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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Deutscher Kongress für Orthopädie und Unfallchirurgie; 74. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 96. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie, 51. Tagung des Berufsverbandes der Fachärzte für Orthopädie; 20101026-20101029; Berlin; DOCIN17-202 /20101021/
    Publication Date: 2010-10-22
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
    Keywords: RECEPTOR ; CANCER ; IN-VITRO ; PROTEIN ; BINDING ; MOLECULE ; SUPERFAMILY ; innate immunity ; DMBT1 ; GP-340 ; SALIVARY AGGLUTININ ; SURFACTANT PROTEIN-D ; SCAVENGER RECEPTOR ; BRAIN-TUMORS ; gestational age ; prematurity ; STREPTOCOCCUS-GORDONII
    Abstract: Deleted in Malignant Brain Tumours 1 (DMBT1) is a secreted scavenger receptor cysteine-rich protein that binds and aggregates various bacteria and viruses in vitro. Studies in adults have shown that DMBT1 is expressed mainly by mucosal epithelia and glands, in particular within the respiratory tract, and plays a role in innate immune defence. We hypothesized that respiratory DMBT1 levels may be influenced by various developmental and clinical factors such as maturity, age and bacterial infection. DMBT1 levels were studied in 205 tracheal aspirate samples of 82 ventilated preterm and full-term infants by enzyme-linked immunosorbent assay. Possible effects of various clinical parameters were tested by multiple regression analysis. DMBT1 levels increased significantly with lung maturity (P 〈 0.0001 for both gestational and postnatal age) and in small-for-gestational-age infants (P = 0.0179). An increase of respiratory DMBT1 levels was detected in neonatal infections (P 〈 0.0001). These results were supported by Western blotting. Immunohistochemical analyses of archived newborn lung sections (n = 17) demonstrated high concentrations of DMBT1 in lungs of neonates with bacterial infections. Our data show that preterm infants are able to up-regulate DMBT1 in infection as an unspecific immune reaction
    Type of Publication: Journal article published
    PubMed ID: 17991292
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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
    Abstract: Next-generation sequencing has dramatically increased genome-wide profiling options and conceptually initiates the possibility for personalized cancer therapy. State-of-the-art sequencing studies yield large candidate gene sets comprising dozens or hundreds of mutated genes. However, few technologies are available for the systematic downstream evaluation of these results to identify novel starting points of future cancer therapies.We improved and extended a site-specific recombination-based system for systematic analysis of the individual functions of a large number of candidate genes. This was facilitated by a novel system for the construction of isogenic constitutive and inducible gain- and loss-of-function cell lines. Additionally, we demonstrate the construction of isogenic cell lines with combinations of the traits for advanced functional in vitro analyses. In a proof-of-concept experiment, a library of 108 isogenic melanoma cell lines was constructed and 8 genes were identified that significantly reduced viability in a discovery screen and in an independent validation screen. Here, we demonstrate the broad applicability of this recombination-based method and we proved its potential to identify new drug targets via the identification of the tumor suppressor DUSP6 as potential synthetic lethal target in melanoma cell lines with BRAF V600E mutations and high DUSP6 expression.
    Type of Publication: Journal article published
    PubMed ID: 28423600
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  • 5
    Keywords: CELLS ; GROWTH-FACTOR ; IN-VITRO ; CELL ; Germany ; human ; VITRO ; SYSTEM ; NEW-YORK ; PROTEIN ; ACTIVATION ; MECHANISM ; KERATINOCYTES ; mechanisms ; PHOSPHORYLATION ; ASSAY ; MEMBRANE ; CELL-LINE ; DELIVERY ; PROTEIN-KINASE-C ; ARACHIDONIC-ACID ; TYROSINE-PHOSPHORYLATION ; C-GAMMA-1 ; EGF-RECEPTOR ; HaCaT cells,arachidonic acid,DAG,IP,calcium,sorbitol ; OSMOTIC-STRESS ; PHOSPHATIDIC-ACID
    Abstract: Human keratinocytes are exposed to strong physical changes, and have the potentiality to react to external stimuli by switching on adaptation mechanisms. In hyperosmotically shocked keratinocytes a rapid and strong increase in calcium has been observed. We showed that this increase could not be prevented by growing the cells in medium devoid of calcium and in the presence of EGTA, indicating that the intracellular calcium increase was due to delivery from internal stores. Further, we observed an increased synthesis of dyacylglycerol and inositol trisphosphates after shock, suggesting that phospholipase C mediates both events. Our experiments demonstrated that osmotic shock in human keratinocytes leads to activation of phospholipase C-gamma1, as measured using an in vitro assay system. This activation is independent of protein tyrosine phosphorylation and corresponded to a relocation of the enzyme to perinuclear membranes as shown by immunofluorescence
    Type of Publication: Journal article published
    PubMed ID: 15014953
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  • 6
    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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  • 7
    Keywords: RECEPTOR ; CANCER ; CANCER CELLS ; EXPRESSION ; tumor ; Germany ; DISEASE ; GENE ; GENES ; GENOME ; PROTEIN ; RNA ; TUMORS ; IDENTIFICATION ; LESIONS ; immunohistochemistry ; MICROARRAY DATA ; expression profiling ; pancreatic cancer ; pancreatic carcinoma ; review ; PANCREATIC-CANCER ; DUCTAL ADENOCARCINOMA ; MEDIATED APOPTOSIS ; development ; CYSTIC LESIONS ; pancreatic tumor ; EXPERIMENT ANNOTATIONS ; Fas-activated serine/threonine kinase ; PAPILLARY MUCINOUS NEOPLASMS ; siRNA silencing
    Abstract: Aim: The diversity in the aggressiveness of cystic tumors of the pancreas - ranging from the usually benign serous cystadenoma to lesions of variable degrees of malignancy - was utilized for the identification of molecular factors that are involved in the occurrence of malignancy. Methods: We analyzed the transcript profiles of different cystic tumor types. The results were confirmed at the protein level by immunohistochemistry. Also, functional studies with siRNA silencing were performed. Results: Expression variations at the RNA and protein level were identified that are closely correlated with the degree of malignancy. Besides, all tumors could be classified effectively by this means. Many of the identified factors had not previously been known to be associated with malignant cystic lesions. siRNA silencing of the gene with the most prominent variation - the anti-apoptotic factor FASTK (Fas-activated serine/threonine kinase) - revealed a regulative effect on several genes known to be relevant to the development of tumors. Conclusion: By a molecular analysis of rare types of pancreatic cancer, which are less frequent in terms of disease, variations could be identified that could be critical for the regulation of malignancy and thus relevant to the treatment of also the majority of pancreatic tumors. Copyright (C) 2008 S. Karger AG, Basel and IAP
    Type of Publication: Journal article published
    PubMed ID: 19077453
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  • 8
    Keywords: CELLS ; proliferation ; SURVIVAL ; GENE ; GENE-EXPRESSION ; RNA ; INFECTION ; MALIGNANCIES ; KAPPA-B ; TARGETS ; C-MYC ; EPSTEIN-BARR-VIRUS ; protein expression ; HUMAN B-CELLS ; MICRORNA ; ENCODED MICRORNAS ; HUMAN GAMMA-HERPESVIRUSES ; III PROGRAM ; PAR-CLIP
    Abstract: Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus linked to a number of B cell cancers and lymphoproliferative disorders. During latent infection, EBV expresses 25 viral pre-microRNAs (miRNAs) and induces the expression of specific host miRNAs, such as miR-155 and miR-21, which potentially play a role in viral oncogenesis. To date, only a limited number of EBV miRNA targets have been identified; thus, the role of EBV miRNAs in viral pathogenesis and/or lymphomagenesis is not well defined. Here, we used photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) combined with deep sequencing and computational analysis to comprehensively examine the viral and cellular miRNA targetome in EBV strain B95-8-infected lymphoblastoid cell lines (LCLs). We identified 7,827 miRNA-interaction sites in 3,492 cellular 3'UTRs. 531 of these sites contained seed matches to viral miRNAs. 24 PAR-CLIP-identified miRNA: 3'UTR interactions were confirmed by reporter assays. Our results reveal that EBV miRNAs predominantly target cellular transcripts during latent infection, thereby manipulating the host environment. Furthermore, targets of EBV miRNAs are involved in multiple cellular processes that are directly relevant to viral infection, including innate immunity, cell survival, and cell proliferation. Finally, we present evidence that myc-regulated host miRNAs from the miR-17/92 cluster can regulate latent viral gene expression. This comprehensive survey of the miRNA targetome in EBV-infected B cells represents a key step towards defining the functions of EBV-encoded miRNAs, and potentially, identifying novel therapeutic targets for EBV-associated malignancies
    Type of Publication: Journal article published
    PubMed ID: 22291592
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  • 9
    Abstract: We describe a novel approach for the detection of small non-coding RNAs in single cells by Single Molecule Localization Microscopy (SMLM). We used a modified SMLM-setup and applied this instrument in a first proof-of-principle concept to human cancer cell lines. Our method is able to visualize single microRNA (miR)-molecules in fixed cells with a localization accuracy of 10-15 nm, and is able to quantify and analyse clustering and localization in particular subcellular sites, including exosomes. We compared the metastasis-site derived (SW620) and primary site derived (SW480) human colorectal cancer (CRC) cell lines, and (as a proof of principle) evaluated the metastasis relevant miR-31 as a first example. We observed that the subcellular distribution of miR-31 molecules in both cell lines was very heterogeneous with the largest subpopulation of optically acquired weakly metastatic cells characterized by a low number of miR-31 molecules, as opposed to a significantly higher number in the majority of the highly metastatic cells.Furthermore, the highly metastatic cells had significantly more miR-31-molecules in the extracellular space, which were visualized to co-localize with exosomes in significantly higher numbers. From this study, we conclude that miRs are not only aberrantly expressed and regulated, but also differentially compartmentalized in cells with different metastatic potential. Taken together, this novel approach, by providing single molecule images of miRNAs in cellulo can be used as a powerful supplementary tool in the analysis of miRNA function and behaviour and has far reaching potential in defining metastasis-critical subpopulations within a given heterogeneous cancer cell population.
    Type of Publication: Journal article published
    PubMed ID: 26561203
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  • 10
    Keywords: EXPRESSION ; IN-VITRO ; SURVIVAL ; Germany ; MODEL ; VITRO ; CLASSIFICATION ; CDNA ; GENOME ; microarray ; RNA ; SAMPLE ; SAMPLES ; MESSENGER-RNA ; BREAST-CANCER ; NO ; AMPLIFICATION ; microarrays ; REQUIRES ; PARAMETERS ; STATISTICAL-ANALYSIS ; DIFFERENTIAL EXPRESSION ; QUANTITIES ; LACKING ; REQUIREMENT ; bias ; PNEUMOPERITONEUM
    Abstract: Background: The requirement of a large amount of high-quality RNA is a major limiting factor for microarray experiments using biopsies. An average microarray experiment requires 10-100 mug of RNA. However, due to their small size, most biopsies do not yield this amount. Several different approaches for RNA amplification in vitro have been described and applied for microarray studies. In most of these, systematic analyses of the potential bias introduced by the enzymatic modifications are lacking. Results: We examined the sources of error introduced by the T7 RNA polymerase based RNA amplification method through hybridisation studies on microarrays and performed statistical analysis of the parameters that need to be evaluated prior to routine laboratory use. The results demonstrate that amplification of the RNA has no systematic influence on the outcome of the microarray experiment. Although variations in differential expression between amplified and total RNA hybridisations can be observed, RNA amplification is reproducible, and there is no evidence that it introduces a large systematic bias. Conclusions: Our results underline the utility of the T7 based RNA amplification for use in microarray experiments provided that all samples under study are equally treated
    Type of Publication: Journal article published
    PubMed ID: 15119961
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