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  • GENE-EXPRESSION  (9)
  • CELL  (7)
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  • 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: 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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  • 3
    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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  • 4
    Keywords: DISEASES ; GENE-EXPRESSION ; TRANSPORT ; MOTIF ; GAMMA ; ANNOTATION ; COMMON VARIANTS ; WIDE ASSOCIATION ; HAPMAP ; ENRICHMENT ANALYSIS
    Abstract: In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional consequences of such single-nucleotide polymorphisms (SNPs) in the affected genes or their regulatory regions. The Global Test was applied to detect schizophrenia-associated pathways using discovery and replication datasets comprising 5,040 and 5,082 individuals of European ancestry, respectively. Information concerning functional gene-sets was retrieved from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and the Molecular Signatures Database. Fourteen of the gene-sets or pathways identified in the discovery dataset were confirmed in the replication dataset. These include functional processes involved in transcriptional regulation and gene expression, synapse organization, cell adhesion, and apoptosis. For two genes, i.e. CTCF and CACNB2, evidence for association with schizophrenia was available (at the gene-level) in both the discovery study and published data from the Psychiatric Genomics Consortium schizophrenia study. Furthermore, these genes mapped to four of the 14 presently identified pathways. Several of the SNPs assigned to CTCF and CACNB2 have potential functional consequences, and a gene in close proximity to CACNB2, i.e. ARL5B, was identified as a potential gene of interest. Application of the present hierarchical approach thus allowed: (1) identification of novel biological gene-sets or pathways with potential involvement in the etiology of schizophrenia, as well as replication of these findings in an independent cohort; (2) detection of genes of interest for future follow-up studies; and (3) the highlighting of novel genes in previously reported candidate regions for schizophrenia.
    Type of Publication: Journal article published
    PubMed ID: 24901509
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  • 5
    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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  • 6
    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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  • 7
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; SURVIVAL ; tumor ; CELL ; Germany ; IN-VIVO ; VITRO ; VIVO ; GENE ; transcription ; cell line ; TISSUE ; TUMORS ; LINES ; PATIENT ; ACTIVATION ; TRANSCRIPTION FACTOR ; MARKER ; REDUCTION ; TISSUES ; CELL-LINES ; NO ; AMPLIFICATION ; COPY NUMBER ; ASSAY ; NUMBER ; RATES ; CELL-LINE ; chemotherapy ; LINE ; MELANOMA ; METASTATIC MELANOMA ; PCR ; ONCOGENE ; MALIGNANT-MELANOMA ; MELANOMA PATIENTS ; real-time PCR ; cell lines ; ONCOLOGY ; RE ; PATIENT SURVIVAL ; chemosensitivity ; LINEAGE ; REAL-TIME ; TUMOR TISSUE ; biomarker ; analysis ; methods ; USA ; correlation ; cancer research ; in vivo ; LINEAGE SURVIVAL ; MITF ; quantitative ; MELANOMAS ; LUMINESCENCE ; chemotherapeutics ; MASTER REGULATOR
    Abstract: Purpose: The microphthalmia-associated transcription factor (MITF) is regarded as a key oncogene of the melanocytic lineage since it was detected by a genome-wide analysis to be strongly amplified in 15% to 20% of metastatic melanomas. MITF gene amplification was shown to be associated with a reduced survival in metastatic melanoma patients, and reduction of MITF activity was shown to sensitize melanoma cell lines to chemotherapeutics, suggesting the intratumoral MITF gene copy number as a predictive biomarker of response and survival after chemotherapy. Patients and Methods: To validate this hypothesis, we investigated MITF gene amplification in tumor tissues obtained from 116 metastatic melanoma patients before an individualized sensitivity-directed chemotherapy using quantitative real-time PCR. MITF amplification rates were correlated with tumor chemosensitivity quantified by an ATP-based luminescence assay and with chemotherapy outcome in terms of response and survival. Results: Of 116 tumor tissues, 104 were evaluable for MITF gene amplification. Strong amplification (〉= 4 copies per cell) was detected in 24 of 104 tissues (23%), whereas 62 of 104 tissues (60%) harbored 〉3 copies per cell. Strong MITF gene amplification was associated with a reduced disease-specific survival (P = 0.031). However, no correlation was found between MITF copy number and in vitro chemosensitivity or in vivo chemotherapy response. Conclusion: Our findings suggest that strong amplifications of the melanoma oncogene MITF affects patient survival but does not influence tumor chemosensitivity and chemotherapy response. Thus, the MITF gene copy number seems a useful prognostic marker in metastatic melanoma but could not be confirmed as a predictive marker of chemosensitivity and chemotherapy response
    Type of Publication: Journal article published
    PubMed ID: 17975146
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  • 8
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; INVASION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; SITE ; SITES ; GENE ; GENES ; transcription ; COMPONENTS ; MOLECULES ; TISSUE ; MECHANISM ; FAMILY ; TRANSCRIPTION FACTOR ; IMPACT ; CARCINOGENESIS ; INDUCTION ; mechanisms ; BINDING ; SIGNAL ; MOLECULE ; ALPHA ; cytokines ; TARGET ; DELETION ; CHROMATIN ; PROMOTER ; MEMBRANE ; PROMOTERS ; MUTATION ; inactivation ; DERIVATIVES ; REGION ; CANCER-CELLS ; REGIONS ; MUTATIONS ; BETA ; SUPERFAMILY ; GROWTH-FACTOR-BETA ; TRANSCRIPTIONAL REGULATION ; GAMMA-2 CHAIN ; CYTOKINE ; molecular ; ONCOLOGY ; FAMILIES ; TUMOR SUPPRESSION ; TUMOR-SUPPRESSOR ; basement membrane ; TRANSFECTION ; TGF-BETA ; interaction ; MOLECULAR-MECHANISMS ; methods ; SUPPRESSOR ; TGF beta ; SIGNALS ; COLON-CARCINOMA CELLS ; BARRIER ; ENGLAND ; UPSTREAM ; response ; synthesis ; Smad4 ; SUPPRESSOR E-CADHERIN ; chromatin immunoprecipitation ; tumor suppressor ; FUNCTIONAL INACTIVATION ; BINDING SITE ; ACTIVATOR PROTEIN-1 ; AP-1 COMPLEX
    Abstract: Background: Functional inactivation of the tumor suppressor Smad4 in colorectal and pancreatic carcinogenesis occurs coincident with the transition to invasive growth. Breaking the basement membrane ( BM) barrier, a prerequisite for invasive growth, can be due to tumor induced proteolytic tissue remodeling or to reduced synthesis of BM molecules by incipient tumor cells. Laminin-332 (laminin-5), a heterotrimeric BM component composed of alpha 3-, beta 3- and gamma 2-chains, has recently been identified as a target structure of Smad4 and represents the first example for expression control of an essential BM component by a tumor and invasion suppressor. Biochemically Smad4 is a transmitter of signals of the TGF beta superfamily of cytokines. We have reported previously, that Smad4 functions as a positive transcriptional regulator of constitutive and of TGF beta-induced transcription of all three genes encoding Laminin-332, LAMA3, LAMB3 and LAMC2. Methods: Promoter-reporter constructs harboring 4 kb upstream regions, each of the three genes encoding Laminin-322 as well as deletion and mutations constructs were established. Promoter activities and TGF beta induction were assayed through transient transfections in Smad4-negative human cancer cells and their stable Smad4-positive derivatives. Functionally relevant binding sites were subsequently confirmed through chromatin immunoprecipitation. Results: Herein, we report that Smad4 mediates transcriptional regulation through three different mechanisms, namely through Smad4 binding to a functional SBE site exclusively in the LAMA3 promoter, Smad4 binding to AP1 (and Sp1) sites presumably via interaction with AP1 family components and lastly a Smad4 impact on transcription of AP1 factors. Whereas Smad4 is essential for positive regulation of all three genes, the molecular mechanisms are significantly divergent between the LAMA3 promoter as compared to the LAMB3 and LAMC2 promoters. Conclusion: We hypothesize that this divergence in modular regulation of the three promoters may lay the ground for uncoupled regulation of Laminin-332 in Smad4-deficient tumor cells in response to stromally expressed cytokines acting on budding tumor cells
    Type of Publication: Journal article published
    PubMed ID: 18664273
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  • 9
    Keywords: EXPRESSION ; SURVIVAL ; carcinoma ; CELL ; Germany ; CLASSIFICATION ; DIAGNOSIS ; FOLLOW-UP ; RISK ; SITE ; SITES ; GENES ; PROTEIN ; TISSUE ; TUMORS ; PATIENT ; IMPACT ; IDENTIFICATION ; REGION ; RECURRENCE ; REGIONS ; SQUAMOUS-CELL CARCINOMA ; HEAD ; NECK ; pathology ; relapse ; PROTEOMICS ; PROTEOMIC ANALYSIS ; NECK-CANCER ; CELL CARCINOMA ; ONCOLOGY ; HNSCC ; PROFILES ; prospective ; SELDI-TOF-MS ; SQUAMOUS-CELL ; PROFILE ; field cancerization ; tumours ; HEAD-AND-NECK ; Follow up ; proteomic ; biomarker protein profiles ; CHROMOSOME-17 ; ORAL EPITHELIAL DYSPLASIA ; pharynx and oesophagus carcinoma
    Abstract: 'Field cancerization' in head and neck squamous cell carcinoma (HNSCC) is poorly understood and it may extend from the pharynx into the oesophagus. Both local recurrences and second primary carcinomas/second field tumours may originate from field cancerization. Our prospective pilot study aimed at the identification of patients suffering from field cancerization on the basis of mucosal protein profiles. Five mucosal biopsies from the oropharynx, hypopharynx and from three regions of the oesophagus were taken from 24 patients. Protein profiles were generated from the mucosal biopsies. After classifier learning, using the profiles of the patients without tumour diagnosis (n = 9), we were able to discriminate between the different mucosal sites and between healthy mucosa and HNSCC using tumour and healthy tissue samples. Mucosal biopsies of tumour patients (n = 15) revealed changes in the protein profiles similar to those in the tumours. During 42 months median follow-up, six tumour patients experienced local recurrences and second field tumours, of which three occurred in the oesophagus. In all six cases, tumour relapse was correctly predicted by altered mucosal protein profiles (p = 0.007, Fisher's exact test, two-tailed). Consequently, molecular field cancerization had a strong impact on progression-free survival (p = 0.007, log-rank test). Protein profiles of small diagnostic biopsies hold great promise to improve personalized risk assessment in HNSCC. Larger studies are needed to further substantiate these findings. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
    Type of Publication: Journal article published
    PubMed ID: 20593486
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  • 10
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; SITES ; GENE-EXPRESSION ; cell line ; DIFFERENTIATION ; NEUROBLASTOMA-CELLS ; CLEAVAGE ; AMPLIFICATION ; REGIONS ; DNA-DAMAGE ; REVEALS ; TUMOR-SUPPRESSOR ; senescence ; miRNA ; 3p25.3 ; p53 stabilization
    Abstract: Several microRNA (miRNA) loci are found within genomic regions frequently deleted in primary neuroblastoma, including miR-885-5p at 3p25.3. In this study, we demonstrate that miR-885-5p is downregulated on loss of 3p25.3 region in neuroblastoma. Experimentally enforced miR-885-5p expression in neuroblastoma cell lines inhibits proliferation triggering cell cycle arrest, senescence and/or apoptosis. miR-885-5p leads to the accumulation of p53 protein and activates the p53 pathway, resulting in upregulation of p53 targets. Enforced miR-885-5p expression consistently leads to downregulation of cyclin-dependent kinase (CDK2) and mini-chromosome maintenance protein (MCM5). Both genes are targeted by miR-885-5p via predicted binding sites within the 3'-untranslated regions (UTRs) of CDK2 and MCM5. Transcript profiling after miR-885-5p introduction in neuroblastoma cells reveals alterations in expression of multiple genes, including several p53 target genes and a number of factors involved in p53 pathway activity. Taken together, these data provide evidence that miR-885-5p has a tumor suppressive role in neuroblastoma interfering with cell cycle progression and cell survival.
    Type of Publication: Journal article published
    PubMed ID: 21233845
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