To Örebro University

oru.seÖrebro University Publications
Change search
Refine search result
1234567 1 - 50 of 340
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Aho, Vilma
    et al.
    Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Ollila, Hanna M
    Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Genomics and Biomarkers Unit, Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland; Department of Psychiatry, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; Stanford University Center for Sleep Sciences, Palo Alto CA, United States.
    Kronholm, Erkki
    Department of Chronic Disease Prevention, Population Studies Unit, National Institute for Health and Welfare, Turku, Finland.
    Bondia-Pons, Isabel
    VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Soininen, Pasi
    Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
    Kangas, Antti J
    Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland.
    Hilvo, Mika
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Seppälä, Ilkka
    Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, School of Medicine, Tampere, Finland.
    Kettunen, Johannes
    Genomics and Biomarkers Unit, Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland; Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
    Oikonen, Mervi
    Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
    Raitoharju, Emma
    Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, School of Medicine, Tampere, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Kähönen, Mika
    Department of Clinical Physiology, University of Tampere, Tampere University Hospital, Tampere, Finland.
    Viikari, Jorma S A
    Department of Medicine, University of Turku, Turku, Finland; Division of Medicine, Turku University Hospital, Turku, Finland.
    Härmä, Mikko
    Brain and Work Research Centre, Finnish Institute of Occupational Health, Helsinki, Finland.
    Sallinen, Mikael
    Brain and Work Research Centre, Finnish Institute of Occupational Health, Helsinki, Finland; Agora Center, University of Jyväskylä, Jyväskylä, Finland.
    Olkkonen, Vesa M
    Minerva Foundation Institute for Medical Research, Helsinki, Finland; Institute of Biomedicine, Anatomy, University of Helsinki, Helsinki, Finland.
    Alenius, Harri
    Unit of Excellence for Immunotoxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
    Jauhiainen, Matti
    Genomics and Biomarkers Unit, Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland.
    Paunio, Tiina
    Genomics and Biomarkers Unit, Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland; Department of Psychiatry, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    Lehtimäki, Terho
    Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, School of Medicine, Tampere, Finland.
    Salomaa, Veikko
    Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
    Orešič, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Raitakari, Olli T
    Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
    Ala-Korpela, Mika
    Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland; Oulu University Hospital, Oulu, Finland; Computational Medicine, School of Social and Community Medicine, Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
    Porkka-Heiskanen, Tarja
    Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses2016In: Scientific Reports, E-ISSN 2045-2322, Vol. 6, article id 24828Article in journal (Refereed)
    Abstract [en]

    Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases.

  • 2.
    Ahola-Erkkilä, Sofia
    et al.
    Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Carroll, Christopher J.
    Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Peltola-Mjösund, Katja
    Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Tulkki, Valtteri
    Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Tyynismaa, Henna
    Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
    Suomalainen, Anu
    Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Department of Neurology, Helsinki, University Central Hospital, Helsinki, Finland.
    Ketogenic diet slows down mitochondrial myopathy progression in mice2010In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 10, p. 1974-1984Article in journal (Refereed)
    Abstract [en]

    Mitochondrial dysfunction is a major cause of neurodegenerative and neuromuscular diseases of adult age and of multisystem disorders of childhood. However, no effective treatment exists for these progressive disorders. Cell culture studies suggested that ketogenic diet (KD), with low glucose and high fat content, could select against cells or mitochondria with mutant mitochondrial DNA (mtDNA), but proper patient trials are still lacking. We studied here the transgenic Deletor mouse, a disease model for progressive late-onset mitochondrial myopathy, accumulating mtDNA deletions during aging and manifesting subtle progressive respiratory chain (RC) deficiency. We found that these mice have widespread lipidomic and metabolite changes, including abnormal plasma phospholipid and free amino acid levels and ketone body production. We treated these mice with pre-symptomatic long-term and post-symptomatic shorter term KD. The effects of the diet for disease progression were followed by morphological, metabolomic and lipidomic tools. We show here that the diet decreased the amount of cytochrome c oxidase negative muscle fibers, a key feature in mitochondrial RC deficiencies, and prevented completely the formation of the mitochondrial ultrastructural abnormalities in the muscle. Furthermore, most of the metabolic and lipidomic changes were cured by the diet to wild-type levels. The diet did not, however, significantly affect the mtDNA quality or quantity, but rather induced mitochondrial biogenesis and restored liver lipid levels. Our results show that mitochondrial myopathy induces widespread metabolic changes, and that KD can slow down progression of the disease in mice. These results suggest that KD may be useful for mitochondrial late-onset myopathies.

  • 3.
    Ahonen, Linda
    et al.
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Jäntti, Sirkku
    Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Suvitaival, Tommi
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Theilade, Simone
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Risz, Claudia
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Kostiainen, Risto
    Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
    Rossing, Peter
    Steno Diabetes Center Copenhagen, Gentofte, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Targeted Clinical Metabolite Profiling Platform for the Stratification of Diabetic Patients2019In: Metabolites, ISSN 2218-1989, E-ISSN 2218-1989, Vol. 9, no 9, article id E184Article in journal (Refereed)
    Abstract [en]

    Several small molecule biomarkers have been reported in the literature for prediction and diagnosis of (pre)diabetes, its co-morbidities, and complications. Here, we report the development and validation of a novel, quantitative method for the determination of a selected panel of 34 metabolite biomarkers from human plasma. We selected a panel of metabolites indicative of various clinically-relevant pathogenic stages of diabetes. We combined these candidate biomarkers into a single ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method and optimized it, prioritizing simplicity of sample preparation and time needed for analysis, enabling high-throughput analysis in clinical laboratory settings. We validated the method in terms of limits of detection (LOD) and quantitation (LOQ), linearity (R2), and intra- and inter-day repeatability of each metabolite. The method's performance was demonstrated in the analysis of selected samples from a diabetes cohort study. Metabolite levels were associated with clinical measurements and kidney complications in type 1 diabetes (T1D) patients. Specifically, both amino acids and amino acid-related analytes, as well as specific bile acids, were associated with macro-albuminuria. Additionally, specific bile acids were associated with glycemic control, anti-hypertensive medication, statin medication, and clinical lipid measurements. The developed analytical method is suitable for robust determination of selected plasma metabolites in the diabetes clinic.

    Download full text (pdf)
    Targeted Clinical Metabolite Profiling Platform for the Stratification of Diabetic Patients
  • 4.
    Alves, Marina Amaral
    et al.
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Lamichhane, Santosh
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Dickens, Alex
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    McGlinchey, Aidan J
    Örebro University, School of Medical Sciences.
    Ribeiro, Henrique C.
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Sen, Partho
    Örebro University, School of Medical Sciences. Örebro University Hospital. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Wei, Fang
    Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, P. R. China.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Systems biology approaches to study lipidomes in health and disease2021In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1866, no 2, article id 158857Article, review/survey (Refereed)
    Abstract [en]

    Lipids have many important biological roles, such as energy storage sources, structural components of plasma membranes and as intermediates in metabolic and signaling pathways. Lipid metabolism is under tight homeostatic control, exhibiting spatial and dynamic complexity at multiple levels. Consequently, lipid-related disturbances play important roles in the pathogenesis of most of the common diseases. Lipidomics, defined as the study of lipidomes in biological systems, has emerged as a rapidly-growing field. Due to the chemical and functional diversity of lipids, the application of a systems biology approach is essential if one is to address lipid functionality at different physiological levels. In parallel with analytical advances to measure lipids in biological matrices, the field of computational lipidomics has been rapidly advancing, enabling modeling of lipidomes in their pathway, spatial and dynamic contexts. This review focuses on recent progress in systems biology approaches to study lipids in health and disease, with specific emphasis on methodological advances and biomedical applications.

  • 5.
    Andelic, Nada
    et al.
    Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, Institute of Health and Society, Research Centre for Habilitation and Rehabilitation Models and Services (CHARM), University of Oslo, Oslo, Norway.
    Røe, Cecilie
    Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Brunborg, Cathrine
    Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
    Zeldovich, Marina
    Institute of Medical Psychology and Medical Sociology, University Medical Center, Göttingen, Germany.
    Løvstad, Marianne
    Research Department, Sunnaas Rehabilitation Hospital, Bjørnemyr, Norway; Department of Psychology, Faculty of Social Sciences, University of Oslo, Oslo, Norway.
    Løke, Daniel
    Research Department, Sunnaas Rehabilitation Hospital, Bjørnemyr, Norway; Department of Psychology, Faculty of Social Sciences, University of Oslo, Oslo, Norway.
    Borgen, Ida M
    Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Oslo, Norway; Department of Psychology, Faculty of Social Sciences, University of Oslo, Oslo, Norway.
    Voormolen, Daphne C
    Department of Public Health, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
    Howe, Emilie I
    Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Forslund, Marit V
    Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Oslo, Norway.
    Dahl, Hilde M
    Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Child Neurology, Oslo University Hospital, Oslo, Norway.
    von Steinbuechel, Nicole
    Institute of Medical Psychology and Medical Sociology, University Medical Center, Göttingen, Germany.
    Frequency of fatigue and its changes in the first 6 months after traumatic brain injury: results from the CENTER-TBI study2021In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 268, no 1, p. 61-73Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Fatigue is one of the most commonly reported subjective symptoms following traumatic brain injury (TBI). The aims were to assess frequency of fatigue over the first 6 months after TBI, and examine whether fatigue changes could be predicted by demographic characteristics, injury severity and comorbidities.

    METHODS: Patients with acute TBI admitted to 65 trauma centers were enrolled in the study Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI). Subjective fatigue was measured by single item on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), administered at baseline, three and 6 months postinjury. Patients were categorized by clinical care pathway: admitted to an emergency room (ER), a ward (ADM) or an intensive care unit (ICU). Injury severity, preinjury somatic- and psychiatric conditions, depressive and sleep problems were registered at baseline. For prediction of fatigue changes, descriptive statistics and mixed effect logistic regression analysis are reported.

    RESULTS: Fatigue was experienced by 47% of patients at baseline, 48% at 3 months and 46% at 6 months. Patients admitted to ICU had a higher probability of experiencing fatigue than those in ER and ADM strata. Females and individuals with lower age, higher education, more severe intracranial injury, preinjury somatic and psychiatric conditions, sleep disturbance and feeling depressed postinjury had a higher probability of fatigue.

    CONCLUSION: A high and stable frequency of fatigue was found during the first 6 months after TBI. Specific socio-demographic factors, comorbidities and injury severity characteristics were predictors of fatigue in this study.

  • 6.
    Andersen, Gregers Stig Tig
    et al.
    Steno Diabetes Center, Gentofte, Denmark.
    Thybo, Tanja
    Steno Diabetes Center, Gentofte, Denmark.
    Cederberg, Henna
    Department of Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Steno Diabetes Center, Gentofte, Denmark.
    Esteller, Manel B.
    Cancer Epigenetics and Biology Program, Spanish Biomedical Research Centre Network for Epidemiology and Public Health, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Barcelona, Spain.
    Zorzano, Antonio
    Institute for Research in Biomedicine, Barcelona, Spain; Departament de Bioquímica I Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
    Carr, Bernadette M.
    Voluntary Health Insurance Board, Dublin, Ireland.
    Walker, Mark G.
    University of Newcastle-on-Tyne, Newcastle, United Kingdom.
    Cobb, Jeff E.
    Metabolon Inc., Durham NC, United States.
    Clissmann, C.
    Pintail Ltd., Dublin, Ireland.
    O'Gorman, Donal J.
    Centre for Preventive Medicine, School of Health and Human Performance, Dublin City University, Dublin, Ireland.
    Nolan, John J.
    Steno Diabetes Center, Gentofte, Denmark.
    The DEXLIFE study methods: identifying novel candidate biomarkers that predict progression to type 2 diabetes in high risk individuals2014In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 106, no 2, p. 383-389, article id S0168-8227(14)00319-2Article in journal (Refereed)
    Abstract [en]

    The incidence of type 2 diabetes (T2D) is rapidly increasing worldwide and T2D is likely to affect 592 million people in 2035 if the current rate of progression is continued. Today, patients are diagnosed with T2D based on elevated blood glucose, either directly or indirectly (HbA1c). However, the information on disease progression is limited. Therefore, there is a need to identify novel early markers of glucose intolerance that reflect the underlying biology and the overall physiological, metabolic and clinical characteristics of progression towards diabetes. In the DEXLIFE study, several clinical cohorts provide the basis for a series of clinical, physiological and mechanistic investigations in combination with a range of--omic technologies to construct a detailed metabolic profile of high-risk individuals across multiple cohorts. In addition, an exercise and dietary intervention study is conducted, that will assess the impact on both plasma biomarkers and specific functional tissue-based markers. The DEXLIFE study will provide novel diagnostic and predictive biomarkers which may not only effectively detect the progression towards diabetes in high risk individuals but also predict responsiveness to lifestyle interventions known to be effective in the prevention of diabetes.

  • 7.
    Andersson, Linda
    et al.
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Cinato, Mathieu
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Mardani, Ismena
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Miljanovic, Azra
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Arif, Muhammad
    Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, Sweden.
    Koh, Ara
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Precision Medicine, School of Medicine, Sungkyunkwan University (SKKU), Suwon, Republic of Korea.
    Lindbom, Malin
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Laudette, Marion
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Bollano, Entela
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Omerovic, Elmir
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Klevstig, Martina
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Henricsson, Marcus
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Fogelstrand, Per
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Swärd, Karl
    Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Ekstrand, Matias
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Levin, Max
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Wikström, Johannes
    Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Doran, Stephen
    Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Sinisalu, Lisanna
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku, Turku, Finland.
    Tivesten, Åsa
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Adiels, Martin
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Bergo, Martin O.
    Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden.
    Proia, Richard
    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA.
    Mardinoglu, Adil
    Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK.
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Borén, Jan
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Levin, Malin C.
    Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, the Sahlgrenska Academy at University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking2021In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 42, no 43, p. 4481-4492Article in journal (Refereed)
    Abstract [en]

    AIMS: Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.

    METHODS AND RESULTS: Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors.

    CONCLUSIONS: Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.

  • 8.
    Anstee, Quentin M.
    et al.
    Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
    Darlay, Rebecca
    Population & Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
    Cockell, Simon
    Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
    Meroni, Marica
    Department of Pathophysiology and Transplantation, University of Milan, Translational Medicine - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
    Govaere, Olivier
    Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
    Tiniakos, Dina
    Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Dept of Pathology, Aretaieio Hospital, National & Kapodistrian University of Athens, Greece.
    Burt, Alastair D.
    Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia.
    Bedossa, Pierre
    Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
    Palmer, Jeremy
    Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
    Liu, Yang-Lin
    Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
    Aithal, Guruprasad P.
    NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.
    Allison, Michael
    Liver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University NHS Foundation Trust, United Kingdom.
    Yki-Järvinen, Hannele
    Department of Medicine, University of Helsinki, Helsinki, Finland & Helsinki University Hospital, Helsinki, Finland.
    Vacca, Michele
    Liver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University NHS Foundation Trust, United Kingdom; Department of Biochemistry and Wellcome Trust/MRC Institute of Metabolic Science, MRC Metabolic Diseases Unit, Metabolic Research Laboratories, University of Cambridge, UK.
    Dufour, Jean-Francois
    University Clinic for Visceral Surgery and Medicine, University of Berne, Freiburgstrasse, Berne, Switzerland.
    Invernizzi, Pietro
    Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy.
    Prati, Daniele
    Department of Pathophysiology and Transplantation, University of Milan, Translational Medicine - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
    Ekstedt, Mattias
    Division of Gastroenterology and Hepatology, Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
    Kechagias, Stergios
    Division of Gastroenterology and Hepatology, Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
    Francque, Sven
    Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.
    Petta, Salvatore
    Sezione di Gastroenterologia, Dipartimento Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro", Università di Palermo, Palermo, Italy.
    Bugianesi, Elisabetta
    Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
    Clement, Karine
    Sorbonne University, Inserm, Nutrition and obesity: Systemic approaches, Nutrition department, Pitié-Salpêtrière hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
    Ratziu, Vlad
    Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
    Schattenberg, Jörn M.
    NAFLD Research Center, Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
    Valenti, Luca
    Department of Pathophysiology and Transplantation, University of Milan, Translational Medicine - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
    Day, Christopher P.
    Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
    Cordell, Heather J.
    Population & Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
    Daly, Ann K.
    Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
    EPoS, Consortium Investigators
    Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort2020In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 73, no 3, p. 505-515Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most GWAS studies have adopted radiologically assessed hepatic triglyceride content as reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a genome-wide association study (GWAS) encompassing the full spectrum of histologically characterized NAFLD.

    METHODS: The GWAS involved 1483 European NAFLD cases and 17781 genetically-matched population controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance.

    RESULTS: Case-control analysis identified signals showing p-values ≤ 5 x 10-8 at four locations (chromosome (chr) 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with two other signals with p<1 x10-7 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits steatosis, disease activity score, NAS and fibrosis showed that the PNPLA3 signal (rs738409) was genome-wide significantly associated with steatosis, fibrosis and NAS score and identified a new signal (PYGO1 rs62021874) with close to genome-wide significance for steatosis (p=8.2 x 10-8). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR SNP also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (≥F3), the signals on chromosomes 2, 19 and 22 remained genome-wide significant. With the exception of GCKR/C2ORF16, the genome-wide significant signals replicated.

    CONCLUSIONS: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting relevance of Wnt signalling pathways in NAFLD pathogenesis.

  • 9.
    Antila, Kari
    et al.
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Lötjönen, Jyrki
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Thurfjell, Lennart
    GE Healthcare, Stockholm, Sweden.
    Laine, Jarmo
    Nexstim Ltd, Helsinki, Finland.
    Massimini, Marcello
    University of Milan, Milan, Italy.
    Rueckert, Daniel
    Imperial College London, London, United Kingdom.
    Zubarev, Roman A.
    Karolinska Institutet, Stockholm, Sweden.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Tampere, Finland.
    van Gils, Mark
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Mattila, Jussi
    VTT Technical Research Centre of Finland, Tampere, Finland.
    Hviid Simonsen, Anja
    Rigshospitalet, Copenhagen, Denmark.
    Waldemar, Gunhild
    Rigshospitalet, Copenhagen, Denmark.
    Soininen, Hilkka
    University of Eastern Finland, Kuopio, Finland.
    The PredictAD project: development of novel biomarkers and analysis software for early diagnosis of the Alzheimer's disease2013In: Interface Focus, ISSN 2042-8898, E-ISSN 2042-8901, Vol. 3, no 2, article id 20120072Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is the most common cause of dementia affecting 36 million people worldwide. As the demographic transition in the developed countries progresses towards older population, the worsening ratio of workers per retirees and the growing number of patients with age-related illnesses such as AD will challenge the current healthcare systems and national economies. For these reasons AD has been identified as a health priority, and various methods for diagnosis and many candidates for therapies are under intense research. Even though there is currently no cure for AD, its effects can be managed. Today the significance of early and precise diagnosis of AD is emphasized in order to minimize its irreversible effects on the nervous system. When new drugs and therapies enter the market it is also vital to effectively identify the right candidates to benefit from these. The main objective of the PredictAD project was to find and integrate efficient biomarkers from heterogeneous patient data to make early diagnosis and to monitor the progress of AD in a more efficient, reliable and objective manner. The project focused on discovering biomarkers from biomolecular data, electrophysiological measurements of the brain and structural, functional and molecular brain images. We also designed and built a statistical model and a framework for exploiting these biomarkers with other available patient history and background data. We were able to discover several potential novel biomarker candidates and implement the framework in software. The results are currently used in several research projects, licensed to commercial use and being tested for clinical use in several trials.

  • 10.
    Arora, Tulika
    et al.
    Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Velagapudi, Vidya
    VTT Technical Research Centre of Finland, Espoo, Finland; Metabolomics Unit, Institute for Molecular Medicine Finland FIMM, Helsinki, Finland.
    Pournaras, Dimitri J.
    Department of Bariatric Surgery, Musgrove Park Hospital, Taunton, United Kingdom.
    Welbourn, Richard
    Department of Bariatric Surgery, Musgrove Park Hospital, Taunton, United Kingdom.
    le Roux, Carel W.
    Diabetes Complications Research Centre, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; Gastrosurgical Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Bäckhed, Fredrik
    Department of Molecular and Clinical Medicine, Institute of Medicie, University of Gothenburg, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, University of Copenhagen, Copenhagen, Denmark.
    Roux-en-Y Gastric Bypass Surgery Induces Early Plasma Metabolomic and Lipidomic Alterations in Humans Associated with Diabetes Remission2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 5, article id e0126401Article in journal (Refereed)
    Abstract [en]

    Roux-en-Y gastric bypass (RYGB) is an effective method to attain sustained weight loss and diabetes remission. We aimed to elucidate early changes in the plasma metabolome and lipidome after RYGB. Plasma samples from 16 insulin-resistant morbidly obese subjects, of whom 14 had diabetes, were subjected to global metabolomics and lipidomics analysis at pre-surgery and 4 and 42 days after RYGB. Metabolites and lipid species were compared between time points and between subjects who were in remission and not in remission from diabetes 2 years after surgery. We found that the variables that were most discriminatory between time points were decanoic acid and octanoic acid, which were elevated 42 days after surgery, and sphingomyelins (18:1/21:0 and 18:1/23:3), which were at their lowest level 42 days after surgery. Insulin levels were lower at 4 and 42 days after surgery compared with pre-surgery levels. At 4 days after surgery, insulin levels correlated positively with metabolites of branched chain and aromatic amino acid metabolism and negatively with triglycerides with long-chain fatty acids. Of the 14 subjects with diabetes prior to surgery, 7 were in remission 2 years after surgery. The subjects in remission displayed higher pre-surgery levels of tricarboxylic acid cycle intermediates and triglycerides with long-chain fatty acids compared with subjects not in remission. Thus, metabolic alterations are induced soon after surgery and subjects with diabetes remission differ in the metabolic profiles at pre- and early post-surgery time points compared to patients not in remission.

  • 11.
    Aura, Anna-Marja
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland.
    Gopalacharyulu, Peddinti
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Bounsaythip, Catherine
    University of Helsinki, Helsinki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Oksman-Caldentey, Kirsi-Marja
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Drug metabolome of the simvastatin formed by human intestinal microbiota in vitro2011In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 7, no 2, p. 437-446Article in journal (Refereed)
    Abstract [en]

    The human colon contains a diverse microbial population which contributes to degradation and metabolism of food components. Drug metabolism in the colon is generally poorly understood. Metabolomics techniques and in vitro colon models are now available which afford detailed characterization of drug metabolites in the context of colon metabolism. The aim of this work was to identify novel drug metabolites of Simvastatin (SV) by using an anaerobic human in vitro colon model at body temperature coupled with systems biology platform, excluding the metabolism of the host liver and intestinal epithelia. Comprehensive two-dimensional gas chromatography with a time-of-flight mass spectrometry (GC×GC-TOFMS) was used for the metabolomic analysis. Metabolites showing the most significant differences in the active faecal suspension were elucidated in reference with SV fragmentation and compared with controls: inactive suspension or buffer with SV, or with active suspension alone. Finally, time courses of selected metabolites were investigated. Our data suggest that SV is degraded by hydrolytic cleavage of methylbutanoic acid from the SV backbone. Metabolism involves demethylation of dimethylbutanoic acid, hydroxylation/dehydroxylation and β-oxidation resulting in the production of 2-hydroxyisovaleric acid (3-methyl-2-hydroxybutanoic acid), 3-hydroxybutanoic acid and lactic acid (2-hydroxypropanoic acid), and finally re-cyclisation of heptanoic acid (possibly de-esterified and cleaved methylpyranyl arm) to produce cyclohexanecarboxylic acid. Our study elucidates a pathway of colonic microbial metabolism of SV as well as demonstrates the applicability of the in vitro colon model and metabolomics to the discovery of novel drug metabolites from drug response profiles.

  • 12.
    Aura, Anna-Marja
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Gopalacharyulu, Peddinti
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Cheynier, Veronique
    Sciences Pour l'œNologie, Institut national de la recherche agronomique (INRA), Montpellier, France.
    Souquet, Jean-Marc
    Sciences Pour l'œNologie, Institut national de la recherche agronomique (INRA), Montpellier, France.
    Bes, Magali
    Unité Expérimentale de Pech Rouge, Institut national de la recherche agronomique (INRA), Gruissan, France.
    Le Bourvellec, Carine
    Sécurité et Qualité des Produits d'Origine Végétale, Institut national de la recherche agronomique (INRA), Avignon, France.
    Guyot, Sylvain
    Cidricoles et Biotransformation des Fruits et Légumes, Institut national de la recherche agronomique (INRA), Le Rheu, France.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Characterization of microbial metabolism of Syrah grape products in an in vitro colon model using targeted and non-targeted analytical approaches2013In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 52, no 2, p. 833-846Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Syrah red grapes are used in the production of tannin-rich red wines. Tannins are high molecular weight molecules, proanthocyanidins (PAs), and poorly absorbed in the upper intestine. In this study, gut microbial metabolism of Syrah grape phenolic compounds was investigated.

    METHODS: Syrah grape pericarp was subjected to an enzymatic in vitro digestion model, and red wine and grape skin PA fraction were prepared. Microbial conversion was screened using an in vitro colon model with faecal microbiota, by measurement of short-chain fatty acids by gas chromatography (GC) and microbial phenolic metabolites using GC with mass detection (GC-MS). Red wine metabolites were further profiled using two-dimensional GC mass spectrometry (GCxGC-TOFMS). In addition, the effect of PA structure and dose on conversion efficiency was investigated by GC-MS.

    RESULTS: Red wine exhibited a higher degree of C1-C3 phenolic acid formation than PA fraction or grape pericarp powders. Hydroxyphenyl valeric acid (flavanols and PAs as precursors) and 3,5-dimethoxy-4-hydroxybenzoic acid (anthocyanin as a precursor) were identified from the red wine metabolite profile. In the absence of native grape pericarp or red wine matrix, the isolated PAs were found to be effective in the dose-dependent inhibition of microbial conversions and short-chain fatty acid formation.

    CONCLUSIONS: Metabolite profiling was complementary to targeted analysis. The identified metabolites had biological relevance, because the structures of the metabolites resembled fragments of their grape phenolic precursors or were in agreement with literature data.

  • 13.
    Aye, Cho-Cho
    et al.
    The Department of Cellular and Molecular Physiology, Institute of Translational Medicine, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
    Hammond, Dean E.
    The Department of Cellular and Molecular Physiology, Institute of Translational Medicine, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
    Rodriguez-Cuenca, Sergio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK.
    Doherty, Mary K.
    Division of Biomedical Sciences, Centre for Health Science, University of the Highlands and Islands, Old Perth Road, Inverness IV2 3JH, UK.
    Whitfield, Phillip D.
    Division of Biomedical Sciences, Centre for Health Science, University of the Highlands and Islands, Old Perth Road, Inverness IV2 3JH, UK; Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, Garscube Campus, University of Glasgow, Glasgow G61 1BD, UK.
    Phelan, Marie M.
    Centre for Nuclear Magnetic Resonance, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
    Yang, Chenjing
    The Department of Cellular and Molecular Physiology, Institute of Translational Medicine, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
    Perez-Perez, Rafael
    Instituto de Investigación, Hospital Universitario 12 de Octubre, Avda. de Córdoba s/n, 28041 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, 28029 Madrid, Spain.
    Li, Xiaoxin
    The Department of Cellular and Molecular Physiology, Institute of Translational Medicine, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
    Diaz-Ramos, Angels
    Institute for Research in Biomedicine, C/Baldiri Reixac 10, 08028 Barcelona, Spain.
    Peddinti, Gopal
    Technical Research Centre of Finland, 02044 Espoo, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Technical Research Centre of Finland, 02044 Espoo, Finland; Turku Centre for Biotechnology, University of Turku and Abo Akademi University, 20520 Turku, Finland.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
    Zorzano, Antonio
    Institute for Research in Biomedicine, C/Baldiri Reixac 10, 08028 Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain; Department de Bioquimica i Biomedicina, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain.
    Ugalde, Cristina
    Instituto de Investigación, Hospital Universitario 12 de Octubre, Avda. de Córdoba s/n, 28041 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, 28029 Madrid, Spain.
    Mora, Silvia
    The Department of Cellular and Molecular Physiology, Institute of Translational Medicine, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK; Department de Bioquimica i Biomedicina, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.
    CBL/CAP Is Essential for Mitochondria Respiration Complex I Assembly and Bioenergetics Efficiency in Muscle Cells2023In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 4, article id 3399Article in journal (Refereed)
    Abstract [en]

    CBL is rapidly phosphorylated upon insulin receptor activation. Mice whole body CBL depletion improved insulin sensitivity and glucose clearance; however, the precise mechanisms remain unknown. We depleted either CBL or its associated protein SORBS1/CAP independently in myocytes and assessed mitochondrial function and metabolism compared to control cells. CBL- and CAP-depleted cells showed increased mitochondrial mass with greater proton leak. Mitochondrial respiratory complex I activity and assembly into respirasomes were reduced. Proteome profiling revealed alterations in proteins involved in glycolysis and fatty acid degradation. Our findings demonstrate CBL/CAP pathway couples insulin signaling to efficient mitochondrial respiratory function and metabolism in muscle.

  • 14.
    Barbarroja, Nuria
    et al.
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Rodriguez-Cuenca, Sergio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Camargo, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Lipids and Atherosclerosis Research Unit, Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Pirraco, Ana
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal.
    Relat, Joana
    Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
    Cuadrado, Irene
    Departamento de Farmacología, Universidad Complutense de Madrid, Madrid, Spain.
    Pellegrinelli, Vanessa
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Medina-Gomez, Gema
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lopez-Pedrera, Chary
    Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Tinahones, Francisco J.
    CIBER in Physiopathology of Obesity and Nutrition (CB06/03), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigación Biomédica de Málaga, Hospital Virgen de la Victoria, Malaga, Spain.
    Symons, J. David
    College of Health, University of Utah, Salt Lake City UT, United States; Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City UT, United States.
    Summers, Scott A.
    Program in Cardiovascular and Metabolic Disorders, Duke-National University, Singapore Graduate Medical School, Singapore, Singapore.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 4, p. 1180-1192Article in journal (Refereed)
    Abstract [en]

    Adipose tissue dysfunction is an important determinant of obesity-associated, lipid-induced metabolic complications. Ceramides are well-known mediators of lipid-induced insulin resistance in peripheral organs such as muscle. DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway. Functional suppression of DEGS1 activity results in substantial changes in ceramide species likely to affect fundamental biological functions such as oxidative stress, cell survival, and proliferation. Here, we show that degs1 expression is specifically decreased in the adipose tissue of obese patients and murine models of genetic and nutritional obesity. Moreover, loss-of-function experiments using pharmacological or genetic ablation of DEGS1 in preadipocytes prevented adipogenesis and decreased lipid accumulation. This was associated with elevated oxidative stress, cellular death, and blockage of the cell cycle. These effects were coupled with increased dihydroceramide content. Finally, we validated in vivo that pharmacological inhibition of DEGS1 impairs adipocyte differentiation. These data identify DEGS1 as a new potential target to restore adipose tissue function and prevent obesity-associated metabolic disturbances.

  • 15.
    Beger, Richard D.
    et al.
    Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, USA.
    Dunn, Warwick
    School of Biosciences, Phenome Centre Birmingham and Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UK.
    Schmidt, Michael A.
    Advanced Pattern Analysis and Countermeasures Group, Research Innovation Center, Colorado State University, Fort Collins, USA.
    Gross, Steven S.
    Department of Pharmacology, Weill Cornell Medical College, New York, USA.
    Kirwan, Jennifer A.
    School of Biosciences, University of Birmingham, Birmingham, UK.
    Cascante, Marta
    Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain.
    Brennan, Lorraine
    UCD Institute of Food and Health, UCD, Belfield, Ireland.
    Wishart, David S.
    Departments of Computing Science and Biological Sciences, University of Alberta, Edmonton, Canada.
    Oresic, Matej
    Turku Centre for Biotechnology, University of Turku, Turku, Finland.
    Hankemeier, Thomas
    Division of Analytical Biosciences and Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University & Netherlands Metabolomics Centre, Leiden, The Netherlands.
    Broadhurst, David I.
    School of Science, Edith Cowan University, Perth, Australia.
    Lane, Andrew N.
    Center for Environmental Systems Biochemistry, Department Toxicology and Cancer Biology, Markey Cancer Center, Lexington, USA.
    Suhre, Karsten
    Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Doha, Qatar.
    Kastenmüller, Gabi
    Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich, Oberschleißheim, Germany.
    Sumner, Susan J.
    Discovery Sciences, RTI International, Research Triangle Park, Durham, USA.
    Thiele, Ines
    University of Luxembourg, Luxembourg Centre for Systems Biomedicine, Campus Belval, Esch-Sur-Alzette, Luxembourg.
    Fiehn, Oliver
    West Coast Metabolomics Center, UC Davis, Davis, USA; Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia.
    Kaddurah-Daouk, Rima
    Psychiatry and Behavioral Sciences, Duke Internal Medicine and Duke Institute for Brain Sciences and Center for Applied Genomics and Precision Medicine, Duke University Medical Center, Durham, USA.
    Metabolomics enables precision medicine: "A White Paper, Community Perspective"2016In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 12, no 10, article id 149Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION BACKGROUND TO METABOLOMICS: Metabolomics is the comprehensive study of the metabolome, the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids. The study of metabolism at the global or "-omics" level is a rapidly growing field that has the potential to have a profound impact upon medical practice. At the center of metabolomics, is the concept that a person's metabolic state provides a close representation of that individual's overall health status. This metabolic state reflects what has been encoded by the genome, and modified by diet, environmental factors, and the gut microbiome. The metabolic profile provides a quantifiable readout of biochemical state from normal physiology to diverse pathophysiologies in a manner that is often not obvious from gene expression analyses. Today, clinicians capture only a very small part of the information contained in the metabolome, as they routinely measure only a narrow set of blood chemistry analytes to assess health and disease states. Examples include measuring glucose to monitor diabetes, measuring cholesterol and high density lipoprotein/low density lipoprotein ratio to assess cardiovascular health, BUN and creatinine for renal disorders, and measuring a panel of metabolites to diagnose potential inborn errors of metabolism in neonates.

    OBJECTIVES OF WHITE PAPER—EXPECTED TREATMENT OUTCOMES AND METABOLOMICS ENABLING TOOL FOR PRECISION MEDICINE: We anticipate that the narrow range of chemical analyses in current use by the medical community today will be replaced in the future by analyses that reveal a far more comprehensive metabolic signature. This signature is expected to describe global biochemical aberrations that reflect patterns of variance in states of wellness, more accurately describe specific diseases and their progression, and greatly aid in differential diagnosis. Such future metabolic signatures will: (1) provide predictive, prognostic, diagnostic, and surrogate markers of diverse disease states; (2) inform on underlying molecular mechanisms of diseases; (3) allow for sub-classification of diseases, and stratification of patients based on metabolic pathways impacted; (4) reveal biomarkers for drug response phenotypes, providing an effective means to predict variation in a subject's response to treatment (pharmacometabolomics); (5) define a metabotype for each specific genotype, offering a functional read-out for genetic variants: (6) provide a means to monitor response and recurrence of diseases, such as cancers: (7) describe the molecular landscape in human performance applications and extreme environments. Importantly, sophisticated metabolomic analytical platforms and informatics tools have recently been developed that make it possible to measure thousands of metabolites in blood, other body fluids, and tissues. Such tools also enable more robust analysis of response to treatment. New insights have been gained about mechanisms of diseases, including neuropsychiatric disorders, cardiovascular disease, cancers, diabetes and a range of pathologies. A series of ground breaking studies supported by National Institute of Health (NIH) through the Pharmacometabolomics Research Network and its partnership with the Pharmacogenomics Research Network illustrate how a patient's metabotype at baseline, prior to treatment, during treatment, and post-treatment, can inform about treatment outcomes and variations in responsiveness to drugs (e.g., statins, antidepressants, antihypertensives and antiplatelet therapies). These studies along with several others also exemplify how metabolomics data can complement and inform genetic data in defining ethnic, sex, and gender basis for variation in responses to treatment, which illustrates how pharmacometabolomics and pharmacogenomics are complementary and powerful tools for precision medicine.

    CONCLUSIONS KEY SCIENTIFIC CONCEPTS AND RECOMMENDATIONS FOR PRECISION MEDICINE: Our metabolomics community believes that inclusion of metabolomics data in precision medicine initiatives is timely and will provide an extremely valuable layer of data that compliments and informs other data obtained by these important initiatives. Our Metabolomics Society, through its "Precision Medicine and Pharmacometabolomics Task Group", with input from our metabolomics community at large, has developed this White Paper where we discuss the value and approaches for including metabolomics data in large precision medicine initiatives. This White Paper offers recommendations for the selection of state of-the-art metabolomics platforms and approaches that offer the widest biochemical coverage, considers critical sample collection and preservation, as well as standardization of measurements, among other important topics. We anticipate that our metabolomics community will have representation in large precision medicine initiatives to provide input with regard to sample acquisition/preservation, selection of optimal omics technologies, and key issues regarding data collection, interpretation, and dissemination. We strongly recommend the collection and biobanking of samples for precision medicine initiatives that will take into consideration needs for large-scale metabolic phenotyping studies.

  • 16.
    Bondia-Pons, Isabel
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland; Department of Food Science and Physiology, University of Navarra, Pamplona, Spain.
    Maukonen, Johanna
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Rissanen, Aila
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
    Saarela, Maria
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Kaprio, Jaakko
    Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland.
    Hakkarainen, Antti
    Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland.
    Lundbom, Jesper
    Department of Radiology, Hospital District of Helsinki and Uusimaa (HUS) Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
    Lundbom, Nina
    Department of Radiology, Hospital District of Helsinki and Uusimaa (HUS) Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Pietiläinen, Kirsi H.
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Metabolome and fecal microbiota in monozygotic twin pairs discordant for weight: a Big Mac challenge2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 9, p. 4169-4179Article in journal (Refereed)
    Abstract [en]

    Postprandial responses to food are complex, involving both genetic and environmental factors. We studied postprandial responses to a Big Mac meal challenge in monozygotic co-twins highly discordant for body weight. This unique design allows assessment of the contribution of obesity, independent of genetic liability. Comprehensive metabolic profiling using 3 analytical platforms was applied to fasting and postprandial serum samples from 16 healthy monozygotic twin pairs discordant for weight (body mass index difference >3 kg/m(2)). Nine concordant monozygotic pairs were examined as control pairs. Fecal samples were analyzed to assess diversity of the major bacterial groups by using 5 different validated bacterial group specific denaturing gradient gel electrophoresis methods. No differences in fecal bacterial diversity were detected when comparing co-twins discordant for weight (ANOVA, P<0.05). We found that within-pair similarity is a dominant factor in the metabolic postprandial response, independent of acquired obesity. Branched chain amino acids were increased in heavier as compared with leaner co-twins in the fasting state, but their levels converged postprandially (paired t tests, FDR q<0.05). We also found that specific bacterial groups were associated with postprandial changes of specific metabolites. Our findings underline important roles of genetic and early life factors in the regulation of postprandial metabolite levels.

  • 17.
    Bondia-Pons, Isabel
    et al.
    Department of Public Health and Clinical Nutrition, Clinical Nutrition, Food and Health Research Centre, University of Eastern Finland, Kuopio, Finland.
    Nordlund, Emilia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Katina, Kati
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Aura, Anna-Marja
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Kolehmainen, Marjukka
    Department of Public Health and Clinical Nutrition, Clinical Nutrition, Food and Health Research Centre, University of Eastern Finland, Kuopio, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Mykkänen, Hannu
    Department of Public Health and Clinical Nutrition, Clinical Nutrition, Food and Health Research Centre, University of Eastern Finland, Kuopio, Finland.
    Poutanen, Kaisa
    Department of Public Health and Clinical Nutrition, Clinical Nutrition, Food and Health Research Centre, University of Eastern Finland, Kuopio, Finland; VTT Technical Research Centre of Finland, Espoo, Finland.
    Postprandial differences in the plasma metabolome of healthy Finnish subjects after intake of a sourdough fermented endosperm rye bread versus white wheat bread2011In: Nutrition Journal, ISSN 1475-2891, E-ISSN 1475-2891, Vol. 10, article id 116Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The mechanism behind the lowered postprandial insulin demand observed after rye bread intake compared to wheat bread is unknown. The aim of this study was to use the metabolomics approach to identify potential metabolites related to amino acid metabolism involved in this mechanism.

    METHODS: A sourdough fermented endosperm rye bread (RB) and a standard white wheat bread (WB) as a reference were served in random order to 16 healthy subjects. Test bread portions contained 50 g available carbohydrate. In vitro hydrolysis of starch and protein were performed for both test breads. Blood samples for measuring glucose and insulin concentrations were drawn over 4 h and gastric emptying rate (GER) was measured. Changes in the plasma metabolome were investigated by applying a comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics platform (GC × GC-TOF-MS).

    RESULTS: Plasma insulin response to RB was lower than to WB at 30 min (P = 0.004), 45 min (P = 0.002) and 60 min (P < 0.001) after bread intake, and plasma glucose response was significantly higher at time point 90 min after RB than WB intake (P = 0.045). The starch hydrolysis rate was higher for RB than WB, contrary to the in vitro protein digestibility. There were no differences in GER between breads. From 255 metabolites identified by the metabolomics platform, 26 showed significant postprandial relative changes after 30 minutes of bread intake (p and q values < 0.05). Among them, there were changes in essential amino acids (phenylalanine, methionine, tyrosine and glutamic acid), metabolites involved in the tricarboxylic acid cycle (alpha-ketoglutaric, pyruvic acid and citric acid) and several organic acids. Interestingly, the levels of two compounds involved in the tryptophan metabolism (picolinic acid, ribitol) significantly changed depending on the different bread intake.

    CONCLUSIONS: A single meal of a low fibre sourdough rye bread producing low postprandial insulin response brings in several changes in plasma amino acids and their metabolites and some of these might have properties beneficial for health.

  • 18.
    Bondia-Pons, Isabel
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland; Department of Food Science and Physiology, Research Building, University of Navarra, Pamplona, Spain.
    Pöhö, Päivi
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Bozzetto, Lutgarda
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Vetrani, Claudia
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Patti, Lidia
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Aura, Anna-Marja
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Annuzzi, Giovanni
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Rivellese, Angela Albarosa
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Isoenergetic diets differing in their n-3 fatty acid and polyphenol content reflect different plasma and HDL-fraction lipidomic profiles in subjects at high cardiovascular risk2014In: Molecular Nutrition & Food Research, ISSN 1613-4125, E-ISSN 1613-4133, Vol. 58, no 9, p. 1873-1882Article in journal (Refereed)
    Abstract [en]

    SCOPE: Dysregulation of lipid homeostasis is related to multiple major healthcare problems. The aim of this study was to investigate the effects of n-3 fatty acid (FA) and polyphenol rich diets on plasma and HDL fraction lipidomic profiles in subjects at high cardiovascular risk.

    METHODS AND RESULTS: Ultra performance LC coupled to quadrupole TOF/MS mass spectrometry global lipidomic profiling was applied to plasma and HDL fraction from an 8 wk randomized intervention with four isoenergetic diets, differing in their natural n-3 FA and polyphenols content, in 78 subjects with a high BMI, abdominal obesity, and at least one other feature of the metabolic syndrome. Dependency network analysis showed a different pattern of associations between lipidomics, dietary, and clinical variables after the dietary interventions. The most remarkable associations between variables were observed after the diet high in n-3 FA and polyphenols, as the inverse association between gallic acid intake and LDL cholesterol levels, which was indirectly associated with a HDL cluster exclusively comprised lysophospholipids.

    CONCLUSION: This is the first human randomized controlled trial showing direct and indirect associations with lipid molecular species and clinical variables of interest in the evaluation of the metabolic syndrome after diets naturally rich in polyphenols.

  • 19.
    Bowden, John A.
    et al.
    Marine Biochemical Sciences Group, Chemical Sciences Division, Hollings Marine Laboratory, National Institute of Standards and Technology, Charleston SC, USA.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Hollings Marine Laboratory, Marine Biochemical Sciences Group, National Institute of Standards and Technology, Charleston SC, United States; Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta GA, United States.
    Zhou, Senlin
    Department of Chemistry and Biochemistry, Wayne State University, Detroit MI, USA.
    Harmonizing Lipidomics: NIST Interlaboratory Comparison Exercise for Lipidomics using Standard Reference Material 1950 Metabolites in Frozen Human Plasma2017In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 58, no 12, p. 2275-2288Article in journal (Refereed)
    Abstract [en]

    As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950 Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each lab using a different lipidomics workflow. A total of 1527 unique lipids were measured across all laboratories, and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra- and inter-laboratory quality control and method validation. These analyses were performed using non-standardized laboratory-independent workflows. The consensus locations were also compared to a previous examination of SRM 1950 by the LIPID MAPS consortium. While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.

  • 20.
    Brial, François
    et al.
    UMRS 1124 INSERM, Université de Paris Descartes, Paris, France.
    Chilloux, Julien
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
    Nielsen, Trine
    Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Kobenhavn, Denmark.
    Vieira-Silva, Sara
    Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
    Falony, Gwen
    Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
    Andrikopoulos, Petros
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; National Heart & Lung Institute, Section of Genomic & Environmental Medicine, Imperial College London, London, UK.
    Olanipekun, Michael
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; National Heart & Lung Institute, Section of Genomic & Environmental Medicine, Imperial College London, London, UK.
    Hoyles, Lesley
    Department of Biosciences, Nottingham Trent University, Nottingham, UK.
    Djouadi, Fatima
    Centre de Recherche des Cordeliers, Université Paris Descartes, Paris, France; Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Paris, France.
    Neves, Ana L.
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
    Rodriguez-Martinez, Andrea
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
    Mouawad, Ghiwa Ishac
    UMRS 1124 INSERM, Université de Paris Descartes, Paris, France.
    Pons, Nicolas
    Metagenopolis, INRAE, Paris, Île-de-France, France.
    Forslund, Sofia
    Forslund Lab, Max Delbrück Centrum für Molekulare Medizin Experimental and Clinical Research Center, Berlin, Berlin, Germany.
    Le-Chatelier, Emmanuelle
    Metagenopolis, INRAE, Paris, Île-de-France, France.
    Le Lay, Aurélie
    UMRS 1124 INSERM, Université de Paris Descartes, Paris, France.
    Nicholson, Jeremy
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
    Hansen, Torben
    Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Kobenhavn, Denmark.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Clément, Karine
    INSERM, U1166, team 6 Nutriomique, Université Pierre et Marie Curie-Paris 6, Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.
    Oresic, Matej
    Örebro University, School of Medical Sciences.
    Bork, Peer
    Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
    Ehrlich, Stanislav Dusko
    Metagenopolis, INRAE, Paris, Île-de-France, France; Center for Host Microbiome Interactions, King's College London Dental Institute, London, UK.
    Raes, Jeroen
    Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium; Center for Microbiology, Vlaams Instituut voor Biotechnologie, Leuven, Belgium.
    Pedersen, Oluf Borbye
    Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium; Center for Microbiology, Vlaams Instituut voor Biotechnologie, Leuven, Belgium.
    Gauguier, Dominique
    UMRS 1124 INSERM, Université de Paris Descartes, Paris, France.
    Dumas, Marc-Emmanuel
    Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; National Heart & Lung Institute, Section of Genomic & Environmental Medicine, Imperial College London, London, UK; McGill Genome Centre & Department of Human Genetics, McGill University, Montréal, Québec, Canada; European Genomics Institute for Diabetes, INSERM U1283, CNRS UMR8199, Institut Pasteur de Lille, Lille University Hospital, Unversity of Lille, Lille, France.
    Human and preclinical studies of the host-gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health2021In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 70, no 11, p. 2105-2114Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Gut microbial products are involved in regulation of host metabolism. In human and experimental studies, we explored the potential role of hippurate, a hepatic phase 2 conjugation product of microbial benzoate, as a marker and mediator of metabolic health.

    DESIGN: In 271 middle-aged non-diabetic Danish individuals, who were stratified on habitual dietary intake, we applied 1H-nuclear magnetic resonance (NMR) spectroscopy of urine samples and shotgun-sequencing-based metagenomics of the gut microbiome to explore links between the urine level of hippurate, measures of the gut microbiome, dietary fat and markers of metabolic health. In mechanistic experiments with chronic subcutaneous infusion of hippurate to high-fat-diet-fed obese mice, we tested for causality between hippurate and metabolic phenotypes.

    RESULTS: In the human study, we showed that urine hippurate positively associates with microbial gene richness and functional modules for microbial benzoate biosynthetic pathways, one of which is less prevalent in the Bacteroides 2 enterotype compared with Ruminococcaceae or Prevotella enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate concentration, independently of gene richness, accounts for links with metabolic health. In the high-fat-fed mice experiments, we demonstrate causality through chronic infusion of hippurate (20 nmol/day) resulting in improved glucose tolerance and enhanced insulin secretion.

    CONCLUSION: Our human and experimental studies show that a high urine hippurate concentration is a general marker of metabolic health, and in the context of obesity induced by high-fat diets, hippurate contributes to metabolic improvements, highlighting its potential as a mediator of metabolic health.

  • 21.
    Brockmöller, Scarlet F.
    et al.
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Bucher, Elmar
    Medical Biotechnology, VTT Technical Research Centre of Finland, University of Turku, Turku, Finland.
    Müller, Berit M.
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Budczies, Jan
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Hilvo, Mika
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Griffin, Julian L.
    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Kallioniemi, Olli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Iljin, Kristiina
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Loibl, Sibylle
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Darb-Esfahani, Silvia
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Sinn, Bruno V.
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Klauschen, Frederick
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Prinzler, Judith
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Bangemann, Nikola
    Breast Cancer Center, Charité University Hospital, Berlin, Germany.
    Ismaeel, Fakher
    Department of Gynaecology and Obstetrics, DRK Kliniken Köpenick, Berlin, Germany; Department of Gynaecology and Obstetrics, Charité University Hospital, Berlin, Germany.
    Fiehn, Oliver
    Genome Center, University of California-Davis, Davis CA, United States.
    Dietel, Manfred
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Denkert, Carsten
    Institute of Pathology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
    Integration of metabolomics and expression of glycerol-3-phosphate acyltransferase (GPAM) in breast cancer-link to patient survival, hormone receptor status, and metabolic profiling2012In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 11, no 2, p. 850-60Article in journal (Refereed)
    Abstract [en]

    Changes in lipid metabolism are an important but not well-characterized hallmark of cancer. On the basis of our recent findings of lipidomic changes in breast cancer, we investigated glycerol-3-phosphate acyltransferase (GPAM), a key enzyme in the lipid biosynthesis of triacylglycerols and phospholipids. GPAM protein expression was evaluated and linked to metabolomic and lipidomic profiles in a cohort of human breast carcinomas. In addition, GPAM mRNA expression was analyzed using the GeneSapiens in silico transcriptiomics database. High cytoplasmic GPAM expression was associated with hormone receptor negative status (p = 0.013). On the protein (p = 0.048) and mRNA (p = 0.001) levels, increased GPAM expression was associated with a better overall survival. Metabolomic analysis by GC-MS showed that sn-glycerol-3-phosphate, the substrate of GPAM, was elevated in breast cancer compared to normal breast tissue. LC-MS based lipidomic analysis identified significantly higher levels of phospholipids, especially phosphatidylcholines in GPAM protein positive tumors. In conclusion, our results suggest that GPAM is expressed in human breast cancer with associated changes in the cellular metabolism, in particular an increased synthesis of phospholipids, the major structural component of cellular membranes.

  • 22.
    Budczies, Jan
    et al.
    Institute of Pathology, Charité University Hospital, Berlin, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Brockmöller, Scarlet F.
    Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.
    Müller, Berit M.
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Barupal, Dinesh K.
    International Agency for Research on Cancer (IARC), Lyon, France.
    Richter-Ehrenstein, Christiane
    Interdisciplinary Breast Center, Charité University Hospital, Berlin, Germany.
    Kleine-Tebbe, Anke
    Breast Center, DRK Kliniken Berlin, Berlin, Germany.
    Griffin, Julian L.
    Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.
    Dietel, Manfred
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Denkert, Carsten
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Fiehn, Oliver
    Genome Center, University of California Davis, Davis CA, United States.
    Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer: alterations in glutamine and beta-alanine metabolism2013In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 94, p. 279-288, article id S1874-3919(13)00511-3Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: Molecular subtyping of breast cancer is necessary for therapy selection and mandatory for all breast cancer patients. Metabolic alterations are considered a hallmark of cancer and several metabolic drugs are currently being investigated in clinical trials. However, the dependence of metabolic alterations on breast cancer subtypes has not been investigated on -omics scale. Thus, 204 estrogen receptor positive (ER+) and 67 estrogen receptor negative (ER-) breast cancer tissues were investigated using GC-TOFMS based metabolomics. 19 metabolites were detected as altered in a predefined training set (2/3 of tumors) and could be validated in a predefined validation set (1/3 of tumors). The metabolite changes included increases in beta-alanine, 2-hydroyglutarate, glutamate, xanthine and decreases in glutamine in the ER- subtype. Beta-alanine demonstrated the strongest change between ER- and ER+ breast cancer (fold change=2.4, p=1.5E-20). In a correlation analysis with genome-wide expression data in a subcohort of 154 tumors, we found a strong negative correlation (Spearman R=-0.62) between beta-alanine and 4-aminobutyrate aminotransferase (ABAT). Immunohistological analysis confirmed down-regulation of the ABAT protein in ER- breast cancer. In a Kaplan-Meier analysis of a large external expression data set, the ABAT transcript was demonstrated to be a positive prognostic marker for breast cancer (HR=0.6, p=3.2E-15).

    BIOLOGICAL SIGNIFICANCE: It is well-known for more than a decade that breast cancer exhibits distinct gene expression patterns depending on the molecular subtype defined by estrogen receptor (ER) and HER2 status. Here, we show that breast cancer exhibits distinct metabolomics patterns depending on ER status. Our observation supports the current view of ER+ breast cancer and ER- breast as different diseases requiring different treatment strategies. Metabolic drugs for cancer including glutaminase inhibitors are currently under development and tested in clinical trials. We found glutamate enriched and glutamine reduced in ER- breast cancer compared to ER+ breast cancer and compared to normal breast tissues. Thus, metabolomics analysis highlights the ER- subtype as a preferential target for glutaminase inhibitors. For the first time, we report on a regulation of beta-alanine catabolism in cancer. In breast cancer, ABAT transcript expression was variable and correlated with ER status. Low ABAT transcript expression was associated with low ABAT protein expression and high beta-alanine concentration. In a large external microarray cohort, low ABAT expression shortened recurrence-free survival in breast cancer, ER+ breast cancer and ER- breast cancer.

  • 23.
    Budczies, Jan
    et al.
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Denkert, Carsten
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Müller, Berit M.
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Brockmöller, Scarlet F.
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Klauschen, Frederick
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Györffy, Balazs
    Institute of Pathology, Charité University Hospital, Berlin, Germany; Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Dietel, Manfred
    Institute of Pathology, Charité University Hospital, Berlin, Germany.
    Richter-Ehrenstein, Christiane
    Interdisciplinary Breast Center, Charité University Hospital, Berlin, Germany.
    Marten, Ulrike
    Institute of Pathology, DRK Kliniken Berlin, Berlin, Germany.
    Salek, Reza M.
    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
    Griffin, Julian L.
    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
    Hilvo, Mika
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Wohlgemuth, Gert
    Genome Center, University of California Davis, Davis CA, United States.
    Fiehn, Oliver
    Genome Center, University of California Davis, Davis CA, United States.
    Remodeling of central metabolism in invasive breast cancer compared to normal breast tissue - a GC-TOFMS based metabolomics study2012In: BMC Genomics, E-ISSN 1471-2164, Vol. 13, no 1, article id 334Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Changes in energy metabolism of the cells are common to many kinds of tumors and are considered a hallmark of cancer. Gas chromatography followed by time-of-flight mass spectrometry (GC-TOFMS) is a well-suited technique to investigate the small molecules in the central metabolic pathways. However, the metabolic changes between invasive carcinoma and normal breast tissues were not investigated in a large cohort of breast cancer samples so far.

    RESULTS: A cohort of 271 breast cancer and 98 normal tissue samples was investigated using GC-TOFMS-based metabolomics. A total number of 468 metabolite peaks could be detected; out of these 368 (79%) were significantly changed between cancer and normal tissues (p<0.05 in training and validation set). Furthermore, 13 tumor and 7 normal tissue markers were identified that separated cancer from normal tissues with a sensitivity and a specificity of >80%. Two-metabolite classifiers, constructed as ratios of the tumor and normal tissues markers, separated cancer from normal tissues with high sensitivity and specificity. Specifically, the cytidine-5-monophosphate / pentadecanoic acid metabolic ratio was the most significant discriminator between cancer and normal tissues and allowed detection of cancer with a sensitivity of 94.8% and a specificity of 93.9%.

    CONCLUSIONS: For the first time, a comprehensive metabolic map of breast cancer was constructed by GC-TOF analysis of a large cohort of breast cancer and normal tissues. Furthermore, our results demonstrate that spectrometry-based approaches have the potential to contribute to the analysis of biopsies or clinical tissue samples complementary to histopathology.

  • 24.
    Burla, Bo
    et al.
    Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, Singapore.
    Arita, Makoto
    Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan; Division of Physiological Chemistry and Metabolism, Keio University Faculty of Pharmacy, Tokyo, Japan.
    Arita, Masanori
    National Institute of Genetics, Shizuoka, Japan and RIKEN Center for Sustainable Resource Science, Yokohama, Japan.
    Bendt, Anne K.
    Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, Singapore.
    Cazenave-Gassiot, Amaury
    Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore.
    Dennis, Edward A.
    Departments of Pharmacology and Chemistry and Biochemistry, School of Medicine, University of California at San Diego, La Jolla, CA, USA.
    Ekroos, Kim
    Lipidomics Consulting Ltd., Esbo, Finland.
    Han, Xianlin
    Barshop Institute for Longevity and Aging Studies and Department of Medicine-Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
    Ikeda, Kazutaka
    Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.
    Liebisch, Gerhard
    Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany.
    Lin, Michelle K.
    Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore.
    Loh, Tze Ping
    Department of Laboratory Medicine, National University Hospital, Singapore.
    Meikle, Peter J.
    Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
    Orešič, Matej
    Örebro University, School of Medical Sciences. Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
    Quehenberger, Oswald
    Departments of Pharmacology and Medicine, School of Medicine, University of California at San Diego, La Jolla, CA, USA.
    Shevchenko, Andrej
    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
    Torta, Federico
    Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore.
    Wakelam, Michael J. O.
    Babraham Institute, Cambridge, United Kingdom.
    Wheelock, Craig E.
    Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Wenk, Markus R.
    Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, Singapore; Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore.
    MS-based lipidomics of human blood plasma: a community-initiated position paper to develop accepted guidelines2018In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 59, no 10, p. 2001-2017Article in journal (Refereed)
    Abstract [en]

    Human blood is a self-regenerating lipid-rich biological fluid that is routinely collected in hospital settings. The inventory of lipid molecules found in blood plasma (plasma lipidome) offers insights into individual metabolism and physiology in health and disease. Disturbances in the plasma lipidome also occur in conditions that are not directly linked to lipid metabolism; therefore, plasma lipidomics based on MS is an emerging tool in an array of clinical diagnostics and disease management. However, challenges exist in the translation of such lipidomic data to clinical applications. These relate to the reproducibility, accuracy, and precision of lipid quantitation, study design, sample handling, and data sharing. This position paper emerged from a workshop that initiated a community-led process to elaborate and define a set of generally accepted guidelines for quantitative MS-based lipidomics of blood plasma or serum, with harmonization of data acquired on different instrumentation platforms across independent laboratories as an ultimate goal. We hope that other fields may benefit from and follow such a precedent.

  • 25.
    Böhm, Julia K.
    et al.
    Department of Medicine, Faculty of Health, Institute for Research in Operative Medicine, Witten/Herdecke University, Cologne, Germany.
    Güting, Helge
    Department of Medicine, Faculty of Health, Institute for Research in Operative Medicine, Witten/Herdecke University, Cologne, Germany.
    Thorn, Sophie
    Emergency and Trauma Centre, Alfred Health, Melbourne, Australia.
    Schäfer, Nadine
    Department of Medicine, Faculty of Health, Institute for Research in Operative Medicine, Witten/Herdecke University, Cologne, Germany.
    Rambach, Victoria
    Department of Medicine, Faculty of Health, Institute for Research in Operative Medicine, Witten/Herdecke University, Cologne, Germany.
    Schöchl, Herbert
    Department of Anaesthesiology and Intensive Care, AUVA Trauma Hospital, Academic Teaching Hospital of the Paracelsus Medical University, Salzburg, Austria; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Centre, Vienna, Austria.
    Grottke, Oliver
    Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany.
    Rossaint, Rolf
    Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany.
    Stanworth, Simon
    NHS Blood and Transplant, Oxford University Hospital NHS Foundation Trust, Headley Way, Oxford, UK.
    Curry, Nicola
    NHS Blood and Transplant, Oxford University Hospital NHS Foundation Trust, Headley Way, Oxford, UK.
    Lefering, Rolf
    Department of Medicine, Faculty of Health, Institute for Research in Operative Medicine, Witten/Herdecke University, Cologne, Germany.
    Maegele, Marc
    Department of Medicine, Faculty of Health, Institute for Research in Operative Medicine, Witten/Herdecke University, Cologne, Germany; MaeDepartment of Traumatology, Orthopaedic Surgery and Sports Traumatology, Cologne-Merheim Medical Centre (CMMC), Witten/Herdecke University, Campus Cologne-Merheim, Cologne, Germany.
    CENTER-TBI Participants and Investigators, -
    Global Characterisation of Coagulopathy in Isolated Traumatic Brain Injury (iTBI): A CENTER-TBI Analysis2021In: Neurocritical Care, ISSN 1541-6933, E-ISSN 1556-0961, Vol. 35, no 1, p. 184-196Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Trauma-induced coagulopathy in patients with traumatic brain injury (TBI) is associated with high rates of complications, unfavourable outcomes and mortality. The mechanism of the development of TBI-associated coagulopathy is poorly understood.

    METHODS: This analysis, embedded in the prospective, multi-centred, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, aimed to characterise the coagulopathy of TBI. Emphasis was placed on the acute phase following TBI, primary on subgroups of patients with abnormal coagulation profile within 4 h of admission, and the impact of pre-injury anticoagulant and/or antiplatelet therapy. In order to minimise confounding factors, patients with isolated TBI (iTBI) (n = 598) were selected for this analysis.

    RESULTS: Haemostatic disorders were observed in approximately 20% of iTBI patients. In a subgroup analysis, patients with pre-injury anticoagulant and/or antiplatelet therapy had a twice exacerbated coagulation profile as likely as those without premedication. This was in turn associated with increased rates of mortality and unfavourable outcome post-injury. A multivariate analysis of iTBI patients without pre-injury anticoagulant therapy identified several independent risk factors for coagulopathy which were present at hospital admission. Glasgow Coma Scale (GCS) less than or equal to 8, base excess (BE) less than or equal to - 6, hypothermia and hypotension increased risk significantly.

    CONCLUSION: Consideration of these factors enables early prediction and risk stratification of acute coagulopathy after TBI, thus guiding clinical management.

  • 26.
    Büki, Andras
    et al.
    Örebro University, School of Medical Sciences. Department of Neurosurgery.
    Tsitsopoulos, P.
    Department of Neurosurgery, Hippokration General Hospital, Aristotle University School of Medicine, Thessaloniki, Greece.
    Oresic, Matej
    Örebro University, School of Medical Sciences.
    Mondello, S.
    Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy.
    BIOMARKERS OF TRAUMATIC BRAIN- AND SPINAL CORD INJURY2022In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 39, no 15-16, p. A7-A7, article id 19Article in journal (Other academic)
    Abstract [en]

    Biomarkers of traumatic brain injury have long been investigated, yet their application in real life clinical practice is less than widespread.

    Research efforts under the umbrella of InTBIR and specifically CENTER TBI provided novel results based on a bulk of data collected.

    The symposium aims to provide an update on contemporary knowledge on purported clinical application of core biomarkers while also sharing novel data on emerging markers and novel technologies and approaches that may further improve our diagnostic and prognostic capabilities in the treatment of traumatic brain injury.

    The session will provide a critical review and update on biomarkers of spinal cord injury.

  • 27.
    Caesar, Robert
    et al.
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Orešič, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
    Bäckhed, Fredrik
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism2016In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 57, no 3, p. 474-481Article in journal (Refereed)
    Abstract [en]

    The gut microbiota influences many aspects of host metabolism. We have previously shown that the presence of a gut microbiota remodels lipid composition. Here we investigated how interaction between gut microbiota and dietary lipids regulates lipid composition in the liver and plasma, and gene expression in the liver. Germ-free and conventionally raised mice were fed a lard or fish oil diet for 11 weeks. We performed lipidomics analysis of the liver and serum and microarray analysis of the liver. As expected, most of the variation in the lipidomics dataset was induced by the diet, and abundance of most lipid classes differed between mice fed lard and fish oil. However, the gut microbiota also affected lipid composition. The gut microbiota increased hepatic levels of cholesterol and cholesteryl esters in mice fed lard, but not in mice fed fish oil. Serum levels of cholesterol and cholesteryl esters were not affected by the gut microbiota. Genes encoding enzymes involved in cholesterol biosynthesis were downregulated by the gut microbiota in mice fed lard and were expressed at a low level in mice fed fish oil independent of microbial status. In summary, we show that gut microbiota-induced regulation of hepatic cholesterol metabolism is dependent on dietary lipid composition.

  • 28.
    Carobbio, Stefania
    et al.
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Hagen, Rachel M.
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lelliott, Christopher J.
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Slawik, Marc
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Endocrine Research Unit, Medizinische Klinik-Innenstadt, Ludwig-Maximilians University, Munich, Germany.
    Medina-Gomez, Gema
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Departamento de Bioquímica, Fisiología y Genética Molecular, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, , Madrid, Spain.
    Tan, Chong-Yew
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Sicard, Audrey
    Laboratory of Obesity, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, Toulouse, France.
    Atherton, Helen J.
    MRC Human Nutrition Research, Elsie Widdowson Laboratory, University of Cambridge, Cambridge, United Kingdom.
    Barbarroja, Nuria
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Hospital Virgen de la Victoria, CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Malaga, Spain.
    Bjursell, Mikael
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Bohlooly-Y, Mohammad
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Virtue, Sam
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Tuthill, Antoinette
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lefai, Etienne
    Lyon CarMeN Laboratory, Human Nutrition Research Center, Lyon1 University, Lyon, France.
    Laville, Martine
    Lyon CarMeN Laboratory, Human Nutrition Research Center, Lyon1 University, Lyon, France.
    Wu, Tingting
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Considine, Robert V.
    Division of Endocrinology and Metabolism, School of Medicine, Indiana University, Indianapolis IN, United States.
    Vidal, Hubert
    Lyon CarMeN Laboratory, Human Nutrition Research Center, Lyon1 University, Lyon, France.
    Langin, Dominique
    Laboratory of Obesity, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, Toulouse, France; Laboratory of Clinical Biochemistry, Toulouse, France.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Department of Medicine, Obesity Research Unit, Helsinki University Central Hospital, Helsinki, Finland.
    Tinahones, Francisco J.
    Departamento de Bioquímica, Fisiología y Genética Molecular, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Spain.
    Fernandez-Real, Jose Manuel
    Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, CIBERobn Fisiopatología de la Obesidad y Nutrición, Girona, Spain.
    Griffin, Julian L.
    MRC Human Nutrition Research, Elsie Widdowson Laboratory, University of Cambridge, Cambridge, United Kingdom.
    Sethi, Jaswinder K.
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    López, Miguel
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity2013In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 11, p. 3697-3708Article in journal (Refereed)
    Abstract [en]

    The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.

  • 29.
    Castillo, S.
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, I.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Miettinen, J.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Data analysis tool for comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry2011In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 83, no 8, p. 3058-3067Article in journal (Refereed)
    Abstract [en]

    Data processing and identification of unknown compounds in comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC x GC/TOFMS) analysis is a major challenge, particularly when large sample sets are analyzed. Herein, we present a method for efficient treatment of large data sets produced by GC x GC/TOFMS implemented as a freely available open source software package, Guineu. To handle large data sets and to efficiently utilize all the features available in the vendor software (baseline correction, mass spectral deconvolution, peak picking, integration, library search, and signal-to-noise filtering), data preprocessed by instrument software are used as a starting point for further processing. Our software affords alignment of the data, normalization, data filtering, and utilization of retention indexes in the verification of identification as well as a novel tool for automated group-type identification of the compounds. Herein, different features of the software are studied in detail and the performance of the system is verified by the analysis of a large set of standard samples as well as of a large set of authentic biological samples, including the control samples. The quantitative features of our GC x GC/TOFMS methodology are also studied to further demonstrate the method performance and the experimental results confirm the reliability of the developed procedure. The methodology has already been successfully used for the analysis of several thousand samples in the field of metabolomics.

  • 30.
    Castro Alves, Victor
    et al.
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Lipidomics in nutrition research2022In: Current opinion in clinical nutrition and metabolic care, ISSN 1363-1950, E-ISSN 1473-6519, Vol. 25, no 5, p. 311-318Article, review/survey (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW: This review focuses on the recent findings from lipidomics studies as related to nutrition and health research.

    RECENT FINDINGS: Several lipidomics studies have investigated malnutrition, including both under- and overnutrition. Focus has been both on the early-life nutrition as well as on the impact of overfeeding later in life. Multiple studies have investigated the impact of different macronutrients in lipidome on human health, demonstrating that overfeeding with saturated fat is metabolically more harmful than overfeeding with polyunsaturated fat or carbohydrate-rich food. Diet rich in saturated fat increases the lipotoxic lipids, such as ceramides and saturated fatty-acyl-containing triacylglycerols, increasing also the low-density lipoprotein aggregation rate. In contrast, diet rich in polyunsaturated fatty acids, such as n-3 fatty acids, decreases the triacylglycerol levels, although some individuals are poor responders to n-3 supplementation.

    SUMMARY: The results highlight the benefits of lipidomics in clinical nutrition research, also providing an opportunity for personalized nutrition. An area of increasing interest is the interplay of diet, gut microbiome, and metabolome, and how they together impact individuals' responses to nutritional challenges.

  • 31.
    Chester, Lucy A.
    et al.
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Englund, Amir
    National Addiction Centre (NAC), Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Chesney, Edward
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Oliver, Dominic
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Psychiatry, Oxford University, Warneford Hospital, Oxford, United Kingdom.
    Wilson, Jack
    The Matilda Centre for Research in Mental Health and Substance Use, The University of Sydney, New South Wales, Australia.
    Sovi, Simina
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Dickens, Alex M.
    Turku Bioscience Center, University of Turku and Åbo Akademi University, Turku, Finland; Department of Chemistry, University of Turku, Turku, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Center, University of Turku and Åbo Akademi University, Turku, Finland.
    Linderman, Tuomas
    Turku Bioscience Center, University of Turku and Åbo Akademi University, Turku, Finland.
    Hodsoll, John
    Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Minichino, Amedeo
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Psychiatry, Oxford University, Warneford Hospital, Oxford, United Kingdom.
    Strang, John
    National Addiction Centre (NAC), Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Murray, Robin M
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Freeman, Tom P.
    Department of Psychology, University of Bath, Bath, United Kingdom.
    McGuire, Philip
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Psychiatry, Oxford University, Warneford Hospital, Oxford, United Kingdom.
    Effects of Cannabidiol and Delta-9-Tetrahydrocannabinol on Plasma Endocannabinoid Levels in Healthy Volunteers: A Randomized Double-Blind Four-Arm Crossover Study2022In: Cannabis and cannabinoid research, ISSN 2378-8763Article in journal (Refereed)
    Abstract [en]

    Background: The effects of cannabis are thought to be mediated by interactions between its constituents and the endocannabinoid system. Delta-9-tetrahydrocannabinol (THC) binds to central cannabinoid receptors, while cannabidiol (CBD) may influence endocannabinoid function without directly acting on cannabinoid receptors. We examined the effects of THC coadministered with different doses of CBD on plasma levels of endocannabinoids in healthy volunteers.

    Methods: In a randomized, double-blind, four-arm crossover study, healthy volunteers (n=46) inhaled cannabis vapor containing 10 mg THC plus either 0, 10, 20, or 30 mg CBD, in four experimental sessions. The median time between sessions was 14 days (IQR=20). Blood samples were taken precannabis inhalation and at 0-, 5-, 15-, and 90-min postinhalation. Plasma concentrations of THC, CBD, anandamide, 2-arachidonoylglycerol (2-AG), and related noncannabinoid lipids were measured using liquid chromatography-mass spectrometry.

    Results: Administration of cannabis induced acute increases in plasma concentrations of anandamide (+18.0%, 0.042 ng/mL [95%CI: 0.023-0.062]), and the noncannabinoid ethanolamides, docosatetraenylethanolamide (DEA; +35.8%, 0.012 ng/mL [95%CI: 0.008-0.016]), oleoylethanolamide (+16.1%, 0.184 ng/mL [95%CI: 0.076-0.293]), and N-arachidonoyl-L-serine (+25.1%, 0.011 ng/mL [95%CI: 0.004-0.017]) (p<0.05). CBD had no significant effect on the plasma concentration of anandamide, 2-AG or related noncannabinoid lipids at any of three doses used. Over the four sessions, there were progressive decreases in the preinhalation concentrations of anandamide and DEA, from 0.254 ng/mL [95%CI: 0.223-0.286] to 0.194 ng/mL [95%CI: 0.163-0.226], and from 0.039 ng/mL [95%CI: 0.032-0.045] to 0.027 ng/mL [95%CI: 0.020-0.034] (p<0.05), respectively.

    Discussion: THC induced acute increases in plasma levels of anandamide and noncannabinoid ethanolamides, but there was no evidence that these effects were influenced by the coadministration of CBD. It is possible that such effects may be evident with higher doses of CBD or after chronic administration. The progressive reduction in pretreatment anandamide and DEA levels across sessions may be related to repeated exposure to THC or participants becoming less anxious about the testing procedure and requires further investigation. The study was registered on clinicaltrials.gov (NCT05170217).

  • 32.
    Citerio, Giuseppe
    et al.
    School of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy; Neurointensive Care Unit, Ospedale San Gerardo, Azienda Socio-Sanitaria Territoriale Di Monza, Monza, Italy.
    Robba, Chiara
    Anesthesia and Intensive Care, Policlinico San Martino, IRCCS for Oncology and Neuroscience, Genoa, Italy; Department of Surgical Science and Integrated Diagnostic, University of Genoa, Genoa, Italy.
    Rebora, Paola
    School of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy; Bicocca Bioinformatics Biostatistics and Bioimaging Center B4, School of Medicine and Surgery, University of Milano - Bicocca, Milan, Italy.
    Petrosino, Matteo
    School of Medicine and Surgery, UniversitBicocca Bioinformatics Biostatistics and Bioimaging Center B4, School of Medicine and Surgery, University of Milano - Bicocca, Milan, Italy.
    Rossi, Eleonora
    Department of Clinical-Surgical, Diagnostic and Paediatric Sciences, Unit of Anaesthesia and Intensive Care, University of Pavia, Pavia, Italy.
    Malgeri, Letterio
    Anesthesia and Intensive Care, School of Medicine, Messina, Italy.
    Stocchetti, Nino
    Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Physiopathology and Transplantation, Milan University, Milan, Italy.
    Galimberti, Stefania
    School of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy; Bicocca Bioinformatics Biostatistics and Bioimaging Center B4, School of Medicine and Surgery, University of Milano - Bicocca, Milan, Italy.
    Menon, David K.
    Neurocritical Care Unit, Addenbrooke's Hospital, Cambridge, UK.
    Management of arterial partial pressure of carbon dioxide in the first week after traumatic brain injury: results from the CENTER-TBI study2021In: Intensive Care Medicine, ISSN 0342-4642, E-ISSN 1432-1238, Vol. 47, no 9, p. 961-973Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To describe the management of arterial partial pressure of carbon dioxide (PaCO2) in severe traumatic brain-injured (TBI) patients, and the optimal target of PaCO2 in patients with high intracranial pressure (ICP).

    METHODS: Secondary analysis of CENTER-TBI, a multicentre, prospective, observational, cohort study. The primary aim was to describe current practice in PaCO2 management during the first week of intensive care unit (ICU) after TBI, focusing on the lowest PaCO2 values. We also assessed PaCO2 management in patients with and without ICP monitoring (ICPm), and with and without intracranial hypertension. We evaluated the effect of profound hyperventilation (defined as PaCO2 < 30 mmHg) on long-term outcome.

    RESULTS: We included 1100 patients, with a total of 11,791 measurements of PaCO2 (5931 lowest and 5860 highest daily values). The mean (± SD) PaCO2 was 38.9 (± 5.2) mmHg, and the mean minimum PaCO2 was 35.2 (± 5.3) mmHg. Mean daily minimum PaCO2 values were significantly lower in the ICPm group (34.5 vs 36.7 mmHg, p < 0.001). Daily PaCO2 nadir was lower in patients with intracranial hypertension (33.8 vs 35.7 mmHg, p < 0.001). Considerable heterogeneity was observed between centers. Management in a centre using profound hyperventilation (HV) more frequently was not associated with increased 6 months mortality (OR = 1.06, 95% CI = 0.77-1.45, p value = 0.7166), or unfavourable neurological outcome (OR 1.12, 95% CI = 0.90-1.38, p value = 0.3138).

    CONCLUSIONS: Ventilation is manipulated differently among centers and in response to intracranial dynamics. PaCO2 tends to be lower in patients with ICP monitoring, especially if ICP is increased. Being in a centre which more frequently uses profound hyperventilation does not affect patient outcomes.

  • 33.
    Clish, Clary B.
    et al.
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Davidov, Eugene
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Oresic, Matej
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Plasterer, Thomas N.
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Lavine, Gary
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Londo, Tom
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Meys, Michael
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Snell, Philip
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Stochaj, Wayne
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Adourian, Aram
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Zhang, Xiang
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Morel, Nicole
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Neumann, Eric
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Verheij, Elwin
    TNO Pharma, Zeist, Netherlands.
    Vogels, Jack T. W. E.
    TNO Pharma, Zeist, Netherlands.
    Havekes, Louis M.
    TNO Prevention and Health, Gaubius Laboratorium, Leiden, Netherlands; Departments of Cardiology and Internal Medicine and Leiden Center for Cardiovascular Research, Leiden University Medical Center, Leiden, Netherlands.
    Afeyan, Noubar
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Regnier, Fred
    Department of Chemistry, Purdue University, Lafayette, Indiana, USA.
    van der Greef, Jan
    Beyond Genomics, Inc., Waltham, Massachusetts, USA; TNO Pharma, Zeist, Netherlands; Division of Analytical Biosciences, Leiden/Amsterdam Centre for Drug Research, Leiden University, Leiden, Netherlands.
    Naylor, Stephen
    Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Integrative biological analysis of the APOE*3-leiden transgenic mouse2004In: Omics, ISSN 1536-2310, E-ISSN 1557-8100, Vol. 8, no 1, p. 3-13Article in journal (Refereed)
    Abstract [en]

    Integrative (or systems biology) is a new approach to analyzing biological entities as integrated systems of genetic, genomic, protein, metabolite, cellular, and pathway events that are in flux and interdependent. Here, we demonstrate the application of intregrative biological analysis to a mammalian disease model, the apolipoprotein E3-Leiden (APO*E3) transgenic mouse. Mice selected for the study were fed a normal chow diet and sacrificed at 9 weeks of age-conditions under which they develop only mild type I and II atherosclerotic lesions. Hepatic mRNA expression analysis showed a 25% decrease in APO A1 and a 43% increase in liver fatty acid binding protein expression between transgenic and wild type control mice, while there was no change in PPAR-alpha expression. On-line high performance liquid chromatography-mass spectrometry quantitative profiling of tryptic digests of soluble liver proteins and liver lipids, coupled with principle component analysis, enabled rapid identification of early protein and metabolite markers of disease pathology. These included a 44% increase in L-FABP in transgenic animals compared to controls, as well as an increase in triglycerides and select bioactive lysophosphatidylcholine species. A correlation analysis of identified genes, proteins, and lipids was used to construct an interaction network. Taken together, these results indicate that integrative biology is a powerful tool for rapid identification of early markers and key components of pathophysiologic processes, and constitute the first application of this approach to a mammalian system.

  • 34.
    Curtis, R. Keira
    et al.
    University of Cambridge Department of Clinical Biochemistry, Box 232, Addenbrooke’s Hospital, Hills Road, Cambridge, UK.
    Oresic, Matej
    Technical Research Centre of Finland, VTT Biotechnology, Espoo, Finland.
    Vidal-Puig, Antonio
    University of Cambridge Department of Clinical Biochemistry, Box 232, Addenbrooke’s Hospital, Hills Road, Cambridge, UK.
    Pathways to the analysis of microarray data2005In: Trends in Biotechnology, ISSN 0167-7799, E-ISSN 1879-3096, Vol. 23, no 8, p. 429-435Article, review/survey (Refereed)
    Abstract [en]

    The development of microarray technology allows the simultaneous measurement of the expression of many thousands of genes. The information gained offers an unprecedented opportunity to fully characterize biological processes. However, this challenge will only be successful if new tools for the efficient integration and interpretation of large datasets are available. One of these tools, pathway analysis, involves looking for consistent but subtle changes in gene expression by incorporating either pathway or functional annotations. We review several methods of pathway analysis and compare the performance of three, the binomial distribution, z scores, and gene set enrichment analysis, on two microarray datasets. Pathway analysis is a promising tool to identify the mechanisms that underlie diseases, adaptive physiological compensatory responses and new avenues for investigation.

  • 35.
    Davidov, Eugene
    et al.
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Clish, Clary B.
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Oresic, Matej
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Meys, Michael
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Stochaj, Wayne
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Snell, Philip
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Lavine, Gary
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Londo, Thomas R.
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Adourian, Aram
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Zhang, Xiang
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Johnston, Mark
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Morel, Nicole
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Marple, Edward W.
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Plasterer, Thomas N.
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Neumann, Eric
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Verheij, Elwin
    TNO Pharma, Zeist, The Netherlands.
    Vogels, Jack T. W. E.
    TNO Pharma, Zeist, The Netherlands.
    Havekes, Louis M.
    TNO Prevention and Health, Gaubius Laboratorium, Leiden, The Netherlands; Departments of Cardiology and Internal Medicine and Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
    van der Greef, Jan
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA; TNO Pharma, Zeist, The Netherlands; Departments of Cardiology and Internal Medicine and Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
    Naylor, Stephen
    1Beyond Genomics, Inc., Waltham, Massachusetts, USA.
    Methods for the differential integrative omic analysis of plasma from a transgenic disease animal model2004In: Omics, ISSN 1536-2310, E-ISSN 1557-8100, Vol. 8, no 4, p. 267-288Article in journal (Refereed)
    Abstract [en]

    Multitiered quantitative analysis of biological systems is rapidly becoming the desired approach to study hierarchical functional interactions between proteins and metabolites. We describe here a novel systematic approach to analyze organisms with complex metabolic regulatory networks. By using precise analytical methods to measure biochemical constituents and their relative abundance in whole plasma of transgenic ApoE*3-Leiden mice and an isogenic wild-type control group, simultaneous snapshots of metabolic and protein states were obtained. Novel data processing and multivariate analysis tools such as Impurity Resolution Software (IMPRESS) and Windows-based linear fit program (WINLIN) were used to compare protein and metabolic profiles in parallel. Canonical correlations of the resulting data show quantitative relationships between heterogeneous components in the TG animals. These results, obtained solely from whole plasma analysis allowed us, in a rapid manner, to corroborate previous findings as well as find new events pertaining to dominant and peripheral events in lipoprotein metabolism of a genetically modified mammalian organism in relation to ApoE3, a key mediator of lipoprotein metabolism.

  • 36.
    de Mas, Igor Marin
    et al.
    Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain;; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain.
    Selivanov, Vitaly A.
    Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain; A.N.Belozersky Institute of Physico-Chemical Biology, Moscow, Russia.
    Marin, Silvia
    Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain;; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain.
    Roca, Josep
    Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS),Centro de Investigación Biomédica en Red de Enfermedade Respiratorias (CIBERES) Universitat de Barcelona, Barcelona, Spain.
    Oresic, Matej
    Technical Research Centre of Finland, Espoo, Finland; Institute for Molecular Medicine, Helsinki, Finland.
    Agius, Loranne
    Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle, UK.
    Cascante, Marta
    Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain.
    Compartmentation of glycogen metabolism revealed from 13C isotopologue distributions2011In: BMC Systems Biology, E-ISSN 1752-0509, Vol. 5, article id 175Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Stable isotope tracers are used to assess metabolic flux profiles in living cells. The existing methods of measurement average out the isotopic isomer distribution in metabolites throughout the cell, whereas the knowledge of compartmental organization of analyzed pathways is crucial for the evaluation of true fluxes. That is why we accepted a challenge to create a software tool that allows deciphering the compartmentation of metabolites based on the analysis of average isotopic isomer distribution.

    RESULTS: The software Isodyn, which simulates the dynamics of isotopic isomer distribution in central metabolic pathways, was supplemented by algorithms facilitating the transition between various analyzed metabolic schemes, and by the tools for model discrimination. It simulated 13C isotope distributions in glucose, lactate, glutamate and glycogen, measured by mass spectrometry after incubation of hepatocytes in the presence of only labeled glucose or glucose and lactate together (with label either in glucose or lactate). The simulations assumed either a single intracellular hexose phosphate pool, or also channeling of hexose phosphates resulting in a different isotopic composition of glycogen. Model discrimination test was applied to check the consistency of both models with experimental data. Metabolic flux profiles, evaluated with the accepted model that assumes channeling, revealed the range of changes in metabolic fluxes in liver cells.

    CONCLUSIONS: The analysis of compartmentation of metabolic networks based on the measured 13C distribution was included in Isodyn as a routine procedure. The advantage of this implementation is that, being a part of evaluation of metabolic fluxes, it does not require additional experiments to study metabolic compartmentation. The analysis of experimental data revealed that the distribution of measured 13C-labeled glucose metabolites is inconsistent with the idea of perfect mixing of hexose phosphates in cytosol. In contrast, the observed distribution indicates the presence of a separate pool of hexose phosphates that is channeled towards glycogen synthesis.

  • 37.
    de Mello, V. D. F.
    et al.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Lankinen, M.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland; VTT Technical Research Centre of Finland, Espoo, Finland.
    Schwab, U.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland; Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
    Kolehmainen, M.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Lehto, S.
    Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
    Seppänen-Laakso, T.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Pulkkinen, L.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Uusitupa, M
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Erkkilä, A. T.
    Department of Public Health, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease2009In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 12, p. 2612-2615Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: Ceramides and IL-6 have a role in immune-inflammatory responses and cardiovascular diseases, and are suggested to be involved in insulin and glucose metabolism. We sought to assess the associations of circulating levels of IL-6, TNF-alpha and high-sensitivity C reactive protein (hsCRP), which are inflammatory markers related to insulin resistance (IR), with the plasma lipid metabolites ceramides and diacylglycerols (DAG) in patients with CHD.

    METHODS: Cross-sectional analyses were carried out on data from 33 patients with CHD. Serum levels of the inflammatory markers and plasma lipid metabolites (lipidomics approach performed by ultra-performance liquid chromatography coupled to electrospray ionisation MS) were measured at the same time point as insulin resistance (IR) (HOMA-IR index).

    RESULTS: Serum circulating levels of IL-6 were strongly correlated with plasma ceramide concentrations (r = 0.59, p < 0.001). Adjustments for serum TNF-alpha or hsCRP levels, smoking, BMI, age, sex or HOMA-IR did not change the results (p < 0.001). After adjustments for the effect of serum inflammatory markers (TNF-alpha or hsCRP), HOMA-IR and BMI the correlation between plasma DAG and serum IL-6 (r = 0.33) was also significant (p < 0.03). In a linear regression model, circulating levels of both ceramides and TNF-alpha had a significant independent influence on circulating levels of IL-6, altogether accounting for 41% of its variation (p < 0.001).

    CONCLUSIONS/INTERPRETATION: Our results strongly suggest that the link between ceramides, IR and inflammation is related to the inflammatory marker IL-6. Ceramides may contribute to the induction of inflammation involved in IR states that frequently coexist with CHD.

  • 38.
    de Mello, Vanessa D. F.
    et al.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Erkkilä, Arja T.
    Department of Public Health, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Schwab, Ursula S.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland; Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
    Pulkkinen, Leena
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Kolehmainen, Marjukka
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Atalay, Mustafa
    Department of Physiology, Institute of Biomedicine, University of Kuopio, Kuopio, Finland.
    Mussalo, Hanna
    Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
    Lankinen, Maria
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland; VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Lehto, Seppo
    Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
    Uusitupa, Matti
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    The effect of fatty or lean fish intake on inflammatory gene expression in peripheral blood mononuclear cells of patients with coronary heart disease2009In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 48, no 8, p. 447-455Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Little is known about the effect of fish consumption on gene expression of inflammation-related genes in immune cells in coronary heart disease (CHD).

    AIM OF THE STUDY: We sought to evaluate the effect of a fatty fish (FF) or a lean fish (LF) diet on the modulation of inflammatory and endothelial function-related genes in peripheral blood mononuclear cells (PBMCs) of subjects with CHD, and its association with serum fatty acid (FA) profile and lipid metabolic compounds.

    METHODS: Data from 27 patients randomized into an 8-week FF (n = 10; mean +/- SD: 4.3 +/- 0.4 portions of fish per week), LF (n = 11; 4.7 +/- 1.1 portions of fish per week), or control diet (n = 6; 0.6 +/- 0.4 portions of fish per week) were analyzed. The mRNA expression was measured using real-time PCR.

    RESULTS: The effect of the intervention on the mRNA expression of the genes studied did not differ among groups. In the FF group, however, the decrease in arachidonic acid to eicosapentaenoic acid (AA:EPA) ratio in cholesterol ester and phospholipid fractions strongly correlated with the change in IL1B mRNA levels (r (s) = 0.60, P = 0.06 and r (s) = 0.86, P = 0.002, respectively). In the LF group, the decrease in palmitic acid and total saturated FAs in cholesterol esters correlated with the change in intercellular cell adhesion molecule-1 (ICAM1) expression (r (s) = 0.64, P = 0.04 for both). Circulating levels of soluble ICAM-1 decreased only in the LF group (P < 0.05).

    CONCLUSIONS: The intake of FF or LF diet did not alter the expression of inflammatory and endothelial function-related genes in PBMCs of patients with CHD. However, the decrease in AA:EPA ratio in serum lipids in the FF group may induce an anti-inflammatory response at mRNA levels in PBMCs. A LF diet might benefit endothelial function, possibly mediated by the changes in serum FA composition.

  • 39.
    Denkert, Carsten
    et al.
    Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
    Bucher, Elmar
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland, Espoo and Turku, Finland.
    Hilvo, Mika
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland, Espoo and Turku, Finland.
    Salek, Reza
    Department of Biochemistry, University of Cambridge, Cambridge, UK.
    Oresic, Matej
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland, Espoo and Turku, Finland.
    Griffin, Julian
    Department of Biochemistry, University of Cambridge, Cambridge, UK.
    Brockmöller, Scarlet
    Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
    Klauschen, Frederick
    Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
    Loibl, Sibylle
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Barupal, Dinesh Kumar
    Genome Center, University of California, Davis CA, USA.
    Budczies, Jan
    Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
    Iljin, Kristiina
    Biotechnology for Health and Well-being, VTT Technical Research Centre of Finland, Espoo and Turku, Finland.
    Nekljudova, Valentina
    German Breast Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
    Fiehn, Oliver
    Genome Center, University of California, Davis CA, USA.
    Metabolomics of human breast cancer: new approaches for tumor typing and biomarker discovery2012In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 4, no 4, article id 37Article, review/survey (Refereed)
    Abstract [en]

    Breast cancer is the most common cancer in women worldwide, and the development of new technologies for better understanding of the molecular changes involved in breast cancer progression is essential. Metabolic changes precede overt phenotypic changes, because cellular regulation ultimately affects the use of small-molecule substrates for cell division, growth or environmental changes such as hypoxia. Differences in metabolism between normal cells and cancer cells have been identified. Because small alterations in enzyme concentrations or activities can cause large changes in overall metabolite levels, the metabolome can be regarded as the amplified output of a biological system. The metabolome coverage in human breast cancer tissues can be maximized by combining different technologies for metabolic profiling. Researchers are investigating alterations in the steady state concentrations of metabolites that reflect amplified changes in genetic control of metabolism. Metabolomic results can be used to classify breast cancer on the basis of tumor biology, to identify new prognostic and predictive markers and to discover new targets for future therapeutic interventions. Here, we examine recent results, including those from the European FP7 project METAcancer consortium, that show that integrated metabolomic analyses can provide information on the stage, subtype and grade of breast tumors and give mechanistic insights. We predict an intensified use of metabolomic screens in clinical and preclinical studies focusing on the onset and progression of tumor development.

  • 40.
    Dickens, Alex M.
    et al.
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Borgan, Faith
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Laurikainen, Heikki
    Department of Psychiatry, University of Turku, Turku, Finland; Turku PET Centre, Turku University Hospital, Turku, Finland.
    Lamichhane, Santosh
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Marques, Tiago
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Rönkkö, Tuukka
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Veronese, Mattia
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Lindeman, Tuomas
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Howes, Oliver
    Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.
    Hietala, Jarmo
    Department of Psychiatry, University of Turku, Turku, Finland; Turku PET Centre, Turku University Hospital, Turku, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Links between central CB1-receptor availability and peripheral endocannabinoids in patients with first episode psychosis2020In: NPJ schizophrenia, E-ISSN 2334-265X, Vol. 6, no 1, article id 21Article in journal (Refereed)
    Abstract [en]

    There is an established, link between psychosis and metabolic abnormalities, such as altered glucose metabolism and dyslipidemia, which often precede the initiation of antipsychotic treatment. It is known that obesity-associated metabolic disorders are promoted by activation of specific cannabinoid targets (endocannabinoid system (ECS)). Our recent data suggest that there is a change in the circulating lipidome at the onset of first episode psychosis (FEP). With the aim of characterizing the involvement of the central and peripheral ECSs, and their mutual associations; here, we performed a combined neuroimaging and metabolomic study in patients with FEP and healthy controls (HC). Regional brain cannabinoid receptor type 1 (CB1R) availability was quantified in two, independent samples of patients with FEP (n = 20 and n = 8) and HC (n = 20 and n = 10), by applying three-dimensional positron emission tomography, using two radiotracers, [11C]MePPEP and [18F]FMPEP-d2. Ten endogenous cannabinoids or related metabolites were quantified in serum, drawn from these individuals during the same imaging session. Circulating levels of arachidonic acid and oleoylethanolamide (OEA) were reduced in FEP individuals, but not in those who were predominantly medication free. In HC, there was an inverse association between levels of circulating arachidonoyl glycerol, anandamide, OEA, and palmitoyl ethanolamide, and CB1R availability in the posterior cingulate cortex. This phenomenon was, however, not observed in FEP patients. Our data thus provide evidence of cross talk, and dysregulation between peripheral endocannabinoids and central CB1R availability in FEP.

  • 41.
    Dickens, Alex M.
    et al.
    Turku Bioscience Center, University of Turku and Åbo Akademi University, Turku, Finland.
    Sen, Partho
    Turku Bioscience Center, University of Turku and Åbo Akademi University, Turku, Finland.
    Kempton, Matthew J.
    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Barrantes-Vidal, Neus
    Departament de Psicologia Clínica i de la Salut, Universitat Autònoma de Barcelona, Fundació Sanitària Sant Pere Claver, Spanish Mental Health Research Network, Barcelona, Spain.
    Iyegbe, Conrad
    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Nordentoft, Merete
    Mental Health Center Copenhagen and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Center Glostrup, Mental Health Services in the Capital Region of Copenhagen, University of Copenhagen, Glostrup, Denmark.
    Pollak, Thomas
    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Riecher-Rössler, Anita
    University Psychiatric Hospital, Basel, Switzerland.
    Ruhrmann, Stephan
    Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
    Sachs, Gabriele
    Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
    Bressan, Rodrigo
    Lab Interdisciplinar Neurociências Clínicas, Departimento Psiquiatria, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
    Krebs, Marie-Odile
    University of Paris, Groupe Hospitalier Universitaire Paris Sainte-Anne, Centre d'Évaluation Pour Jeunes Adultes et Adolescents, Institut National de la Santé et de la Recherche Médicale, Institut de Psychiatrie, Paris, France.
    Amminger, G. Paul
    Centre for Youth Mental Health, University of Melbourne, Parkville, Victoria, Australia.
    de Haan, Lieuwe
    Department of Psychiatry, Amsterdam University Medical Center, Faculty of Behavioural and Movement Sciences, Vrije Universiteit, Amsterdam, The Netherlands.
    van der Gaag, Mark
    Department of Clinical Psychology and EMGO+ Institute for Health and Care Research, Faculty of Behavioural and Movement Sciences, Vrije Universiteit, Amsterdam, The Netherlands; Department of Psychosis Research, Parnassia Psychiatric Institute, The Hague, The Netherlands.
    Valmaggia, Lucia
    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Center, University of Turku and Åbo Akademi University, Turku, Finland.
    McGuire, Philip
    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Dysregulated Lipid Metabolism Precedes Onset of Psychosis2021In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 89, no 3, p. 288-297Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A key clinical challenge in the management of individuals at clinical high risk for psychosis (CHR) is that it is difficult to predict their future clinical outcomes. Here, we investigated if the levels of circulating molecular lipids are related to adverse clinical outcomes in this group.

    METHODS: Serum lipidomic analysis was performed in 263 CHR individuals and 51 healthy control subjects, who were then clinically monitored for up to 5 years. Machine learning was used to identify lipid profiles that discriminated between CHR and control subjects, and between subgroups of CHR subjects with distinct clinical outcomes.

    RESULTS: At baseline, compared with control subjects, CHR subjects (independent of outcome) had higher levels of triacylglycerols with a low acyl carbon number and a double bond count, as well as higher levels of lipids in general. CHR subjects who subsequently developed psychosis (n = 50) were distinguished from those that did not (n = 213) on the basis of lipid profile at baseline using a model with an area under the receiver operating curve of 0.81 (95% confidence interval = 0.69-0.93). CHR subjects who became psychotic had lower levels of ether phospholipids than CHR individuals who did not (p < .01).

    CONCLUSIONS: Collectively, these data suggest that lipidomic abnormalities predate the onset of psychosis and that blood lipidomic measures may be useful in predicting which CHR individuals are most likely to develop psychosis.

  • 42.
    Dickens, Alex Mountfort
    et al.
    Turku Centre for Biotechnology, University of Turku, Turku, Finland .
    Posti, Jussi P.
    Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital, Turku, Finland; Department of Neurology, University of Turku, Turku, Finland; Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital, Turku, Finland .
    Takala, Riikka Sk.
    Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland .
    Ala-Seppälä, Henna Maria
    Department of Neurology,University of Turku, Turku, Finland .
    Mattila, Ismo
    Steno Diabetes Center AS, Gentofte, Denmark.
    Coles, Jonathan Coles
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Frantzén, Janek
    Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital, Turku, Finland; Department of Neurology, University of Turku, Turku, Finland; Division of Clinical Neurosciences, Department of Neurosurgery,Turku University Hospital, Turku, Finland .
    Hutchinson, Peter John
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Katila, Ari J.
    Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland.
    Kyllönen, Anna
    Department of Neurology, University of Turku, Turku, Finland .
    Maanpää, Henna-Riikka
    Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland.
    Newcombe, Virginia
    Division of Anaesthesia, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom of Great Britain and Norther Ireland.
    Outtrim, Joanne
    Division of Anaesthesia, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Tallus, Jussi
    Division of Anaesthesia, Addenbrooke's Hospital, Hills Road, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Carpenter, Keri
    Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Menon, David
    Head, Division of Anaesthesia, Addenbrooke's Hospital, Cambridge, United Kingdom of Great Britain and Northern Ireland .
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Tenovuo, Olli
    Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital, Turku, Finland; Department of Neurology, University of Turku, Turku, Finland .
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Centre for Biotechnology, University of Turku, Turku, Finland.
    Serum Metabolites Associated with Computed TomographyFindings after Traumatic Brain Injury2018In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 22, p. 2673-2683Article in journal (Refereed)
    Abstract [en]

    There is a need to rapidly detect patients with traumatic brain injury (TBI) who require head computed tomography (CT). Given the energy crisis in the brain following TBI, we hypothesized that serum metabolomics would be a useful tool for developing a set of biomarkers to determine the need for CT and to distinguish between different types of injuries observed. Logistic regression models using metabolite data from the discovery cohort (n=144, Turku, Finland) were used to distinguish between patients with traumatic intracranial findings and negative findings on head CT. The resultant models were then tested in the validation cohort (n=66, Cambridge, UK). The levels of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 were also quantified in the serum from the same patients. Despite there being significant differences in the protein biomarkers in patients with TBI, the model that determined the need for a CT scan validated poorly (AUC=0.64: Cambridge patients). However, using a combination of six metabolites (two amino acids, three sugar derivatives and one ketoacid) it was possible to discriminate patients with intracranial abnormalities on CT and patients with a normal CT (AUC=0.77 in Turku patients and AUC=0.73 in Cambridge patients). Furthermore, a combination of three metabolites could distinguish between diffuse brain injuries and mass lesions (AUC=0.87 in Turku patients and AUC=0.68 in Cambridge patients). This study identifies a set of validated serum polar metabolites, which associate with the need for a CT scan. Additionally, serum metabolites can also predict the nature of the brain injury. These metabolite markers may prevent unnecessary CT scans, thus reducing the cost of diagnostics and radiation load.

  • 43.
    Dijkland, Simone A.
    et al.
    Department of Public Health, Center for Medical Decision Making, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
    Helmrich, Isabel R. A. Retel
    Department of Public Health, Center for Medical Decision Making, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
    Nieboer, Daan
    Department of Public Health, Center for Medical Decision Making, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
    van der Jagt, Mathieu
    Department of Intensive Care, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
    Dippel, Diederik W. J.
    Department of Neurology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
    Menon, David K.
    Division of Anesthesia, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Stocchetti, Nino
    Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Department of Anesthesia and Critical Care, Neuroscience Intensive Care Unit, Milan, Italy.
    Maas, Andrew I. R.
    Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Edegem, Belgium.
    Lingsma, Hester F.
    Department of Public Health, Center for Medical Decision Making, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
    Steyerberg, Ewout W.
    Department of Public Health, Center for Medical Decision Making, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands.
    CENTER-TBI Participants and Investigators, -
    Outcome Prediction after Moderate and Severe Traumatic Brain Injury: External Validation of Two Established Prognostic Models in 1742 European Patients2021In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 38, no 10, p. 1377-1388Article in journal (Refereed)
    Abstract [en]

    The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticoid Randomisation After Significant Head injury (CRASH) prognostic models predict functional outcome after moderate and severe traumatic brain injury (TBI). We aimed to assess their performance in a contemporary cohort of patients across Europe. The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core study is a prospective, observational cohort study in patients presenting with TBI and an indication for brain computed tomography. The CENTER-TBI core cohort consists of 4509 TBI patients available for analyses from 59 centers in 18 countries across Europe and Israel. The IMPACT validation cohort included 1173 patients with GCS ≤12, age ≥14, and 6-month Glasgow Outcome Scale-Extended (GOSE) available. The CRASH validation cohort contained 1742 patients with GCS ≤14, age ≥16, and 14-day mortality or 6-month GOSE available. Performance of the three IMPACT and two CRASH model variants was assessed with discrimination (area under the receiver operating characteristic curve; AUC) and calibration (comparison of observed vs. predicted outcome rates). For IMPACT, model discrimination was good, with AUCs ranging between 0.77 and 0.85 in 1173 patients and between 0.80 and 0.88 in the broader CRASH selection (n = 1742). For CRASH, AUCs ranged between 0.82 and 0.88 in 1742 patients and between 0.66 and 0.80 in the stricter IMPACT selection (n = 1173). Calibration of the IMPACT and CRASH models was generally moderate, with calibration-in-the-large and calibration slopes ranging between -2.02 and 0.61 and between 0.48 and 1.39, respectively. The IMPACT and CRASH models adequately identify patients at high risk for mortality or unfavorable outcome, which supports their use in research settings and for benchmarking in the context of quality-of-care assessment.

  • 44.
    Duszka, Kalina
    et al.
    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; Center for Integrative Genomics, University of Lausanne, Génopode, Lausanne, Switzerland; Department of Nutritional Sciences, University of Vienna, Vienna, Austria.
    Oresic, Matej
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi University,Turku, Finland.
    Le May, Cedric
    Institut du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France.
    König, Jürgen
    Department of Nutritional Sciences, University of Vienna, Vienna, Austria; Vienna Metabolomics Center (VIME), University of Vienna, Vienna, Austria.
    Wahli, Walter
    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; Center for Integrative Genomics, University of Lausanne Génopode, Lausanne, Switzerland; ToxAlim, Research Center in Food Toxicology, National Institute for Agricultural Research (INRA), Toulouse, France.
    PPARγ Modulates Long Chain Fatty Acid Processing in the Intestinal Epithelium2017In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 18, no 12, article id E2559Article in journal (Refereed)
    Abstract [en]

    Nuclear receptor PPARγ affects lipid metabolism in several tissues, but its role in intestinal lipid metabolism has not been explored. As alterations have been observed in the plasma lipid profile of ad libitum fed intestinal epithelium-specific PPARγ knockout mice (iePPARγKO), we submitted these mice to lipid gavage challenges. Within hours after gavage with long chain unsaturated fatty acid (FA)-rich canola oil, the iePPARγKO mice had higher plasma free FA levels and lower gastric inhibitory polypeptide levels than their wild-type (WT) littermates, and altered expression of incretin genes and lipid metabolism-associated genes in the intestinal epithelium. Gavage with the medium chain saturated FA-rich coconut oil did not result in differences between the two genotypes. Furthermore, the iePPARγKO mice did not exhibit defective lipid uptake and stomach emptying; however, their intestinal transit was more rapid than in WT mice. When fed a canola oil-rich diet for 4.5 months, iePPARγKO mice had higher body lean mass than the WT mice. We conclude that intestinal epithelium PPARγ is activated preferentially by long chain unsaturated FAs compared to medium chain saturated FAs. Furthermore, we hypothesize that the iePPARγKO phenotype originates from altered lipid metabolism and release in epithelial cells, as well as changes in intestinal motility.

  • 45.
    Elo, Laura L.
    et al.
    Department of Mathematics, University of Turku, Turku, Finland; Turku Centre for Biotechnology, Turku, Finland.
    Järvenpää, Henna
    Turku Centre for Biotechnology, Turku, Finland.
    Oresic, Matej
    Turku Centre for Biotechnology, Turku, Finland; VTT Biotechnology, Espoo, Finland.
    Lahesmaa, Riitta
    Turku Centre for Biotechnology, Turku, Finland.
    Aittokallio, Tero
    Department of Mathematics, University of Turku, Turku, Finland; Turku Centre for Biotechnology, Turku, Finland; Systems Biology Unit, Institut Pasteur, Paris, France.
    Systematic construction of gene coexpression networks with applications to human T helper cell differentiation process2007In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 23, no 16, p. 2096-2103Article in journal (Refereed)
    Abstract [en]

    MOTIVATION: Coexpression networks have recently emerged as a novel holistic approach to microarray data analysis and interpretation. Choosing an appropriate cutoff threshold, above which a gene-gene interaction is considered as relevant, is a critical task in most network-centric applications, especially when two or more networks are being compared.

    RESULTS: We demonstrate that the performance of traditional approaches, which are based on a pre-defined cutoff or significance level, can vary drastically depending on the type of data and application. Therefore, we introduce a systematic procedure for estimating a cutoff threshold of coexpression networks directly from their topological properties. Both synthetic and real datasets show clear benefits of our data-driven approach under various practical circumstances. In particular, the procedure provides a robust estimate of individual degree distributions, even from multiple microarray studies performed with different array platforms or experimental designs, which can be used to discriminate the corresponding phenotypes. Application to human T helper cell differentiation process provides useful insights into the components and interactions controlling this process, many of which would have remained unidentified on the basis of expression change alone. Moreover, several human-mouse orthologs showed conserved topological changes in both systems, suggesting their potential importance in the differentiation process.

    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

  • 46.
    Elo, Laura L.
    et al.
    Biomathematics Research Group, Department of Mathematics, University of Turku, Turku, Finland; Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland.
    Järvenpää, Henna
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland; Turku Graduate School of Biomedical Sciences, Turku, Finland.
    Tuomela, Soile
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland; Turku Graduate School of Biomedical Sciences, Turku, Finland.
    Raghav, Sunil
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland.
    Ahlfors, Helena
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland; The National Graduate School in Informational and Structural Biology, Åbo Akademi University, Turku, Finland.
    Laurila, Kirsti
    Department of Signal Processing, Tampere University of Technology, Tampere, Finland.
    Gupta, Bhawna
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland.
    Lund, Riikka J.
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland; Department of Biological Science, University of Sheffield, Sheffield, United Kingdom.
    Tahvanainen, Johanna
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland; Drug Discovery Graduate School, University of Turku, Turku, Finland.
    Hawkins, R. David
    Ludwig Institute for Cancer Research, University of California, San Diego CA, United States.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Lähdesmäki, Harri
    Department of Signal Processing, Tampere University of Technology, Tampere, Finland; Department of Information and Computer Science, Helsinki University of Technology, Helsinki, Finland.
    Rasool, Omid
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland.
    Rao, Kanury V.
    Biomathematics Research Group, Department of Mathematics, University of Turku, Turku, Finland.
    Aittokallio, Tero
    International Centre for Genetic Engineering and Biotechnology, New Delhi, India; Immune Disease Institute, Harvard Medical School, Boston MA, United States.
    Lahesmaa, Riitta
    Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland; Immune Disease Institute, Harvard Medical School, Boston MA, United States.
    Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming2010In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 32, no 6, p. 852-862Article in journal (Refereed)
    Abstract [en]

    Dissecting the molecular mechanisms by which T helper (Th) cells differentiate to effector Th2 cells is important for understanding the pathogenesis of immune-mediated diseases, such as asthma and allergy. Because the STAT6 transcription factor is an upstream mediator required for interleukin-4 (IL-4)-induced Th2 cell differentiation, its targets include genes important for this process. Using primary human CD4(+) T cells, and by blocking STAT6 with RNAi, we identified a number of direct and indirect targets of STAT6 with ChIP sequencing. The integration of these data sets with detailed kinetics of IL-4-driven transcriptional changes showed that STAT6 was predominantly needed for the activation of transcription leading to the Th2 cell phenotype. This integrated genome-wide data on IL-4- and STAT6-mediated transcription provide a unique resource for studies on Th cell differentiation and, in particular, for designing interventions of human Th2 cell responses.

  • 47.
    Elo, Laura L.
    et al.
    Department of Mathematics, University of Turku, Turku, Finland; Turku Centre for Biotechnology, Turku, Finland.
    Katajamaa, Mikko
    Turku Centre for Biotechnology, Turku, Finland.
    Lund, Riikka
    Turku Centre for Biotechnology, Turku, Finland.
    Oresic, Matej
    Turku Centre for Biotechnology, Turku, Finland; VTT Biotechnology, Espoo, Finland.
    Lahesmaa, Riitta
    Turku Centre for Biotechnology, Turku, Finland.
    Aittokallio, Tero
    Department of Mathematics, University of Turku, Turku, Finland; Turku Centre for Biotechnology, Turku, Finland; Systems Biology Unit, Institut Pasteur, Paris, France.
    Improving identification of differentially expressed genes by integrative analysis of Affymetrix and Illumina arrays2006In: Omics, ISSN 1536-2310, E-ISSN 1557-8100, Vol. 10, no 3, p. 369-380Article in journal (Refereed)
    Abstract [en]

    Together with the widely used Affymetrix microarrays, the recently introduced Illumina platform has become a cost-effective alternative for genome-wide studies. To efficiently use data from both array platforms, there is a pressing need for methods that allow systematic integration of multiple datasets, especially when the number of samples is small. To address these needs, we introduce a meta-analytic procedure for combining Affymetrix and Illumina data in the context of detecting differentially expressed genes between the platforms. We first investigate the effect of different expression change estimation procedures within the platforms on the agreement of the most differentially expressed genes. Using the best estimation methods, we then show the benefits of the integrative analysis in producing reproducible results across bootstrap samples. In particular, we demonstrate its biological relevance in identifying small but consistent changes during T helper 2 cell differentiation.

  • 48.
    Fan, Yong
    et al.
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
    Støving, René Klinkby
    Center for Eating Disorders, Odense University Hospital, and Research Unit for Medical Endocrinology, Mental Health Services in the Region of Southern Denmark, Open Patient data Explorative Network (OPEN) and Clinical Institute, University of Southern Denmark, Odense, Denmark.
    Berreira Ibraim, Samar
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Thirion, Florence
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Arora, Tulika
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
    Lyu, Liwei
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark; Department of Medicine, University of Copenhagen and Herlev-Gentofte University Hospital, Copenhagen, Denmark.
    Stankevic, Evelina
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
    Hansen, Tue Haldor
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
    Déchelotte, Pierre
    INSERM U1073 Research Unit and TargEDys, Rouen University, Rouen, France.
    Sinioja, Tim
    Örebro University, School of Science and Technology.
    Ragnarsdottir, Oddny
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Pons, Nicolas
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Galleron, Nathalie
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Quinquis, Benoît
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Levenez, Florence
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Roume, Hugo
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
    Falony, Gwen
    Laboratory of Molecular bacteriology, Department of Microbiology and Immunology, Rega Institute Ku Leuven, Leuven, Belgium; Center for Microbiology, VIB, Leuven, Belgium; Institute of Medical Microbiology and Hygiene and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Institute of Molecular Biology (IMB), Mainz, Germany.
    Vieira-Silva, Sara
    Laboratory of Molecular bacteriology, Department of Microbiology and Immunology, Rega Institute Ku Leuven, Leuven, Belgium; Center for Microbiology, VIB, Leuven, Belgium; Institute of Medical Microbiology and Hygiene and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Institute of Molecular Biology (IMB), Mainz, Germany.
    Raes, Jeroen
    Laboratory of Molecular bacteriology, Department of Microbiology and Immunology, Rega Institute Ku Leuven, Leuven, Belgium; Center for Microbiology, VIB, Leuven, Belgium.
    Clausen, Loa
    Department of Child and Adolescent Psychiatry, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
    Telléus, Gry Kjaersdam
    Unit for Psychiatric Research, Aalborg University Hospital, Aalborg, Denmark; Department of Communication and Psychology, The Faculty of Social Sciences and Humanities, Aalborg University, Aalborg, Denmark.
    Bäckhed, Fredrik
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark; The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Clinical Physiology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Ehrlich, S. Dusko
    Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France; Department of Clinical and Movement Neurosciences, University College London, London, UK.
    Pedersen, Oluf
    Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark; Department of Medicine, University of Copenhagen and Herlev-Gentofte University Hospital, Copenhagen, Denmark.
    The gut microbiota contributes to the pathogenesis of anorexia nervosa in humans and mice2023In: Nature Microbiology, E-ISSN 2058-5276, Vol. 8, no 5, p. 787-802Article in journal (Refereed)
    Abstract [en]

    Anorexia nervosa (AN) is an eating disorder with a high mortality. About 95% of cases are women and it has a population prevalence of about 1%, but evidence-based treatment is lacking. The pathogenesis of AN probably involves genetics and various environmental factors, and an altered gut microbiota has been observed in individuals with AN using amplicon sequencing and relatively small cohorts. Here we investigated whether a disrupted gut microbiota contributes to AN pathogenesis. Shotgun metagenomics and metabolomics were performed on faecal and serum samples, respectively, from a cohort of 77 females with AN and 70 healthy females. Multiple bacterial taxa (for example, Clostridium species) were altered in AN and correlated with estimates of eating behaviour and mental health. The gut virome was also altered in AN including a reduction in viral-bacterial interactions. Bacterial functional modules associated with the degradation of neurotransmitters were enriched in AN and various structural variants in bacteria were linked to metabolic features of AN. Serum metabolomics revealed an increase in metabolites associated with reduced food intake (for example, indole-3-propionic acid). Causal inference analyses implied that serum bacterial metabolites are potentially mediating the impact of an altered gut microbiota on AN behaviour. Further, we performed faecal microbiota transplantation from AN cases to germ-free mice under energy-restricted feeding to mirror AN eating behaviour. We found that the reduced weight gain and induced hypothalamic and adipose tissue gene expression were related to aberrant energy metabolism and eating behaviour. Our 'omics' and mechanistic studies imply that a disruptive gut microbiome may contribute to AN pathogenesis.

  • 49.
    Fang, Wei
    et al.
    Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, Hubei, PR China.
    Santosh, Lamichhane
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, Hubei, PR China; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Lipidomes in health and disease: Analytical strategies and considerations2019In: TrAC. Trends in analytical chemistry, ISSN 0165-9936, E-ISSN 1879-3142, Vol. 120, article id 115664Article, review/survey (Refereed)
    Abstract [en]

    Lipidomics is a rapidly-growing field which focuses on global characterization of lipids at molecular and systems levels. As small changes in the concentrations of lipids may have important physiological consequences, much attention in the field has recently been paid to more accurate quantitation and identification of lipids. Community-wide efforts have been initiated, aiming to develop best practices for lipidomic analyses and reporting of lipidomic data. Nevertheless, current approaches for comprehensive analysis of lipidomes have some inherent challenges and limitations. Additionally, there is, currently, limited knowledge concerning the impacts of various external and internal exposures on lipid levels. In this review, we discuss the recent progress in lipidomics analysis, with a primary focus on analytical approaches, as well as on the different sources of variation in quantifying lipid levels, both technical and biological.

    Download full text (pdf)
    Lipidomes in health and disease: Analytical strategies and considerations
  • 50.
    Fart, Frida
    et al.
    Örebro University, School of Medical Sciences.
    Salihovic, Samira
    Örebro University, School of Medical Sciences. Örebro University, School of Science and Technology.
    McGlinchey, Aidan J
    Örebro University, School of Medical Sciences.
    Gareau, Melanie G.
    Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Schoultz, Ida
    Örebro University, School of Medical Sciences.
    Perfluoroalkyl substances are increased in patients with late-onset ulcerative colitis and induce intestinal barrier defects ex vivo in murine intestinal tissue2021In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 56, no 11, p. 1286-1295Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Environmental factors are strongly implicated in late-onset of inflammatory bowel disease. Here, we investigate whether high levels of perfluoroalkyl substances are associated with (1) late-onset inflammatory bowel disease, and (2) disturbances of the bile acid pool. We further explore the effect of the specific perfluoroalkyl substance perfluorooctanoic acid on intestinal barrier function in murine tissue.

    METHODS: Serum levels of perfluoroalkyl substances and bile acids were assessed by ultra-performance liquid chromatography coupled to a triple-quadrupole mass spectrometer in matched samples from patients with ulcerative colitis (n = 20) and Crohn's disease (n = 20) diagnosed at the age of ≥55 years. Age and sex-matched blood donors (n = 20), were used as healthy controls. Ex vivo Ussing chamber experiments were performed to assess the effect of perfluorooctanoic acid on ileal and colonic murine tissue (n = 9).

    RESULTS: The total amount of perfluoroalkyl substances was significantly increased in patients with ulcerative colitis compared to healthy controls and patients with Crohn's disease (p < .05). Ex vivo exposure to perfluorooctanoic acid induced a significantly altered ileal and colonic barrier function. The distribution of bile acids, as well as the correlation pattern between (1) perfluoroalkyl substances and (2) bile acids, differed between patient and control groups.

    DISCUSSION: Our results demonstrate that perfluoroalkyl substances levels are increased in patients with late-onset ulcerative colitis and may contribute to the disease by inducing a dysfunctional intestinal barrier.

1234567 1 - 50 of 340
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf