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  • 1.
    Bhandage, Amol K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. Uppsala University.
    Shen, Qiujin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Pei, Yu
    Karolinska Institute, Stockholm, Sweden.
    Deng, Qiaolin
    Karolinska Institute, Stockholm, Sweden.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABA Regulates Release of Inflammatory Cytokines From Peripheral Blood Mononuclear Cells and CD4+ T Cells and Is Immunosuppressive in Type 1 Diabetes2018In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 30, p. 283-294Article in journal (Refereed)
    Abstract [en]

    The neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule in the brain and in pancreatic islets. Here, we demonstrate that GABA regulates cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells. In anti-CD3 stimulated PBMCs, GABA (100nM) inhibited release of 47 cytokines in cells from patients with type 1 diabetes (T1D), but only 16 cytokines in cells from nondiabetic (ND) individuals. CD4+ T cells from ND individuals were grouped into responder or non-responder T cells according to effects of GABA (100nM, 500nM) on the cell proliferation. In the responder T cells, GABA decreased proliferation, and inhibited secretion of 37 cytokines in a concentration-dependent manner. In the non-responder T cells, GABA modulated release of 8 cytokines. GABA concentrations in plasma from T1D patients and ND individuals were correlated with 10 cytokines where 7 were increased in plasma of T1D patients. GABA inhibited secretion of 5 of these cytokines from both T1D PBMCs and ND responder T cells. The results identify GABA as a potent regulator of both Th1- and Th2-type cytokine secretion from human PBMCs and CD4+ T cells where GABA generally decreases the secretion.

  • 2.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Osteoglycin - A switch from angiogenesis to T-cell recruitment?2018In: EBioMedicine, E-ISSN 2352-3964, Vol. 35, p. 22-23Article in journal (Other academic)
  • 3.
    Enroth, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallmans, Göran
    Umea Univ, Dept Biobank Res, SE-90187 Umea, Sweden..
    Grankvist, Kjell
    Umea Univ, Dept Med Biosci, Clin Chem, SE-90185 Umea, Sweden..
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Effects of Long-Term Storage Time and Original Sampling Month on Biobank Plasma Protein Concentrations2016In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 12, p. 309-314Article in journal (Refereed)
    Abstract [en]

    The quality of clinical biobank samples is crucial to their value for life sciences research. A number of factors related to the collection and storage of samples may affect the biomolecular composition. We have studied the effect of long-time freezer storage, chronological age at sampling, season and month of the year and on the abundance levels of 108 proteins in 380 plasma samples collected from 106 Swedish women. Storage time affected 18 proteins and explained 4.8-34.9% of the observed variance. Chronological age at sample collection after adjustment for storage-time affected 70 proteins and explained 1.1-33.5% of the variance. Seasonal variation had an effect on 15 proteins and month (number of sun hours) affected 36 proteins and explained up to 4.5% of the variance after adjustment for storage-time and age. The results show that freezer storage time and collection date (month and season) exerted similar effect sizes as age on the protein abundance levels. This implies that information on the sample handling history, in particular storage time, should be regarded as equally prominent covariates as age or gender and need to be included in epidemiological studies involving protein levels.

  • 4.
    Faria, Vanda
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Center for Pain and the Brain, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
    Gingnell, Malin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    M. Hoppe, Johanna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Hjorth, Olof
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Alaie, Iman
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hultberg, Sara
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Wahlstedt, Kurt
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Engman, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Månsson, Kristoffer N.T.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.; Department of Psychology, Stockholm University, Stockholm, Sweden.
    Carlbring, Per
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Andersson, Gerhard
    Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden.
    Reis, Margareta
    Department of Medical and Health Sciences, Division of Drug Research, Linköping University, Linköping, Sweden.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder: A Randomized Trial2017In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, no 24, p. 179-188, article id S2352-3964(17)30385-7Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety, but their efficacy relative to placebo has been questioned. We aimed to test how manipulation of verbally induced expectancies, central for placebo, influences SSRI treatment outcome and brain activity in patients with social anxiety disorder (SAD).

    METHODS: We did a randomized clinical trial, within an academic medical center (Uppsala, Sweden), of individuals fulfilling the DSM-IV criteria for SAD, recruited through media advertising. Participants were 18years or older and randomized in blocks, through a computer-generated sequence by an independent party, to nine weeks of overt or covert treatment with escitalopram (20mg daily). The overt group received correct treatment information whereas the covert group was treated deceptively with the SSRI described, by the psychiatrist, as active placebo. The treating psychiatrist was necessarily unmasked while the research staff was masked from intervention assignment. Treatment efficacy was assessed primarily with the self-rated Liebowitz Social Anxiety Scale (LSAS-SR), administered at week 0, 1, 3, 6 and 9, also yielding a dichotomous estimate of responder status (clinically significant improvement). Before and at the last week of treatment, brain activity during an emotional face-matching task was assessed with functional magnetic resonance imaging (fMRI) and during fMRI sessions, anticipatory speech anxiety was also assessed with the Spielberger State-Trait Anxiety Inventory - State version (STAI-S). Analyses included all randomized patients with outcome data at posttreatment. This study is registered at ISRCTN, number 98890605.

    FINDINGS: Between March 17th 2014 and May 22nd 2015, 47 patients were recruited. One patient in the covert group dropped out after a few days of treatment and did not provide fMRI data, leaving 46 patients with complete outcome data. After nine weeks of treatment, overt (n=24) as compared to covert (n=22) SSRI administration yielded significantly better outcome on the LSAS-SR (adjusted difference 21.17, 95% CI 10.69-31.65, p<0.0001) with more than three times higher response rate (50% vs. 14%; χ(2)(1)=6.91, p=0.009) and twice the effect size (d=2.24 vs. d=1.13) from pre-to posttreatment. There was no significant between-group difference on anticipatory speech anxiety (STAI-S), both groups improving with treatment. No serious adverse reactions were recorded. On fMRI outcomes, there was suggestive evidence for a differential neural response to treatment between groups in the posterior cingulate, superior temporal and inferior frontal gyri (all z thresholds exceeding 3.68, p≤0.001). Reduced social anxiety with treatment correlated significantly with enhanced posterior cingulate (z threshold 3.24, p=0.0006) and attenuated amygdala (z threshold 2.70, p=0.003) activity.

    INTERPRETATION: The clinical and neural effects of escitalopram were markedly influenced by verbal suggestions. This points to a pronounced placebo component in SSRI-treatment of SAD and favors a biopsychosocial over a biomedical explanatory model for SSRI efficacy.

    FUNDING RESOURCES: The Swedish Research Council for Working Life and Social Research (grant 2011-1368), the Swedish Research Council (grant 421-2013-1366), Riksbankens Jubileumsfond - the Swedish Foundation for Humanities and Social Sciences (grant P13-1270:1).

  • 5.
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Common and Distinct Gray Matter Alterations in Social Anxiety Disorder and Major Depressive Disorder2017In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 21, p. 53-54Article in journal (Other academic)
  • 6.
    Frick, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Stockholm Univ, Dept Psychol, Stockholm, Sweden.
    Månsson, Kristoffer N.T.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Stockholm Univ, Dept Psychol, Stockholm, Sweden;Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Brain changes in social anxiety disorder run in the family2018In: EBioMedicine, E-ISSN 2352-3964, Vol. 36, p. 5-6Article in journal (Other academic)
  • 7.
    Grootens, Jennine
    et al.
    Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Ungerstedt, Johanna S.
    Karolinska Inst, Dept Med Huddinge, S-14186 Stockholm, Sweden;Karolinska Univ Hosp, Hematol Ctr, S-17176 Stockholm, Sweden.
    Ekoff, Maria
    Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Rönnberg, Elin
    Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Klimkowska, Monika
    Karolinska Univ Hosp Huddinge, Dept Clin Pathol & Cytol, S-14186 Stockholm, Sweden.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Arock, Michel
    Ecole Normale Super, Mol & Cellular Oncol, F-94235 Cachan, France;Hop La Pitie Salpetriere, Clin Hematol Lab, F-75013 Paris, France.
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Dahlin, Joakim S.
    Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis2019In: EBioMedicine, E-ISSN 2352-3964, Vol. 43, p. 150-158Article in journal (Refereed)
    Abstract [en]

    Background: Systemic mastocytosis (SM) is a haematological disease characterised by organ infiltration by neoplastic mast cells. Almost all SM patients have a mutation in the gene encoding the tyrosine kinase receptor KIT causing a D816V substitution and autoactivation of the receptor. Mast cells and CD34(+) haematopoietic progenitors can carry the mutation: however, in which progenitor cell subset the mutation arises is unknown. We aimed to investigate the distribution of the D816V mutation in single mast cells and single haematopoietic stem and progenitor cells.

    Methods: Fluorescence-activated single-cell index sorting and KIT D816V mutation assessment were applied to analyse mast cells and >10,000 CD34(+) bone marrow progenitors across 10 haematopoietic progenitor subsets. In vitro assays verified cell-forming potential.

    Findings: We found that in SM 60-99% of the mast cells harboured the KIT D816V mutation. Despite increased frequencies of mast cells in SM patients compared with control subjects, the haematopoietic progenitor subset frequencies were comparable. Nevertheless, the mutation could be detected throughout the haematopoietic landscape of SM patients, from haematopoietic stem cells to more lineage-primed progenitors. In addition, we demonstrate that Fc epsilon RI+ bone marrow progenitors exhibit mast cell-forming potential, and we describe aberrant CD45RA expression on SM mast cells for the first time.

    Interpretation: The KIT D816V mutation arises in early haematopoietic stem and progenitor cells and the mutation frequency is approaching 100% in mature mast cells, which express the aberrant marker CD45RA.

  • 8.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Smedje, Hans
    Division of Child and Adolescent Psychiatry, Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Daniilidou, Makrina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Öhman, Inger
    Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden.
    Yue, Qun-Ying
    Medical Products Agency, Uppsala, Sweden.
    Cavalli, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Magnusson, Patrik K. E.
    Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival2019In: EBioMedicine, E-ISSN 2352-3964, Vol. 40, p. 595-604Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy.

    METHODS: We tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p < 5 × 10-8, and the nominal threshold was p < 0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation.

    FINDINGS: Carrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p = 7.9 × 10-9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10-9, and this was replicated, OR = 3.4 [95% CI 1.2-9.6], p = 0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR = 2.0 [95% CI 1.4, 2.8], p = 0.0002.

    INTERPRETATION: We found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.

  • 9.
    Huttner, Hagen B.
    et al.
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden; Univ Hosp Erlangen, Dept Neurol, Erlangen, Germany.
    Bergmann, Olaf
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden; Tech Univ Dresden, DFG Ctr Regenerat Therapies Dresden, Dresden, Germany.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    El Cheikh, Raouf
    Aix Marseille Univ, Inserm S 911, CRO2, SMARTc Pharmacokinet Unit, Marseille, France.
    Nakamura, Makoto
    Univ Hosp Hannover, Dept Neurosurg, Hannover, Germany.
    Tortora, Angelo
    Univ Hosp Hannover, Dept Neurosurg, Hannover, Germany.
    Heinke, Paula
    Tech Univ Dresden, DFG Ctr Regenerat Therapies Dresden, Dresden, Germany.
    Coras, Roland
    Univ Hosp Erlangen, Dept Neuropathol, Erlangen, Germany.
    Englund, Elisabet
    Univ Hosp Lund, Dept Pathol, Lund, Sweden.
    Eyuepoglu, Ilker Y.
    Univ Hosp Erlangen, Dept Neurosurg, Erlangen, Germany.
    Kuramatsu, Joji B.
    Univ Hosp Erlangen, Dept Neurol, Erlangen, Germany.
    Roeder, Sebastian S.
    Univ Hosp Erlangen, Dept Neurol, Erlangen, Germany.
    Kloska, Stephan P.
    Univ Hosp Erlangen, Dept Neuroradiol, Erlangen, Germany.
    Muehlen, Iris
    Univ Hosp Erlangen, Dept Neuroradiol, Erlangen, Germany.
    Doerfler, Arnd
    Univ Hosp Erlangen, Dept Neuroradiol, Erlangen, Germany.
    Schwab, Stefan
    Univ Hosp Erlangen, Dept Neurol, Erlangen, Germany.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics. Uppsala Univ, Dept Phys & Astron, Div Ion Phys, Uppsala, Sweden..
    Bernard, Samuel
    Univ Lyon, CNRS, UMR 5208, Inst Camille Jordan, Villeurbanne, France.
    Frisen, Jonas
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.
    Meningioma growth dynamics assessed by radiocarbon retrospective birth dating2018In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 27, p. 176-181Article in journal (Refereed)
    Abstract [en]

    It is not known how long it takes from the initial neoplastic transformation of a cell to the detection of a tumor, which would be valuable for understanding tumor growth dynamics. Meningiomas show a broad histological, genetic and clinical spectrum, are usually benign and considered slowly growing. There is an intense debate regarding their age and growth pattern and when meningiomas should be resected. We have assessed the age and growth dynamics of 14 patients with meningiomas (WHO grade I: n = 6 with meningothelial and n = 6 with fibrous subtype, as well as n = 2 atypical WHO grade II meningiomas) by combining retrospective birth-dating of cells by analyzing incorporation of nuclear-bomb-test-derived 14C, analysis of cell proliferation, cell density, MRI imaging and mathematical modeling. We provide an integrated model of the growth dynamics of benign meningiomas. The mean age of WHO grade I meningiomas was 22.1 ± 6.5 years, whereas atypical WHO grade II meningiomas originated 1.5 ± 0.1 years prior to surgery (p < 0.01). We conclude that WHO grade I meningiomas are very slowly growing brain tumors, which are resected in average two decades after time of origination.

  • 10.
    Jokinen, Jussi
    et al.
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden; Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden.
    Boström, Adrian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dadfar, Ali
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chatzittofis, Andreas
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden; Univ Cyprus, Sch Med, Nicosia, Cyprus.
    Åsberg, Marie
    Karolinska Inst, Dept Clin Sci, Stockholm, Sweden.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Epigenetic Changes in the CRH Gene are Related to Severity of Suicide Attempt and a General Psychiatric Risk Score in Adolescents2018In: EBioMedicine, E-ISSN 2352-3964, Vol. 27, p. 123-133, article id S2352-3964(17)30499-1Article in journal (Refereed)
    Abstract [en]

    The aim of this study, comprising 88 suicide attempters, was to identify hypothalamic-pituitary-adrenal (HPA) -axis coupled CpG-sites showing methylation shifts linked to severity of the suicide attempt. Candidate methylation loci were further investigated as risk loci for a general psychiatric risk score in two cohorts of adolescents (cohort 1 and 2). The genome-wide methylation pattern was measured in whole blood using the Illumina Infinium Methylation EPIC BeadChip. Subjects were stratified into high-risk and low-risk groups based on the severity of the suicidal behavior. We included CpG sites located within 2000 basepairs away from transcriptional start site of the following HPA-axis coupled genes: corticotropin releasing hormone (CRH), corticotropin releasing hormone binding protein (CRHBP), corticotropin releasing hormone receptor 1 (CRHR1), corticotropin releasing hormone receptor 2 (CRHR2), FK506-binding protein 51 (FKBP5) and the glucocorticoid receptor (NR3C1). The methylation state of two corticotropin releasing hormone (CRH)-associated CpG sites were significantly hypomethylated in the high-risk group of suicide attempters (n = 31) (cg19035496 and cg23409074) (p < 0.001). Adolescent cohort 1 and 2 consisted of 129 and 93 subjects, respectively, and were stratified by the in silico generated DAWBA measurements of a general psychiatric risk score into high-risk group (>~50% risk) or controls. In adolescent cohort 2, cg19035496 was hypermethylated in subjects with a high general psychiatric risk score. Our results show epigenetic changes in the CRH gene related to severity of suicide attempt in adults and a general psychiatric risk score in adolescents.

  • 11.
    Kling, Teresia
    et al.
    Gothenburg Univ, Sahlgrenska Acad, Sahlgrenska Canc Ctr, Inst Biomed,Dept Pathol, S-41124 Gothenburg, Sweden..
    Ferrarese, Roberto
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany..
    Ailin, Darren Oh
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Biol, Schnzlestr 1, D-79104 Freiburg, Germany..
    Johansson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heiland, Dieter Henrik
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany..
    Dai, Fangping
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany..
    Vasilikos, Ioannis
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany..
    Weyerbrock, Astrid
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany..
    Jornsten, Rebecka
    Univ Gothenburg, Math Sci, SE-41296 Gothenburg, Sweden.;Chalmers, SE-41296 Gothenburg, Sweden..
    Carro, Maria Stella
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany..
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Integrative Modeling Reveals Annexin A2-mediated Epigenetic Control of Mesenchymal Glioblastoma2016In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 12, p. 72-85Article in journal (Refereed)
    Abstract [en]

    Glioblastomas are characterized by transcriptionally distinct subtypes, but despite possible clinical relevance, their regulation remains poorly understood. The commonly used molecular classification systems for GBM all identify a subtype with high expression of mesenchymal marker transcripts, strongly associated with invasive growth. We used a comprehensive data-driven network modeling technique (augmented sparse inverse covariance selection, aSICS) to define separate genomic, epigenetic, and transcriptional regulators of glioblastoma subtypes. Our model identified Annexin A2 (ANXA2) as a novel methylation-controlled positive regulator of the mesenchymal subtype. Subsequent evaluation in two independent cohorts established ANXA2 expression as a prognostic factor that is dependent on ANXA2 promoter methylation. ANXA2 knockdown in primary glioblastoma stem cell-like cultures suppressed known mesenchymal master regulators, and abrogated cell proliferation and invasion. Our results place ANXA2 at the apex of a regulatory cascade that determines glioblastoma mesenchymal transformation and validate aSICS as a general methodology to uncover regulators of cancer subtypes.

  • 12.
    Korol, Sergiy V
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Yang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gandasi, Nikhil R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Barg, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Laver, Derek
    University of Newcastle, Callaghan, Australia.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells2018In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 30Article in journal (Refereed)
    Abstract [en]

    In human pancreatic islets, the neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule synthesized by and released from the insulin-secreting β cells. The effective, physiological GABA concentration range within human islets is unknown. Here we use native GABAA receptors in human islet β cells as biological sensors and reveal that 100-1000nM GABA elicit the maximal opening frequency of the single-channels. In saturating GABA, the channels desensitized and stopped working. GABA modulated insulin exocytosis and glucose-stimulated insulin secretion. GABAA receptor currents were enhanced by the benzodiazepine diazepam, the anesthetic propofol and the incretin glucagon-like peptide-1 (GLP-1) but not affected by the hypnotic zolpidem. In type 2 diabetes (T2D) islets, single-channel analysis revealed higher GABA affinity of the receptors. The findings reveal unique GABAA receptors signaling in human islets β cells that is GABA concentration-dependent, differentially regulated by drugs, modulates insulin secretion and is altered in T2D.

  • 13.
    Li, Wei
    et al.
    Southeast Univ, Sch Med, Inst Diabet, Dept Endocrinol,Zhongda Hosp, Nanjing, Jiangsu, Peoples R China.
    Xie, Bo
    Southeast Univ, Sch Med, Inst Diabet, Dept Endocrinol,Zhongda Hosp, Nanjing, Jiangsu, Peoples R China.
    Qiu, Shanhu
    Southeast Univ, Sch Med, Inst Diabet, Dept Endocrinol,Zhongda Hosp, Nanjing, Jiangsu, Peoples R China.
    Huang, Xin
    Southeast Univ, Sch Publ Hlth, Nanjing, Jiangsu, Peoples R China.
    Chen, Juan
    Southeast Univ, Sch Med, Inst Diabet, Dept Endocrinol,Zhongda Hosp, Nanjing, Jiangsu, Peoples R China.
    Wang, Xinling
    Peoples Hosp Xinjiang Uyghur Autonomous Reg, Dept Endocrinol, Urumqi, Peoples R China.
    Li, Hong
    Kunming Med Univ, Affiliated Hosp 1, Dept Endocrinol, Kunming, Yunnan, Peoples R China.
    Chen, Qingyun
    Guangxi Med Univ, Affiliated Hosp 1, Dept Endocrinol, Nanning, Peoples R China.
    Wang, Qing
    Jilin Univ, China Japan Union Hosp, Dept Endocrinol, Changchun, Jilin, Peoples R China.
    Tu, Ping
    Third Hosp Nanchang, Dept Endocrinol, Nanchang, Jiangxi, Peoples R China.
    Zhang, Lihui
    Hebei Med Univ, Hosp 2, Dept Endocrinol, Shijiazhuang, Hebei, Peoples R China.
    Yan, Sunjie
    Fujian Med Univ, Affiliated Hosp 1, Diabet Res Inst, Dept Endocrinol, Fuzhou, Fujian, Peoples R China.
    Li, Kaili
    Xinjiang Uygur Autonomous Reg Hosp Tradit Chinese, Dept Endocrinol, Urumqi, Peoples R China.
    Maimaitiming, Jimilanmu
    Peoples Hosp Xinjiang Uyghur Autonomous Reg, Dept Endocrinol, Urumqi, Peoples R China.
    Nian, Xin
    Kunming Med Univ, Affiliated Hosp 1, Dept Endocrinol, Kunming, Yunnan, Peoples R China.
    Liang, Min
    Guangxi Med Univ, Affiliated Hosp 1, Dept Endocrinol, Nanning, Peoples R China.
    Wen, Yan
    Jilin Univ, China Japan Union Hosp, Dept Endocrinol, Changchun, Jilin, Peoples R China.
    Liu, Jiang
    Wang, Mian
    Hebei Med Univ, Hosp 2, Dept Endocrinol, Shijiazhuang, Hebei, Peoples R China.
    Zhang, Yongze
    Fujian Med Univ, Affiliated Hosp 1, Diabet Res Inst, Dept Endocrinol, Fuzhou, Fujian, Peoples R China.
    Ma, Li
    Xinjiang Uygur Autonomous Reg Hosp Tradit Chinese, Dept Endocrinol, Urumqi, Peoples R China.
    Wu, Hang
    Southeast Univ, Sch Med, Inst Diabet, Dept Endocrinol,Zhongda Hosp, Nanjing, Jiangsu, Peoples R China.
    Wang, Xuyi
    Southeast Univ, Sch Med, Inst Diabet, Dept Endocrinol,Zhongda Hosp, Nanjing, Jiangsu, Peoples R China.
    Wang, Xiaohang
    Southeast Univ, Sch Med, Inst Diabet, Dept Endocrinol,Zhongda Hosp, Nanjing, Jiangsu, Peoples R China.
    Liu, Jingbao
    Southeast Univ, Sch Med, Inst Diabet, Dept Endocrinol,Zhongda Hosp, Nanjing, Jiangsu, Peoples R China.
    Cai, Min
    Southeast Univ, Sch Med, Inst Diabet, Dept Endocrinol,Zhongda Hosp, Nanjing, Jiangsu, Peoples R China.
    Wang, Zhiyao
    Suzhou MetroHlth Med Technol Co LTD, Suzhou, Peoples R China.
    Guo, Lin
    Suzhou MetroHlth Med Technol Co LTD, Suzhou, Peoples R China.
    Chen, Fangqun
    Suzhou MetroHlth Med Technol Co LTD, Suzhou, Peoples R China.
    Wang, Bei
    Southeast Univ, Sch Publ Hlth, Nanjing, Jiangsu, Peoples R China.
    Sandberg, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sun, Zilin
    Southeast Univ, Sch Med, Inst Diabet, Dept Endocrinol,Zhongda Hosp, Nanjing, Jiangsu, Peoples R China.
    Non-lab and semi-lab algorithms for screening undiagnosed diabetes: A cross-sectional study2018In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 35, p. 307-316Article in journal (Refereed)
    Abstract [en]

    Background: The terrifying undiagnosed rate and high prevalence of diabetes have become a public emergency. A high efficiency and cost-effective early recognition method is urgently needed. We aimed to generate innovative, user-friendly nomograms that can be applied for diabetes screening in different ethnic groups in China using the non-lab or noninvasive semi-lab data. Methods: This multicenter, multi-ethnic, population-based, cross-sectional study was conducted in eight sites in China by enrolling subjects aged 20-70. Sociodemographic and anthropometric characteristics were collected. Blood and urine samples were obtained 2 h following a standard 75 g glucose solution. In the final analysis, 10,794 participants were included and randomized into model development (n - 8096) and model validation (n = 2698) group with a ratio of 3:1. Nomograms were developed by the stepwise binary logistic regression. The nomograms were validated internally by a bootstrap sampling method in the model development set and externally in the model validation set. The area under the receiver operating characteristic curve (AUC) was used to assess the screening performance of the nomograms. Decision curve analysis was applied to calculate the net benefit of the screening model. Results: The overall prevalence of undiagnosed diabetes was 9.8% (1059/10794) according to ADA criteria. The non-lab model revealed that gender, age, body mass index, waist circumference, hypertension, ethnicities, vegetable daily consumption and family history of diabetes were independent risk factors for diabetes. By adding 2 h post meal glycosuria qualitative to the non-lab model, the semi-lab model showed an improved Akaike information criterion (AIC: 4506 to 3580). The AUC of the semi-lab model was statistically larger than the non-lab model (0.868 vs 0.763, P < 0.001). The optimal cutoff probability in semi-lab and non-lab nomograms were 0.088 and 0.098, respectively. The sensitivity and specificity were 76.3% and 81.6%, respectively in semi-lab nomogram, and 72.1% and 673% in non-lab nomogram at the optimal cut off point. The decision curve analysis also revealed a bigger decrease of avoidable OGTT test (52 per 100 subjects) in the semi-lab model compared to the non-lab model (36 per 100 subjects) and the existed New Chinese Diabetes Risk Score (NCDRS, 35 per 100 subjects). Conclusion: The non-lab and semi-lab nomograms appear to be reliable tools for diabetes screening, especially in developing countries. However, the semi-lab model outperformed the non-lab model and NCDRS prediction systems and might be worth being adopted as decision support in diabetes screening in China.

  • 14.
    Lin, Chun-Yu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Infect Control Ctr, Div Infect Dis,Dept Internal Med, Kaohsiung 807, Taiwan;Kaohsiung Med Univ, Sepsis Res Ctr, Ctr Dengue Fever Control & Res, Sch Med,Grad Inst Med, Kaohsiung, Taiwan.
    Kolliopoulos, Constantinos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Huang, Chung-Hao
    Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Infect Control Ctr, Div Infect Dis,Dept Internal Med, Kaohsiung 807, Taiwan;Kaohsiung Med Univ, Sepsis Res Ctr, Ctr Dengue Fever Control & Res, Sch Med,Grad Inst Med, Kaohsiung, Taiwan.
    Tenhunen, Jyrki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Tampere Univ Hosp, Dept Intens Care, Crit Care Med Res Grp, Tampere, Finland.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Chen, Yen-Hsu
    Kaohsiung Med Univ, Sepsis Res Ctr, Ctr Dengue Fever Control & Res, Sch Med,Grad Inst Med, Kaohsiung, Taiwan;Kaohsiung Municipal Tatung Hosp, Dept Internal Med, 68 Jhonghua 3rd Rd, Kaohsiung 80145, Taiwan;Natl Chiao Tung Univ, Coll Biol Sci & Technol, Dept Biol Sci & Technol, Hsinchu, Taiwan.
    Heldin, Paraskevi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    High levels of serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrity2019In: EBioMedicine, E-ISSN 2352-3964, Vol. 48, p. 425-441Article in journal (Refereed)
    Abstract [en]

    Background: A main pathological feature of severe dengue virus infection is endothelial hyper-permeability. The dengue virus nonstructural protein 1 (NS1) has been implicated in the vascular leakage that characterizes severe dengue virus infection, however, the molecular mechanisms involved are not known.

    Methods: A cohort of 250 dengue patients has been followed from the onset of symptoms to the recovery phase. Set urn hyaluronan levels and several other clinical parameters were recorded. The effect of NS1 treatment of cultured fibroblasts and endothelial cells on the expressions of hyaluronan synthetic and catabolic enzymes and the hyaluronan receptor CD44, were determined, as have the effects on the formation of hyaluronan-rich matrices and endothelial permeability.

    Findings: Elevated serum hyaluronan levels (70 ng/ml) during early infection was found to be an independent predictor for occurrence of warning signs, and thus severe dengue fever. High circulating levels of the viral protein NS1, indicative of disease severity, correlated with high concentrations of serum hyaluronan. NS1 exposure decreased the expression of CD44 in differentiating endothelial cells impairing the integrity of vessel-like structures, and promoted the synthesis of hyaluronan in dermal fibroblasts and endothelial cells in synergy with dengue-induced pro-inflammatory mediators. Deposited hyaluronan-rich matrices around cells cultured in vitro recruited CD44-expressing macrophage-like cells, suggesting a mechanism for enhancement of inflammation. In cultured endothelial cells, perturbed hyaluronan-CD44 interactions enhanced endothelial permeability through modulation of VE-cadherin and cytoskeleton re-organization, and exacerbated the NS1-induced disruption of endothelial integrity.

    Interpretation: Pharmacological targeting of hyaluronan biosynthesis and/or its CD44-mediated signaling may limit the life-threatening vascular leakiness during moderate-to-severe dengue virus infection. 

  • 15.
    Parmar, Priyanka
    et al.
    Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Univ Oulu, Bioctr Oulu, Oulu, Finland.
    Lowry, Estelle
    Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Univ Oulu, Bioctr Oulu, Oulu, Finland.
    Cugliari, Giovanni
    Univ Turin, Dept Med Sci, Turin, Italy;IIGM, Turin, Italy.
    Suderman, Matthew
    Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit, Populat Hlth Sci, Bristol, Avon, England.
    Wilson, Rory
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany.
    Karhunen, Ville
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
    Andrew, Toby
    Imperial Coll London, Dept Med, Genom Common Dis, London, England.
    Wiklund, Petri
    Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla, Finland.
    Wielscher, Matthias
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
    Guarrera, Simonetta
    Univ Turin, Dept Med Sci, Turin, Italy;IIGM, Turin, Italy.
    Teumer, Alexander
    Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany.
    Lehne, Benjamin
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
    Milani, Lili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    de Klein, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
    Mishra, Pashupati P.
    Fimlab Labs, Dept Clin Chem, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
    Melton, Phillip E.
    Curtin Univ, Sch Pharm & Biomed Sci, Bentley, WA, Australia;Univ Western Australia, Curtin UWA Ctr Genet Origins Hlth & Dis, Sch Biomed Sci, Crawley, Australia.
    Mandaviya, Pooja R.
    Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands.
    Kasela, Silva
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    Nano, Jana
    Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands.
    Zhang, Weihua
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England.
    Zhang, Yan
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Uitterlinden, Andre G.
    Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands;Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands.
    Peters, Annette
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
    Schoettker, Ben
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany;Heidelberg Univ, Network Aging Res, Bergheimer Str, Heidelberg, Germany.
    Gieger, Christian
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
    Anderson, Denise
    Univ Western Australia, Telethon Kids Inst, Perth, WA, Australia.
    Boomsma, Dorret, I
    Vrije Univ Amsterdam, Sch Publ Hlth, Dept Biol Psychol, Amsterdam, Netherlands.
    Grabe, Hans J.
    Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany;German Ctr Neurodegenerat Dis DZNF, Site Rostock Greifswald, Greifswald, Germany.
    Panico, Salvatore
    Univ Naples Federico II, Dept Clin Med & Surg, Naples, Italy.
    Veldink, Jan H.
    Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands.
    van Meurs, Joyce B. J.
    Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands.
    van den Berg, Leonard
    Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands.
    Beilin, Lawrence J.
    Univ Western Australia, Med Sch, Perth, WA, Australia.
    Franke, Lude
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
    Loh, Marie
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;ASTAR, TLGM, 8A Biomed Grove,Level 5, Singapore, Singapore;Univ Oulu, Inst Hlth Sci, Oulu, Finland.
    van Greevenbroek, Marleen M. J.
    Maastricht Univ, Dept Internal Med, Med Ctr, Maastricht, Netherlands;Maastricht Univ, Sch Cardiovasc Dis CARIM, Med Ctr, Maastricht, Netherlands.
    Nauck, Matthias
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany;Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany.
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Dept Clin Physiol, Tampere, Finland.
    Hurme, Mikko A.
    Fac Med & Life Sci Univ Tampere, Dept Microbiol & Immunol, Tampere, Finland.
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland.
    Franco, Oscar H.
    Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands.
    Slagboom, P. Eline
    Leiden Univ, Dept Biomed Data Sci, Mol Epidemiol, Med Ctr, Leiden, Netherlands.
    van der Harst, Pim
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands;Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands;ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.
    Kunze, Sonja
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany.
    Felix, Stephan B.
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.
    Zhang, Tao
    Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA;Shandong Univ, Sch Publ Hlth, Dept Biostat, Jinan, Shandong, Peoples R China.
    Chen, Wei
    Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA.
    Mori, Trevor A.
    Univ Western Australia, Med Sch, Perth, WA, Australia.
    Bonnefond, Amelie
    Imperial Coll London, Dept Med, Genom Common Dis, London, England;Univ Lille, EGID, Inst Pasteur Lille, CMS UMR 8199, Lille, France.
    Heijmans, Bastiaan T.
    Leiden Univ, Dept Biomed Data Sci, Mol Epidemiol, Med Ctr, Leiden, Netherlands.
    Muka, Taulant
    Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands.
    Kooner, Jaspal S.
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England;Imperial Coll London, Natl Heart & Lung Inst, London, England;Childrens Minnesota Res Inst, Childrens Hosp & Clin, Minneapolis, MN 55404 USA.
    Fischer, Krista
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    Waldenberger, Melanie
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
    Froguel, Philippe
    Imperial Coll London, Dept Med, Genom Common Dis, London, England;Univ Lille, EGID, Inst Pasteur Lille, CMS UMR 8199, Lille, France.
    Huang, Rae-Chi
    Univ Western Australia, Telethon Kids Inst, Perth, WA, Australia.
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
    Rathmann, Wolfgang
    Heine Univ, Inst Biometr & Epidemiol, Leibniz Ctr Diabet Res Heinrich, German Diabet Ctr, Dusseldorf, Germany.
    Relton, Caroline L.
    Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit, Populat Hlth Sci, Bristol, Avon, England.
    Matullo, Giuseppe
    Univ Turin, Dept Med Sci, Turin, Italy;IIGM, Turin, Italy.
    Brenner, Hermann
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany;Heidelberg Univ, Network Aging Res, Bergheimer Str, Heidelberg, Germany.
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Li, Shengxu
    Childrens Minnesota Res Inst, Childrens Hosp & Clin, Minneapolis, MN 55404 USA.
    Chambers, John C.
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England;Imperial Coll Healthcare NHS Trust, London, England;Nanyang Technol Univ Singapore, Lee Kong Chian Sch Med, Singapore, Singapore.
    Jarvelin, Marjo-Riitta
    Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Univ Oulu, Bioctr Oulu, Oulu, Finland;Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;Brunel Univ London, Dept Life Sci, Coll Hlth & Life Sci, Uxbridge, Middx, England.
    Sebert, Sylvain
    Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Univ Oulu, Bioctr Oulu, Oulu, Finland;Univ Oulu, Med Res Ctr MRC Oulu, Oulu Univ Hosp, Oulu, Finland.
    Association of maternal prenatal smoking GFI1-locus and cardiometabolic phenotypes in 18,212 adults2018In: EBioMedicine, E-ISSN 2352-3964, Vol. 38, p. 206-216Article in journal (Refereed)
    Abstract [en]

    Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n= 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0.012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 x 10(-7) < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 x 10(-8) < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. Interpretation: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. Fund: European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH.

  • 16.
    Shen, Qiujin
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Polom, Karol
    Univ Siena, Dept Gen Surg & Surg Oncol, Siena, Italy;Gdansk Med Univ, Dept Surg Oncol, Gdansk, Poland.
    Williams, Coralie
    Ariana Pharmaceut, Paris, France.
    de Oliveira, Felipe Marques Souza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Guergova-Kuras, Mariana
    Ariana Pharmaceut, Paris, France.
    Lisacek, Frederique
    Swiss Inst Bioinformat, Proteome Informat Grp, Geneva, Switzerland;Univ Geneva, Comp Sci Dept, Geneva, Switzerland;Univ Geneva, Sect Biol, Geneva, Switzerland.
    Karlsson, Niclas G.
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Med Biochem & Cell Biol, Gothenburg, Sweden.
    Roviello, Franco
    Univ Siena, Dept Gen Surg & Surg Oncol, Siena, Italy.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A targeted proteomics approach reveals a serum protein signature as diagnostic biomarker for resectable gastric cancer2019In: EBioMedicine, E-ISSN 2352-3964, Vol. 44, p. 322-333Article in journal (Refereed)
    Abstract [en]

    Background: Gastric cancer (GC) is the third leading cause of cancer death. Early detection is a key factor to reduce its mortality. Methods: We retrospectively collected pre- and postoperative serum samples as well as tumour tissues and adjacent normal tissues from 100 GC patients. Serum samples from non-cancerous patients were served as controls (n = 50). A high-throughput protein detection technology, multiplex proximity extension assays (PEA), was applied to measure levels of over 300 proteins. Alteration of each protein was analysed by univariate analysis. Elastic-net logistic regression was performed to select serum proteins into the diagnostic model. Findings: We identified 19 serum proteins (CEACAM5, CA9, MSLN, CCL20, SCF, TGF-alpha, MMP-1, MMP-10, IGF-1, CDCPI, PPIA, DDAH-1, HMOX-1, FLI1, IL-7, ZBTB-17, APBB1IP, KAZALD-1, and ADAMTS-15) that together distinguish GC cases from controls with a diagnostic sensitivity of 93%, specificity of 100%, and area under receiver operating characteristic curve (AUC) of 0.99 (95% CI: 0.98-1). Moreover, the 19-serum protein signature pro-vided an increased diagnostic capacity in patients at TNMI-II stage (sensitivity 89%, specificity 100%, AUC 0.99) and in patients with high miaosatellite instability (MSI) (91%. 98%, and 0.99) compared to individual proteins. These promising results will inspire a large-scale independent cohort study to be pursued for validating the proposed protein signature. Interpretation: Based on targeted proteomics and elastic-net logistic regression, we identified a 19-serum protein signature which could contribute to clinical GC diagnosis, especially for patients at early stage and those with high MSI. (C) 2019 The Authors. Published by Elsevier B.V.

  • 17.
    Strömberg, Nicklas
    et al.
    Umeå Univ, Dept Odontol Cariol, Umeå, Sweden.
    Esberg, Anders
    Umeå Univ, Dept Odontol Cariol, Umeå, Sweden.
    Sheng, Nongfei
    Umeå Univ, Dept Odontol Cariol, Umeå, Sweden.
    Mårell, Lena
    Umeå Univ, Dept Odontol Cariol, Umeå, Sweden.
    Löfgren-Burström, Anna
    Umeå Univ, Dept Odontol Cariol, Umeå, Sweden.
    Danielsson, Karin
    Umeå Univ, Dept Odontol Cariol, Umeå, Sweden.
    Källestål, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Umeå Univ, Dept Odontol Cariol, Umeå, Sweden.
    Genetic- and Lifestyle-dependent Dental Caries Defined by the Acidic Proline-rich Protein Genes PRH1 and PRH22017In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 26, p. 38-46, article id S2352-3964(17)30462-0Article in journal (Refereed)
    Abstract [en]

    Dental caries is a chronic infectious disease that affects billions of people with large individual differences in activity. We investigated whether PRH1 and PRH2 polymorphisms in saliva acidic proline-rich protein (PRP) receptors for indigenous bacteria match and predict individual differences in the development of caries. PRH1 and PRH2 variation and adhesion of indigenous and cariogenic (Streptococcus mutans) model bacteria were measured in 452 12-year-old Swedish children along with traditional risk factors and related to caries at baseline and after 5-years. The children grouped into low-to-moderate and high susceptibility phenotypes for caries based on allelic PRH1, PRH2 variation. The low-to-moderate susceptibility children (P1 and P4a) experienced caries from eating sugar or bad oral hygiene or infection by S. mutans. The high susceptibility P4a (Db, PIF, PRP12) children had more caries despite receiving extra prevention and irrespective of eating sugar or bad oral hygiene or S. mutans-infection. They instead developed 3.9-fold more caries than P1 children from plaque accumulation in general when treated with orthodontic multibrackets; and had basic PRP polymorphisms and low DMBT1-mediated S. mutans adhesion as additional susceptibility traits. The present findings thus suggest genetic autoimmune-like (P4a) and traditional life style (P1) caries, providing a rationale for individualized oral care.

  • 18.
    Thulin, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Eriksson, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Reversion of High-level Mecillinam Resistance to Susceptibility in Escherichia coli During Growth in Urine.2017In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 23, p. 111-118Article in journal (Refereed)
    Abstract [en]

    Mecillinam (amdinocillin) is a β-lactam antibiotic used to treat uncomplicated urinary tract infections (UTIs). We have previously shown that inactivation of the Escherichia coli cysB gene is the major cause of mecillinam resistance (Mec(R)) in clinical isolates. In this study, we used different E. coli strains (laboratory and clinical isolates) that were Mec(R) due to cysB mutations to determine how mecillinam susceptibility was affected during growth in urine compared to growth in the commonly used growth medium Mueller Hinton (MHB). We also examined mecillinam susceptibility when bacteria were grown in urine obtained from 48 different healthy volunteers. Metabolome analysis was done on the urine samples and the association between the mecillinam susceptibility patterns of the bacteria and urine metabolite levels was studied. Two major findings with clinical significance are reported. First, Mec(R)E. coli cysB mutant strains (both laboratory and clinical isolates) were always more susceptible to mecillinam when grown in urine as compared to laboratory medium, with many strains showing complete phenotypic susceptibility in urine. Second, the degree of reversion to susceptibility varied between urine samples obtained from different individuals. This difference was correlated with osmolality such that in urine with low osmolality the Mec(R) mutants were more susceptible to mecillinam than in urine with high osmolality. This is the first example describing conditional resistance where a genetically stable antibiotic resistance can be phenotypically reverted to susceptibility by metabolites present in urine. These findings have several important clinical implications regarding the use of mecillinam to treat UTIs. First, they suggest that mecillinam can be used to treat also those clinical strains that are identified as Mec(R) in standard laboratory tests. Second, the results suggest that testing of mecillinam susceptibility in the laboratory ought to be performed in media that mimics urine to obtain clinically relevant susceptibility testing results. Third, these findings imply that changes in patient behavior, such as increased water intake or use of diuretics to reduce urine osmolality and increased intake of cysteine, might induce antibiotic susceptibility in an infecting Mec(R)E. coli strain and thereby increase treatment efficiency.

  • 19.
    Wickman, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Inst Environm Med, Stockholm, Sweden; Stockholm Cty Council, Ctr Occupat & Environm Med, Stockholm, Sweden.
    Lupinek, Christian
    Med Univ Vienna, Ctr Pathophysiol Infectiol & Immunol, Dept Pathophysiol & Allergy Res, Div Immunopathol, Vienna, Austria.
    Andersson, Niklas
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden; Stockholm Cty Council, Ctr Occupat & Environm Med, Stockholm, Sweden.
    Belgrave, Danielle
    Imperial Coll, Dept Paediat, London, England.
    Asarnoj, Anna
    Karolinska Inst, Dept Med, Immunol & Allergy Unit, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden; Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden; Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.
    Benet, Marta
    Ctr Res Environm Epidemiol CREAL, ISGlobal, Barcelona, Spain.
    Pinart, Mariona
    Ctr Res Environm Epidemiol CREAL, ISGlobal, Barcelona, Spain.
    Wieser, Sandra
    Med Univ Vienna, Ctr Pathophysiol Infectiol & Immunol, Dept Pathophysiol & Allergy Res, Div Immunopathol, Vienna, Austria.
    Garcia-Aymerich, Judith
    Ctr Res Environm Epidemiol CREAL, ISGlobal, Barcelona, Spain.
    Baar, Alexandra
    Med Univ Vienna, Ctr Pathophysiol Infectiol & Immunol, Dept Pathophysiol & Allergy Res, Div Immunopathol, Vienna, Austria.
    Pershagen, Göran
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden; Stockholm Cty Council, Ctr Occupat & Environm Med, Stockholm, Sweden.
    Simpson, Angela
    Univ Manchester, Div Infect Immun & Resp Med, Fac Biol Med & Hlth, Manchester, Lancs, England.
    Kull, Inger
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden; Stockholm Cty Council, Ctr Occupat & Environm Med, Stockholm, Sweden; Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden.
    Bergström, Anna
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden; Stockholm Cty Council, Ctr Occupat & Environm Med, Stockholm, Sweden.
    Melén, Erik
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden; Stockholm Cty Council, Ctr Occupat & Environm Med, Stockholm, Sweden; Sachs Children & Youth Hosp, Dept Paediat, Stockholm, Sweden.
    Hamsten, Carl
    Karolinska Inst, Dept Med, Immunol & Allergy Unit, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Antó, Josep M.
    Ctr Res Environm Epidemiol CREAL, ISGlobal, Barcelona, Spain; UPF, Hosp del Mar, Med Res Inst, IMIM, Barcelona, Spain; CIBERESP, Barcelona, Spain; UPF, Barcelona, Spain.
    Bousquet, Jean
    Univ Hosp, Montpellier, France; INSERM, VIMA Ageing & Chron Dis, Paris, France; U1168, Epidemiol & Publ Hlth Approaches, Paris, France; Univ Versailles St Quentin En Yvelines, UVSQ, Versailles, France.
    Custovic, Adnan
    Imperial Coll, Dept Paediat, London, England.
    Valenta, Rudolf
    Med Univ Vienna, Ctr Pathophysiol Infectiol & Immunol, Dept Pathophysiol & Allergy Res, Div Immunopathol, Vienna, Austria.
    van Hage, Marianne
    Karolinska Inst, Dept Med, Immunol & Allergy Unit, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Detection of IgE Reactivity to a Handful of Allergen Molecules in Early Childhood Predicts Respiratory Allergy in Adolescence2017In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 26, p. 91-99Article in journal (Refereed)
    Abstract [en]

    Background: Sensitization in early childhood may precede respiratory allergy in adolescence.

    Methods: IgE reactivity against 132 allergen molecules was evaluated using the MeDALL microarray in sera obtained from a random sample of 786 children at the age of 4, 8 and 16 years in a population based birth cohort (BAMSE). Symptoms were analyzed by questionnaire at ages 4, 8 and 16 years. Clinically and independent relevant allergen molecules accounting for ≥ 90% of IgE reactivities in sensitized individuals and at all time-points were identified as risk molecules and used to predict respiratory allergy. The data was replicated in the Manchester Asthma and Allergy Study (MAAS) birth cohort by studying IgE reactivity with the use of a commercial IgE microarray. Sera were obtained from children at the ages of 3, 5, 8 and 11 years (N = 248) and the outcome was studied at 11 years.

    Findings: In the BAMSE cohort 4 risk molecules could be identified, i.e.: Ara h 1 (peanut), Bet v 1 (birch), Fel d 1 (cat), Phl p 1 (grass). For MAAS the corresponding number of molecules was 5: Der p 1 (dust mite), Der f 2 (dust mite), Phl p 1 (grass), Phl p 5 (grass), Fel d 1 (cat). In BAMSE, early IgE reactivity to ≥ 3 of 4 allergen molecules at four years predicted incident and persistent asthma and/or rhinitis at 16 years (87% and 95%, respectively). The corresponding proportions in the MAAS cohort at 16 years were 100% and 100%, respectively, for IgE reactivity to ≥ 3 of 5 risk molecules.

    Interpretations: IgE reactivity to a few allergen molecules early in life identifies children with a high risk of asthma and/or rhinitis at 16 years. These findings will be of importance for developing preventive strategies for asthma and rhinitis in children.

  • 20.
    Xie, Yuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Jiang, Yiwen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Johansson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Marinescu, Voichita Dana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindberg, Nanna
    Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA..
    Segerman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Niklasson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Baskaran, Sathishkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Sreedharan, Smitha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Everlien, Isabelle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Hermansson, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Libard, Sylwia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Holland, Eric Charles
    Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA..
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes2015In: EBioMedicine, E-ISSN 2352-3964, Vol. 2, no 10, p. 1351-1363Article in journal (Refereed)
    Abstract [en]

    Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called gliomastem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional sub-types. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.

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