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  • DKFZ Publication Database  (10)
  • GENE  (6)
  • IN-VITRO  (5)
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  • DKFZ Publication Database  (10)
Keywords
  • 1
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; INHIBITOR ; carcinoma ; CELL ; Germany ; INHIBITION ; THERAPY ; LUNG-CANCER ; GENE ; PROTEIN ; SAMPLE ; SAMPLES ; TISSUE ; kidney ; FAMILY ; tumour ; ALPHA ; TARGET ; ISOFORM ; immunohistochemistry ; DIFFERENCE ; resistance ; CANCER-CELLS ; BETA ; STRATEGIES ; IMMUNOTHERAPY ; NORMAL TISSUE ; sensitivity ; OVEREXPRESSION ; CANCER-THERAPY ; protein expression ; TRANSCRIPTS ; CELL CARCINOMA ; renal cell carcinoma ; ONCOLOGY ; ADULT ; RE ; THERAPIES ; INCREASE ; cancer therapy ; REAL-TIME ; SURVIVIN ; NUCLEAR ; ML-IAP ; inhibitor of apoptosis ; apoptotic ; quantitative ; livin/ML-IAP ; APOPTOSIS PROTEIN ; CYTOPLASM ; tumour therapy ; Livin/ML-IAP/KIAP ; MELANOMA INHIBITOR
    Abstract: The antiapoptotic Livin/ML-IAP gene has recently gained much attention as a potential new target for cancer therapy. Reports indicating that livin is expressed almost exclusively in tumours, but not in the corresponding normal tissue, suggested that the targeted inhibition of livin may present a novel tumour-specific therapeutic strategy. Here, we compared the expression of livin in renal cell carcinoma and in non-tumorous adult kidney tissue by quantitative real-time reverse transcription-PCR, immunoblotting, and immunohistochemistry. We found that livin expression was significantly increased in tumours (P=0.0077), but was also clearly detectable in non-tumorous adult kidney. Transcripts encoding Livin isoforms alpha and beta were found in both renal cell carcinoma and normal tissue, without obvious qualitative differences. Livin protein in renal cell carcinoma samples exhibited cytoplasmic and/or nuclear staining. In non-tumorous kidney tissue, Livin protein expression was only detectable in specific cell types and restricted to the cytoplasm. Thus, whereas the relative overexpression of livin in renal cell carcinoma indicates that it may still represent a therapeutic target to increase the apoptotic sensitivity of kidney cancer cells, this strategy is likely to be not tumour-specific
    Type of Publication: Journal article published
    PubMed ID: 17968430
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  • 2
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; human ; SYSTEM ; SITE ; GENE ; GENES ; HYBRIDIZATION ; SAMPLE ; PATIENT ; COMPLEX ; BINDING ; BIOLOGY ; MOLECULAR-BIOLOGY ; ASSOCIATION ; DISORDER ; polymorphism ; VARIANTS ; TARGET ; IN-SITU ; ASSAY ; MUTATION ; genetics ; etiology ; REGION ; REGIONS ; REPLICATION ; HEALTHY ; LUCIFERASE ; heredity ; ANTAGONIST ; MANAGEMENT ; molecular biology ; molecular ; DISORDERS ; VARIANT ; NEURONS ; analysis ; EPITHELIUM ; pooled analysis ; HTR3A ; ENGLAND ; MUTATION ANALYSIS ; DYSFUNCTION ; UNTRANSLATED REGION ; POOLED-ANALYSIS ; UK ; 5-HT3 ; ABDOMINAL-PAIN ; ALOSETRON
    Abstract: Diarrhea predominant irritable bowel syndrome (IBS-D) is a complex disorder related to dysfunctions in the serotonergic system. As cis-regulatory variants can play a role in the etiology of complex conditions, we investigated the untranslated regions (UTRs) of the serotonin receptor type 3 subunit genes HTR3A and HTR3E. Mutation analysis was carried out in a pilot sample of 200 IBS patients and 100 healthy controls from the UK. The novel HTR3E 3'-UTR variant c.*76G 〉 A (rs62625044) was associated with female IBS-D (P = 0.033, OR = 8.53). This association was confirmed in a replication study, including 119 IBS-D patients and 195 controls from Germany (P = 0.0046, OR = 4.92). Pooled analysis resulted in a highly significant association of c.*76G 〉 A with female IBS-D (P = 0.0002, OR = 5.39). In a reporter assay, c.*76G 〉 A affected binding of miR-510 to the HTR3E 3'-UTR and caused elevated luciferase expression. HTR3E and miR-510 co-localize in enterocytes of the gut epithelium as shown by in situ hybridization and RT-PCR. This is the first example indicating micro RNA-related expression regulation of a serotonin receptor gene with a cis-regulatory variant affecting this regulation and appearing to be associated with female IBS-D
    Type of Publication: Journal article published
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  • 3
    Keywords: brain ; SPECTRA ; CELLS ; IN-VITRO ; tumor ; AGENTS ; CELL ; human ; MODEL ; VITRO ; DISEASE ; TUMORS ; MICE ; ACTIVATION ; LIGAND ; BINDING ; SUPPRESSION ; MOLECULE ; RECOGNITION ; ACID ; GLYCOPROTEIN ; PATHOGENESIS ; DOSE-RESPONSE ; LIGANDS ; EPITHELIAL-CELLS ; specificity ; DMBT1 ; AGENT ; AGGREGATION ; MOTIF ; PRODUCTS ; brain tumor ; BRAIN-TUMORS ; COLITIS ; interaction ; SODIUM ; pattern recognition ; structure ; brain tumors ; LPS ; Genetic ; genetic study ; BRAIN-TUMOR ; A
    Abstract: Deleted in malignant brain tumors 1 (DMBT1) is a secreted glycoprotein displaying a broad bacterial-binding spectrum. Recent functional and genetic studies linked DMBT1 to the suppression of LPS-induced TLR4-mediated NF-kappaB activation and to the pathogenesis of Crohn's disease. Here, we aimed at unraveling the molecular basis of its function in mucosal protection and of its broad pathogen-binding specificity. We report that DMBT1 directly interacts with dextran sulfate sodium (DSS) and carrageenan, a structurally similar sulfated polysaccharide, which is used as a texturizer and thickener in human dietary products. However, binding of DMBT1 does not reduce the cytotoxic effects of these agents to intestinal epithelial cells in vitro. DSS and carrageenan compete for DMBT1-mediated bacterial aggregation via interaction with its bacterial-recognition motif. Competition and ELISA studies identify poly-sulfated and poly-phosphorylated structures as ligands for this recognition motif, such as heparansulfate, LPS, and lipoteichoic acid. Dose-response studies in Dmbt1(-/-) and Dmbt1(+/+) mice utilizing the DSS-induced colitis model demonstrate a differential response only to low but not to high DSS doses. We propose that DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands providing a molecular basis for its broad bacterial-binding specificity and its inhibitory effects on LPS-induced TLR4-mediated NF-kappaB activation.
    Type of Publication: Journal article published
    PubMed ID: 19189310
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  • 4
    Keywords: ENVIRONMENT ; CANCER ; GROWTH ; IN-VITRO ; tumor ; carcinoma ; IN-VIVO ; MODEL ; tumor growth ; SURGERY ; AIR ; animals ; BODY-WEIGHT ; METASTASIS ; IMPLANTATION ; PRESSURE ; CARBON-DIOXIDE ; helium ; INSUFFLATION ; laparoscopy ; RANDOMIZED TRIAL ; experimental studies ; experimental study ; hepatectomy ; insufflation gas
    Abstract: Background: After exposure of neoplastic tissue to helium, a significant reduction of tumor growth has been detected in experimental studies, both in vitro and in vivo. This tumor- suppressive effect of helium is controversly discussed in the literature. It was therefore the aim of this study to investigate the influence of pneumoperitoneum with CO2, room air, or helium in a tumor-bearing small animal model comparing laparoscopic partial hepatic resection for hepatocellular carcinoma with conventional open partial hepatectomy. Methods: One-hundred forty-eight male American Cancer Institute rats underwent partial hepatectomy for curative resection of previously induced hepatocellular carcinoma (Morris hepatoma 3924A). Resection was performed either in open laparotomy (n = 30) or laparoscopically under the employment of CO2 (n = 30), room air (n = 30), or helium (n = 30) for the pneumoperitoneum. Twenty-eight animals served as controls receiving anesthesia but no tumor resection. All animals were sacrificed on postoperative days 21, 35, or 56 for autopsy and evaluation of possible tumor recurrence and metastasis. Results: Significant reduction of postoperative tumor recurrence and metastasis was observed in the group of animals receiving laparoscopic tumor resection under helium insufflation compared to open surgery or laparoscopic resection with air pneumoperitoneum. Conclusions: The results of this study suggest a suppressive effect of helium pneumoperitoneum on postoperative tumor growth and metastatic spread. Furthermore, tumor exposure to room air appears to have a stimulative influence on tumor recurrence and metastasis compared to a pneumoperitoneum established with CO2
    Type of Publication: Journal article published
    PubMed ID: 12632132
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  • 5
    Keywords: brain ; RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; INVASION ; tumor ; CELL ; Germany ; VITRO ; DISEASE ; GENE ; PROTEIN ; PROTEINS ; COMPONENTS ; TUMORS ; PATIENT ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; BINDING ; RECOGNITION ; TARGET ; MUTATION ; COMPONENT ; LINE ; MUTATIONS ; EPITHELIAL-CELLS ; FACTOR-KAPPA-B ; NF-kappa B ; TNF-ALPHA ; SALIVARY AGGLUTININ ; SURFACTANT PROTEIN-D ; INFLAMMATORY-BOWEL-DISEASE ; MALIGNANT BRAIN-TUMORS ; SCAVENGER RECEPTOR ; CYTOKINE ; BRAIN-TUMORS ; STREPTOCOCCUS-MUTANS ; secretion ; PATHOGENS ; USA ; function ; immunology ; INHIBIT ; CYSTEINE-RICH DOMAINS ; DYSFUNCTION ; PURPLE SEA-URCHIN ; SEROTYPE-C STRAIN
    Abstract: Mucosal epithelial cell layers are constantly exposed to a complex resident microflora. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by pathogen binding. This report describes the regulation and function of DMBT1 in intestinal epithelial cells, which form the primary immunological barrier for invading pathogens. We report that intestinal epithelial cells up-regulate DMBT1 upon proinflammatory stimuli (e.g., TNF-alpha, LPS). We demonstrate that DMBT1 is a target gene for the intracellular pathogen receptor NOD2 via NF-kappa B activation. DMBT1 is strongly up-regulated in the inflamed intestinal mucosa of Crohn's disease patients with wild-type, but not with mutant NOD2. We show that DMBT1 inhibits cytoinvasion of Salmonella enterica and LPS- and muramyl dipeptide-induced NF-kappa B activation and cytokine secretion in vitro. Thus, DMBT1 may play an important role in the first line of mucosal defense conferring immune exclusion of bacterial cell wall components. Dysregulated intestinal DMBT1 expression due to mutations in the NOD2/CARD15 gene may be part of the complex pathophysiology of barrier dysfunction in Crohn's disease
    Type of Publication: Journal article published
    PubMed ID: 17548659
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  • 6
    Keywords: RECEPTOR ; EXPRESSION ; DISEASE ; GENE ; GENES ; RNA ; MICROARRAY DATA ; innate immunity ; INFLAMMATORY-BOWEL-DISEASE ; inflammatory bowel disease ; laser microdissection ; pattern recognition receptor ; RIG-I ; EXPRESSION DATA ; ARRAYEXPRESS ; Crohn's disease ; NOD2 CARD15 MUTATIONS ; PUBLIC REPOSITORY ; retinoic acid-inducible gene I
    Abstract: BACKGROUND: A defective innate immune response may contribute to the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). Employing a global gene expression analysis, this study was aimed at identifying specifically regulated genes within the epithelial compartment in inflammatory bowel disease (IBD). METHODS: The epithelial fraction of human ileal mucosa samples from surgical specimens was obtained by laser microdissection. Gene expression was examined by global expression profiling (n = 18, Affymetrix), quantitative reverse-transcription polymerase chain reaction (RT-PCR) (n = 35), immunoblot analysis (n = 9), and immunohistochemistry (n = 25). RESULTS: Global expression profiling revealed a pronounced downregulation of the retinoic acid-inducible gene I (RIG-I) within the epithelial layer of the ileum in patients with CD but not with UC. The downregulation of RIG-I was confirmed by quantitative RT-PCR, immunoblot analysis, and immunohistochemistry. CONCLUSIONS: Epithelial downregulation of RIG-I, a known pattern recognition receptor for viral components, might contribute to alterations of the innate mucosal immune response, particularly in CD.
    Type of Publication: Journal article published
    PubMed ID: 21213277
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  • 7
  • 8
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; IN-VITRO ; SURVIVAL ; tumor ; carcinoma ; CELL ; Germany ; THERAPY ; INFORMATION ; DEATH ; DISEASE ; incidence ; MORTALITY ; microarray ; PROTEIN ; SAMPLE ; SAMPLES ; TISSUE ; TUMORS ; PATIENT ; LIGAND ; SERA ; prognosis ; T-CELL ; ASSOCIATION ; PERFORMANCE ; NEOPLASIA ; PROGRESSION ; immunohistochemistry ; METASTASIS ; SUPERFAMILY ; MULTIVARIATE ; CARCINOMAS ; NORMAL TISSUE ; gene amplification ; OVEREXPRESSION ; PROGNOSTIC FACTOR ; SERUM ; CELL CARCINOMA ; ELISA ; renal cell carcinoma ; ONCOLOGY ; REGRESSION ; THERAPIES ; MEDIATED APOPTOSIS ; PROGNOSTIC-FACTOR ; ADJUVANT THERAPY ; TUMOR TISSUE ; LEVEL ; analysis ; methods ; FAS LIGAND ; SERUM-LEVELS ; USA ; HIGH-GRADE ; PROGRESSION-FREE SURVIVAL ; PROBABILITY ; RENAL-CELL ; DCR3 ; lymph node metastasis ; PERFORMANCE STATUS
    Abstract: Background: Decoy receptor 3 (DcR3) is a soluble protein that binds to and inactivates the death ligand CD95L. Here, we studied a possible association between DcR3 expression and prognosis in patients with renal cell carcinomas (RCCs). Methods: A tissue microarray containing RCC tumor tissue samples and corresponding normal tissue samples was generated. Decoy receptor 3 expression in tumors of 560 patients was examined by immunohistochemistry. The effect of DcR3 expression on disease-specific survival and progression-free survival was assessed using univariate analysis and multivariate Cox regression analysis. Decoy receptor 3 serum levels were determined by ELISA. Findings: High DcR3 expression was associated with high-grade (P = .005) and high-stage (P = .048) RCCs. The incidence of distant metastasis (P = .03) and lymph node metastasis (P = .002) was significantly higher in the group with high DcR3 expression. Decoy receptor 3 expression correlated negatively with disease-specific survival (P 〈 .001) and progression-free survival (P 〈 .001) in univariate analyses. A multivariate Cox regression analysis retained DcR3 expression as an independent prognostic factor that outperformed the Karnofsky performance status. In patients with high-stage RCCs expressing DcR3, the 2-year survival probability was 25%, whereas in patients with DcR3-negative tumors, the survival probability was 65% (P 〈 .001). Moreover, DcR3 serum levels were significantly higher in patients with high-stage localized disease (P = .007) and metastatic disease ( P = .001). Interpretation: DcR3 expression is an independent prognostic factor of RCC progression and mortality. Therefore, the assessment of DcR3 expression levels offers valuable prognostic information that could be used to select patients for adjuvant therapy studies
    Type of Publication: Journal article published
    PubMed ID: 18813347
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  • 9
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; DEATH ; DISEASE ; SITES ; GENE ; GENE-EXPRESSION ; SAMPLES ; transcription ; PATIENT ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; T cells ; T-CELL ; AMPLIFICATION ; immunohistochemistry ; gene expression ; ASSAY ; resistance ; INDUCED APOPTOSIS ; PATHOGENESIS ; EPITHELIAL-CELLS ; INVOLVEMENT ; KAPPA-B ; expression profiling ; microdissection ; ULCERATIVE-COLITIS ; inflammation ; INFLAMMATORY-BOWEL-DISEASE ; CANDIDATE GENES ; INTERCELLULAR-ADHESION MOLECULE-1 ; FAS LIGAND ; DYSFUNCTION ; POLYMERASE ; DEATH LIGAND ; MONOCYTE ADHESION
    Abstract: Aims: Both epithelial barrier dysfunction and apoptosis resistance of immune cells contribute to the pathogenesis of Crohn's disease. The soluble decoy receptor 3 (DcR3) acts in an anti-apoptotic manner by neutralising the death ligand CD95L. Here, we investigated the possible involvement of DcR3 in Crohn's disease. Methods: The epithelial fraction of human small intestinal mucosa samples was obtained by laser microdissection. Expression of DcR3 was examined by global gene expression profiling, quantitative reverse transcription polymerase chain reaction, immunoblot analysis, and immunohistochemistry. DcR3 concentrations in the serum of patients with Crohn's disease were measured by enzyme-linked immunosorbent assay. Apoptosis assays were performed to study the effects of DcR3 in intestinal epithelial cells and lamina propria T cells. Results: DcR3 is over-expressed in the epithelial layer of ileum specimens in patients with Crohn's disease, both at actively inflamed and non-active sites. DcR3 serum levels are significantly elevated in patients with active and non-active Crohn's disease as compared to healthy controls. The expression of DcR3 in intestinal epithelial cells is induced by tumour necrosis factor a. Increased DcR3 expression is associated with activation of nuclear factor kappa B (NF-kappa B) and results in protection of intestinal epithelial cells and lamina propria T cells from CD95L-induced apoptosis. Conclusions: DcR3 may promote inflammation in Crohn's disease by inhibiting CD95L-induced apoptosis of epithelial and immune cells as well as by inducing NF-kappa B activation
    Type of Publication: Journal article published
    PubMed ID: 19039087
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  • 10
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; IN-VITRO ; SURVIVAL ; tumor ; carcinoma ; CELL ; Germany ; THERAPY ; DEATH ; microarray ; SAMPLES ; MONOCLONAL-ANTIBODY ; SURGERY ; PATIENT ; NF-KAPPA-B ; LIGAND ; prognosis ; ASSOCIATION ; immunohistochemistry ; METASTASIS ; PROGNOSTIC-FACTORS ; CARCINOMA-CELLS ; TRAIL ; DEATH RECEPTORS ; CYTOTOXICITY ; APOPTOSIS-INDUCING LIGAND ; THERAPIES ; MEDIATED APOPTOSIS ; ENHANCEMENT ; development ; therapeutic ; DEATH LIGAND
    Abstract: Purpose: The death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-R) are involved in immune surveillance and tumor development. Here, we studied a possible association between the expression of TRAIL/TRAIL-Rs and the prognosis in patients with renal cell carcinomas (RCC). Experimental Design: A tissue microarray containing RCC tumor tissue samples and corresponding normal tissue samples from 838 patients was generated. Expression of TRAIL and TRAIL-Rs was examined by immunohistochemistry and the effect of TRAIL and TRAIL-R expression on disease-specific survival was assessed. Results: High TRAIL-R2 expression levels were associated with high-grade RCCs (P 〈 0.001) and correlated negatively with disease-specific survival (P = 0.01). Similarly, high TRAIL expression was associated with a shorter disease-specific survival (P = 0.01). In contrast, low TRAIL-R4 expression was associated with high-stage RCCs (P 〈 0.001) as well as with the incidence of distant metastasis (P = 0.03) and correlated negatively with disease-specific survival (P = 0.02). In patients without distant metastasis, multivariate Cox regression analyses revealed that TRAIL-R2 and TRAIL are independent prognostic factors for cancer-specific survival (in addition to tumor extent, regional lymph node metastasis, grade of malignancy, and type of surgery). Conclusion: High TRAIL-R2, high TRAIL, and low TRAIL-R4 expression levels are associated with a worse disease-specific survival in patients with RCCs. Therefore, the assessment of TRAIL/TRAIL-R expression offers valuable prognostic information that could be used to select patients for adjuvant therapy studies. Moreover, our findings are of relevance for a potential experimental therapeutic administration of TRAIL-R agonists in patients with RCCs
    Type of Publication: Journal article published
    PubMed ID: 19147771
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