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  • 1
    Keywords: DISEASE ; METABOLISM ; ALPHA ; ACID ; inactivation ; DIFFERENTIAL EXPRESSION ; 5-LIPOXYGENASE ; MOLECULAR-MECHANISMS ; prostaglandins ; NONALCOHOLIC FATTY LIVER
    Abstract: BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has a broad spectrum of disease states ranging from mild steatosis characterized by an abnormal retention of lipids within liver cells to steatohepatitis (NASH) showing fat accumulation, inflammation, ballooning and degradation of hepatocytes, and fibrosis. Ultimately, steatohepatitis can result in liver cirrhosis and hepatocellular carcinoma. METHODOLOGY AND RESULTS: In this study we have analyzed three different mouse strains, A/J, C57BL/6J, and PWD/PhJ, that show different degrees of steatohepatitis when administered a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) containing diet. RNA-Seq gene expression analysis, protein analysis and metabolic profiling were applied to identify differentially expressed genes/proteins and perturbed metabolite levels of mouse liver samples upon DDC-treatment. Pathway analysis revealed alteration of arachidonic acid (AA) and S-adenosylmethionine (SAMe) metabolism upon other pathways. To understand metabolic changes of arachidonic acid metabolism in the light of disease expression profiles a kinetic model of this pathway was developed and optimized according to metabolite levels. Subsequently, the model was used to study in silico effects of potential drug targets for steatohepatitis. CONCLUSIONS: We identified AA/eicosanoid metabolism as highly perturbed in DDC-induced mice using a combination of an experimental and in silico approach. Our analysis of the AA/eicosanoid metabolic pathway suggests that 5-hydroxyeicosatetraenoic acid (5-HETE), 15-hydroxyeicosatetraenoic acid (15-HETE) and prostaglandin D2 (PGD2) are perturbed in DDC mice. We further demonstrate that a dynamic model can be used for qualitative prediction of metabolic changes based on transcriptomics data in a disease-related context. Furthermore, SAMe metabolism was identified as being perturbed due to DDC treatment. Several genes as well as some metabolites of this module show differences between A/J and C57BL/6J on the one hand and PWD/PhJ on the other.
    Type of Publication: Journal article published
    PubMed ID: 25347188
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  • 2
    Keywords: CELLS
    Abstract: A sudden increase in pentose phosphate pathway (PPP) activity, the fastest known cellular response to oxidative stress, protects cells through timely generation of NADPH. Originally discovered in budding yeast, Kuehne and colleagues demonstrate the conservation of this mechanism in human cells and reveal its importance for skin cells exposed to UV light.
    Type of Publication: Journal article published
    PubMed ID: 26295959
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  • 3
    Abstract: Human susceptibility to obesity is mainly genetic, yet the underlying evolutionary drivers causing variation from person to person are not clear. One theory rationalizes that populations that have adapted to warmer climates have reduced their metabolic rates, thereby increasing their propensity to store energy. We uncover here the function of a gene that supports this theory. THADA is one of the genes most strongly selected during evolution as humans settled in different climates. We report here that THADA knockout flies are obese, hyperphagic, have reduced energy production, and are sensitive to the cold. THADA binds the sarco/ER Ca2+ ATPase (SERCA) and acts on it as an uncoupler. Reducing SERCA activity in THADA mutant flies rescues their obesity, pinpointing SERCA as a key effector of THADA function. In sum, this identifies THADA as a regulator of the balance between energy consumption and energy storage, which was selected during human evolution.
    Type of Publication: Journal article published
    PubMed ID: 28399403
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  • 4
    Keywords: EXPRESSION ; GENE ; DIFFERENTIATION ; IDENTIFICATION ; EMBRYONIC STEM-CELLS ; HYPERMETHYLATION ; SUPPRESSOR ; methylome ; CANCER GENOME ; CPG ISLAND SHORES
    Abstract: Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.
    Type of Publication: Journal article published
    PubMed ID: 24847876
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  • 5
    Keywords: SIGNAL-TRANSDUCTION ; ACUTE MYELOID-LEUKEMIA ; NEURAL STEM-CELLS ; DISTINCT SUBGROUPS ; ONCOGENIC MUTATIONS ; MAPK PATHWAY ACTIVATION ; HUMAN GLIOBLASTOMA ; NOONAN-SYNDROME ; MUTATIONAL PROCESSES ; CANCER GENOMES
    Abstract: Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.
    Type of Publication: Journal article published
    PubMed ID: 23817572
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  • 6
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    Nature Publishing Group (NPG)
    Publication Date: 2011-12-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gruning, Nana-Maria -- Ralser, Markus -- England -- Nature. 2011 Dec 7;480(7376):190-1. doi: 10.1038/480190a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22158241" target="_blank"〉PubMed〈/a〉
    Keywords: Anaerobiosis ; Cell Respiration ; Cell Survival ; Disease Progression ; Glycolysis ; Humans ; Lactic Acid/metabolism ; Neoplasms/drug therapy/enzymology/*metabolism/*pathology ; Oxidative Stress ; Pentose Phosphate Pathway ; Pyruvate Kinase/metabolism ; Pyruvic Acid/metabolism ; Reactive Oxygen Species/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2014-05-23
    Description: Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hovestadt, Volker -- Jones, David T W -- Picelli, Simone -- Wang, Wei -- Kool, Marcel -- Northcott, Paul A -- Sultan, Marc -- Stachurski, Katharina -- Ryzhova, Marina -- Warnatz, Hans-Jorg -- Ralser, Meryem -- Brun, Sonja -- Bunt, Jens -- Jager, Natalie -- Kleinheinz, Kortine -- Erkek, Serap -- Weber, Ursula D -- Bartholomae, Cynthia C -- von Kalle, Christof -- Lawerenz, Chris -- Eils, Jurgen -- Koster, Jan -- Versteeg, Rogier -- Milde, Till -- Witt, Olaf -- Schmidt, Sabine -- Wolf, Stephan -- Pietsch, Torsten -- Rutkowski, Stefan -- Scheurlen, Wolfram -- Taylor, Michael D -- Brors, Benedikt -- Felsberg, Jorg -- Reifenberger, Guido -- Borkhardt, Arndt -- Lehrach, Hans -- Wechsler-Reya, Robert J -- Eils, Roland -- Yaspo, Marie-Laure -- Landgraf, Pablo -- Korshunov, Andrey -- Zapatka, Marc -- Radlwimmer, Bernhard -- Pfister, Stefan M -- Lichter, Peter -- England -- Nature. 2014 Jun 26;510(7506):537-41. doi: 10.1038/nature13268. Epub 2014 May 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2]. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2]. ; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany. ; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Dusseldorf, Moorenstrasse 5, Dusseldorf 40225, Germany. ; Department of Neuropathology, NN Burdenko Neurosurgical Institute, 4th Tverskaya-Yamskaya 16, Moscow 125047, Russia. ; Tumor Initiation and Maintenance Program, National Cancer Institute (NCI)-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 2880 Torrey Pines Scenic Drive, La Jolla, California 92037, USA. ; 1] Queensland Brain Institute, University of Queensland, QBI Building, St Lucia, Queensland 4072, Australia [2] Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands. ; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, Heidelberg 69117, Germany. ; 1] Division of Translational Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany. ; Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands. ; 1] Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany [2] Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, Bonn 53105, Germany. ; Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany. ; Cnopf'sche Kinderklinik, Nurnberg Children's Hospital, St.-Johannis-Muhlgasse 19, Nurnberg 90419, Germany. ; 1] Program in Developmental and Stem Cell Biology, The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada [2] Division of Neurosurgery, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada [3] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; 1] Department of Neuropathology, Heinrich Heine University Dusseldorf, Moorenstrasse 5, Dusseldorf 40225, Germany [2] German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Institute of Pharmacy and Molecular Biotechnology (IPMB), University of Heidelberg, Heidelberg 69120, Germany [3] Bioquant Center, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg 69120, Germany [4] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] Department of Neuropathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany [2] Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 220-221, Heidelberg, 69120 Germany. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany. ; 1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24847876" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Cell Line, Tumor ; Chromatin/genetics/metabolism ; Chromatin Immunoprecipitation ; DNA Methylation/*genetics ; Female ; *Gene Expression Regulation, Neoplastic ; *Gene Silencing ; Genome/genetics ; Histones/metabolism ; Humans ; Medulloblastoma/*genetics/pathology ; Mice ; Promoter Regions, Genetic/genetics ; RNA-Binding Proteins/genetics ; Sequence Analysis, DNA/*methods ; Transcription Factors/metabolism ; Transcription, Genetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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