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  • 11
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    Keywords: Germany ; TOOL ; GENE ; GENES ; microarray ; SACCHAROMYCES-CEREVISIAE ; transcription ; COMPLEX ; COMPLEXES ; IDENTIFICATION ; MICROARRAY DATA ; NUMBER ; COLORECTAL-CANCER ; adenocarcinoma ; CLUSTER ; SINGLE ; GENE ONTOLOGY
    Abstract: Motivation: The functional interpretation of microarray datasets still represents a time-consuming and challenging task. Up to now functional categories that are relevant for one or more experimental context(s) have been commonly extracted from a set of regulated genes and presented in long lists. Results: To facilitate interpretation, we integrated Gene Ontology (GO) annotations into Correspondence Analysis to display genes, experimental conditions and gene-annotations in a single plot. The position of the annotations in these plots can be directly used for the functional interpretation of clusters of genes or experimental conditions without the need for comparing long lists of annotations. Correspondence Analysis is not limited in the number of experimental conditions that can be compared simultaneously, allowing an easy identification of characterizing annotations even in complex experimental settings. Due to the rapidly increasing amount of annotation data available, we apply an annotation filter. Hereby the number of displayed annotations can be significantly reduced to a set of descriptive ones, further enhancing the interpretability of the plot. We validated the method on transcription data from Saccharomyces cerevisiae and human pancreatic adenocarcinomas
    Type of Publication: Journal article published
    PubMed ID: 15746280
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  • 13
    Keywords: EXPRESSION ; GROWTH ; CELL ; Germany ; PATHWAY ; GENE ; GENES ; GENOME ; PROTEIN ; METABOLISM ; LINES ; REDUCTION ; BIOLOGY ; METABOLITES ; ACID ; IDENTIFICATION ; PROMOTER ; LINE ; REGION ; ARABIDOPSIS-THALIANA ; SCIENCE ; GENE FAMILY ; development ; SULFUR METABOLISM ; OXIDASE ; CELL BIOLOGY ; SYNTHASE PROTEIN COMPLEX ; Type ; 5'-ADENYLYLSULFATE REDUCTASE ; GLUTAMATE-CYSTEINE LIGASE ; GLUTATHIONE BIOSYNTHESIS ; SERINE ACETYLTRANSFERASE ; TRANSGENIC PLANTS
    Abstract: The role of sulfite reductase (SiR) in assimilatory reduction of inorganic sulfate to sulfide has long been regarded as insignificant for control of flux in this pathway. Two independent Arabidopsis thaliana T-DNA insertion lines (sir1-1 and sir1-2), each with an insertion in the promoter region of SiR, were isolated. sir1-2 seedlings had 14% SiR transcript levels compared with the wild type and were early seedling lethal. sir1-1 seedlings had 44% SiR transcript levels and were viable but strongly retarded in growth. In mature leaves of sir1-1 plants, the levels of SiR transcript, protein, and enzymatic activity ranged between 17 and 28% compared with the wild type. The 28-fold decrease of incorporation of S-35 label into Cys, glutathione, and protein in sir1-1 showed that the decreased activity of SiR generated a severe bottleneck in the assimilatory sulfate reduction pathway. Root sulfate uptake was strongly enhanced, and steady state levels of most of the sulfur-related metabolites, as well as the expression of many primary metabolism genes, were changed in leaves of sir1-1. Hexose and starch contents were decreased, while free amino acids increased. Inorganic carbon, nitrogen, and sulfur composition was also severely altered, demonstrating strong perturbations in metabolism that differed markedly from known sulfate deficiency responses. The results support that SiR is the only gene with this function in the Arabidopsis genome, that optimal activity of SiR is essential for normal growth, and that its downregulation causes severe adaptive reactions of primary and secondary metabolism
    Type of Publication: Journal article published
    PubMed ID: 20424176
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  • 14
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; GROWTH ; proliferation ; MICROSCOPY ; PATHWAY ; NETWORK ; DEATH ; GENE-EXPRESSION ; ACTIVATION ; IDENTIFICATION ; MITOCHONDRIA ; pancreatic cancer ; unfolded protein response ; endoplasmic reticulum stress ; ENDOPLASMIC-RETICULUM-STRESS ; GARCINOL ; HYPERFORIN ; mitochondrial membrane potential ; nemorosone ; polycyclic polyprenylated acylphloroglucinols ; ST-JOHNS-WORT ; THAPSIGARGIN
    Abstract: BACKGROUND AND PURPOSE Pancreatic cancer is one of the leading cancer-related causes of death due to high chemo-resistance and fast metastasation. Nemorosone, a polycyclic polyprenylated acylphloroglucinol, has recently been identified as a promising anticancer agent. Here, we examine its growth-inhibitory effects on pancreatic cancer cells. Based on transcription profiling, a molecular mode of action is proposed. EXPERIMENTAL APPROACH Nemorosone cytotoxicity was assessed by the resazurin proliferation assay on pancreatic cancer cells and fibroblasts. Apoptosis was determined by Annexin V/propidium iodide staining as well as cytochrome c and caspase activation assays. Staining with the voltage-dependent dye JC-1 and fluorescence microscopy were used to detect effects on mitochondrial membrane potential. Total RNA was isolated from treated cell lines and subjected to microarray analysis, subsequent pathway identification and modelling. Gene expression data were validated by quantitative polymerase chain reaction and siRNA-mediated gene knock-down. KEY RESULTS Nemorosone significantly inhibited cancer cell growth, induced cytochrome c release and subsequent caspase-dependent apoptosis, rapidly abolished mitochondrial membrane potential and elevated cytosolic calcium levels, while fibroblasts were largely unaffected. Expression profiling revealed 336 genes to be affected by nemorosone. A total of 75 genes were altered in all three cell lines, many of which were within the unfolded protein response (UPR) network. DNA damage inducible transcript 3 was identified as a key regulator in UPR-mediated cell death. CONCLUSIONS AND IMPLICATIONS Nemorosone could be a lead compound for the development of novel anticancer drugs amplifying the already elevated UPR level in solid tumours, thus driving them into apoptosis. This study forms the basis for further investigations identifying nemorosone's direct molecular target(s)
    Type of Publication: Journal article published
    PubMed ID: 21091652
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  • 15
    Keywords: EXPRESSION ; IN-VIVO ; THERAPY ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; PROTEIN ; DNA ; INFECTION ; cell cycle ; CELL-CYCLE ; IDENTIFICATION ; MICROARRAY DATA ; VECTOR ; CANCER-CELLS ; ORIGIN ; COMPETENT ADENOVIRUS ; E1A
    Abstract: Adenoviruses (Ads), especially HAdV-5, have been genetically equipped with tumor-restricted replication potential to enable applications in oncolytic cancer therapy. Such oncolytic adenoviruses have been well tolerated in cancer patients, but their anti-tumor efficacy needs to be enhanced. In this regard, it should be considered that cancer cells, dependent on their tissue of origin, can differ substantially from the normal host cells to which Ads are adapted by complex virus-host interactions. Consequently, viral replication efficiency, a key determinant of oncolytic activity, might be suboptimal in cancer cells. Therefore, we have analyzed both the replication kinetics of HAdV-5 and the virus-induced transcriptome in human bronchial epithelial cells (HBEC) in comparison to cancer cells. This is the first report on genome-wide expression profiling of Ads in their native host cells. We found that E1A expression and onset of viral genome replication are most rapid in HBEC and considerably delayed in melanoma cells. In squamous cell lung carcinoma cells, we observed intermediate HAdV-5 replication kinetics. Infectious particle production, viral spread and lytic activity of HAdV-5 were attenuated in melanoma cells versus HBEC. Expression profiling at the onset of viral genome replication revealed that HAdV-5 induced the strongest changes in the cellular transcriptome in HBEC, followed by lung cancer and melanoma cells. We identified prominent regulation of genes involved in cell cycle and DNA metabolism, replication and packaging in HBEC, which is in accord with the necessity to induce S phase for viral replication. Strikingly, in melanoma cells HAdV-5 triggered opposing regulation of said genes and, in contrast to lung cancer cells, no weak S phase induction was detected when using the E2F promoter as reporter. Our results provide a rationale for improving oncolytic adenoviruses either by adaptation of viral infection to target tumor cells or by modulating tumor cell functions to better support viral replication
    Type of Publication: Journal article published
    PubMed ID: 22140489
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  • 16
    Keywords: EXPRESSION ; GENE ; ACTIVATION ; KAPPA-B ; REVEALS ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; TRAIL-INDUCED APOPTOSIS ; PANCREATIC-CANCER ; molecular diagnostics ; CLINICAL PROTEOMICS
    Abstract: PurposeIn this study, plasma samples from a multicentric case-control study on lymphoma were analyzed for the identification of proteins useful for diagnosis. Experimental designThe protein content in the plasma of 100 patients suffering from the three most common B-cell lymphomas and 100 control samples was studied with antibody microarrays composed of 810 antibodies that target cancer-associated proteins. Sample pools were screened for an identification of marker proteins. Then, the samples were analyzed individually to validate the usability of these markers. ResultsMore than 200 proteins with disease-associated abundance changes were found. The evaluation on individual patients confirmed some molecules as robust informative markers while others were inadequate for this purpose. In addition, the analysis revealed distinct subgroups for each of the three investigated B-cell lymphoma subtypes. With this information, we delineated a classifier that discriminates the different lymphoma entities. Conclusions and clinical relevanceVariations in plasma protein abundance permit discrimination between different patient groups. After validation on a larger study cohort, the findings could have diagnostic as well as differential diagnostic potential. Beside this, methodological aspects were critically evaluated, such as the value of sample pooling for the identification of biomarkers that are useful for a diagnosis on individual patients.
    Type of Publication: Journal article published
    PubMed ID: 24323458
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  • 17
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; SURVIVAL ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; PATHWAY ; PATHWAYS ; THERAPY ; VITRO ; COMMON ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; microarray ; LINES ; ACTIVATION ; MECHANISM ; prognosis ; mechanisms ; CELL-LINES ; DNA TOPOISOMERASE-II ; gene expression ; MICROARRAY DATA ; ASSAY ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; CANCER-CELLS ; POOR-PROGNOSIS ; FLOW-CYTOMETRY ; cell lines ; expression profiling ; pancreatic cancer ; DISSECTION ; signaling ; AGENT ; PANCREATIC-CANCER ; THERAPIES ; CANDIDATE GENES ; RIBONUCLEOTIDE REDUCTASE ; artemisinin ; artesunate ; ANTIMALARIAL ARTESUNATE ; pharmacology ; FALCIPARUM-MALARIA ; anti-tumor activity ; therapeutic ; CANCER-CELL-LINES ; FUNCTIONAL-ROLE ; CLINICAL BENEFIT ; Ingenuity Pathway Analysis ; Topoisomerase
    Abstract: Pancreatic cancer is one of the most aggressive human malignancies, with an extremely poor prognosis. The paucity of curative therapies has translated into an overall 5-year survival rate of less than 5%, underscoring a desperate need for new therapeutic options. Artesunate (ART), clinically used as antimalarial agent, has recently revealed remarkable anti-tumor activity. However, the mechanisms underlying those activities in pancreatic cancer are not yet known. Here we evaluated the anti-tumor activity of Artesunate and the possible underlying mechanisms in pancreatic cancer. MiaPaCa-2 (poorly differentiated) and BxPC-3 (moderately differentiated) pancreatic cancer cell lines were treated with Artesunate and the effect was monitored by a tetrazolium-based assay (MTS) for evaluating cell viability and by flow cytometry and caspase 3/7 activation for apoptosis evaluation. In addition cDNA arrays were used to identify differentially expressed genes. The microarray data were then validated by RT-PCR and Western blotting. Moreover, pathways associated with these expression changes were identified using the Ingenuity Pathway Analysis. The expression analysis identified a common set of genes that were regulated by Artesunate in pancreatic cancer. Our results provide the first in vitro evidence for the therapeutic utility of Artesunate in pancreatic cancer. Moreover, we identified Artesunate as a novel topoisomerase Hot inhibitor that inhibits pancreatic cancer growth through modulation of multiple signaling pathways. The present analysis is a starting point for the generation of hypotheses on candidate genes and for a more detailed dissection of the functional role of individual genes for the activity of Artesunate in tumor cells. (C) 2009 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19393226
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  • 18
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    Keywords: CANCER ; Germany ; ALGORITHM ; INFORMATION ; GENE ; GENES ; microarray ; validation ; MOTIFS ; BIOLOGY ; CELL-CYCLE ; SEQUENCE ; MICROARRAY DATA ; ARRAYS ; NUMBER ; DATABASE ; B-CELLS ; SCIENCE ; METAANALYSIS ; methods ; PROFILES ; STEM ; Species ; PROBABILITIES ; CO-INERTIA ANALYSIS ; EXPRESSION DATA ; SISTER-CHROMATID COHESION
    Abstract: Motivation: Cross-species meta-analyses of microarray data usually require prior affiliation of genes based on orthology information that often relies on sequence similarity. Results: We present an algorithm merging microarray datasets on the basis of co-expression alone, without any requirement for orthology information to affiliate genes. Combining existing methods such as co-inertia analysis, back-transformation, Hungarian matching and majority voting in an iterative non-greedy hill-climbing approach, it affiliates arrays and genes at the same time, maximizing the co-structure between the datasets. To introduce the method, we demonstrate its performance on two closely and two distantly related datasets of different experimental context and produced on different platforms. Each pair stems from two different species. The resulting cross-species dynamic Bayesian gene networks improve on the networks inferred from each dataset alone by yielding more significant network motifs, as well as more of the interactions already recorded in KEGG and other databases. Also, it is shown that our algorithm converges on the optimal number of nodes for network inference. Being readily extendable to more than two datasets, it provides the opportunity to infer extensive gene regulatory networks
    Type of Publication: Journal article published
    PubMed ID: 20200011
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  • 20
    Abstract: BACKGROUND: Up to now, microarray data are mostly assessed in context with only one or few parameters characterizing the experimental conditions under study. More explicit experiment annotations, however, are highly useful for interpreting microarray data, when available in a statistically accessible format. RESULTS: We provide means to preprocess these additional data, and to extract relevant traits corresponding to the transcription patterns under study. We found correspondence analysis particularly well-suited for mapping such extracted traits. It visualizes associations both among and between the traits, the hereby annotated experiments, and the genes, revealing how they are all interrelated. Here, we apply our methods to the systematic interpretation of radioactive (single channel) and two-channel data, stemming from model organisms such as yeast and drosophila up to complex human cancer samples. Inclusion of technical parameters allows for identification of artifacts and flaws in experimental design. CONCLUSION: Biological and clinical traits can act as landmarks in transcription space, systematically mapping the variance of large datasets from the predominant changes down toward intricate details.
    Type of Publication: Journal article published
    PubMed ID: 17181856
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