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  • GENE  (21)
  • 1
    Keywords: CELLS ; EXPRESSION ; Germany ; SYSTEMS ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; SACCHAROMYCES-CEREVISIAE ; METABOLISM ; COMPLEX ; COMPLEXES ; SEQUENCE ; METABOLITES ; gene expression ; ESCHERICHIA-COLI ; DATABASE ; OXYGEN ; CLUSTER ; MATRIX ; SYNTHETASE ; EXTRACTION ; LEVEL ; ENZYME ; TECHNOLOGY ; EXPRESSION PATTERNS ; CHAIN AMINO-ACIDS ; K-12
    Abstract: Background: Microarray technology produces gene expression data on a genomic scale for an endless variety of organisms and conditions. However, this vast amount of information needs to be extracted in a reasonable way and funneled into manageable and functionally meaningful patterns. Genes may be reasonably combined using knowledge about their interaction behaviour. On a proteomic level, biochemical research has elucidated an increasingly complete image of the metabolic architecture, especially for less complex organisms like the well studied bacterium Escherichia coli. Results: We sought to discover central components of the metabolic network, regulated by the expression of associated genes under changing conditions. We mapped gene expression data from E. coli under aerobic and anaerobic conditions onto the enzymatic reaction nodes of its metabolic network. An adjacency matrix of the metabolites was created from this graph. A consecutive ones clustering method was used to obtain network clusters in the matrix. The wavelet method was applied on the adjacency matrices of these clusters to collect features for the classifier. With a feature extraction method the most discriminating features were selected. We yielded network sub-graphs from these top ranking features representing formate fermentation, in good agreement with the anaerobic response of heterofermentative bacteria. Furthermore, we found a switch in the starting point for NAD biosynthesis, and an adaptation of the l-aspartate metabolism, in accordance with its higher abundance under anaerobic conditions. Conclusion: We developed and tested a novel method, based on a combination of rationally chosen machine learning methods, to analyse gene expression data on the basis of interaction data, using a metabolic network of enzymes. As a case study, we applied our method to E. coli under oxygen deprived conditions and extracted physiologically relevant patterns that represent an adaptation of the cells to changing environmental conditions. In general, our concept may be transferred to network analyses on biological interaction data, when data for two comparable states of the associated nodes are made available
    Type of Publication: Journal article published
    PubMed ID: 16524469
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  • 2
    Keywords: tumor ; Germany ; COHORT ; GENE ; HYBRIDIZATION ; TUMORS ; PATIENT ; MARKER ; SEQUENCE ; DELETION ; STAGE ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; COPY NUMBER ; PATTERNS ; microarrays ; NUMBER ; MARKERS ; REGION ; REGIONS ; PHENOTYPE ; REVEALS ; CHILDREN ; SEGMENTS ; 1p ; neuroblastoma ; CHROMOSOMES ; SUBSET ; CYTOGENETIC ANALYSIS ; BREAKPOINTS ; MYCN-AMPLIFICATION ; function ; LOSSES ; HIGH-RESOLUTION ANALYSIS ; genomic ; GENOMIC ALTERATIONS ; 11Q ; CGH ANALYSIS ; DNA-COPY-NUMBER
    Abstract: The study of genomic alterations in neuroblastoma is of particular importance since several cytogenetic markers proved to be closely associated with the clinical phenotype. To disclose patterns of gains and losses, we performed high-resolution oligonucleotide array-based comparative genomic hybridization (aCGH). A total cohort of 90 patients was classified into 6 subsets according to tumor stage and outcome: Stages 1-3+ (with event), Stage 1-3- (no event), Stage 4+/-, and Stage 4S+/-. The aberration patterns in Stages 1-3- and 4S- tumors differed from all other groups as they were predominantly characterized by losses (3, 4, 14, X) and gains (7, 17) of whole chromosomes. However, 59/65 (91%) tumors of Stages 1-3+ or Stage 4 revealed numerous structural copy number alterations (sCNA). While deletions in chromosomes 1, 3, and I I discriminated outcome in Stage 4, there were no specific sCNA that distinguished tumor stage within the subgroup of unfavorable tumors. sCNA in 1p, 3p, 11q, 17q, or MYCN amplification (MNA) was seen among 22/24 patients who died, 10/12 with metastatic relapses, and 5/9 with local recurrences. Detailed breakpoint analyses on chromosomes 1, 3, 11, and 17 disclosed preferred breaking areas, although breakpoints were not identical. Amplifications were found in 18 patients and involved 2p24 (MYCN) and other segments of chromosome 2, as well as regions on chromosome arms 6q, 12q, and 17q. One single feature in 21q21.1 (BU678720, without known function yet) attracted particular attention since five patients showed a homozygous loss of this sequence. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. (c) 2006 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16958102
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  • 3
    Keywords: ENVIRONMENT ; SPECTRA ; CELLS ; EXPRESSION ; GROWTH ; CELL ; Germany ; PATHWAY ; PATHWAYS ; INFORMATION ; SYSTEM ; SYSTEMS ; GENE ; GENE-EXPRESSION ; GENOME ; microarray ; SACCHAROMYCES-CEREVISIAE ; METABOLISM ; DOWN-REGULATION ; treatment ; culture ; PATTERNS ; gene expression ; MICROARRAY DATA ; ESCHERICHIA-COLI ; UP-REGULATION ; OXYGEN ; CLUSTERS ; TRANSCRIPTIONAL REGULATION ; CLUSTER ; RE ; PRODUCTS ; HYDROGEN-PEROXIDE ; EXCRETION ; LEVEL ; methods ; PROFILES ; EXPRESSION PROFILES ; technique ; uptake ; E ; SPECTRUM ; microbiology ; image processing ; TOPOLOGY ; METABOLIC PATHWAYS ; SALMONELLA-TYPHIMURIUM ; ADAPTIVE RESPONSE ; ANAEROBIC RESPIRATION ; DEOXYRIBONUCLEOTIDE SYNTHESIS ; FUMARATE REDUCTASE ; MULTIORGANISM DATABASE
    Abstract: Background: Biochemical investigations over the last decades have elucidated an increasingly complete image of the cellular metabolism. To derive a systems view for the regulation of the metabolism when cells adapt to environmental changes, whole genome gene expression profiles can be analysed. Moreover, utilising a network topology based on gene relationships may facilitate interpreting this vast amount of information, and extracting significant patterns within the networks. Results: Interpreting expression levels as pixels with grey value intensities and network topology as relationships between pixels, allows for an image-like representation of cellular metabolism. While the topology of a regular image is a lattice grid, biological networks demonstrate scale-free architecture and thus advanced image processing methods such as wavelet transforms cannot directly be applied. In the study reported here, one-dimensional enzyme-enzyme pairs were tracked to reveal sub-graphs of a biological interaction network which showed significant adaptations to a changing environment. As a case study, the response of the hetero-fermentative bacterium E. coli to oxygen deprivation was investigated. With our novel method, we detected, as expected, an up-regulation in the pathways of hexose nutrients up-take and metabolism and formate fermentation. Furthermore, our approach revealed a down-regulation in iron processing as well as the up-regulation of the histidine biosynthesis pathway. The latter may reflect an adaptive response of E. coli against an increasingly acidic environment due to the excretion of acidic products during anaerobic growth in a batch culture. Conclusion: Based on microarray expression profiling data of prokaryotic cells exposed to fundamental treatment changes, our novel technique proved to extract system changes for a rather broad spectrum of the biochemical network
    Type of Publication: Journal article published
    PubMed ID: 17488495
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  • 4
    Keywords: DISTINCT ; GENE ; BREAST-CANCER ; COPY-NUMBER ; SONIC HEDGEHOG ; GERMLINE ; LI-FRAUMENI-SYNDROME ; ACUTE MYELOID-LEUKEMIA ; telomere length ; FAMILIAL SYNDROME
    Abstract: Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acutemyeloid leukemia. These findings connect p53 status and chr
    Type of Publication: Journal article published
    PubMed ID: 22265402
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  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; carcinoma ; GENE ; GENE-EXPRESSION ; COMPLEXES ; BREAST-CANCER ; COMPARATIVE GENOMIC HYBRIDIZATION ; gene expression ; MUTATION ; METASTASIS ; SIGNALING PATHWAYS ; SOLID TUMORS ; PRIMARY TUMORS ; SUBTYPES ; GENETIC ALTERATIONS ; LYMPH-NODE METASTASES
    Abstract: Introduction: With the improvement of therapeutic options for the treatment of breast cancer, the development of brain metastases has become a major limitation to life expectancy in many patients. Therefore, our aim was to identify molecular markers associated with the development of brain metastases in breast cancer. Methods: Patterns of chromosomal aberrations in primary breast tumors and brain metastases were compared with array-comparative genetic hybridization (CGH). The most significant region was further characterized in more detail by microsatellite and gene-expression analysis, and finally, the possible target gene was screened for mutations. Results: The array CGH results showed that brain metastases, in general, display similar chromosomal aberrations as do primary tumors, but with a notably higher frequency. Statistically significant differences were found at nine different chromosomal loci, with a gain and amplification of EGFR (7p11.2) and a loss of 10q22.3-qter being among the most significant aberrations in brain metastases (P 〈 0.01; false discovery rate (fdr) 〈 0.04). Allelic imbalance (AI) patterns at 10q were further verified in 77 unmatched primary tumors and 21 brain metastases. AI at PTEN loci was found significantly more often in brain metastases (52%) and primary tumors with a brain relapse (59%) compared with primary tumors from patients without relapse (18%; P = 0.003) or relapse other than brain tumors (12%; P = 0.006). Loss of PTEN was especially frequent in HER2-negative brain metastases (64%). Furthermore, PTEN mRNA expression was significantly downregulated in brain metastases compared with primary tumors, and PTEN mutations were frequently found in brain metastases. Conclusions: These results demonstrate that brain metastases often show very complex genomic-aberration patterns, suggesting a potential role of PTEN and EGFR in brain metastasis formation
    Type of Publication: Journal article published
    PubMed ID: 22429330
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  • 6
    Keywords: IN-VIVO ; GENE ; ALZHEIMERS-DISEASE ; IMMUNOREACTIVITY ; FRONTOTEMPORAL DEMENTIA ; CEREBROSPINAL-FLUID BIOMARKERS ; BUNINA BODIES ; CHROMOGRANIN PEPTIDES ; ALS PATIENTS ; EL-ESCORIAL
    Abstract: BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal disorder of the motor neuron system with poor prognosis and marginal therapeutic options. Current clinical diagnostic criteria are based on electrophysiological examination and exclusion of other ALS-mimicking conditions. Neuroprotective treatments are, however, most promising in early disease stages. Identification of disease-specific CSF biomarkers and associated biochemical pathways is therefore most relevant to monitor disease progression, response to neuroprotective agents and to enable early inclusion of patients into clinical trials. METHODS AND FINDINGS: CSF from 35 patients with ALS diagnosed according to the revised El Escorial criteria and 23 age-matched controls was processed using paramagnetic bead chromatography for protein isolation and subsequently analyzed by MALDI-TOF mass spectrometry. CSF protein profiles were integrated into a Random Forest model constructed from 153 mass peaks. After reducing this peak set to the top 25%, a classifier was built which enabled prediction of ALS with high accuracy, sensitivity and specificity. Further analysis of the identified peptides resulted in a panel of five highly sensitive ALS biomarkers. Upregulation of secreted phosphoprotein 1 in ALS-CSF samples was confirmed by univariate analysis of ELISA and mass spectrometry data. Further quantitative validation of the five biomarkers was achieved in an 80-plex Multiple Reaction Monitoring mass spectrometry assay. CONCLUSIONS: ALS classification based on the CSF biomarker panel proposed in this study could become a valuable predictive tool for early clinical risk stratification. Of the numerous CSF proteins identified, many have putative roles in ALS-related metabolic processes, particularly in chromogranin-mediated secretion signaling pathways. While a stand-alone clinical application of this classifier will only be possible after further validation and a multicenter trial, it could be readily used to complement current ALS diagnostics and might also provide new insights into the pathomechanisms of this disease in the future.
    Type of Publication: Journal article published
    PubMed ID: 22970211
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  • 7
    Keywords: CANCER ; GENE ; GENOME ; MUTATIONS ; STEM-CELLS ; ZINC-FINGER PROTEIN ; T-CELL LYMPHOMAGENESIS ; MYC ; SUPER-ENHANCERS ; SUBGROUP
    Abstract: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
    Type of Publication: Journal article published
    PubMed ID: 25043047
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  • 8
    Keywords: GENE ; BREAST-CANCER ; METHYLATION ; QUANTITIES ; SINGLE CELLS ; TRANSCRIPTS ; LIBRARIES ; RNA-SEQ ; SEQUENCING DATA ; CIRCULATING TUMOR DNA
    Abstract: Massive parallel sequencing (MPS) technologies have paved the way into new areas of research including individualized medicine. However, sequencing of trace amounts of DNA or RNA still remains a major challenge, especially for degraded nucleic acids like circulating DNA. This together with high cost and time requirements impedes many important applications of MPS in medicine and fundamental science. We have established a fast, cheap and highly efficient protocol called 'Capture and Amplification by Tailing and Switching' (CATS) to directly generate ready-to-sequence libraries for MPS from nanogram and picogram quantities of both DNA and RNA. Furthermore, those DNA libraries are strand-specific, can be prepared within 2-3 h and do not require preliminary sample amplification steps. To exemplify the capacity of the technique, we have generated and sequenced DNA libraries from hundred-picogram amounts of circulating nucleic acids isolated from human blood plasma, one nanogram of mRNA-enriched total RNA from cultured cells and few nanograms of bisulfite-converted DNA. The approach for DNA library preparation from minimal and fragmented input described here will find broad application in diverse research areas such as translational medicine including therapy monitoring, prediction, prognosis and early detection of various human disorders and will permit high-throughput DNA sequencing from previously inaccessible material such as minute forensic and archeological samples.
    Type of Publication: Journal article published
    PubMed ID: 24922482
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  • 9
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; carcinoma ; Germany ; INHIBITION ; GENE ; PROTEIN ; PROTEINS ; LINES ; INFECTION ; MECHANISM ; prognosis ; CARCINOGENESIS ; mechanisms ; CELL-LINES ; E7 ; DELETION ; LESIONS ; PROGRESSION ; CARCINOMA CELLS ; WOMEN ; COLORECTAL-CANCER ; CERVICAL-CANCER ; LINE ; TUMOR-SUPPRESSOR GENE ; human papillomavirus ; CARCINOMA-CELLS ; BETA ; CERVICAL-CARCINOMA ; CARCINOMAS ; squamous cell carcinoma ; intraepithelial neoplasia ; UTERINE CERVIX ; GROWTH-FACTOR-BETA ; POOR-PROGNOSIS ; cell lines ; GENOMIC INSTABILITY ; FACTOR-BETA ; molecular ; DEFICIENCY ; TUMOR-SUPPRESSOR ; TUMOR-GROWTH ; TGF-BETA ; MOLECULAR-MECHANISMS ; RESPONSIVENESS ; carcinoma cell ; CIN lesion ; cytogenetic ; DPC4 INACTIVATION ; multistep carcinogenesis ; PAPILLOMAVIRUS INFECTIONS ; SUPPRESSOR ; TGF beta ; tumor suppressor gene
    Abstract: Squamous cell carcinoma of the uterine cervix is one of the most frequent cancers affecting women worldwide. Carcinomas arise from cervical intraepithelial lesions, in which infection with high-risk human papillomavirus types has led to deregulated growth control through the actions of the viral E6 and E7 oncoproteins. The molecular mechanisms underlying progression to invasive tumor growth are poorly understood. One important feature, however, is the escape from growth inhibition by transforming growth factor beta (TGF-beta). Loss of chromosomal arm 18q is among the most frequent cytogenetic alterations in cervical cancers and has been associated with poor prognosis. Since the TGF-beta response is mediated by Smad proteins and the tumor suppressor gene Smad4 resides at 18q21, we have analysed the Smad4 gene for cervical cancer-associated alterations in cell lines and primary carcinomas. Here, we report Smad4 deficiency in four out of 13 cervical cancer cell lines which is due to an intronic rearrangement or deletions of 30 exons. All cell lines, however, showed either absent or moderate responsiveness to TGF-beta irrespective of their Smad4 status. In 41 primary squamous cervical carcinomas analysed, 10 samples showed loss of Smad4 protein expression and 26 samples a reduced expression. Altogether, our results strongly suggest that Smad4 gene alterations are involved in cervical carcinogenesis
    Type of Publication: Journal article published
    PubMed ID: 15531914
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  • 10
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; SURVIVAL ; tumor ; TUMOR-CELLS ; CELL ; human ; KINASE ; PATHWAY ; PATHWAYS ; TYROSINE KINASE ; COHORT ; DEATH ; LONG-TERM ; GENE ; DIFFERENTIATION ; TUMORS ; NEUROBLASTOMA-CELLS ; PATIENT ; ACTIVATION ; MECHANISM ; DOMAIN ; BINDING ; CELL-DEATH ; REGION ; LONG-TERM SURVIVAL ; specificity ; DOMAINS ; neuroblastoma ; signaling ; NEURONS ; medulloblastoma ; interaction ; LEVEL ; cell death ; TECHNOLOGY ; USA ; pediatric ; MEDIATOR ; TYROSINE ; 2-HIT MECHANISM ; CEREBRAL CAVERNOUS MALFORMATIONS ; P75 NEUROTROPHIN RECEPTOR
    Abstract: The TrkA receptor tyrosine kinase is crucial for differentiation and survival of nerve-growth-factor-dependent neurons. Paradoxically, TrkA also induces cell death in pediatric tumor cells of neural origin, via an unknown mechanism. Here, we show that CCM2, a gene product associated with cerebral cavernous malformations, interacts with the juxtamembrane region of TrkA via its phosphotyrosine binding (PTB) domain and mediates TrkA-induced death in diverse cell types. Both the PTB and Karet domains of CCM2 are required for TrkA-dependent cell death, such that the PTB domain determines the specificity of the interaction, and the Karet domain links to death pathways. Downregulation of CCM2 in medulloblastoma or neuroblastoma cells attenuates TrkA-dependent death. Combined high expression levels of CCM2 and TrkA are correlated with long-term survival in a large cohort of human neuroblastoma patients. Thus, CCM2 is a key mediator of TrkA-dependent cell death in pediatric neuroblastic tumors
    Type of Publication: Journal article published
    PubMed ID: 19755102
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