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  • 1
    Keywords: EXPRESSION ; Germany ; SITE ; SITES ; GENE ; GENE-EXPRESSION ; GENES ; GENOME SEQUENCE ; PROTEIN ; CONTRAST ; ACID ; gene expression ; EFFICACY ; CONSERVATION ; Jun ; SELECTION ; nutrition ; PHYLOGENETIC ANALYSIS ; REQUIREMENT ; AMINO-ACID ; CODON ; HIGH EXPRESSION ; APHIDS ; Blochmannia ; Buchnera ; insects ; NONSYNONYMOUS SUBSTITUTION ; substitution rates ; SYMBIONT ; WIGGLESWORTHIA
    Abstract: Most endosymbiotic bacteria have extremely reduced genomes, accelerated evolutionary rates, and strong AT base compositional bias thought to reflect reduced efficacy of selection and increased mutational pressure. Here, we present a comparative study of evolutionary forces shaping five fully sequenced bacterial endosymbionts of insects. The results of this study were three-fold: (i) Stronger conservation of high expression genes at not just nonsynonymous, but also synonymous, sites. (ii) Variation in amino acid usage strongly correlates with GC content and expression level of genes. This pattern is largely explained by greater conservation of high expression genes, leading to their higher GC content. However, we also found indication of selection favoring GC-rich amino acids that contrasts with former studies. (iii) Although the specific nutritional requirements of the insect host are known to affect gene content of endosymbionts, we found no detectable influence on substitution rates, amino acid usage, or codon usage of bacterial genes involved in host nutrition. (c) 2005 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15935576
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  • 2
    Keywords: CANCER ; EXPRESSION ; tumor ; Germany ; human ; THERAPY ; INFORMATION ; TOOL ; DISEASE ; RISK ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; microarray ; SAMPLE ; SAMPLES ; PATIENT ; DNA ; MECHANISM ; prognosis ; mechanisms ; BIOLOGY ; BREAST ; breast cancer ; BREAST-CANCER ; DELETION ; IDENTIFICATION ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; PATTERNS ; gene expression ; CHROMOSOMAL-ABERRATIONS ; TUMOR PROGRESSION ; statistics ; ABERRATIONS ; DELETIONS ; DNA methylation ; REGION ; REGIONS ; bioinformatics ; PARAMETERS ; ONCOGENE ; CLASS-I ; DNA AMPLIFICATION ; IMBALANCES ; METHYLATION ; CHROMOSOMAL IMBALANCES ; P53 STATUS ; SINGLE ; RE ; PATTERN ; THERAPIES ; PATIENT SURVIVAL ; LEVEL ; analysis ; methods ; computational biology ; RISK STRATIFICATION ; genomic ; microbiology ; transcriptome ; CONTACT ; ARRAY-CGH ; MYC ; aberration ; HUMAN-BREAST ; DNA-METHYLATION ; biotechnology ; chromosomal aberration
    Abstract: Motivation: In cancer, chromosomal imbalances like amplifications and deletions, or changes in epigenetic mechanisms like DNA methylation influence the transcriptional activity. These alterations are often not limited to a single gene but affect several genes of the genomic region and may be relevant for the disease status. For example, the ERBB2 amplicon (17q21) in breast cancer is associated with poor patient prognosis. We present a general, unsupervised method for genome-wide gene expression data to systematically detect tumor patients with chromosomal regions of distinct transcriptional activity. The method aims to find expression patterns of adjacent genes with a consistently decreased or increased level of gene expression in tumor samples. Such patterns have been found to be associated with chromosomal aberrations and clinical parameters like tumor grading and thus can be useful for risk stratification or therapy. Results: Our approach was applied to 12 independent human breast cancer microarray studies comprising 1422 tumor samples. We prioritized chromosomal regions and genes predominantly found across all studies. The result highlighted not only regions which are well known to be amplified like 17q21 and 11q13, but also others like 8q24 (distal to MYC) and 17q24-q25 which may harbor novel putative oncogenes. Since our approach can be applied to any microarray study it may become a valuable tool for the exploration of transcriptional changes in diverse disease types. Availability: The R source codes which implement the method and an exemplary analysis are available at http://www.dkfz.de/mga2/people/buness/CTP/. Contact: a.buness@gmx.de Supplementary information: Supplementary data are available at Bioinformatics online
    Type of Publication: Journal article published
    PubMed ID: 17599933
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  • 3
    Keywords: ACTIVATION, ANTIGEN, ASSOCIATION, BIOPSY, CANCER, cancer risk, CANCER-RISK, CELLS, DIFFERENTIAL EXPR
    Abstract: Background: Insufficient sensitivity and specificity of prostate biopsies for cancer detection. Objectives: Based on evidence from our microarray analyses, we hypothesized that considerable molecular changes precede morphologically detectable malignant transformation of prostate epithelial tissues. The identification of such changes could lead to novel strategies in the clinical management of prostate cancer. Design, Setting, and Participants: Histologically normal, fresh prostate tissue from prostate cancer patients, healthy donors, and cancer suspect patients with continuous negative biopsies were analyzed. Measurements: To identify molecular changes between 29 tumor-free prostate tissues from healthy donors and 27 patients with proven prostate cancer, we performed a global microarray screening. 'Based on this screening as well as literature data, we selected a subset of 29 genes for validation by arrayed real-time reverse transcription-polymerase chain reaction (RT-PCR) using histologically tumor-free biopsy samples from 114 patients representing three prostate cancer risk groups. Results and Limitations: We identified five genes (FOS, EGR1, MYC, TFRC, and FOLH1), which displayed significant differential expression between morphologically normal prostate tissues from men of each of the three risk groups. These results were independent from age, prostate-specific antigen (PSA), frequency and timing of previous prostate biopsies, tissue composition, tumor stage, and tumor grade. in univariate logistic regression analyses, the transcript levels of these genes were found to be highly indicative for the presence or absence of cancer in the entire prostate. The study was designed as a proof of principle. The clinical relevance of our results has to be evaluated in a larger clinical setting. Conclusions: Our results suggest a measurable molecular cancer phenotype in histologically normal prostate tissue indicating the presence of prostate cancer elsewhere in the organ. (C) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18501497
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  • 4
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; SURVIVAL ; tumor ; Germany ; CLASSIFICATION ; DIAGNOSIS ; GENE ; GENE-EXPRESSION ; microarray ; ACCURACY ; BREAST ; breast cancer ; BREAST-CANCER ; IDENTIFICATION ; gene expression ; VECTOR ; STRATEGIES ; ROBUSTNESS ; CONSTRUCTION ; ESTROGEN-RECEPTOR ; INTEGRATION ; ESTROGEN ; PROFILES ; estrogen receptor ; SIGNATURE ; PRIMARY BREAST-CANCER ; STRATEGY ; BENEFIT
    Abstract: Background: The increasing number of gene expression microarray studies represents an important resource in biomedical research. As a result, gene expression based diagnosis has entered clinical practice for patient stratification in breast cancer. However, the integration and combined analysis of microarray studies remains still a challenge. We assessed the potential benefit of data integration on the classification accuracy and systematically evaluated the generalization performance of selected methods on four breast cancer studies comprising almost 1000 independent samples. To this end, we introduced an evaluation framework which aims to establish good statistical practice and a graphical way to monitor differences. The classification goal was to correctly predict estrogen receptor status (negative/positive) and histological grade (low/high) of each tumor sample in an independent study which was not used for the training. For the classification we chose support vector machines (SVM), predictive analysis of microarrays (PAM), random forest (RF) and k-top scoring pairs (kTSP). Guided by considerations relevant for classification across studies we developed a generalization of kTSP which we evaluated in addition. Our derived version (DV) aims to improve the robustness of the intrinsic invariance of kTSP with respect to technologies and preprocessing. Results: For each individual study the generalization error was benchmarked via complete cross-validation and was found to be similar for all classification methods. The misclassification rates were substantially higher in classification across studies, when each single study was used as an independent test set while all remaining studies were combined for the training of the classifier. However, with increasing number of independent microarray studies used in the training, the overall classification performance improved. DV performed better than the average and showed slightly less variance. In particular, the better predictive results of DV in across platform classification indicate higher robustness of the classifier when trained on single channel data and applied to gene expression ratios. Conclusions: We present a systematic evaluation of strategies for the integration of independent microarray studies in a classification task. Our findings in across studies classification may guide further research aiming on the construction of more robust and reliable methods for stratification and diagnosis in clinical practice
    Type of Publication: Journal article published
    PubMed ID: 20042109
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  • 5
    Keywords: COMBINATION ; Germany ; GENERATION ; GENOME ; microarray ; PROTEIN ; PROTEINS ; MONOCLONAL-ANTIBODY ; BIOLOGY ; MOLECULAR-BIOLOGY ; antibodies ; antibody ; microarrays ; ARRAYS ; NUMBER ; REPRODUCIBILITY ; FUSION ; FUSION PROTEINS ; SURFACE ; MONOCLONAL-ANTIBODIES ; IMMOBILIZATION ; PROTEOMICS ; protein microarray ; PROTEIN MICROARRAYS ; FUSION PROTEIN ; SERUM ; molecular biology ; molecular ; RECOMBINANT ; ARRAY ; RESOURCE ; ANTIBODY MICROARRAYS ; CHIP ; 3D ; monoclonal antibodies ; monoclonal antibody ; ALLERGEN-SPECIFIC IGE ; DYES ; FLUORESCENT DYES
    Abstract: To process large numbers of samples in parallel is one potential of protein microarrays for research and diagnostics. However, the application of protein arrays is currently hampered by the lack of comprehensive technological knowledge about the suitability of 2-D and 3-D slide surface coatings. We have performed a systematic study to analyze how both surface types perform in combination with different fluorescent dyes to generate significant and reproducible data. In total, we analyzed more than 100 slides containing 1152 spots each. Slides were probed against different monoclonal antibodies (mAbs) and recombinant fusion proteins. We found two surface coatings to be most suitable for protein and antibody (Ab) immobilization. These were further subjected to quantitative analyses by evaluating intraslide and slide-to-slide reproducibilities, and the linear range of target detection. in summary, we demonstrate that only suitable combinations of surface and fluorescent dyes allow the generation of highly reproducible data
    Type of Publication: Journal article published
    PubMed ID: 16267812
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  • 6
    Keywords: EXPRESSION ; SURVIVAL ; Germany ; DENSITY ; TOOL ; DISEASE ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; TISSUE ; ACCURACY ; HEART ; TIME ; PATIENT ; COMPLEX ; COMPLEXES ; BIOMARKERS ; DOWN-REGULATION ; IDENTIFICATION ; PATTERNS ; gene expression ; microarrays ; ARRAYS ; COUNTRIES ; PATHOGENESIS ; INVOLVEMENT ; IMMUNE-RESPONSE ; FAILURE ; RECEPTORS ; DILATED CARDIOMYOPATHY ; MANAGEMENT ; IMPLEMENTATION ; ANGIOTENSIN-II ; TECHNICAL ASPECTS ; PROFILES ; TECHNOLOGY ; EVENTS ; ONTOLOGY ; SIGNATURE ; downregulation ; prospective ; prospective study ; cardiomyopathies ; CARDIOMYOPATHY ; HUMAN ATRIAL ; HUMAN MYOCARDIUM ; MICROARRAY PLATFORMS ; OLIGONUCLEOTIDE MICROARRAYS ; STAGE HEART-FAILURE
    Abstract: OBJECTIVES This study was designed to identify a common gene expression signature in dilated cardiomyopathy (DCM) across different microarray studies. BACKGROUND Dilated cardiomyopathy is a common cause of heart failure in Western countries. Although gene expression arrays have emerged as a powerful tool for delineating complex disease patterns, differences in platform technology, tissue heterogeneity, and small sample sizes obscure the underlying pathophysiologic events and hamper a comprehensive interpretation of different microarray studies in heart failure. METHODS We accounted for tissue heterogeneity and technical aspects by performing 2 genome-wide expression studies based on cDNA and short-oligonucleotide microarray platforms which comprised independent septal and left ventricular tissue samples from nonfailing (NF) (n 20) and DCM (n = 20) hearts. RESULTS Concordant results emerged for major gene ontology classes between cDNA and oligonucleotide microarrays. Notably, immune response processes displayed the most pronounced down-regulation on both microarray types, linking this functional gene class to the pathogenesis of end-stage DCM. Furthermore, a robust set of 27 genes was identified that classified DCM and NF samples with 〉 90% accuracy in a total of 108 myocardial samples from our cDNA and oligonucleotide microarray studies as well as 2 publicly available datasets. CONCLUSIONS For the first time, independent microarray datasets pointed to significant involvement of immune response processes in end-stage DCM. Moreover, based on 4 independent microarray datasets, we present a robust gene expression signature of DCM, encouraging future prospective studies for the implementation of disease biomarkers in the management of patients with heart failure
    Type of Publication: Journal article published
    PubMed ID: 17045896
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  • 7
    Keywords: EXPRESSION ; Germany ; SITE ; GENE ; GENES ; PROTEIN ; PROTEINS ; SACCHAROMYCES-CEREVISIAE ; transcription ; COMPLEX ; COMPLEXES ; DNA ; DOMAIN ; BINDING ; SEQUENCE ; chromosome ; ELEMENT ; MUTANT ; PATTERNS ; CHROMATIN ; DIFFERENCE ; Drosophila ; DROSOPHILA-MELANOGASTER ; PROMOTER ; ELEMENTS ; PROMOTERS ; DNA-BINDING ; REGION ; REGIONS ; METHYLTRANSFERASE ACTIVITY ; REPRESSION ; REGULATOR ; REGULATORS ; DOMAINS ; BINDS ; BINDING PROTEIN ; TRANSCRIPTS ; BINDING-PROTEIN ; PATTERN ; HOMEOTIC GENE ; assembly ; gene regulation ; TARGET GENES ; RECOVERY ; USA ; function ; POLYCOMB GROUP PROTEINS ; TRITHORAX GROUP PROTEINS ; Response Elements ; MAINTENANCE ; antermapedia ; bithorax ; BITHORAX COMPLEX ; ChIP-on-chip ; HOX ; inactive
    Abstract: Drosophila Polycomb group (PcG) and Trithorax group (TrxG) proteins are responsible for the maintenance of stable transcription patterns of many developmental regulators, such as the homeotic genes. We have used ChIP-on-chip to compare the distribution of several PcG/TrxG proteins, as well as histone modifications in active and repressed genes across the two homeotic complexes ANT-C and BX-C. Our data indicate the colocalization of the Polycomb repressive complex 1 (PRC1) with Trx and the DNA binding protein Pleiohomeotic (Pho) at discrete sequence elements as well as significant chromatin assembly differences in active and inactive regions. Trx binds to the promoters of active genes and noncoding transcripts. Most strikingly, in the active state, Pho covers extended chromatin domains over many kilobases. This feature of Pho, observed on many polytene chromosome puffs, reflects a previously unclescribed function. At the hsp70 gene, we demonstrate in mutants that Pho is required for transcriptional recovery after heat shock. Besides its presumptive function in recruiting PcG complexes to their site of action, our results now uncover that Pho plays an additional role in the repression of already induced genes
    Type of Publication: Journal article published
    PubMed ID: 17921257
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  • 8
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; proliferation ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; INHIBITION ; PATHWAY ; COMMON ; NEW-YORK ; GENE ; GENES ; microarray ; RNA ; cell cycle ; CELL-CYCLE ; CYCLE ; E7 ; papillomavirus ; TARGET ; IDENTIFICATION ; gene expression ; MICROARRAY DATA ; WOMEN ; genetics ; cervical cancer ; CERVICAL-CANCER ; human papillomavirus ; CANCER-CELLS ; HPV ; E6 ; ONCOGENE ; TRANSFORMATION ; HUMAN-PAPILLOMAVIRUS ; CERVICAL-CARCINOMA ; PHENOTYPE ; TARGETS ; C-MYC ; MICROARRAY ANALYSIS ; TUMOR CELLS ; heredity ; BIOPSY ; RE ; INTERFERENCE ; RNA INTERFERENCE ; HELA-CELLS ; regulation ; TYPE-16 E6 ; TARGET GENES ; analysis ; TUMOR-CELL ; RNA processing ; EXPRESSION PROFILES ; USA ; E6 and E7 ; E2 PROTEIN ; transcriptome ; BIOPSIES ; viral ; MEDICINE ; comparison ; MAINTENANCE
    Abstract: Specific types of hurnan papillornaviruses (HPVs) cause cervical cancer, the second most common tumor in women worldwide. Both cellular transformation and the maintenance of the oncogenic phenotype of HPVpositive tumor cells are linked to the expression of the viral E6 and E7 oncogenes. To identify downstream cellular target genes for the viral oncogenes, we silenced endogenous E6 and E7 expression in HPV-positive HeLa cells by RNA interference (RNAi). Subsequently, we assessed changes of the cellular transcriptorne by genome-wide microarray analysis. We identified 648 genes, which were either downregulated (360 genes) or upregulated (288 genes), upon inhibition of E6/E7 expression. A large fraction of these genes is involved in tumor-relevant processes, such as apoptosis control, cell cycle regulation, or spindle formation. Others may represent novel cellular targets for the HPV oncogenes, such as a large group of CMYC-associated genes involved in RNA processing and splicing. Comparison with published microarray data revealed a substantial concordance between the genes repressed by RNAi-mediated E6/E7 silencing in HeLa cells and genes reported to be upregulated in HPV-positive cervical cancer biopsies
    Type of Publication: Journal article published
    PubMed ID: 17589817
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  • 9
    Keywords: Germany ; PATHWAYS ; ALGORITHM ; ALGORITHMS ; COMMON ; NETWORK ; GENE ; TIME ; CONTRAST ; BIOLOGY ; CYCLE ; NUMBER ; statistics ; EFFICIENT ; RECONSTRUCTION ; SINGLE ; RNA INTERFERENCE ; Bayesian networks ; LEADS ; interaction ; methods ; computational biology ; USA ; microbiology ; MATTER ; SET ; biotechnology ; simulation study ; gene networks ; computational molecular biology ; linear algebra ; PERTURBATIONS ; structural and functional genomics ; STRUCTURE DISCOVERY
    Abstract: The matter of concern are algorithms for the discrimination of direct from indirect regulatory effects from an interaction graph built up by error-prone measurements. Many of these algorithms can be cast as a rule for the removal of a single edge of the graph, such that the remaining graph is still consistent with the data. A set of mild conditions is given under which iterated application of such a rule leads to a unique minimal consistent graph. We show that three of the common methods for direct interactions search fulfill these conditions, thus providing a justification of their use. The main issues a reconstruction algorithm has to deal with, are the noise in the data, the presence of regulatory cycles, and the direction of the regulatory effects. We introduce a novel rule that, in contrast to the previously mentioned methods, simultaneously takes into account all these aspects. An efficient algorithm for the computation of the minimal graph is given, whose time complexity is cubic in the number of vertices of the graph. Finally, we demonstrate the utility of our method in a simulation study
    Type of Publication: Journal article published
    PubMed ID: 17990974
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  • 10
    Keywords: ACTIVATION, ANTIGEN, assembly, CANCER, CANCER CELLS, CANCER-CELLS, CELL, CELLS, COLON-CANCER, colore
    Abstract: Most malignant features of cancer cells are triggered by activated oncogenes and the loss of tumor suppressors due to mutation or epigenetic inactivation. It is still unclear, to what extend the escape of emerging cancer cells from recognition and elimination by the immune system is determined by similar mechanisms. We compared the transcriptomes of HCT116 colorectal cancer cells deficient in DNA methyltransferases (DNMTs) and of cells, in which the RAS pathway as the major growth-promoting signaling system is blocked by inhibition of MAPK. We identified the MHC Class I genes HLA-A1/A2 and the ULBP2 gene encoding 1 of the 8 known ligands of the activating NK receptor NKG2D among a cluster of immune genes up-regulated under the conditions of both DNMT-deficiency and MEK-inhibition. Bisulphite sequencing analyses of HCT116 with DNMT deficiency or after MEK-inhibition showed that de-methylation of the ULPB2 promoter correlated with its enhanced surface expression. The HLA-A promoters were not methylated indicating that components of the HLA assembly machinery were also suppressed in DNMT-deficient and MEK-inhibited cells. Increased HLA-A2 surface expression was correlated with enhanced recognition and lysis by A2-specific CTL. On the contrary, elevated ULBP2 expression was not reflected by enhanced recognition and lysis by NK cells. Cosuppression of HLA Class I and NKG2D ligands and genes encoding peptide transporters or proteasomal genes mediates a strong functional link between RAS activation, DNMT activity and disruption of the antigen presenting system controlling immune recognition in colorectal cancer cells. (C) 2009 UICC
    Type of Publication: Journal article published
    PubMed ID: 19569244
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