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  • genetics  (16)
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  • 1
    Keywords: EXPRESSION ; SURVIVAL ; NETWORK ; NETWORKS ; GENE ; LINKAGE ; SUSCEPTIBILITY ; LYMPHOMA ; MALIGNANCIES ; genetics ; molecular ; FEATURES ; MALIGNANCY ; REGRESSION ; review ; FAMILIES ; CANDIDATE GENES ; CLL ; PREDISPOSITION ; leukaemia ; USA ; ENGLAND ; EXPANSION ; chronic lymphocytic leukaemia ; B-CELL LYMPHOCYTOSIS ; CHALLENGES ; family studies ; genetic association
    Abstract: Although the familial aspect of chronic lymphocytic leukaemia (CLL) has been appreciated for decades, it is only with the recent confluence of improved molecular and gene technologies and world-wide collaborative networks that accelerated progress has become apparent. In this summary we highlight selected themes in the genetics of CLL emphasizing the opportunities and challenges of this malignancy
    Type of Publication: Journal article published
    PubMed ID: 18021078
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  • 2
    Keywords: CANCER ; EXPRESSION ; INHIBITOR ; proliferation ; CELL ; CELL-PROLIFERATION ; human ; QUANTIFICATION ; SYSTEM ; SYSTEMS ; TOOL ; DISEASE ; DISEASES ; GENE ; GENE-EXPRESSION ; SAMPLE ; SAMPLES ; TISSUE ; DNA ; MECHANISM ; TISSUES ; mechanisms ; BIOLOGY ; SEQUENCE ; SEQUENCES ; DISORDER ; SCHIZOPHRENIA ; NEOPLASIA ; PATTERNS ; gene expression ; DISRUPTION ; genetics ; REPRODUCIBILITY ; EFFICACY ; DNA methylation ; INSTABILITY ; UNITED-STATES ; ELECTROPHORESIS ; sensitivity ; METHYLATION ; GENOMIC INSTABILITY ; HYPERMETHYLATION ; INHIBITORS ; molecular biology ; HUMAN CANCER ; 5-methylcytosine ; cell proliferation ; CPG ISLANDS ; TECHNOLOGY ; microfluidics ; USA ; ACCURATE ; CANCER GENETICS ; epigenetic ; STATE ; Genetic ; ISLANDS ; RESTRICTION ; DNA/analysis/chemistry/genetics *DNA Methylation DNA Restriction Enzymes Electrophoresis,Polyacrylam ; METHYLATION INHIBITOR
    Abstract: DNA methylation is the best-studied epigenetic modification, and in mammals it describes the conversion of cytosine to 5-methylcytosine in the context of CpG dinucleotides. In recent years, it has become evident that epigenetic mechanisms are severely disrupted in human neoplasia, and evidence suggests that alterations of DNA methylation patterns may be an integral mechanism in the etiology of other diseases such as bipolar disorder and schizophrenia. The main effect of altered DNA methylation is the disruption of normal patterns of gene expression through genomic instability and hypermethylation of CpG islands, which together could lead to uncontrolled cell proliferation. DNA methylation can be reversed through pharmacological intervention via the systemic administration of DNA methylation inhibitors. Thus, the ability to accurately quantify DNA methylation levels in genomic sequences is a prerequisite to assess not only treatment efficacy, but also the effect of the DNA methylation inhibitors on bystander tissues. Several methods are currently available for the analysis of DNA methylation. Nonetheless, accurate and reproducible quantification of DNA methylation remains challenging. Here, we describe Bio-COBRA, a modified protocol for combined bisulfite restriction analysis (COBRA) that incorporates an electrophoresis step in microfluidics chips. Microfluidics technology involves the handling of small amounts of liquid in miniaturized systems. Bio-COBRA provides a platform for the rapid and quantitative assessment of DNA methylation patterns in large sample sets. Its sensitivity and reproducibility also make it an excellent tool for the analysis of DNA methylation in clinical samples
    Type of Publication: Journal article published
    PubMed ID: 18987820
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  • 3
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; COMBINATION ; MODEL ; VITRO ; SITE ; SITES ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; TISSUE ; LINES ; DNA ; CARCINOGENESIS ; BREAST ; breast cancer ; BREAST-CANCER ; PROGRESSION ; genetics ; DNA methylation ; inactivation ; PCR ; REGION ; TRANSFORMATION ; EPITHELIAL-CELLS ; CARCINOMAS ; NETHERLANDS ; histone deacetylase inhibitor ; METHYLATION ; HYPERMETHYLATION ; ESTRADIOL ; PATTERN ; SCIENCE ; CPG ISLANDS ; ESTROGEN ; 17-BETA-ESTRADIOL ; EPIGENETIC CHANGES ; MESENCHYMAL TRANSITION ; Genetic ; heregulin ; Cell transformation ; ERBB RECEPTOR FAMILY ; HISTONE-DEACETYLASE INHIBITORS ; Neuregulin
    Abstract: Epigenetic inactivation of genes by DNA hypermethylation plays an important role in carcinogenesis An in vitro model of human breast epithelial cell transformation was used to study epigenetic changes induced by estradiol during the neoplastic process Different stages of tumor initiation and progression are represented in this model being MCF-10F the normal stage; trMCF cells, the transformed stage, bsMCF cells, the invasive stage and, caMCF cells, the tumor stage Global methylation studies by restriction landmark genomic scanning (RLGS) showed an increased DNA methylation during the in the invasive and tumor stages Expression studies showed that NRG1 (neuregulin 1), CSS3 (chondroitin sulfate synthase 3) and SNIP (SNAP-25-interacting protein) were downregulated in the invasive and tumor cells. The transformed cells showed low expression of STXBP6(amysin)compared to the parental cells MCF-10F The treatment of these cells with the demethylating agent 5-aza-dC alone or in combination with the histone deacetylase inhibitor trichostatin increased the expression of NRG1, STXBP6, CSS3 and SNIP confirming that DNA methylation plays an Important role in the regulation of the expression of these genes The NRG1 exon 1 has a region located between -136 and +79 (considering +1, the translational initiation site) rich in CpG sites that was analyzed by methylation specific PCR (MSP) NRG1 exon 1 showed progressive changes in the methylation pattern associated with the progression of the neoplastic process in this model; NRG1 exon 1 was unmethylated in MCF-10F and trMCF cells, becoming hypermethylated in the invasive (bsMCF) and tumor (caMCF) stages Studies of human breast tissue samples showed that NRG1 exon 1 was partially methylated in 14 out of 17 (82.4%) invasive carcinomas although it was unmethylated in normal tissues (8 out of 10 normal breast tissue samples) Furthermore, NRG1 exon 1 was partially methylated in 9 out of 14(64.3%) morphologically normal tissue samples adjacent to invasive carcinomas. (C) 2010 Elsevier B V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20193695
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  • 4
    Keywords: CANCER ; proliferation ; PATHWAY ; BIOLOGY ; PROTEIN-KINASE ; genetics ; DNA methylation ; intraepithelial neoplasia ; ABERRANT METHYLATION ; CELL TRANSDIFFERENTIATION
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here, we determine the contribution of epigenetically silenced genes to the development of PDAC. We analyzed enriched, highly methylated DNAs from PDACs, chronic pancreatitis (CP) and normal tissues using CpG island microarrays and identified WNK2 as a prominent candidate tumor suppressor gene being downregulated early in PDAC development. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanIN), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in tumor than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein expressions were lower in PDAC and CP compared with normal tissues both in patients and mouse models. Overexpression of WNK2 led to reduced cell growth, and WNK2 expression in tissues correlated negatively with pERK1/2 expression, a downstream target of WNK2 responsible for cell proliferation. Downregulation of WNK2 by promoter hypermethylation occurs early in PDAC pathogenesis and may support tumor cell growth via the ERK-MAPK pathway.
    Type of Publication: Journal article published
    PubMed ID: 23912455
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  • 5
    Keywords: CELLS ; EXPRESSION ; CELL ; human ; NETWORKS ; SITE ; SITES ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; microarray ; RNA ; transcription ; LINES ; MECHANISM ; mechanisms ; IDENTIFICATION ; PATTERNS ; gene expression ; microarrays ; PROMOTER ; PROMOTERS ; genetics ; HUMAN GENOME ; HUMAN GENES ; METHYLATION ; heredity ; PATTERN ; GENOME-WIDE ANALYSIS ; ARRAY ; genomics ; RESOURCE ; analysis ; CHIP ; USA ; microbiology ; ENGLAND ; biotechnology ; PLATFORM ; BREAST-CANCER CELLS ; synthesis ; STATE ; GENOME-WIDE ; ESTROGEN-RECEPTOR-ALPHA ; TRANSCRIPTION INITIATION
    Abstract: Background: Independent lines of evidence suggested that a large fraction of human genes possess multiple promoters driving gene expression from distinct transcription start sites. Understanding which promoter is employed in which cellular context is required to unravel gene regulatory networks within the cell. Results: We have developed a custom microarray platform that tiles roughly 35,000 alternative putative promoters from nearly 7,000 genes in the human genome. To demonstrate the utility of this array platform, we have analyzed the patterns of promoter usage in 17 beta-estradiol (E2)-treated and untreated MCF7 cells and show widespread usage of alternative promoters. Most intriguingly, we show that the downstream promoter in E2-sensitive multiple promoter genes tends to be very close to the 3'-terminus of the gene, suggesting exotic mechanisms of expression regulation in these genes. Conclusion: The usage of alternative promoters greatly multiplies the transcriptional complexity available within the human genome. The fact that many of these promoters are incapable of driving the synthesis of a meaningful protein-encoding transcript further complicates the story
    Type of Publication: Journal article published
    PubMed ID: 18655706
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  • 6
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; human ; IN-VIVO ; MODEL ; MODELS ; VIVO ; CLASSIFICATION ; COMMON ; DISEASE ; DISTINCT ; GENE ; SAMPLE ; SAMPLES ; transcription ; TISSUE ; TUMORS ; DNA ; MECHANISM ; mechanisms ; T cell ; T-CELL ; BIOLOGY ; SEQUENCE ; SEQUENCES ; SUSCEPTIBILITY ; BREAST-CANCER ; culture ; MOUSE ; STAGE ; PROGRESSION ; LYMPHOMA ; PATTERNS ; PROMOTER ; TUMOR PROGRESSION ; genetics ; COLORECTAL-CANCER ; DNA methylation ; inactivation ; p53 ; EVOLUTION ; PHENOTYPE ; MOUSE MODEL ; SELECTION ; specificity ; OVEREXPRESSION ; METHYLATION ; TUMOR CELLS ; heredity ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; HYPERMETHYLATION ; HETEROGENEITY ; EPIGENETIC INACTIVATION ; targeting ; PROGRAM ; PATTERN ; TUMOR-SUPPRESSOR ; HUMAN CANCER ; ACUTE MYELOID-LEUKEMIA ; LIBRARIES ; CELL LYMPHOMA ; CPG ISLANDS ; GENE-TRANSCRIPTION ; development ; TUMOR-CELL ; SUPPRESSOR ; PROFILES ; EVENTS ; SIGNATURE ; DISEASE PROGRESSION ; USA ; CPG ISLAND HYPERMETHYLATION ; HUMAN CANCERS ; PROMOTER METHYLATION ; CANCERS ; in vivo ; genomic ; GENETIC ALTERATION ; RARE ; PREDICT ; CpG island ; MYC ; TUMOR-DEVELOPMENT ; DNA-METHYLATION ; scanning ; CELL LYMPHOMAS ; evidence ; TUMOR SUPPRESSORS ; CAUSAL ROLE ; DNA HYPOMETHYLATION
    Abstract: Hypermethylation of CpG islands is a common epigenetic alteration associated with cancer. Global patterns of hypermethylation are tumor-type specific and nonrandom. The biological significance and the underlying mechanisms of tumor-specific aberrant promoter methylation remain unclear, but some evidence suggests that this specificity involves differential sequence susceptibilities, the targeting of DNA methylation activity to specific promoter sequences, or the selection of rare DNA methylation events during disease progression. Using restriction landmark genomic scanning on samples derived from tissue culture and in vivo models of T cell lymphomas, we found that MYC overexpression gave rise to a specific signature of CpG island hypermethylation. This signature reflected gene transcription profiles and was detected only in advanced stages of disease. The further inactivation of the Pten, p53, and E2f2 tumor suppressors in MYC-induced lymphomas resulted in distinct and diagnostic CpG island methylation signatures. Our data suggest that tumor-specific DNA methylation in lymphomas arises as a result of the selection of rare DNA methylation events during the course of tumor development. This selection appears to be driven by the genetic configuration of tumor cells, providing experimental evidence for a causal role of DNA hypermethylation in tumor progression and an explanation for the tremendous epigenetic heterogeneity observed in the evolution of human cancers. The ability to predict genome-wide epigenetic silencing based on relatively few genetic alterations will allow for a more complete classification of tumors and understanding of tumor cell biology
    Type of Publication: Journal article published
    PubMed ID: 17907813
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  • 7
    Keywords: CANCER ; EXPRESSION ; COMBINATION ; human ; MODEL ; MODELS ; GENERATION ; INFORMATION ; SYSTEM ; TOOL ; CLONING ; GENOME ; TISSUE ; COMPLEX ; COMPLEXES ; DNA ; SEQUENCE ; SEQUENCES ; MOUSE ; IDENTIFICATION ; PATTERNS ; NUMBER ; genetics ; DNA methylation ; TUMOR-SUPPRESSOR GENE ; HUMAN GENOME ; MIGRATION ; FRAGMENTS ; METHYLATION ; heredity ; HYPERMETHYLATION ; PATTERN ; genomics ; CPG ISLANDS ; development ; bias ; ENZYME ; methods ; LIBRARY ; USA ; CPG ISLAND HYPERMETHYLATION ; genomic ; FRAGMENT ; microbiology ; ENGLAND ; IMPROVEMENT ; LOCI ; CpG island ; NOV ; biotechnology ; scanning ; GENOMES ; CURVED DNA ; EPIGENETIC ALTERATIONS
    Abstract: Background: Restriction landmark genomic scanning (RLGS) is one of the most successfully applied methods for the identification of aberrant CpG island hypermethylation in cancer, as well as the identification of tissue specific methylation of CpG islands. However, a limitation to the utility of this method has been the ability to assign specific genomic sequences to RLGS spots, a process commonly referred to as "RLGS spot cloning." Results: We report the development of a virtual RLGS method (vRLGS) that allows for RLGS spot identification in any sequenced genome and with any enzyme combination. We report significant improvements in predicting DNA fragment migration patterns by incorporating sequence information into the migration models, and demonstrate a median Euclidian distance between actual and predicted spot migration of 0.18 centimeters for the most complex human RLGS pattern. We report the confirmed identification of 795 human and 530 mouse RLGS spots for the most commonly used enzyme combinations. We also developed a method to filter the virtual spots to reduce the number of extra spots seen on a virtual profile for both the mouse and human genomes. We demonstrate use of this filter to simplify spot cloning and to assist in the identification of spots exhibiting tissue-specific methylation. Conclusion: The new vRLGS system reported here is highly robust for the identification of novel RLGS spots. The migration models developed are not specific to the genome being studied or the enzyme combination being used, making this tool broadly applicable. The identification of hundreds of mouse and human RLGS spot loci confirms the strong bias of RLGS studies to focus on CpG islands and provides a valuable resource to rapidly study their methylation
    Type of Publication: Journal article published
    PubMed ID: 18053125
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  • 8
    Keywords: CANCER ; EXPRESSION ; TUMOR-CELLS ; AGENTS ; human ; THERAPY ; COMMON ; GENE ; GENE-EXPRESSION ; GENOME ; DNA ; MESSENGER-RNA EXPRESSION ; treatment ; TARGET ; PATTERNS ; gene expression ; INDUCED APOPTOSIS ; genetics ; DNA methylation ; STRATEGIES ; TARGETS ; H3 METHYLTRANSFERASE ; METHYLATION ; TRENDS ; heredity ; AGENT ; SINGLE ; review ; PATTERN ; THERAPIES ; HISTONE DEACETYLASE INHIBITORS ; PHASE-I TRIAL ; SIGNATURE ; USA ; CPG-ISLAND METHYLATION ; VIEW ; CANCERS ; ENGLAND ; DNA-METHYLATION ; modification ; DEACETYLATION ; EPIGENETIC ALTERATIONS ; DEPSIPEPTIDE FR901228
    Abstract: Alterations in the genome and the epigenome are common in most cancers. Changes in epigenetic signatures, including aberrant DNA methylation and histone deacetylation, are among the most prevalent modifications in cancer and lead to dramatic changes in gene expression patterns. Because DNA methylation and histone deacetylation are reversible processes, they have become attractive as targets for cancer epigenetic therapy, both as single agents and as 'enhancing' agents for other treatment strategies. In this review we discuss our current view of the mammalian epigenome, this view has changed over the years because of the availability of novel technologies. We further demonstrate how the profound understanding of epigenetic alterations in cancer will help develop novel strategies for epigenetic therapies
    Type of Publication: Journal article published
    PubMed ID: 17681396
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  • 9
    Keywords: CANCER ; SURVIVAL ; tumor ; Germany ; LUNG ; CT ; DIAGNOSIS ; INFORMATION ; lung cancer ; LUNG-CANCER ; TOOL ; DEATH ; EPIDEMIOLOGY ; RISK ; GENE ; GENES ; GENOME ; EFFICIENCY ; TIME ; DNA ; MARKER ; RISK-FACTORS ; GENETIC POLYMORPHISMS ; BIOMARKERS ; BIOLOGY ; polymorphism ; POLYMORPHISMS ; FIELD ; BREAST-CANCER ; TARGET ; IDENTIFICATION ; LESIONS ; HEALTH ; ASSAY ; genetics ; CIGARETTE-SMOKING ; risk factors ; smoking ; PROSTATE-CANCER ; DNA methylation ; EFFICIENT ; MARKERS ; TUMOR-SUPPRESSOR GENE ; cancer risk ; HIGH-RISK ; genetic polymorphism ; TARGETS ; HISTONE DEACETYLASE ; non-small cell lung cancer ; BETA-CAROTENE ; ONCOLOGY ; RE ; genomics ; biomarker ; CANCER DEVELOPMENT ; methods ; ASSAYS ; HIGH-THROUGHPUT ; USA ; EPIGENETICS ; cancer research ; RISK-FACTOR ; CANCERS ; CANCER-RISK ; TOOLS ; FHIT GENE ; quantitative ; GENOME-WIDE ASSOCIATION ; modification ; POOLED-ANALYSIS ; MODIFIERS ; epigenetic ; ABERRANT PROMOTER METHYLATION
    Abstract: Lung cancer is the leading cause of cancer-related death and thus a major health problem. The efficiency of current treatment modalities for lung cancer depends strongly on the time of diagnosis, with better chances of survival if a tumor has been detected at an early stage. Thus, there is an urgent need for rapid and efficient early detection methods. Biomarkers represent a possible alternative to current, rather expensive, screening tools such as spiral computer tomography (CT), or may allow the identification of high risk groups for whom screening would be cost efficient. Although most lung cancers are the consequence of smoking, a substantial fraction of molecular-epidemiological studies point to high-prevalence, low-penctrance genetic polymorphisms as modifiers of environmental lung cancer risk. In the past the genomics field has also made significant advances in identifying genetic lesions that can now be harvested with the goal of identifying novel biomarkers for lung cancer. Furthermore, the importance of epigenetic changes that occur during lung cancer development has been reported, but has been underestimated in the past. Novel high-throughput, quantitative assays for the detection of DNA methylation or histone tail modifications are now applied, to search for alterations in the lung cancer genome and will identify novel cancer-related genes that may become attractive targets for treatment, provide new insight into the biology of lung cancers, and could also become useful biomarkers for the early detection of lung cancer in sputum, or may be used as prognostic markers. Thus, an integrative approach in lung cancer research combining epidemiological, genetic and epigenetic information becomes an important concept for the future. (C) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18425819
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  • 10
    Keywords: CANCER ; GROWTH ; tumor ; carcinoma ; CELL ; human ; COMMON ; SUPPORT ; GENE ; GENOME ; HYBRIDIZATION ; microarray ; PROTEIN ; SAMPLE ; SAMPLES ; TISSUE ; LINES ; PATIENT ; ACTIVATION ; DNA ; MECHANISM ; CARCINOGENESIS ; TISSUES ; SKIN ; CELL-LINES ; DISCOVERY ; IN-SITU ; AMPLIFICATION ; COPY NUMBER ; immunohistochemistry ; microarrays ; genetics ; CELL-LINE ; REGION ; ONCOGENE ; HEAD ; CARCINOMAS ; UNITED-STATES ; squamous cell carcinoma ; OVEREXPRESSION ; cell lines ; HaCaT ; CELL CARCINOMA ; SKIN KERATINOCYTES ; HNSCC ; mRNA ; TISSUE MICROARRAYS ; EVENTS ; RNAi ; USA ; head and neck squamous cell carcinoma ; oncogenes ; CANCERS ; immunology ; SQUAMOUS-CELL ; PROMOTES ; virology ; STATE ; Genetic ; WELL ; RESTRICTION ; PROPORTION ; MEDICAL-CENTER ; Adult Aged Blotting,Western Carcinoma,Squamous Cell/*genetics DNA,Neoplasm/metabolism Female Gene Do
    Abstract: Gene amplification, a common mechanism for oncogene activation in cancers, has been used in the discovery of novel oncogenes. Low-level copy number gains are frequently observed in head and neck squamous cell carcinomas (HNSCCs) where numerous amplification events and potential oncogenes have already been reported. Recently, we applied restriction landmark genome scanning to study gene amplifications in HNSCC and located novel and uncharacterized regions in primary tumor samples. Gain on chromosome 8q22.3, the location of YWHAZ (14-3-3zeta), is found in 30-40% HNSCC cases. Data obtained from fluorescence in situ hybridization and immunohistochemistry on HNSCC tissue microarrays confirmed frequent low-level YWHAZ copy number gain and protein overexpression. YWHAZ mRNA was frequently upregulated in patients' tumor tissues. Furthermore, YWHAZ RNAi significantly suppressed the growth rate of HNSCC cell lines, and overexpression of YWHAZ in HaCaT immortalized human skin keratinocytes promotes overgrowth, as well as morphological changes. Reduced YWHAZ levels increased the G1/G0-phase proportion, decreased the S-phase proportion and the rate of DNA synthesis. Based on this evidence, we suggest that YWHAZ is a candidate proto-oncogene and deserves further investigation into its role in HNSCC carcinogenesis
    Type of Publication: Journal article published
    PubMed ID: 19405126
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