT-4), lapatinib was similarly effective in strongly HER2-positive (mainly HER2 homodimers and some HER2/EGFR heterodimers) OE19 and OE33 cells. The HER2-targeting antibodies (trastuzumab and pertuzumab) given alone were largely ineffective in ESCC and EAC cells. However, both antibodies significantly induced antibody-dependent cellular cytotoxicity in EAC (OE19 and OE33) cells upon co-culture with peripheral blood mononuclear cells. The study reveals that overexpression of EGFR and HER2 predominantly results in homodimers in ESCCs and EACs, respectively. Still, some EACs also show HER2 dimerization plasticity, e.g., with HER3. Such RTK dimerization patterns affect responses to EGFR and HER2 targeting inhibitors in ESCC and EAC cells in vitro and hence may influence future prediction for particularly HER2-targeting inhibitors in EACs.
    Type of Publication: Journal article published
    PubMed ID: 24510732
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  • 8
    Keywords: EXPRESSION ; ADVANCED SOLID TUMORS ; PHASE-I ; BREAST-CANCER ; MALIGNANCIES ; OVEREXPRESSION ; ACUTE MYELOID-LEUKEMIA ; OPEN-LABEL ; BI 2536 ; POLO-LIKE-KINASE-1 PLK1
    Abstract: Polo-like kinase 1 (PLK1) is an important regulator of the cell cycle and is overexpressed in various solid and hematological malignancies. Small molecule inhibitors targeting PLK1, such as BI2536 or BI6727 (Volasertib) are a promising therapeutic approach in such malignancies. Here, we show a loss of specifically localized PLK1 in AML blasts in vivo, accompanied by mitotic arrest with transition into apoptosis, in bone marrow biopsies of AML patients after treatment with BI2536. We verify these results in live cell imaging experiments with the AML cell line HL-60, and demonstrate that non-neoplastic, immortalized lymphoblastoid cells are also sensitive to PLK1 inhibition. It is demonstrated that normal granulopoietic precursors have similar PLK1 expression levels as leukemic blasts. These results are in line with the adverse effects of PLK1 inhibition and underline the great potential of PLK1 inhibitors in the treatment of AML.
    Type of Publication: Journal article published
    PubMed ID: 25697066
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  • 9
    Keywords: CELL-PROLIFERATION ; PROTEIN ; POOR-PROGNOSIS ; CANCER-THERAPY ; SPINDLE CHECKPOINT ; OVARIAN-CARCINOMA ; MULTIPOLAR MITOSES ; CHROMOSOMAL PASSENGER COMPLEX ; H3 PHOSPHORYLATION ; C KINASE
    Abstract: Experimental model systems identified phosphorylation of linker histone variant H1.4 at Ser 27 (H1.4S27p) as a novel mitotic mark set by Aurora B kinase. Here, we examined expression of Aurora B and H1.4S27p in colorectal carcinoma (CRC) cell lines (HCT116, DLD1, Caco-2, HT29) and tissue specimens (n = 36), in relation to microsatellite instability (MSI) status and ploidy. In vitro, Aurora B (pro-/meta-/anaphase) and H1.4S27p (pro-/metaphase) were localized in mitotic figures. The proportion of labeled mitoses was significantly different between cell lines for Aurora B (p = 0.019) but not for H1.4S27p (p = 0.879). For Aurora B, these differences were not associated with an altered Aurora B gene copy number (FISH) or messenger RNA (mRNA) expression level (qRT-PCR). Moreover, Aurora B expression and H1.4S27 phosphorylation were no longer coordinated during metaphase in aneuploid HT29 cells (p = 0.039). In CRCs, immunoreactivity for Aurora B or H1.4S27p did not correlate with T- or N-stage, grade, or MSI status. However, metaphase labeling of H1.4S27p was significantly higher in diploid than in aneuploid CRCs (p = 0.011). Aurora B was significantly correlated with H1.4S27p-positive metaphases in MSI (p = 0.010) or diploid (p = 0.003) CRCs. Finally, combined classification of MSI status and ploidy revealed a significant positive correlation of Aurora B with H1.4S27p in metaphases of diploid/MSI (p = 0.010) and diploid/microsatellite-stable (MSS; p = 0.031) but not of aneuploid/MSS (p = 0.458) CRCs. The present study underlines the functional link of Aurora B expression and H1.4S27p during specific phases of mitosis in diploid and/or MSI-positive CRCs in vitro and in situ. Importantly, the study shows that the coordination between Aurora B expression and phosphorylation of H1.4 at Ser 27 is lost in cycling aneuploid CRC cells.
    Type of Publication: Journal article published
    PubMed ID: 25680570
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  • 10
    Abstract: We previously showed that histone deacetylase inhibitor (HDACi) and 5-azacytidine (AZA) treatment selectively induced cell death of esophageal cancer cells. The mechanisms of cancer selectivity, however, remained unclear. Here we examined whether the cancer selectivity of HDACi/AZA treatment is mediated by the thioredoxin (Trx) system and reactive oxygen species (ROS) in esophageal cancer cells. For this, we first analyzed human tissue specimens of 37 esophageal cancer patients by immunohistochemistry for Trx, Trx-interacting protein (TXNIP) and Trx reductase (TXNRD). This revealed a loss or at least reduction of nuclear Trx in esophageal cancer cells, compared with normal epithelial cells (P〈0.001). Although no differences were observed for TXNIP, TXNRD was more frequently expressed in cancer cells (P〈0.001). In the two main histotypes of esophageal squamous cell carcinomas (ESCCs, n=19) and esophageal adenomcarcinomas (EAC, n=16), similar Trx, TXNIP and TXNRD expression patterns were observed. Also in vitro, nuclear Trx was only detectable in non-neoplastic Het-1A cells, but not in OE21/ESCC or OE33/EAC cell lines. Moreover, the two cancer cell lines showed an increased Trx activity, being significant for OE21 (P=0.0237). After treatment with HDACi and/or AZA, ROS were exclusively increased in both cancer cell lines (P=0.048-0.017), with parallel decrease of Trx activity. This was variably accompanied by increased TXNIP levels upon AZA, MS-275 or MS-275/AZA treatment for 6 or 24 h in OE21, but not in Het-1A or OE33 cells. In summary, this study evaluated Trx and its associated proteins TXNIP and TXNRD for the first time in esophageal cancers. The analyses revealed an altered subcellular localization of Trx and strong upregulation of TXNRD in esophageal cancer cells. Moreover, HDACi and AZA disrupted Trx function and induced accumulation of ROS with subsequent apoptosis in esophageal cancer cells exclusively. Trx function is hence an important cellular mediator conferring non-neoplastic cell resistance for HDACi and/or AZA.
    Type of Publication: Journal article published
    PubMed ID: 26692290
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