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  • ddc: 610  (23)
  • CANCER  (16)
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  • 11
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS Current Posters in Otorhinolaryngology - Head and Neck Surgery; VOL: 12; DOC202 /20160411/
    Publication Date: 2016-04-12
    Description: Einleitung: Trotz moderner radioonkologischer Therapieansätze stellt die Entwicklung von Radioresistenz in durch Heterogenität charakterisierten Kopf-Hals-Plattenepithelkarzinomen (HNSCC) ein erhebliches Problem dar. Die Etablierung innovativer präklinischer Modellsysteme für die systematische Charakterisierung von Resistenzmechanismen und Testung neuer gezielter Pharmakotherapeutika ist daher unbedingt erforderlich.Methoden: Das Zusammenspiel zwischen Bestrahlung und Aktivierung der MAP-Kinasen ERK, p38 und JNK wurde in vitro sowie im humanen ex vivo-Kopf-Hals-Karzinommodell untersucht. Nach MAPK-Inhibition erfolgte die Bestrahlung von HNSCC-Zelllinien (p53WT/mut). Das Bestrahlungsansprechen wurde funktionell analysiert und im ex vivo-Modell bestätigt. Ergebnisse: Zwei HNSCC-Linien zeigten eine deutliche strahlungsinduzierte ERK-Phosphorylierung, welche mit Radiosensibilisierung nach MEK-Hemmung im Colony Forming Assay (CFA) assoziiert war, während sich eine Linie mit geringer postradiogener ERK-Phosphorylierung im CFA als weniger sensibel auf MEK-Inhibition erwies. Das heterogene Ansprechen spiegelte sich auch im ex vivo-Modell wider. JNK und p38 zeigten keine relevante bestrahlungsinduzierte Aktivierung. Schlussfolgerungen: Die heterogene strahlungsinduzierte ERK-Phosphorylierung in der Zellkultur und im ex vivo-Modell weist auf einen kontextabhängigen Regulationsmodus hin. Aufgrund der geringen Fallzahl war eine Korrelation mit klinischen Parametern nur begrenzt möglich, jedoch kam es interessanterweise bei Patienten mit geringer basaler ERK-Phosphorylierung und postradiogener Induktion im Verlauf zu einem Rezidiv. In geplanten Studien an großen Kohorten sollte daher diese Subgruppe genauer analysiert werden.Der Erstautor gibt keinen Interessenkonflikt an.
    Keywords: ddc: 610
    Language: German
    Type: article
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  • 12
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  87. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie; 20160504-20160507; Düsseldorf; DOC16hnod251 /20160330/
    Publication Date: 2016-03-31
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 13
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  87. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie; 20160504-20160507; Düsseldorf; DOC16hnod200 /20160330/
    Publication Date: 2016-03-31
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 14
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  85. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie; 20140528-20140601; Dortmund; DOC14hnod300 /20140414/
    Publication Date: 2014-04-15
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 15
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; carcinoma ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; PROTEIN ; SAMPLE ; SAMPLES ; murine ; AP-1 ; CARCINOGENESIS ; tumour ; SKIN ; MOUSE ; TRANSCRIPTION FACTORS ; IDENTIFICATION ; PROGRESSION ; gene expression ; PROMOTERS ; skin carcinogenesis ; METASTASIS ; SSH ; PCR ; TRANSFORMATION ; EPITHELIAL-CELLS ; squamous cell carcinoma ; FRAGMENTS ; MULTISTAGE CARCINOGENESIS ; real-time PCR ; expression profiling ; PHORBOL ESTER ; CDNA MICROARRAY ; NMRI MOUSE SKIN ; tumour promoter
    Abstract: Malignant transformation of mouse skin by chemical carcinogens and tumour promoters, such as the phorbol ester 12-O- tetradecanoylphorbol-13-acetate (TPA), is a multi-stage process that leads to squamous cell carcinoma (SCC) formation. In an effort to identify turnour-associated genes, we studied the influence of short-term TPA-treatment on the gene expression profile of murine skin. A comprehensive microarray with some 5,000 murine gene specific cDNA fragments was established and hybridised with pooled RNA derived from control and TPA-treated dorsal skin samples. Of these genes, 54 were up- and 35 were down-regulated upon TPA application. Additionally, we performed suppression subtractive hybridisation (SSH) with respective RNA pools to generate and analyse a cDNA library enriched for TPA- inducible genes. Expression data of selected genes were confirmed by quantitative real-time PCR and Northern blot analysis. Comparison of microarray and SSH data revealed that 26% of up-regulated genes identified by expression profiling matched with those present in the SSH library. Besides numerous known genes, we identified a large set of unknown cDNAs that represent previously unrecognised TPA-regulated genes in murine skin with potential function in tumour promotion. Additionally, some TPA-induced genes, such as SprrIA, Saa3, junB, II4ralpha, Gp38, RalGDS and Slpi exhibit high basal level in advanced stages of skin carcinogenesis, suggesting that at least a subgroup of the identified TPA-regulated genes may contribute to tumour progression and metastasis. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 12640676
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  • 16
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; SURVIVAL ; carcinoma ; CELL ; Germany ; human ; MODEL ; PATHWAY ; PATHWAYS ; NETWORK ; SUPPORT ; DEATH ; HEPATOCELLULAR-CARCINOMA ; liver ; GENE ; GENES ; PROTEIN ; PROTEINS ; TISSUE ; NF-KAPPA-B ; ACTIVATION ; murine ; CARCINOGENESIS ; INDUCTION ; SIGNAL ; TARGET ; MOUSE ; hepatocarcinogenesis ; hepatocellular carcinoma ; PROGRESSION ; CELL-DEATH ; CELL-LINE ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; RAGE ; MOUSE MODEL ; KAPPA-B ; OXIDATIVE STRESS ; expression profiling ; inflammation ; signaling ; MOLECULAR-MECHANISMS ; cell death ; CANCER PROGRESSION ; USA ; GROWTH-CONTROL ; SUPPRESSOR-CELLS ; nuclear factor kappa B ; COEXPRESSION ; COMPENSATORY PROLIFERATION
    Abstract: The nuclear factor-kappaB (NF-kappa B) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-kappa B-dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated liver carcinogenesis. Expression profiling of NF-kappa B-deficient and NF-kappa B-proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-kappa B target genes, including S100a8 and S100a9. We detected increased co-expression of S100A8 and S100A9 proteins in mouse HCC cells, in human HCC tissue, and in the HCC cell line Hep3B on ectopic RelA expression. Finally, we found a synergistic function for S100A8 and S100A9 in Hep3B cells resulting in a significant induction of reactive oxygen species (ROS), accompanied by enhanced cell survival. Conclusion: We identified S100A8 and S100A9 as novel NF-kappa B target genes in HCC cells during inflammation-associated liver carcinogenesis and provide experimental evidence that increased co-expression of both proteins supports malignant progression by activation of ROS-dependent signaling pathways and protection from cell death. (HEPATOLOGY 2009;50: 1251-1262.)
    Type of Publication: Journal article published
    PubMed ID: 19670424
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  • 17
    Keywords: APOPTOSIS ; CANCER ; PATHWAYS ; PROTEINS ; transcription ; COMPLEX ; MESSENGER-RNA ; CELL-CYCLE ; ARREST ; nucleoporin
    Abstract: The p53 tumor suppressor utilizes multiple mechanisms to selectively regulate its myriad target genes, which in turn mediate diverse cellular processes. Here, using conventional and single-molecule mRNA analyses, we demonstrate that the nucleoporin Nup98 is required for full expression of p21, a key effector of the p53 pathway, but not several other p53 target genes. Nup98 regulates p21 mRNA levels by a posttranscriptional mechanism in which a complex containing Nup98 and the p21 mRNA 3'UTR protects p21 mRNA from degradation by the exosome. An in silico approach revealed another p53 target (14-3-3 sigma) to be similarly regulated by Nup98. The expression of Nup98 is reduced in murine and human hepatocellular carcinomas (HCCs) and correlates with p21 expression in HCC patients. Our study elucidates a previously unrecognized function of wild-type Nup98 in regulating select p53 target genes that is distinct from the well-characterized oncogenic properties of Nup98 fusion proteins.
    Type of Publication: Journal article published
    PubMed ID: 23102701
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  • 18
    Keywords: APOPTOSIS ; CANCER ; PATHWAY ; GROWTH-FACTOR RECEPTOR ; resistance ; microenvironment ; RADIORESISTANCE ; EGFRVIII ; MALIGNANT MAMMARY ; AKT ACTIVATION
    Abstract: Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by high resistance to radiotherapy, which critically depends on both altered signaling pathways within tumor cells and their dynamic interaction with the tumor microenvironment. This study evaluated the prognostic value of the phosphorylation status of AKT on Ser473 and Thr308 for the clinical outcome of patients with advanced HNSCC on radiotherapy. Furthermore, we investigated the impact of AKT(Ser473) phosphorylation [p-AKT(Ser473)] in the context of radioresistance using ex vivo tissue cultures that resemble the complex tissue architecture and paracrine interaction with the tumor microenvironment. In a cohort of 120 patients with advanced HNSCC, who were treated with primary or adjuvant radiotherapy, a significant association was found between relative p-AKT(Ser473) levels and overall survival (p=0.006) as well as progression-free survival (p=0.021), while no significant correlation was revealed for relative p-AKT(Thr308) levels. In ex vivo tissue cultures p-AKT(Ser473) levels were increased upon irradiation and treatment with the PI3K inhibitor LY294002 inhibited both basal and irradiation induced AKT(Ser473) phosphorylation. Strikingly, pretreatment with LY294002 sensitized tissue cultures derived from primary and recurrent tumors to radiotherapy as determined by impaired tumor cell proliferation and enhanced DNA damage. In conclusion, phosphorylation status of AKT(Ser473) in tumor specimens serves as a novel biomarker to identify patients with advanced HNSCC at high risk for treatment failure following radiotherapy, and our data from ex vivo tissue cultures support the assumption that pharmacological inhibition of AKT(Ser473) phosphorylation might circumvent radioresistance to improve efficiency and reduce toxicity of current treatment modalities. What's new? Patients with head and neck squamous cell cancers often develop resistance to radiotherapy. To figure out how, these authors investigated AKT phosphorylation in the tumor cells. AKT kinase boosts cell proliferation when it is activated by phosphorylation at two possible sites. Could the location of phosphorylation predict whether the tumor will develop resistance? These results suggest it could. The authors show that patients with more phosphorylation at serine 473 had worse survival; furthermore, they showed that reducing phosphorylation at this site increased cancer cells' vulnerability to irradiation. Phosphorylation at the other site, threonine 308, did not affect survival.
    Type of Publication: Journal article published
    PubMed ID: 25388642
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  • 19
    Keywords: CANCER ; radiotherapy ; SAFETY ; MEMBRANES ; CELL-CARCINOMA ; IMMUNE CHECKPOINTS ; LIGAND 1 ; NIVOLUMAB ; MPDL3280A ; ANTI-PD-1
    Abstract: Mucosal melanoma of the head and neck is a rare and aggressive tumor entity with a poor prognosis. The standard treatment is radical tumor resection, with or without adjuvant radiation, where conventional chemotherapies in advanced stage or recurrent diseases have shown little benefit. Overexpression of the programmed cell death ligand 1 (PD-L1) is a common feature in human cancer. Although PD-L1 is an acknowledged prognostic biomarker for dismal prognosis in other tumors of the head and neck, expression and clinical relevance of PD-L1 in mucosal melanoma have not been addressed so far. We assessed PD-L1 expression using immunohistochemical staining in 23 tumor samples from patients with primary mucosal melanoma and correlated expression status with clinicopathological and outcome data. Tumors were derived from the nasal cavity (43.5%), nasal sinuses (43.5%), and the conjunctiva (13%). All patients had undergone surgery; 39% of all patients received adjuvant radiation and 13% were administered systemic interferon therapy. The probability of 1- and 5-year overall survival was 87 and 34.8%, respectively. The mean overall survival was 51 months and the mean recurrence-free survival was 23 months. Immunohistochemical staining showed PD-L1 expression in 13% (3/23) of mucosal melanoma. In contrast, prominent PD-L1 staining was detected in 100% of tissue sections from a control group of cutaneous melanoma (n=9). PD-L1 expression in mucosal melanoma was not correlated with age, sex, nor anatomical localization of the tumor. Interestingly, patients with PD-L1-positive mucosal melanoma had a significantly longer recurrence-free survival (P=0.026). In contrast to cutaneous melanoma and some other malignancies, a relevant PD-L1 overexpression in mucosal melanoma could not be confirmed.
    Type of Publication: Journal article published
    PubMed ID: 26352784
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  • 20
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; tumor ; carcinoma ; Germany ; IN-VIVO ; VITRO ; GENE ; PROTEIN ; TUMORS ; MICE ; PATIENT ; FAMILY ; AP-1 ; CARCINOGENESIS ; INDUCTION ; KERATINOCYTES ; SKIN ; BINDING ; fibroblasts ; MOUSE ; c-Fos ; PROMOTER ; MOUSE SKIN ; TRANSFORMATION ; BENIGN ; CARCINOMAS ; squamous cell carcinoma ; GLUCOCORTICOID-RECEPTOR ; SKIN-CANCER ; BINDING PROTEIN ; keratinocyte ; TRANSITION ; MALIGNANT PROGRESSION ; INTERSTITIAL COLLAGENASE ; CELL-CARCINOMA ; dexamethasone ; MOUSE KERATINOCYTES ; RECYCLING ENDOSOMES
    Abstract: Malignant transformation of mouse skin by tumor promoters and chemical carcinogens, such as the phorhol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), is a multistage process leading to the formation of squamous cell carcinomas. it has been shown that mice lacking the AP-1 family member c-Fos exhibit an impaired transition from benign to malignant skin tumors. Here, we demonstrate enhanced expression of the small Ras-related GTPase Rab11a after short-term TPA treatment of mouse back skin. Expression of Rab11a in vivo and in vitro critically depended on c-Fos, because TPA application to the back skin of c-Fos-deficient mice and to mouse embryonic fibroblasts did not induce Rab11a mRNA or protein expression. Moreover, dexamethasone, which is a potent inhibitor of AP-1-mediated transactivation that exhibits anti-inflammatory and antitumor promoting activities, inhibited TPA-induced expression of Rab11a. Within the Rab11a gene promoter, we identified a functional AP-1 binding element that exhibited elevated c-Fos binding activity after TPA treatment of keratinocytes. Enhanced expression was not restricted to chemically induced mouse skin tumors but was also found in tumor specimens derived from patients with epithelial skin tumors. These data identify Rab11a as a novel, tumor-associated c-Fos/AP-1 target and may point to an as yet unrecognized function of Rab11a in the development of skin cancer
    Type of Publication: Journal article published
    PubMed ID: 15972968
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