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  • 1.
    Annerén, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    GTK Tyrosine Kinase-induced Alteration of IRS-protein Signalling in Insulin Producing Cells2002In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 8, no 11, p. 705-713Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Insulin receptor substrate proteins (IRS) mediate various effects of insulin, including regulation of glucose homeostasis, cell growth and survival. To understand the underlying mechanisms explaining the effects of the Src-related tyrosine kinase GTK on beta-cell proliferation and survival, insulin-signalling pathways involving IRS-1 and IRS-2 were studied in islet cells and RINm5F cells overexpressing wild-type and two different mutants of the SRC-related tyrosine kinase GTK. MATERIALS AND METHODS: Islets isolated from transgenic mice and RINm5F cells overexpressing wild-type and mutant GTK were analysed for IRS-1, IRS-2, SHB, AKT and ERK phosphorylation/activity by Western blot analysis. RESULTS: RINm5F cells expressing the kinase active mutant Y504F-GTK and islet cells from GTK(Y504F) -transgenic mice exhibited reduced insulin-induced tyrosine phosphorylation of IRS-1 and IRS-2. In RINm5F cells, the diminished IRS-phosphorylation was accompanied by a reduced insulin-stimulated activation of phosphatidylinositol 3-kinase (PI3K), AKT and Extracellular Signal-Regulated Kinase, partly due to an increased basal activity. In addition, increased tyrosine phosphorylation of the SHB SH2 domain-adaptor protein and its association with IRS-2, IRS-1 and focal adhesion kinase was observed in these cells. RINm5F cells overexpressing wild-type GTK also exhibited reduced activation of IRS-2, PI3K and AKT, whereas cells expressing a GTK mutant with lower kinase activity (GTK(Y394F)) exhibited insignificantly altered responses to insulin compared to the mock transfected cells. Moreover, GTK was shown to associate with and phosphorylate SHB in transiently transfected COS-7 cells, indicating that SHB is a specific substrate for GTK. CONCLUSIONS: The results suggest that GTK signals via SHB to modulate insulin-stimulated pathways in beta cells and this may explain previous results showing an increased beta-cell mass in GTK-transgenic mice.

  • 2.
    Barbu, Andreea R
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Welsh, Nils
    Adenoviral-induced islet cell cytotoxicity is not counteracted by Bcl-2 overexpression2002In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 8, no 11, p. 733-741Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The ability to transfer immunoregulatory, cytoprotective, or anti-apoptotic genes into pancreatic islet cells may allow enhanced resistance against the autoimmune destruction of these cells in type 1 diabetes. We describe here an inducible transduction system for expression of the anti-apoptotic bcl-2 gene in insulin-producing cells as a potential tool for protecting against beta-cell death.

    MATERIALS AND METHODS: Isolated pancreatic rat islet cells or rat insulinoma (RINm5F) cells were transduced using a progesterone antagonist (RU 486) inducible adenoviral vector system, expressing the bcl-2 gene. Bcl-2 overexpression was measured by Western blot assays and flow cytometry analysis. Following exposure to cytokines or to the mitochondrial uncoupler FCCP, cell survival was determined using fluorescence and electron microscopy, and a colorimetric assay (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]- 2H-tetrazolium-5-carboxanilide [XTT]-based) for cell viability. The mitochondrial membrane potential ((m)) was assessed using the lipophilic cationic membrane potential-sensitive dye JC-1.

    RESULTS: The adenoviral gene transfer system induced Bcl-2 expression in more than 70% of beta-cells and the protein expression levels were successfully regulated in response to varying concentrations of progesterone antagonist RU 486. Exposure of islet cells to proinflammatory cytokines IL-1beta, TNF-alpha, and IFN-gamma, or to the mitochondrial uncoupler FCCP resulted in disruption of the mitochondrial membrane potential ((m)) and beta-cell death. Bcl-2 overexpression stabilized (m) and prevented cell death in RINm5F cells but not in islet cells. In addition, prolonged in vitro culture revealed adenoviral-induced islet cell necrosis.

    CONCLUSIONS: The RU 486-regulated adenoviral system can achieve an efficient control of gene transfer at relatively low doses of the adenoviral vector. However, Bcl-2 overexpression in islet cells did not prevent adenoviral- or cytokine-induced toxicity, suggesting that the specific death pathway involved in adenoviral toxicity in beta-cells may bypass the mitochondrial permeability transition event.

  • 3.
    Che, Karlhans Fru
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Shankar, Esaki Muthu
    University of Malaya, Malaysia .
    Muthu, Sundaram
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Messmer, Davorka
    University of California, San Diego, United States.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    p38 Mitogen-Activated Protein Kinase/Signal Transducer and Activator of Transcription-3 Pathway Signaling Regulates Expression of Inhibitory Molecules in T Cells Activated by HIV-1-Exposed Dendritic Cells2012In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 18, no 8, p. 1169-1182Article in journal (Refereed)
    Abstract [en]

    Human immunodeficiency virus type 1 (HIV-1) infection enhances the expression of inhibitory molecules on T cells, leading to T-cell impairment. The signaling pathways underlying the regulation of inhibitory molecules and subsequent onset of T-cell impairment remain elusive. We showed that both autologous and allogeneic T cells exposed to HIV-pulsed dendritic cells (DCs) upregulated cytotoxic T-lymphocyte antigen (CTLA-4), tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), lymphocyte-activation gene-3 (LAG3). T-cell immunoglobulin mucin-3 (TIM-3), CD160 and certain suppression-associated transcription factors, such as B-lymphocyte induced maturation protein-1 (BLIMP-1), deltex homolog 1 protein (DTX1) and forkhead box P3 (FOXP3), leading to T-cell suppression. This induction was regulated by p38 mitogen-activated protein kinase/signal transducer and activator of transcription-3 (P38MAPK/STAT3) pathways, because their blockade significantly abrogated expression of all the inhibitory molecules studied and a subsequent recovery in T-cell proliferation. Neither interleukin-6 (IL-6) nor IL-10 nor growth factors known to activate STAT3 signaling events were responsible for STAT3 activation. Involvement of the P38MAPK/STAT3 pathways was evident because these proteins had a higher level of phosphorylation in the HIV-1-primed cells. Furthermore, blockade of viral CD4 binding and fusion significantly reduced the negative effects DCs imposed on primed T cells. In conclusion, HIV-1 interaction with DCs modulated their functionality, causing them to trigger the activation of the P38MAPK/STAT3 pathway in T cells, which was responsible for the upregulation of inhibitory molecules. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00103

  • 4.
    Danielsson, Anna
    et al.
    Linköping University, Department of Medicine and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Fagerholm, Siri
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Öst, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Franck, Niclas
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences.
    Kjölhede, Preben
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
    Nyström, Fredrik H
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Short-Term Overeating Induces Insulin Resistance in Fat Cells in Lean Human Subjects2009In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 15, no 7-8, p. 228-234Article in journal (Refereed)
    Abstract [en]

    Insulin resistance and type 2 diabetes (T2D) are closely linked to obesity. Numerous prospective studies have reported on weight gain, insulin resistance, and insulin signaling in experimental animals, but not in humans. We examined insulin signaling in adipocytes from lean volunteers, before and at the end of a 4-wk period of consuming a fast-food, high-calorie diet that led to weight gain. We also examined adipocytes from patients with T2D. During the high-calorie diet, subjects gained 10% body weight and 19% total body fat, but stayed lean (body mass index = 24.3 kg/m2) and developed moderate systemic insulin resistance. Similarly to the situation in T2D subjects, in subjects on the high-calorie diet, the amount of insulin receptors was reduced and phosphorylation of IRS1 at tyrosine and at serine-307 (human sequence, corresponding to murine serine-302) were impaired. The amount of insulin receptor substrate protein-1 (IRS1) and the phosphorylation of IRS1 at serine-312 (human sequence, corresponding to murine serine-307) were unaffected by the diet. Unlike the T2D subjects, in subjects on the high-calorie diet, likely owing to the ongoing weight-gain, phosphorylation of MAP-kinases ERK1/2 became hyperresponsive to insulin. To our knowledge this study is the first to investigate insulin signaling during overeating in humans, and it demonstrates that T2D effects on intracellular insulin signaling already occur after 4 wks of a high-calorie diet and that the effects in humans differ from those in laboratory animals.

  • 5.
    Folkersen, Lasse
    et al.
    Department of Bioinformatics, Technical University of Denmark, Lyngby, Denmark.; Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Brynedal, Boel
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Diaz-Gallo, Lina Marcela
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Ramsköld, Daniel
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Shchetynsky, Klementy
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Westerlind, Helga
    nstitute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sundström, Yvonne
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Schepis, Danika
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Hensvold, Aase
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Vivar, Nancy
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Eloranta, Maija-Leena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Brunak, Søren
    Department of Bioinformatics, Technical University of Denmark, Lyngby, Denmark.
    Malmström, Vivianne
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Catrina, Anca
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Moerch, Ulrik Gw
    Klareskog, Lars
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Padyukov, Leonid
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Berg, Louise
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Integration of known DNA, RNA and protein biomarkers provides prediction of anti-TNF response in rheumatoid arthritis: results from the COMBINE study.2016In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 22, p. 322-328Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: In rheumatoid arthritis (RA) several recent efforts have sought to discover means of predicting which patients would benefit from treatment. However, results have been discrepant with few successful replications. Our objective was to build a biobank with DNA, RNA and protein measurements to test the claim that the current state-of-the-art precision medicine will benefit RA patients.

    METHODS: We collected 451 blood samples from 61 healthy individuals and 185 RA patients initiating treatment, before treatment initiation and at a 3 month follow-up time. All samples were subjected to high-throughput RNA sequencing, DNA genotyping, extensive proteomics and flow cytometry measurements, as well as comprehensive clinical phenotyping. Literature review identified 2 proteins, 52 single-nucleotide polymorphisms (SNPs) and 72 gene-expression biomarkers that had previously been proposed as predictors of TNF inhibitor response (∆DAS28-CRP).

    RESULTS: From these published TNFi biomarkers we found that 2 protein, 2 SNP and 8 mRNA biomarkers could be replicated in the 59 TNF initiating patients. Combining these replicated biomarkers into a single signature we found that we could explain 51% of the variation in ∆DAS28-CRP. This corresponds to a sensitivity of 0.73 and specificity of 0.78 for the prediction of three month ∆DAS28-CRP better than -1.2.

    CONCLUSIONS: The COMBINE biobank is currently the largest collection of multi-omics data from RA patients with high potential for discovery and replication. Taking advantage of this we surveyed the current state-of-the-art of drug-response stratification in RA, and identified a small set of previously published biomarkers available in peripheral blood which predicts clinical response to TNF blockade in this independent cohort.

  • 6.
    Folkersen, Lasse
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Wågsäter, Dick
    Karolinska Institutet, Stockholm, Sweden.
    Paloschi, Valentina
    Karolinska Institutet, Stockholm, Sweden.
    Jackson, Veronica
    Karolinska Institutet, Stockholm, Sweden.
    Petrini, Johan
    Karolinska Institutet, Stockholm, Sweden.
    Kurtovic, Sanela
    Karolinska Institutet, Stockholm, Sweden.
    Maleki, Shohreh
    Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Maria J.
    Karolinska Institutet, Stockholm, Sweden.
    Caidahl, Kenneth
    Karolinska Institutet, Stockholm, Sweden.
    Hamsten, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Michel, Jean-Baptiste
    INSERM U698, Paris, France.
    Liska, Jan
    Karolinska Institutet, Stockholm, Sweden.
    Gabrielsen, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Franco-Cereceda, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Per
    Karolinska Institutet, Stockholm, Sweden.
    Unraveling Divergent Gene Expression Profiles in Bicuspid and Tricuspid Aortic Valve Patients with Thoracic Aortic Dilatation: The ASAP Study2011In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 17, no 11-12, p. 1365-1373Article in journal (Refereed)
    Abstract [en]

    Thoracic aortic aneurysm (TAA) is a common complication in patients with a bicuspid aortic valve (BAV), the most frequent congenital heart disorder. For unknown reasons TAA occurs at a younger age, with a higher frequency in BAV patients than in patients with a tricuspid aortic valve (TAV), resulting in an increased risk for aortic dissection and rupture. To investigate the increased TAA incidence in BAV patients, we obtained tissue biopsy samples from nondilated and dilated aortas of 131 BAV and TAV patients. Global gene expression profiles were analyzed from controls and from aortic intima-media and adventitia of patients (in total 345 samples). Of the genes found to be differentially expressed with dilation, only a few (less than4%) were differentially expressed in both BAV and TAV patients. With the use of gene set enrichment analysis, the cell adhesion and extracellular region gene ontology sets were identified as common features of TAA in both BAV and TAV patients. Immune response genes were observed to be particularly overexpressed in the aortic media of dilated TAV samples. The divergent gene expression profiles indicate that there are fundamental differences in TAA etiology in BAV and TAV patients. Immune response activation solely in the aortic media of TAV patients suggests that inflammation is involved in TAA formation in TAV but not in BAV patients. Conversely, genes were identified that were only differentially expressed with dilation in BAV patients. The result has bearing on future clinical studies in which separate analysis of BAV and TAV patients is recommended.

  • 7.
    Futalan, Diahnn
    et al.
    University of California San Diego.
    Huang, Chien-Tze
    University of California San Diego.
    Schmidt-Wolf, Ingo G H
    University of Bonn.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Messmer, Davorka
    University of California San Diego.
    Effect of Oxygen Levels on the Physiology of Dendritic Cells: Implications for Adoptive Cell Therapy2011In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 17, no 9-10, p. 910-916Article in journal (Refereed)
    Abstract [en]

    Dendritic cell (DC)-based adoptive tumor immunotherapy approaches have shown promising results, but the incidence of tumor regression is low and there is an evident call for identifying culture conditions that produce DCs with a more potent Th1 potential. Routinely, DCs are differentiated in CO(2) incubators under atmospheric oxygen conditions (21% O(2)), which differ from physiological oxygen levels of only 3-5% in tissue, where most DCs reside. We investigated whether differentiation and maturation of DCs under physiological oxygen levels could produce more potent T-cell stimulatory DCs for use in adoptive immunotherapy. We found that immature DCs differentiated under physiological oxygen levels showed a small but significant reduction in their endocytic capacity. The different oxygen levels did not influence their stimuli-induced upregulation of cluster of differentiation 54 (CD54), CD40, CD83, CD86, C-C chemokine receptor type 7 (CCR7), C-X-C chemokine receptor type 4 (CXCR4) and human leukocyte antigen (HLA)-DR or the secretion of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and IL-10 in response to lipopolysaccharide (LPS) or a cytokine cocktail. However. DCs differentiated under physiological oxygen level secreted higher levels of IL-12(p70) after exposure to LPS or CD40 ligand. Immature DCs differentiated at physiological oxygen levels caused increased T-cell proliferation, but no differences were observed for mature DCs with regard to T-cell activation. In conclusion, we show that although DCs generated under atmospheric or physiological oxygen conditions are mostly similar in function and phenotype, DCs differentiated under physiological oxygen secrete larger amounts of IL-12(p70). This result could have implications for the use of ex vivo-generated DCs for clinical studies, since DCs differentiated at physiological oxygen could induce increased Th1 responses in vivo.

  • 8. Giha, Hayder A
    et al.
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ekström, Mattias
    Israelsson, Elisabeth
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Arambepola, Gishanthi
    Arnot, David
    Theander, Thor G
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Tornvall, Per
    ElGhazali, Gehad
    Association of a single nucleotide polymorphism in the C-reactive protein gene (-286) with susceptibility to Plasmodium falciparum malaria2010In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 16, no 1-2, p. 27-33Article in journal (Refereed)
    Abstract [en]

    The role of inflammation in malaria pathogenesis is not fully understood, although C-reactive protein (CRP) may have a negative influence on host immunity to infections. An upstream polymorphism, -286 (C > T > A), in the CRP gene is known to influence CRP levels. In this study, a cohort of 192 Sudanese donors, followed for malaria infection for 9 years, had their CRP -286 gene locus genotyped by pyrosequencing. The number of malaria episodes experienced by each individual over the study period was used as an index for malaria susceptibility. The prevalence of the CRP alleles A, C and T were 21%, 52% and 27%, respectively. Importantly, the A-allele, unlike the C- and T-alleles or CRP genotypes, was significantly associated with an increased number of malaria episodes, P = 0.007. The proportion of A-allele carriers among donors not known to have had malaria during the study period was 18%, whereas it was 43% and 63% among donors who had experienced 1-4 and > or =5 malaria episodes, respectively, over the same period (P = 0.002). Furthermore, the A-allele was associated with higher parasite counts. In conclusion, the CRP -286 A-allele was associated with an increased susceptibility to uncomplicated Plasmodium falciparum malaria.

  • 9. Ihalainen, Saara
    et al.
    Soliymani, Rabah
    Iivanainen, Erika
    Mykkänen, Kati
    Sainio, Annele
    Pöyhönen, Minna
    Elenius, Klaus
    Järveläinen, Hannu
    Viitanen, Matti
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Baumann, Marc
    Proteome analysis of cultivated vascular smooth muscle cells from a CADASIL patient2007In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 13, no 5-6, p. 305-314Article in journal (Refereed)
    Abstract [en]

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a vascular dementing disease caused by mutations in NOTCH3 gene, a majority of which are missense mutations leading to an uneven number of cysteine residues in epidermal growth factor like repeats in the extracellular domain of Notch3 receptor (N3ECD). Disease is characterized by degeneration of vascular smooth muscle cells (VSMC) and accumulation of N3ECD on the VSMCs of small and middle-sized arteries. Recent studies have demonstrated that impairment of Notch3 signaling is not the primary cause of the disease. In the present study we have characterized the protein expression pattern of a unique material of genetically genuine cultured human CADASIL VSMCs by proteomic analysis. We identified 11 differentially expressed proteins, which are involved in protein degradation and folding, contraction of VSMCs and cellular stress. Based on the results the misfolding of Notch3 seems to cause endoplasmic reticulum stress and activation of unfolded protein response leading to increased reactive oxygen species and inhibition of cell proliferation. In addition, upregulation of contractile proteins suggests an alteration in the signalling system of VSMC contraction. The accumulation of the N3ECD on the cell surface possibly upregulates the angiotensin II regulatory feedback loop and thereby enhances the readiness of the cells to respond to angiotensin II stimulation.

  • 10. Krivospitskaya, Olesya
    et al.
    Elmabsout, Ali Ateia
    Sundman, Eva
    Soderstrom, Leif A.
    Ovchinnikova, Olga
    Gidlof, Andreas C.
    Scherbak, Nikolai
    Norata, Giuseppe Danilo
    Samnegard, Ann
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Abdel-Halim, Samy M.
    Jansson, Jan-Hakan
    Eriksson, Per
    Sirsjo, Allan
    Olofsson, Peder S.
    A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis2012In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 18, no 4, p. 712-718Article in journal (Refereed)
    Abstract [en]

    All-trans retinoic acid, controlled by cytochrome P450, family 26 (CYP26) enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26 subfamily B, polypeptide 1 (CYP26B1) in atherosclerosis and the effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries, and CYP26B1 and the macrophage marker CD68 were colocalized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic arteries than in normal arteries. Databases were queried for nonsynonymous CYP26B7 single nucleotide polymorphisms (SNPs) and rs2241057 selected for further studies. Constructs of the CYP26B7 variants were created and used for production of purified proteins and transfection of macrophagelike cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions, as determined by angiography. In summary, this study identifies the first CYP26B7 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.

  • 11. Krivospitskaya, Olesya
    et al.
    Elmabsout, Ali Ateia
    Sundman, Eva
    Söderström, Leif A.
    Ovchinnikova, Olga
    Gidlöf, Andreas C.
    Scherbak, Nikolai
    Norata, Giuseppe Danilo
    Samnegård, Ann
    Torma, Hans
    Abdel-Halim, Samy M.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Eriksson, Per
    Sirsjo, Allan
    Olofsson, Peder S.
    A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis2012In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 18, no 4, p. 712-718Article in journal (Refereed)
    Abstract [en]

    All-trans retinoic acid, controlled by cytochrome P450, family 26 (CYP26) enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26 subfamily B, polypeptide 1 (CYP26B1) in atherosclerosis and the effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries, and CYP26B1 and the macrophage marker CD68 were colocalized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic arteries than in normal arteries. Databases were queried for nonsynonymous CYP26B7 single nucleotide polymorphisms (SNPs) and rs2241057 selected for further studies. Constructs of the CYP26B7 variants were created and used for production of purified proteins and transfection of macrophagelike cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions, as determined by angiography. In summary, this study identifies the first CYP26B7 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00094

  • 12.
    Krivospitskaya, Olesya
    et al.
    Örebro University, School of Health and Medical Sciences.
    Elmabsout, Ali Ateia
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sundman, Eva
    Department of Anesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital Solna, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden.
    Söderström, Leif A.
    Department of Anesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital Solna, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ovchinnikova, Olga
    Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Gidlöf, Andreas C.
    Department of Anesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital Solna, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Norata, Giuseppe Danilo
    Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Pharmacological Sciences University of Milan, Milan, Italy.
    Samnegård, Ann
    Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden.
    Törmä, Hans
    Department of Medical Sciences/Dermatology, Uppsala University, Uppsala, Sweden.
    Abdel-Halim, Samy M.
    Division of Respiratory Medicine and Allergology, Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden.
    Jansson, Jan-Håkan
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden; Department of Medicine, Skellefteå Hospital, Skellefteå, Sweden.
    Eriksson, Per
    Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Olofsson, Peder S.
    Department of Anesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital Solna, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, North Shore–Long Island Jewish (LIJ) Health System, New York, United States of America.
    A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis2012In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 18, no 1, p. 712-718Article in journal (Refereed)
    Abstract [en]

    All-trans retinoic acid, controlled by CYP26 enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26B1 in atherosclerosis and effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries and CYP26B1 and the macrophage marker CD68 co-localized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic than normal arteries. Databases were queried for non-synonymous CYP26B1 SNPs and rs2241057 selected for further studies. Constructs of the CYP26B1 variants were created and used for production of purified proteins and transfection of macrophage-like cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions as determined by angiography. In summary, this study identifies the first CYP26B1 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.

  • 13.
    Ma, Zhi
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla T.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Effects of free fatty acid on polymerization of islet amyloid polypeptide (IAPP) in vitro and on amyloid fibril formation in cultivated isolated islets of transgenic mice overexpressing human IAPP2002In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 8, no 12, p. 863-868Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Islet amyloid polypeptide (IAPP) is deposited as amyloid in the islets of Langerhans in type 2 diabetes. The mechanism behind the formation of the cytotoxic fibrils is unknown. Islet amyloid develops in a mouse IAPP null mouse strain that expresses human IAPP (+hIAPP/-mIAPP) after 9 months on a high-fat diet. Herein we investigate the effect that individual free fatty acids (FFAs) exert on formation of amyloid-like fibrils from synthetic IAPP and the effects of FFAs on IAPP polymerization in +hIAPP/-mIAPP islets cultivated in vitro.

    MATERIALS AND METHODS: In the study myristic acid, palmitic acid, stearic acid, oleic acid, and linoleic acid were used together with albumin. Thioflavin T (Th T) assay was used for quantification of amyloid-like fibrils. Islets were isolated from the +hIAPP/-mIAPP transgenic strain and cultured in the presence of the FFAs for 2 days. Immuno-electron microscopy was used for evaluation.

    RESULTS: The Th T assay showed that all studied FFAs potentiated fibril formation but that myristic acid revealed the highest capacity. In some cells from cultured islets, intragranular aggregates were present. These aggregates had a filamentous appearance and labeled with antibodies against IAPP. In some cells cultured in the presence of linoleic acid, large amounts of intracellular amyloid were present. Earlier, this has not been observed after such a short incubation period.

    CONCLUSIONS: Our studies suggest that FFAs can potentiate amyloid formation in vitro, probably without being integrated in the fibril. Cultivation of +hIAPP/-mIAPP transgenic mouse islets with FFAs results in altered morphology of the secretory granules with appearance of IAPP- immunoreactive fibrillar material. We suggest that such fibrillar material may seed extracellular amyloid formation after exocytosis.

  • 14.
    Mandel, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Larsson, Per
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sarwar, Martuza
    Semenas, Julius
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Khaja, Azharuddin Sajid Syed
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The interplay between AR, EGF receptor and MMP-9 signaling pathways in invasive prostate cancer2018In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 24, p. 1-13, article id UNSP 34Article in journal (Refereed)
    Abstract [en]

    Background: Metastatic Prostate cancer (PCa) cells have gained survival and invasive advantages. Epidermal growth factor (EGA) receptor is a receptor tyrosine kinase, which may mediate signalling to promote progression and invasion of various cancers. In this study, we uncovered the molecular mechanisms underlying the interconnection among the androgen receptor (AR), matrix metalloproteinase-9 (MMP9) and EGFR in promoting PCa progression. Methods: Immunohistochemical analysis of the tissue microarrays consisting of primary and metastatic PCa tissues was performed. The clinical importance of EGFR and its association with survivals were analyzed using three cohorts from MSKCC Prostate Oncogenome Project dataset (For primary tumors, n = 181; for metastatic tumors n = 37) and The Cancer Genome Atlas Prostate Adenocarcinoma Provisional dataset (n = 495). Targeted overexpression or inhibition of the proteins of interests was introduced into PCa cell lines. Treatment of PCa cell lines with the compounds was conducted. Immunoblot analysis was performed. Results: We showed that AR, MMP-9 and EGFR are interconnect factors, which may cooperatively promote PCa progression. Altered EGFR expression was associated with poor disease-free survival in PCa patients. Induced overexpression of AR led to an increase in the expression of EGFR, p-GSK-313 and decrease in p27 expression in PCa cell lines in the presence of androgen stimulation. Overexpression of MMP9 significantly induced EGFR expression in PCa cells. Inhibition of PIP5K1a, a lipid kinase that acts upstream of PI3K/AKT greatly reduced expressions of AR, MMP-9 and EGFR. Conclusions: Our findings also suggest that PCa cells may utilize AR, EGFR and MMP-9 pathways in androgen-dependent as well as in castration-resistant conditions. Our data suggest a new therapeutic potential to block cancer metastasis by targeting AR, EGFR and MMP-9 pathways in subsets of PCa patients.

  • 15. Nader, Gustavo A.
    et al.
    Dastmalchi, Maryam
    Alexanderson, Helene
    Grundtman, Cecilia
    Gernapudi, Ramkishore
    Esbjornsson, Mona
    Wang, Zuyi
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Hoffman, Eric P.
    Nagaraju, Kanneboyina
    Lundberg, Ingrid E.
    A Longitudinal, Integrated, Clinical, Histological and mRNA Profiling Study of Resistance Exercise in Myositis2010In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 16, no 11-12, p. 455-464Article in journal (Refereed)
    Abstract [en]

    Polymyositis and dermatomyositis are orphan, chronic skeletal muscle disorders characterized by weakness, infiltrations by mononuclear inflammatory cells, and fibrosis. Until recently, patients were advised to refrain from physical activity because of fears of exacerbation of muscle inflammation. However, recent studies have shown that moderate exercise training in combination with immunosuppressive drugs can improve muscle performance. Despite the positive effects of exercise training, the molecular mechanisms underlying the exercise-associated clinical improvements remain poorly understood. The present study was designed to define, at the molecular level, the effects of resistance exercise training on muscle performance and disease progression in myositis patients. We evaluated changes in muscle strength, histology and genome-wide mRNA profiles to determine the beneficial effects of exercise and determine the possible molecular changes associated with improved muscle performance. A total of 8 myositis patients underwent a 7-wk resistance exercise training program that resulted in improved muscle strength and increased maximal oxygen uptake (VO2max). Training also resulted in marked reductions in gene expression, reflecting reductions in proinflammatory and profibrotic gene networks, changes that were also accompanied by a reduction in tissue fibrosis. Consistent with the exercise-associated increase in VO2max, a subset of transcripts was associated with a shift toward oxidative metabolism. The changes in gene expression reported in the present study are in agreement with the performance improvements induced by exercise and suggest that resistance exercise training can induce a reduction in inflammation and fibrosis in skeletal muscle.

  • 16.
    Nordquist, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Höglund, Anna-Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Norman, Holly
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Tang, Xiaorui
    Dworkin, Barry
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Transcription factors in muscle atrophy caused by blocked neuromuscular transmission and muscle unloading in rats2007In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 13, no 9-10, p. 461-470Article in journal (Refereed)
    Abstract [en]

    The muscle wasting associated with long-term intensive care unit (ICU) treatment has a negative effect on muscle function resulting in prolonged periods of rehabilitation and a decreased quality of life. To identify mechanisms behind this form of muscle wasting, we have used a rat model designed to mimic the conditions in an ICU. Rats were pharmacologically paralyzed with a postsynaptic blocker of neuromuscular transmission, and mechanically ventilated for one to two weeks, thereby unloading the limb muscles. Transcription factors were analyzed for cellular localization and nuclear concentration in the fast-twitch muscle extensor digitorum longus (EDL) and in the slow-twitch soleus. Significant muscle wasting and upregulation of mRNA for the ubiquitin ligases MAFbx and MuRF1 followed the treatment. The IκB family–member Bcl-3 displayed a concomitant decrease in concentration, suggesting altered κB controlled gene expression, although NFκB p65 was not significantly affected. The nuclear levels of the glucocorticoid receptor (GR) and the thyroid receptor α1 (TRα1) were altered and also suggested as potential mediators of the MAFbx- and MuRF1-induction in the absence of induced Foxo1. We believe that this model, and the strategy of quantifying nuclear proteins, will provide a valuable tool for further, more detailed, analyses of the muscle wasting occurring in patients kept on a mechanical ventilator.

  • 17. Pérez-Andreu, V.
    et al.
    Teruel, R.
    Corral, J.
    Roldán, V.
    García-Barberá, N.
    Salloum-Asfar, S.
    Gómez-Lechón, M. J.
    Bourgeois, S.
    Deloukas, P.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Vicente, V.
    González-Conejero, R.
    Martínez, C.
    miR-133a regulates Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1), a key protein in the Vitamin K cycle2012In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 18, no 11, p. 1466-1472Article in journal (Refereed)
    Abstract [en]

    Regulation of key proteins by microRNAs (miRNAs) is an emergent field in biomedicine. Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) is a relevant molecule for cardiovascular diseases, since it is the target of oral anticoagulant drugs and plays a role in soft tissue calcification. The objective of this study was to determine the influence of miRNAs on the expression of VKORC1. Potential miRNAs targeting VKORC1 mRNA were searched by using online algorithms. Validation studies were carried out in HepG2 cells by using miRNA precursors; direct miRNA interaction was investigated with reporter assays. In silico studies identified two putative conserved binding sites for miR-133a and miR-137 on VKORC1 mRNA. Ex vivo studies showed that only miR-133a was expressed in liver; transfection of miRNA precursors of miR-133a in HepG2 cells reduced VKORC1 mRNA expression in a dosedependent manner, as assessed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) as well as protein expression. Reporter assays in HEK293T cells showed that miR-133a interacts with the 3′UTR of VKORC1. Additionally, miR-133a levels correlated inversely with VKORC1 mRNA levels in 23 liver samples from healthy subjects. In conclusion, miR-133a appears to have a direct regulatory effect on expression of VKORC1 in humans; this regulation may have potential importance for anticoagulant therapy or aortic calcification.

  • 18.
    Sutton, Lesley-Ann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kostareli, Efterpi
    Stalika, Evangelia
    Tsaftaris, Athanasios
    Anagnostopoulos, Achilles
    Darzentas, Nikos
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Stamatopoulos, Kostas
    Temporal dynamics of clonal evolution in chronic lymphocytic leukemia with stereotyped IGHV4-34/IGKV2-30 antigen receptors: longitudinal immunogenetic evidence2013In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 19, p. 230-236Article in journal (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) patients assigned to stereotyped subset 4 possess distinctive patterns of intraclonal diversification (ID) within their immunoglobulin (IG) genes. Although highly indicative of an ongoing response to antigen(s), the critical question concerning the precise timing of antigen involvement is unresolved. Hence, we conducted a large-scale longitudinal study of eight subset 4 cases totaling 511 and 398 subcloned IG heavy and kappa sequences. Importantly, we could establish a hierarchical pattern of subclonal evolution, thus revealing which somatic hypermutations were negatively or positively selected. In addition, distinct clusters of subcloned sequences with cluster-specific mutational profiles were observed initially; however, at later time points, the minor cluster had often disappeared and hence not been selected. Despite the high intensity of ID, it was remarkable that certain residues remained essentially unaltered. These novel findings strongly support a role for persistent antigen stimulation in the clonal evolution of CLL subset 4.

  • 19.
    Sutton, Lesley-Ann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Papadopoulos, Giorgos
    Hadzidimitriou, Anastasia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Papadopoulos, Stavros
    Kostareli, Efterpi
    Rosenquist, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tzovaras, Dimitrios
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    An entity evolving into a community: defining the common ancestor and evolutionary trajectory of chronic lymphocytic leukemia stereotyped subset #42014In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 20, no 1, p. 720-728Article in journal (Refereed)
    Abstract [en]

    Patients with chronic lymphocytic leukemia (CLL) assigned to stereotyped subset #4 express highly homologous B-cell receptor immunoglobulin (BcR IG) sequences with intense intraclonal diversification (ID) in the context of ongoing somatic hypermutation (SHM). Their remarkable biological and clinical similarities strongly support derivation from a common ancestor. We here revisited ID in subset #4 CLL in order to reconstruct their evolutionary history as a community of related clones. To this end, using specialized bioinformatics tools we assessed both IGHV-IGHD-IGHJ rearrangements (n=511) and IGKV-IGKJ rearrangements (n=397) derived from 8 subset #4 cases. Due to high sequence relatedness, a number of subclonal clusters from different cases lay very close to one another, forming a core from which clusters exhibiting greater variation stemmed. Minor subclones from individual cases were mutated to such an extent that they now resembled the sequences of another patient. Viewing the entire subset #4 dataset as a single entity branching through diversification, enabled inference of a common sequence representing the putative ancestral BcR IG expressed by their still elusive common progenitor. These results have implications for improved understanding of the ontogeny of CLL subset #4, as well as the design of studies concerning the antigenic specificity of the clonotypic BcR IGs.

  • 20.
    Wang, Ning
    et al.
    Karolinska Institute.
    Shen, Nan
    Jiao Tong University.
    Vyse, Timothy J.
    Hammersmith Hospital.
    Anand, Vidya
    Hammersmith Hospital.
    Gunnarson, Iva
    Karolinska University Hospital Solna.
    Sturfelt, Gunnar
    University of Lund Hospital.
    Rantapaa-Dahlqvist, Solbritt
    Umeå University Hospital.
    Elvin, Kerstin
    Karolinska University Hospital Huddinge.
    Truedsson, Lennart
    Lund University.
    A. Andersson, Bengt
    Sahlgrens Academy.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Ortqvist, Eva
    Karolinska University Hospital Solna.
    K. Gregersen, Peter
    Feinstein Institute Medical Research.
    W. Behrens, Timothy
    Genentech Inc.
    Hammarstrom, Lennart
    Karolinska Institute.
    Selective IgA Deficiency in Autoimmune Diseases2011In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 17, no 11, p. 1383-1396Article, review/survey (Refereed)
    Abstract [en]

    Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. It has previously been suggested to be associated with a variety of concomitant autoimmune diseases. In this review, we present data on the prevalence of IgAD in patients with Graves disease (GD), systemic lupus erythematosus (SLE), type 1 diabetes (T1D). celiac disease (CD), myasthenia gravis (MG) and rheumatoid arthritis (RA) on the basis of both our own recent large-scale screening results and literature data. Genetic factors are important for the development of both IgAD and various autoimmune disorders, including GD, SLE, T1D, CD, MG and RA, and a strong association with the major histocompatibility complex (MHC) region has been reported. In addition, non-MHC genes, such as interferon-induced helicase 1 (IFH1) and c-type lectin domain family 16, member A (CLEC16A), are also associated with the development of IgAD and some of the above diseases. This indicates a possible common genetic background. In this review, we present suggestive evidence for a shared genetic predisposition between these disorders.

  • 21.
    Westermark, Gunilla
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Gebre-Medhin, S
    Linkoping Univ, Dept Biomed & Surg, Div Med Cell Biol, Linkoping, Sweden Univ Lund, Dept Physiol Sci, Div Mol & Cellular Physiol, S-22100 Lund, Sweden Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden Univ Chicago, Dept Biochem, Chicago, IL 60637 USA Univ Chicago, Howard Hughes Med Inst, Chicago, IL 60637 USA.
    Steiner, DF
    Linkoping Univ, Dept Biomed & Surg, Div Med Cell Biol, Linkoping, Sweden Univ Lund, Dept Physiol Sci, Div Mol & Cellular Physiol, S-22100 Lund, Sweden Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden Univ Chicago, Dept Biochem, Chicago, IL 60637 USA Univ Chicago, Howard Hughes Med Inst, Chicago, IL 60637 USA.
    Westermark, P
    Linkoping Univ, Dept Biomed & Surg, Div Med Cell Biol, Linkoping, Sweden Univ Lund, Dept Physiol Sci, Div Mol & Cellular Physiol, S-22100 Lund, Sweden Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden Univ Chicago, Dept Biochem, Chicago, IL 60637 USA Univ Chicago, Howard Hughes Med Inst, Chicago, IL 60637 USA.
    Islet amyloid development in a mouse strain lacking endogenous islet amyloid polypeptide (IAPP) but expressing human IAPP2000In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 6, no 12, p. 998-1007Article in journal (Refereed)
    Abstract [en]

    Background: Several mouse strains expressing human islet amyloid polypeptide (IAPP) have been created to study development of islet amyloid and its impact on islet cell function. The tendency to form islet amyloid has varied strongly among these strains by factors that have not been elucidated. Because some beta cell granule components are known to inhibit IAPP fibril formation in vitro, we wanted to determine whether a mouse strain expressing human IAPP but lacking the nonamyloidogenic mouse IAPP is more prone to develop islet amyloidosis. Materials and Methods: Such a strain was created by cross-breeding a transgenic mouse strain and an IAPP null mouse strain. Results: when fed a fat-enriched diet, male mice expressing only human IAPP developed islet amyloid earlier and to a higher extent than did mice expressing both human and mouse IAPP. Supporting these results, we found that mouse IAPP dose-dependently inhibits formation of fibrils from human IAPP. Conclusions: Female mice did not develop amyloid deposits, although small extracellular amorphous IAPP deposits were found in some islets. When cultivated in vitro, amyloid deposits occurred within 10 days in islets from either male or female mice expressing only human IAPP. The study shows that formation of islet amyloid may be dependent on the environment, including the presence or absence of fibril inhibitors or promoters.

  • 22.
    Öst, Anita
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Svensson, Kristoffer
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ruishalme, Iida
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Brännmark, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Franck, Niclas
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Krook, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Kjølhede, Preben
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics UHL.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes2010In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 16, no 07-Aug, p. 235-246Article in journal (Refereed)
    Abstract [en]

    The protein kinase mammalian target of rapamycin (mTOR) mediates insulin control ofprotein synthesis, autophagy, mitochondrial function, and, through feedback signaling tophosphorylation of IRS1 at serine residues, mTOR directly controls insulin signaling. Weshow that in adipocytes from patients with type 2 diabetes (T2D) insulin activation of mTORis attenuated and that the resultant phenotype is compatible with, and can be mimicked by,loss of mTOR activation. In T2D adipocytes mitochondrial function is impaired andautophagy strongly upregulated, with concomitant increased autophagic destruction ofmitochondria and lipofuscin particles, and a dependence on autophagy for ATP production.Conversely, mitochondrial dysfunction attenuates insulin activation of mTOR, enhancesautophagy and attenuates feedback to IRS1. Our findings put mTOR in the driver´s seat of aninsulin resistance that in adipocytes can be fuelled by mitochondrial dysfunction,inflammation, ER-stress, or hypoxia.

1 - 22 of 22
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