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  • 1
    Keywords: HYBRIDIZATION ; PROGRESSION ; IMBALANCES ; SCREEN
    Abstract: Embryonal tumors with abundant neuropil and true rosettes (ETANTR) comprise a rare variant of embryonal brain tumors usually occurring in infants. Only 13 cases have been reported in the literature to date and little is known about the molecular pathogenesis of these tumors. Here, we describe a case of ETANTR in a 2-year-old girl presenting with a large tumor in the vermis of the cerebellum. Histological examination showed clusters of small-undifferentiated cells including ependymoblastic-like rosettes admixed with large fibrillar and paucicellular neuropil-like areas indicative for ETANTR. Genomic imbalances were detected by using array-based comparative genomic hybridization. In addition to trisomy of chromosome 2, which has been previously described in ETANTR, array-CGH revealed high-level genomic amplification of 0.89 Mb at chromosome band 19q13.42 covering a microRNA cluster and several protein-coding genes. This aberration has not been described in any other brain tumor to date, indicating a specific aberration in ETANTR. MicroRNAs contained in the microRNA cluster at 19q13.42 including oncomirs miRNA-372 and miRNA-373 were highly up-regulated in the tumor when compared to normal cerebellum or whole brain. In summary, this is the first report on a potentially specific genetic aberration in ETANTR, supporting the hypothesis of a distinct tumor entity.
    Type of Publication: Journal article published
    PubMed ID: 19057917
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  • 2
    Keywords: CANCER ; EXPRESSION ; QUANTIFICATION ; IDENTIFICATION ; AMINO-ACIDS ; POSTTRANSCRIPTIONAL REGULATION ; MESSENGER-RNAS ; BIOGENESIS ; TRANSLATION INITIATION ; CELL-CULTURE ; MICRORNA-BINDING-SITES
    Abstract: Background: MicroRNAs are 22 nucleotides long non-coding RNAs and exert their function either by transcriptional or translational inhibition. Although many microRNA profiles in different tissues and disease states have already been discovered, only little is known about their target proteins. The microRNA miR-155 is deregulated in many diseases, including cancer, where it might function as an oncoMir. Methodology/Principal Findings: We employed a proteomics technique called "stable isotope labelling by amino acids in cell culture" (SILAC) allowing relative quantification to reliably identify target proteins of miR-155. Using SILAC, we identified 46 putative miR-155 target proteins, some of which were previously reported. With luciferase reporter assays, CKAP5 was confirmed as a new target of miR-155. Functional annotation of miR-155 target proteins pointed to a role in cell cycle regulation. Conclusions/Significance: To the best of our knowledge we have investigated for the first time miR-155 target proteins in the HEK293T cell line in large scale. In addition, by comparing our results to previously identified miR-155 target proteins in other cell lines, we provided further evidence for the cell line specificity of microRNAs
    Type of Publication: Journal article published
    PubMed ID: 21799781
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  • 3
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS German Medical Science; VOL: 8; DOC17 /20100805/
    Publication Date: 2010-08-06
    Description: Objective: To compare the treatment costs of insulin glargine (IG; Lantus®) to detemir (ID; Levemir®), both combined with bolus insulin aspart (NovoRapid®) in type 2 diabetes (T2D) in Germany.Methods: Cost comparison was based on data of a 1-year randomised controlled trial . IG was administered once daily and ID once (57% of patients) or twice daily (43%) according to treatment response. At the end of the trial, mean daily basal insulin doses were 0.59 U/kg (IG) and 0.82 U/kg (ID). Aspart doses were 0.32 U/kg (IG) and 0.36 U/kg (ID). Costs were calculated from the German statutory health insurance (SHI) perspective using official 2008 prices. Sensitivity analyses were performed to test robustness of the results.Results: Annual basal and bolus insulin costs per patient were Euro 1,473 (IG) and Euro 1,940 (ID). The cost of lancets and blood glucose test strips were Euro 1,125 (IG) and Euro 1,286 (ID). Annual costs for needles were 〈TextGroup〉 Euro 393 〈/TextGroup〉 (IG) and Euro 449 (ID). The total annual cost per patient of administering IG was Euro 2,991 compared with Euro 3,675 for ID, translating into a 19% annual cost difference of Euro 684/patient. Base case results were robust to varying assumptions for insulin dose, insulin price, change in weight and proportion of ID once daily administrations.Conclusion: IG and ID basal-bolus regimes have comparative safety and efficacy, based on the Hollander study, IG however may represent a significantly more cost saving option for T2D patients in Germany requiring basal-bolus insulin analogue therapy with potential annual cost savings of Euro 684/patient compared to ID.
    Description: Ziel: Vergleich der Behandlungskosten von Insulin glargin (IG; Lantus®) und Insulin detemir (ID; Levemir®) jeweils in Kombination mit Bolusinsulin aspart (NovoRapid®) bei Typ-2-Diabetes (T2D) in Deutschland.Methoden: Der Kostenvergleich basierte auf den Daten einer einjährigen randomisierten, kontrollierten klinischen Studie . IG wurde einmal täglich verabreicht und ID einmal (57% der Patienten) oder zweimal täglich (43%) in Abhängigkeit vom Ansprechen auf die Behandlung. Die durchschnittliche Dosierung des Basalinsulins betrug 0,59 IE/kg (IG) und 0,82 IE/kg (ID) pro Tag. Die durchschnittliche Dosierung für Aspart betrug 0,32 IE/kg (IG-Patienten) und 0,36 IE/kg (ID-Patienten). Die Kosten wurden aus dem Blickwinkel der Gesetzlichen Krankenversicherung unter Verwendung offizieller Preise für 2008 berechnet. Die Robustheit der Ergebnisse wurde anhand von Sensitivitätsanalysen überprüft. Ergebnisse: Die jährlichen Kosten für Basal- und Bolusinsulin betrugen Euro 1.473 (IG) und Euro 1.940 (ID) pro Patient. Die Kosten für Lanzetten und Blutzucker-Teststreifen beliefen sich auf Euro 1.125 (IG) und Euro 1.286 (ID). Die Kosten für Nadeln betrugen Euro 393 (IG) und Euro 449 (ID) pro Patient und Jahr. Die Anwendung von IG war damit insgesamt mit Kosten von Euro 2.991 pro Patient und Jahr verbunden, die von ID mit Kosten von 〈TextGroup〉 Euro 3.675, 〈/TextGroup〉 woraus ein Kostenunterschied von 19% oder Euro 684/pro Patient und Jahr resultiert. Die Ergebnisse des Basisszenarios zeigten sich robust gegenüber veränderten Annahmen hinsichtlich Insulindosis, Insulinpreis, Gewichtsveränderung und Anteil Patienten mit einmal täglicher Verabreichung von ID. Schlussfolgerungen: Basierend auf der klinischen Studie von Hollander sind Basal-Bolus-Behandlungsregime, die auf IG und ID aufbauen, hinsichtlich Sicherheit und Wirksamkeit vergleichbar. Die Behandlung mit IG jedoch ist gegenüber ID mit einer potentiellen Einsparung von Euro 684 pro Patient und Jahr verbunden.
    Keywords: insulin glargine ; insulin detemir ; basal insulin ; type 2 diabetes ; cost analysis ; Insulin glargin ; Insulin detemir ; Basalinsulin ; Typ-2-Diabetes ; Kostenanalyse ; ddc: 610
    Language: English
    Type: article
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  • 4
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; GENE ; GENE-EXPRESSION ; GENES ; MOLECULES ; LINES ; INDUCTION ; BIOLOGY ; CELL-LINES ; MOLECULAR-BIOLOGY ; SEQUENCE ; SEQUENCES ; MOLECULE ; TARGET ; NO ; gene expression ; Drosophila ; CELL-LINE ; MAMMALIAN-CELLS ; SMALL INTERFERING RNAS ; STRATEGIES ; specificity ; DOUBLE-STRANDED-RNA ; molecular biology ; molecular ; RE ; HOMOLOGY ; mRNA ; TARGET GENES ; analysis ; ENGLAND ; SIRNA
    Abstract: Background: Gene knock down by RNAi is a highly effective approach to silence gene expression in experimental as well as therapeutic settings. However, this widely used methodology entails serious pitfalls, especially concerning specificity of the RNAi molecules. Results: We tested the most widely used control siRNA directed against GFP for off-target effects and found that it deregulates in addition to GFP a set of endogenous target genes. The off-target effects were dependent on the amount of GFP siRNA transfected and were detected in a variety of cell lines. Since the respective siRNA molecule specific for GFP is widely used as negative control for RNAi experiments, we studied the complete set of off-target genes of this molecule by genome-wide expression profiling. The detected modulated mRNAs had target sequences homologous to the siRNA as small as 8 basepairs in size. However, we found no restriction of sequence homology to 3'UTR of target genes. Conclusion: We can show that even siRNAs without a physiological target have sequence-specific off-target effects in mammalian cells. Furthermore, our analysis defines the off-target genes affected by the siRNA that is commonly used as negative control and directed against GFP. Since off-target effects can hardly be avoided, the best strategy is to identify false positives and exclude them from the results. To this end, we provide the set of false positive genes deregulated by the commonly used GFP siRNA as a reference resource for future siRNA experiments
    Type of Publication: Journal article published
    PubMed ID: 18577207
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  • 5
    Keywords: APOPTOSIS ; EXPRESSION ; ACTIVATION ; MAMMALIAN-CELLS ; KAPPA-B ; PROGRAMMED CELL-DEATH ; REGULATORS ; RNA INTERFERENCE ; KINASES ; ESCRT-III COMPLEX
    Abstract: In recent years, RNA interference (RNAi) has been widely used to uncover gene function or pathway context of novel genes. In our study, we describe a short-hairpin RNA-based RNAi screening of a set of functionally uncharacterized human genes for their possible capability to inhibit apoptosis. We thereby identified a new antiapoptotic function for CHMP5 (charged multivesicular body protein 5), which was confirmed by overexpression and rescue assays. Furthermore, caspase assays showed that CHMP5 silencing induced caspase cascade activation mainly through extrinsic apoptosis pathway. Based on genome-wide expression array profiling, a possible regulatory role of CHMP5 on apoptosis-associated genes and different signaling pathways including nuclear factor kappa B was revealed. In addition, we found significantly higher CHMP5 mRNA levels in acute myeloid leukemia patients. This observation together with the antiapoptotic feature of CHMP5 suggests a possible oncogenic function for this gene in leukemogenesis.
    Type of Publication: Journal article published
    PubMed ID: 20734392
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  • 6
    Keywords: APOPTOSIS ; EXPRESSION ; SURVIVAL ; DISEASE ; GENES ; LYMPHOMA ; CANCER-CELLS ; GUIDELINES ; MICRORNA ; LC3
    Abstract: Toxicity and relapses from the immunochemotherapy used to treat chronic lymphocytic leukemia (CLL) prompt continued interest in gentle but effective targeted treatment options for the mainly elderly population suffering from this disease. Here, we report the definition of critical CLL cell survival pathways that can be targeted by ectopic reexpression of the miRNA genes miR-130a and miR-143 which are widely downregulated in CLL. Notably, miR-130a inhibited autophagy by reducing autophagosome formation, an effect mediated by downregulation of the genes ATG2B and DICER1, the latter of which is a major component of the miRNA silencing machinery. In support of the concept of a fundamental connection between miRNA disregulation and altered autophagic flux in this cancer, we showed that RNA interference-mediated knockdown of DICER1 expression was sufficient to reduce autophagy in primary or established cultures of CLL cells. Together, our findings show that miR-130a modulates cell survival programs by regulating autophagic flux, and they define roles for miR-130a and Dicer1 in a regulatory feedback loop that mediates CLL cell survival. Cancer Res; 72(7); 1763-72. (c)2012 AACR.
    Type of Publication: Journal article published
    PubMed ID: 22350415
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  • 7
    Keywords: RECEPTOR ; GENE-EXPRESSION ; PROTEIN ; prognosis ; UP-REGULATION ; CANCER DEVELOPMENT ; PROSTAGLANDIN E-2 ; MICRORNA EXPRESSION ; JUNCTIONAL ADHESION MOLECULE ; PREDICTS SURVIVAL
    Abstract: Invasion is a critical step in lung tumor progression. The interaction between tumor cells and their surroundings may play an important role in tumor invasion and metastasis. To better understand the mechanisms of tumor invasion and tumormicroenvironment interactions in lung tumors, total RNA was isolated from the inner tumor, tumor invasion front, adjacent lung, and distant normal lung tissue from 17 patients with primary squamous cell lung carcinoma using punch-aided laser capture microdissection. Messenger RNA expression profiles were obtained by microarray analysis, and microRNA profiles were generated from eight of these samples using TaqMan Low Density Arrays. Statistical analysis of the expression data showed extensive changes in gene expression in the inner tumor and tumor front compared with the normal lung and adjacent lung tissue. Only a few genes were differentially expressed between tumor front and the inner tumor. Several genes were validated by immunohistochemistry. Evaluation of the microRNA data revealed zonal expression differences in nearly a fourth of the microRNAs analyzed. Validation of selected microRNAs by in situ hybridization demonstrated strong expression of hsa-miR-196a in the inner tumor; moderate expression of hsa-miR-224 in the inner tumor and tumor front, and strong expression of hsa-miR-650 in the adjacent lung tissue. Pathway analysis placed the majority of genes differentially expressed between tumor and nontumor cells in intrinsic processes associated with inflammation and extrinsic processes related to lymphocyte physiology. Genes differentially expressed between the inner tumor and the adjacent lung/normal lung tissue affected pathways of arachidonic acid metabolism and eicosanoid signaling.
    Type of Publication: Journal article published
    PubMed ID: 23074073
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  • 8
    Keywords: EXPRESSION ; proliferation ; PATHWAYS ; GENE ; ASSOCIATION ; B-CELLS ; RECRUITMENT ; REPRESSION ; BINDING PROTEIN ; MICRORNA FUNCTIONS
    Abstract: MicroRNAs (miRNAs) are single-stranded, small, non-coding RNAs, which fine-tune protein expression by degrading and/or translationally inhibiting mRNAs. Manipulation of miRNA expression in animal models frequently results in severe phenotypes indicating their relevance in controlling cellular functions, most likely by interacting with multiple targets. To better understand the effect of miRNA activities, genome-wide analysis of their targets are required. MicroRNA profiling as well as transcriptome analysis upon enforced miRNA expression were frequently used to investigate their relevance. However, these approaches often fail to identify relevant miRNAs targets. Therefore, we tested the precision of RNA-interacting protein immunoprecipitation (RIP) using AGO2-specific antibodies, a core component of the "RNA-induced silencing complex" (RISC), followed by RNA sequencing (Seq) in a defined cellular system, the HEK293T cells with stable, ectopic expression of miR-155. Thereby, we identified 100 AGO2-associated mRNAs in miR-155-expressing cells, of which 67 were in silico predicted miR-155 target genes. An integrated analysis of the corresponding expression profiles indicated that these targets were either regulated by mRNA decay or by translational repression. Of the identified miR-155 targets, 17 were related to cell cycle control, suggesting their involvement in the observed increase in cell proliferation of HEK293T cells upon miR-155 expression. Additional, secondary changes within the gene expression profile were detected and might contribute to this phenotype as well. Interestingly, by analyzing RIP-Seq data of HEK-293T cells and two B-cell lines we identified a recurrent disproportional enrichment of several miRNAs, including miR-155 and miRNAs of the miR-17-92 cluster, in the AGO2-associated precipitates, suggesting discrepancies in miRNA expression and activity.
    Type of Publication: Journal article published
    PubMed ID: 23673373
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  • 9
    Keywords: LUNG-CANCER ; HEPATOCELLULAR-CARCINOMA ; GENES ; LINES ; DOWN-REGULATION ; CANCER-CELLS ; MALIGNANT-MELANOMA ; independent growth ; GROUP PROTEIN EZH2 ; MICRORNA EXPRESSION LEVELS
    Abstract: The microRNA miR-101 has been reported to be a tumor suppressor. Here we show that low expression of miR-101 is associated with poor survival in stage IV melanoma patients. We identified microphthalmia-associated transcription factor (MITF) as a direct target of miR-101. In melanoma cells, overexpression of miR-101 downregulated protein levels of MITF and a previously reported target protein, enhancer of zeste homolog 2 (EZH2). Functional assays showed that miR-101 suppressed invasion and proliferation - an outcome that could be phenocopied by siRNA knockdown of MITF and EZH2. Our data suggest that miR-101 might have a beneficial role in melanoma.
    Type of Publication: Journal article published
    PubMed ID: 23962556
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  • 10
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; proliferation ; tumor ; CELL-PROLIFERATION ; Germany ; INHIBITION ; MODEL ; SYSTEM ; TOOL ; DISEASE ; DISEASES ; GENE ; GENE-EXPRESSION ; GENES ; RNA ; MICE ; COMPLEX ; COMPLEXES ; DNA ; COMPARATIVE GENOMIC HYBRIDIZATION ; LYMPHOMA ; gene expression ; MODULATION ; inactivation ; ONCOGENE ; Jun ; IMBALANCES ; FUNCTIONAL GENOMICS ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; MANTLE CELL LYMPHOMA ; CYCLIN D1 ; INTEGRATION ; TUMOR-SUPPRESSOR ; INTERFERENCE ; CANDIDATE GENES ; NON-HODGKINS-LYMPHOMAS ; cell proliferation ; REGULATED GENE ; tumor suppressor gene ; CANDIDATE ; genomic ; PLASMID ; DEFECT ; GENOMIC ALTERATIONS ; BLASTOID VARIANTS ; genetics of disease ; genomic complementation ; SHORT-INTERFERING RNAS ; transgenes oncogenomics
    Abstract: A broad range of malignant diseases, such as mantle cell lymphoma (MCL), is associated with complex genomic alterations, demanding multimodal functional testing of candidate genes. To assess such candidate disease genes, we have developed a bidirectional targeted transgenesis tool, which allows well-controlled modulation of individual gene activities within a cellular MCL system. The engineered versatile transgenesis system permits functional analysis of virtually any candidate gene: for tumor suppressor genes by complementation via integration of respective genomic DNA or for oncogenes by inactivation via integrated shRNA coding plasmids. Complementation by genomic DNA ensures wild-type (WT) regulated gene expression, whereas genomic integration of shRNA coding inserts by an advanced RNAi-strategy mediates specific knock-down of gene expression. Site-specific genomic integration of an unmodified BAC, which contains the CDKN2A/B genes absent in the MCL model system, restored CDKN2A/B expression resulting in the inhibition of cell proliferation. CCND1, strongly overexpressed in the model system, was down-regulated via shRNA expression, again inhibiting proliferation. Notably, the presented site-specific shRNA-strategy circumvents interference by IFN-response induced when using other RNAi gene knock-down methods. In conclusion, we here demonstrate that adequate restoration of a range of different gene activities yields in a desired antiproliferative effect in MCL-derived cells. By antagonizing inactivated tumor suppressor genes or activated oncogenes, the presented approach can be readily used for the functional analysis of a broad range of disease-related genetic defects
    Type of Publication: Journal article published
    PubMed ID: 16636107
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