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  • 1.
    Backman, Max
    et al.
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    La Fleur, Linnea
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Kurppa, Pinja
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Djureinovic, Dijana
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Elfving, Hedvig
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Brunnström, Hans
    Division of Pathology, Lund University, Skåne University Hospital, Lund, Sweden.
    Mattsson, Johanna Sofia Margareta
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Pontén, Victor
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Eltahir, Mohamed
    Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden.
    Mangsbo, Sara
    Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden.
    Isaksson, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Dept. of Respiratory Medicine, Gävle Hospital, Gävle, Sweden..
    Jirström, Karin
    Division of Pathology, Lund University, Skåne University Hospital, Lund, Sweden.
    Kärre, Klas
    Department of Microbiology, Cell and Tumor Biology (MTC), Karolinska Institutet, Stockholm, Sweden..
    Carbone, Ennio
    Department of Microbiology, Cell and Tumor Biology (MTC), Karolinska Institutet, Stockholm, Sweden; Tumor Immunology and Immunopathology Laboratory, Dept. of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy..
    Leandersson, Karin
    Cancer Immunology, Dept. of Translational Medicine, Lund University, Skånes University Hospital, Malmö, Sweden.
    Mezheyeuski, Artur
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Pontén, Fredrik
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Lindskog, Cecilia
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Botling, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Extending the immune phenotypes of lung cancer: Oasis in the desertManuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the anti-tumor effects of immunotherapy. The aim of the study was to characterize patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to tumor mutations and clinicopathological parameters. 

    Methods: Lymphocytes (CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+) and PD-L1+ were annotated on a tissue microarray including 357 operated NSCLC cases. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients based on RNAseq data. 

    Results: We identified somatic mutations (TP53, NF1, KEAP1, CSMD3, LRP1B) that correlated with specific immune cell infiltrates. Hierarchical clustering revealed four immune classes: with (1) high immune cell infiltration (“inflamed”), (2) low immune cell infiltration (“desert”), (3) a mixed phenotype, and (4) a new phenotype with an overall muted inflammatory cell pattern but with an imprint of NK and plasma cells. This latter class exhibited low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, TGFB1), but was linked to better survival and therefore designated “oasis”. Otherwise, the four immune classes were not related to the presence of specific mutations (EGFR, KRAS, TP53) or histologic subtypes. 

    Conclusion: We present a compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC and identified the novel immune class “oasis”. The immune classification helps to better define the immunogenic potency of NSCLC in the era of immunotherapy. 

  • 2. Björling, Erik
    et al.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Oksvold, Per
    Linné, Jerker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kampf, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hober, Sophia
    Uhlén, Mathias
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    A web-based tool for in silico biomarker discovery based on tissue-specific protein profiles in normal and cancer tissues2008In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 7, no 5, p. 825-844Article in journal (Refereed)
    Abstract [en]

    Here we report the development of a publicly available Web-based analysis tool for exploring proteins expressed in a tissue- or cancer-specific manner. The search queries are based on the human tissue profiles in normal and cancer cells in the Human Protein Atlas portal and rely on the individual annotation performed by pathologists of images representing immunohistochemically stained tissue sections. Approximately 1.8 million images representing more than 3000 antibodies directed toward human proteins were used in the study. The search tool allows for the systematic exploration of the protein atlas to discover potential protein biomarkers. Such biomarkers include tissue-specific markers, cell type-specific markers, tumor type-specific markers, markers of malignancy, and prognostic or predictive markers of cancers. Here we show examples of database queries to generate sets of candidate biomarker proteins for several of these different categories. Expression profiles of candidate proteins can then subsequently be validated by examination of the underlying high resolution images. The present study shows examples of search strategies revealing several potential protein biomarkers, including proteins specifically expressed in normal cells and in cancer cells from specified tumor types. The lists of candidate proteins can be used as a starting point for further validation in larger patient cohorts using both immunological approaches and technologies utilizing more classical proteomics tools.

  • 3.
    Carapito, Christine
    et al.
    Univ Strasbourg, Lab Spectrometrie Masse BioOrgan LSMBO, IPHC, CNRS,UMR7178, 25 Rue Becquerel, F-67087 Strasbourg, France..
    Duek, Paula
    SIB, CALIPHO Grp, CMU, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland..
    Macron, Charlotte
    Univ Strasbourg, Lab Spectrometrie Masse BioOrgan LSMBO, IPHC, CNRS,UMR7178, 25 Rue Becquerel, F-67087 Strasbourg, France..
    Seffals, Marine
    Univ Rennes 1, UMS BioSit, Core Facil H2P2, F-35040 Rennes, France..
    Rondel, Karine
    Irset, INSERM, U1085, Protim, Campus Beaulieu, F-35042 Rennes, France..
    Delalande, Francois
    Univ Strasbourg, Lab Spectrometrie Masse BioOrgan LSMBO, IPHC, CNRS,UMR7178, 25 Rue Becquerel, F-67087 Strasbourg, France..
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Freour, Thomas
    CHU Nantes, Serv Med Reprod, 38 Blvd Jean Monnet, F-44093 Nantes, France.;INSERM, UMR1064, F-44093 Nantes, France..
    Vandenbrouck, Yves
    CEA, DRF, BIG, Lab Biol Grande Echelle, 17 Rue Martyrs, F-38054 Grenoble, France.;INSERM, U1038, F-38054 Grenoble, France.;Grenoble Alpes Univ, F-38054 Grenoble, France..
    Lane, Lydie
    SIB, CALIPHO Grp, CMU, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland.;Univ Geneva, Fac Med, Dept Human Prot Sci, 1 Rue Michel Servet, CH-1211 Geneva 4, Switzerland..
    Pineau, Charles
    Irset, INSERM, U1085, Protim, Campus Beaulieu, F-35042 Rennes, France..
    Validating Missing Proteins in Human Sperm Cells by Targeted Mass-Spectrometry- and Antibody-based Methods2017In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 16, no 12, p. 4340-4351Article in journal (Refereed)
    Abstract [en]

    The present study is a contribution to the "neXt50 challenge", a coordinated effort across C-HPP teams to identify the SO most tractable missing proteins (MPs) on each chromosome. We report the targeted search of 38 theoretically detectable MPs from chromosomes 2 and 14 in Triton X-100 soluble and insoluble sperm fractions from a total of 15 healthy donors. A targeted mass spectrometry-based strategy consisting of the development of LC-PRM assays (with heavy labeled synthetic peptides) targeting 92 proteotypic peptides of the 38 selected MPs was used. Out of the 38 selected MPs, 12 were identified with two or more peptides and 3 with one peptide after extensive SDS-PAGE fractionation of the two samples and with overall low-intensity signals. The PRM data are available via ProteomeXchange in PASSEL (PASS01013). Further validation by immunohistochemistry on human testes sections and cytochemistry on sperm smears was performed for eight MPs with antibodies available from the Human Protein Atlas. Deep analysis of human sperm still allows the validation of MPs and therefore contributes to the C-HPP worldwide effort. We anticipate that our results will be of interest to the reproductive biology community because an in-depth analysis of these MPs may identify potential new candidates in the context of human idiopathic infertilities.

  • 4.
    Carreras-Puigvert, Jordi
    et al.
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Zitnik, Marinka
    Univ Ljubljana, Fac Comp & Informat Sci, SI-1000 Ljubljana, Slovenia.; Stanford Univ, Dept Comp Sci, Palo Alto, CA 94305 USA.
    Jemth, Ann-Sofie
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Carter, Megan
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.
    Unterlass, Judith E
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Hallström, Björn
    KTH Royal Inst Technol, Sci Life Lab, Cell Profiling Affin Prote, S-17165 Stockholm, Sweden.
    Loseva, Olga
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Karem, Zhir
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Calderón-Montaño, José Manuel
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Edqvist, Per-Henrik D
    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.
    Matuszewski, Damian J.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ait Blal, Hammou
    KTH Royal Inst Technol, Sci Life Lab, Cell Profiling Affin Prote, S-17165 Stockholm, Sweden.
    Berntsson, Ronnie P A
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.
    Häggblad, Maria
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, S-17165 Stockholm, Sweden.
    Martens, Ulf
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, S-17165 Stockholm, Sweden.
    Studham, Matthew
    Stockholm Univ, Dept Biochem & Biophys, Stockholm Bioinformat Ctr, Sci Life Lab, Box 1031, S-17121 Solna, Sweden.
    Lundgren, Bo
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, S-17165 Stockholm, Sweden.
    Wählby, Carolina
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Sonnhammer, Erik L L
    Stockholm Univ, Dept Biochem & Biophys, Stockholm Bioinformat Ctr, Sci Life Lab, Box 1031, S-17121 Solna, Sweden.
    Lundberg, Emma
    KTH Royal Inst Technol, Sci Life Lab, Cell Profiling Affin Prote, S-17165 Stockholm, Sweden.
    Stenmark, Pål
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.
    Zupan, Blaz
    Univ Ljubljana, Fac Comp & Informat Sci, SI-1000 Ljubljana, Slovenia.; Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.
    Helleday, Thomas
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, no 1, article id 1541Article in journal (Refereed)
    Abstract [en]

    The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.

  • 5.
    Danielsson, Angelika
    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.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fagerberg, Linn
    Hallstrom, Bjorn M.
    Schwenk, Jochen M.
    Uhlen, Mathias
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindskog, Cecilia Bergström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The Human Pancreas Proteome Defined by Transcriptomics and Antibody-Based Profiling2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, p. e115421-Article in journal (Refereed)
    Abstract [en]

    The pancreas is composed of both exocrine glands and intermingled endocrine cells to execute its diverse functions, including enzyme production for digestion of nutrients and hormone secretion for regulation of blood glucose levels. To define the molecular constituents with elevated expression in the human pancreas, we employed a genome-wide RNA sequencing analysis of the human transcriptome to identify genes with elevated expression in the human pancreas. This quantitative transcriptomics data was combined with immunohistochemistry-based protein profiling to allow mapping of the corresponding proteins to different compartments and specific cell types within the pancreas down to the single cell level. Analysis of whole pancreas identified 146 genes with elevated expression levels, of which 47 revealed a particular higher expression as compared to the other analyzed tissue types, thus termed pancreas enriched. Extended analysis of in vitro isolated endocrine islets identified an additional set of 42 genes with elevated expression in these specialized cells. Although only 0.7% of all genes showed an elevated expression level in the pancreas, this fraction of transcripts, in most cases encoding secreted proteins, constituted 68% of the total mRNA in pancreas. This demonstrates the extreme specialization of the pancreas for production of secreted proteins. Among the elevated expression profiles, several previously not described proteins were identified, both in endocrine cells (CFC1, FAM159B, RBPJL and RGS9) and exocrine glandular cells (AQP12A, DPEP1, GATM and ERP27). In summary, we provide a global analysis of the pancreas transcriptome and proteome with a comprehensive list of genes and proteins with elevated expression in pancreas. This list represents an important starting point for further studies of the molecular repertoire of pancreatic cells and their relation to disease states or treatment effects.

  • 6.
    Djureinovic, Dijana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fagerberg, L.
    Hallstrom, B.
    Danielsson, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindskog Bergström, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhlen, M.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The human testis-specific proteome defined by transcriptomics and antibody-based profiling2014In: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 20, no 6, p. 476-488Article in journal (Refereed)
    Abstract [en]

    The testis' function is to produce haploid germ cells necessary for reproduction. Here we have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to characterize the molecular components of the testis. Deep sequencing (RNA-Seq) of normal human testicular tissue from seven individuals was performed and compared with 26 other normal human tissue types. All 20 050 putative human genes were classified into categories based on expression patterns. The analysis shows that testis is the tissue with the most tissue-specific genes by far. More than 1000 genes show a testis-enriched expression pattern in testis when compared with all other analyzed tissues. Highly testis enriched genes were further characterized with respect to protein localization within the testis, such as spermatogonia, spermatocytes, spermatids, sperm, Sertoli cells and Leydig cells. Here we present an immunohistochemistry-based analysis, showing the localization of corresponding proteins in different cell types and various stages of spermatogenesis, for 62 genes expressed at > 50-fold higher levels in testis when compared with other tissues. A large fraction of these genes were unexpectedly expressed in early stages of spermatogenesis. In conclusion, we have applied a genome-wide analysis to identify the human testis-specific proteome using transcriptomics and antibody-based protein profiling, providing lists of genes expressed in a tissue-enriched manner in the testis. The majority of these genes and proteins were previously poorly characterised in terms of localization and function, and our list provides an important starting point to increase our molecular understanding of human reproductive biology and disease.

  • 7.
    Djureinovic, Dijana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hallström, Bjorn M.
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Horie, Masafumi
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan..
    Mattsson, Johanna Sofia Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    La Fleur, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Fagerberg, Linn
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Brunnström, Hans
    Reg Labs Reg Skane, Dept Pathol, Lund, Sweden..
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Madjar, Katrin
    Tech Univ Dortmund, Dept Stat, Dortmund, Germany..
    Rahnenfuehrer, Joerg
    Tech Univ Dortmund, Dept Stat, Dortmund, Germany..
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Koyi, Hirsh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Brandén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Edlund, Karolina
    Tech Univ Dortmund, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Hengstler, Jan G.
    Tech Univ Dortmund, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Lambe, Mats
    Univ Uppsala Hosp, Reg Canc Ctr, Uppsala, Sweden..
    Saito, Akira
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan..
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Profiling cancer testis antigens in non-small-cell lung cancer2016In: JCI INSIGHT, ISSN 2379-3708, Vol. 1, no 10, article id e86837Article in journal (Refereed)
    Abstract [en]

    Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non-small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.

  • 8.
    Djureinovic, Dijana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hallström, Björn
    Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Mattsson, Johanna Sofia Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    La Fleur, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fagerberg, Linn
    Brunnström, Hans
    Lund Univ, Div Pathol, Lund, Sweden..
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ståhle, Elisabeth
    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 Surgical Sciences, Thoracic Surgery.
    Koyi, Hirsh
    Gavle Cent Hosp, Dept Pneumol, S-80187 Gavle, Sweden..
    Lambe, Mats
    Reg Canc Ctr Uppsala Orebro, Uppsala, Sweden..
    Branden, Eva
    Gavle Cent Hosp, Dept Pneumol, S-80187 Gavle, Sweden..
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Uhlen, Mathias
    Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    The Identification of Therapeutic Targets in Lung Cancer Based on Transcriptomic and Proteomic Characterization of Cancer-Testis Antigens2015In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, no 9, p. S256-S256Article in journal (Other academic)
  • 9.
    Edfors, Fredrik
    et al.
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Hober, Andreas
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Linderbäck, Klas
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Maddalo, Gianluca
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Azimi, Alireza
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, SE-17177 Stockholm, Sweden.
    Sivertsson, Åsa
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Tegel, Hanna
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Hober, Sophia
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Szigyarto, Cristina Al-Khalili
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Fagerberg, Linn
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    von Feilitzen, Kalle
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Oksvold, Per
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Forsström, Björn
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden;Tech Univ Denmark, Novo Nordisk Fdn Ctr Biosustainabil, DK-2970 Horsholm, Denmark.
    Enhanced validation of antibodies for research applications2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 4130Article in journal (Refereed)
    Abstract [en]

    There is a need for standardized validation methods for antibody specificity and selectivity. Recently, five alternative validation pillars were proposed to explore the specificity of research antibodies using methods with no need for prior knowledge about the protein target. Here, we show that these principles can be used in a streamlined manner for enhanced validation of research antibodies in Western blot applications. More than 6,000 antibodies were validated with at least one of these strategies involving orthogonal methods, genetic knockdown, recombinant expression, independent antibodies, and capture mass spectrometry analysis. The results show a path forward for efforts to validate antibodies in an application-specific manner suitable for both providers and users.

  • 10.
    Edlund, Karolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Saito, Akira
    Berglund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Göransson-Kultima, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Isaksson, Anders
    Jirström, Karin
    Planck-Sturegård, Maria
    Johansson, Leif
    Lambe, Mats
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Nyberg, Fredrik
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Landelius, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Lamberg, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Östman, Arne
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    CD99 is a novel prognostic stromal marker in non-small cell lung cancer2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, no 10, p. 2264-2273Article in journal (Refereed)
    Abstract [en]

    The complex interaction between cancer cells and the microenvironment plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumour-stroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer (NSCLC). A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened using the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern (BGN, CD99, DCN, EMILIN1, FBN1, PDGFRB, PDLIM5, POSTN, SPARC, TAGLN, TNC, VCAN). The corresponding antibodies were applied on tissue microarrays, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99 was associated with better prognosis in the univariate (p=0.037) and multivariate (p=0.039) analysis. The association was independent from the proportion of tumour stroma, the fraction of inflammatory cells, and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p=0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The results support the concept that stromal properties have an important impact on tumour progression.

  • 11.
    Edlund, Karolina
    et al.
    TU Dortmund Univ, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany.
    Madjar, Katrin
    TU Dortmund Univ, Dept Stat, Dortmund, Germany.
    Mattsson, Johanna Sofia Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Djureinovic, Dijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Brunnström, Hans
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden.
    Koyi, Hirsh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Gävle Cent Hosp, Dept Resp Med, Gävle, Sweden.
    Brandén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Gävle Cent Hosp, Dept Resp Med, Gävle, Sweden.
    Jirström, Karin
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Rahnenführer, Jörg
    TU Dortmund Univ, Dept Stat, Dortmund, Germany.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hengstler, Jan G
    TU Dortmund Univ, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany.
    Prognostic Impact of Tumor Cell Programmed Death Ligand 1 Expression and Immune Cell Infiltration in NSCLC2019In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 14, no 4, p. 628-640, article id S1556-0864(19)30009-7Article in journal (Refereed)
    Abstract [en]

    Introduction: Infiltration of T and B/plasma cells has been linked to NSCLC prognosis, but this has not been thoroughly investigated in relation to the expression of programmed death ligand 1 (PD-L1). Here, we determine the association of lymphocytes and PD-L1 with overall survival (OS) in two retrospective cohorts of operated NSCLC patients who were not treated with checkpoint inhibitors targeting the programmed death 1/PD-L1 axis. Moreover, we evaluate how PD-L1 positivity and clinicopathologic factors affect the prognostic association of lymphocytes.

    Methods: Cluster of differentiation (CD) 3 (CD3)-, CD8-, CD4-, forkhead box P3 (FOXP3)-, CD20-, CD79A-, and immunoglobulin kappa constant (IGKC)-positive immune cells, and tumor PD-L1 positivity, were determined by immunohistochemistry on tissue microarrays (n = 705). Affymetrix data was analyzed for a patient subset, and supplemented with publicly available transcriptomics data (N = 1724). Associations with OS were assessed by Kaplan-Meier plots and uni- and multivariate Cox regression.

    Results: Higher levels of T and B plasma cells were associated with longer OS (p = 0.004 and p < 0.001, for CD8 and IGKC, respectively). Highly proliferative tumors with few lymphocytes had the worst outcome. No association of PD-L1 positivity with OS was observed in a nonstratified patient population; however, a significant association with shorter OS was observed in never-smokers (p = 0.009 and p = 0.002, 5% and 50% cutoff). Lymphocyte infiltration was not associated with OS in PD-L1–positive tumors (50% cutoff). The prognostic association of lymphocyte infiltration also depended on the patients’ smoking history and histologic subtype.

    Conclusions: Proliferation, PD-L1 status, smoking history, and histology should be considered if lymphocyte infiltration is to be used as a prognostic biomarker.

  • 12.
    Ehrstedt, Christoffer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ahlsten, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Strömberg, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Casar Borota, Olivera
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Somatostatin receptor expression and mTOR pathway activation in glioneuronal tumours of childhoodManuscript (preprint) (Other academic)
  • 13.
    Elfving, Hedvig
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Mattsson, Johanna Sofia Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Backman, Max
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Programmed Cell Death Ligand 1 Immunohistochemistry: A Concordance Study Between Surgical Specimen, Biopsy, and Tissue Microarray2019In: Clinical Lung Cancer, ISSN 1525-7304, E-ISSN 1938-0690, Vol. 20, no 4, p. 258-262.e1Article in journal (Refereed)
    Abstract [en]

    Programmed cell death ligand 1 (PD-L1) expression within the same lung cancer tissue is variable. In this study we evaluated if the PD-L1 expression on small biopsy specimens represent the PD-L1 status of the corresponding resection specimen. Our results indicate a relative good agreement between biopsy and surgical specimens, with a discordance in approximately 10% of the cases. Background: The immunohistochemical analysis of programmed cell death ligand 1 (PD-L1) expression in tumor tissue of non-small-cell lung cancer patients has now been integrated in the diagnostic workup. Analysis is commonly done on small tissue biopsy samples representing a minimal fraction of the whole tumor. The aim of the study was to evaluate the correlation of PD-L1 expression on biopsy specimens with corresponding resection specimens. Materials and Methods: In total, 58 consecutive cases with preoperative biopsy and resected tumor specimens were selected. From each resection specimen 2 tumor cores were compiled into a tissue microarray (TMA). Immunohistochemical staining with the antibody SP263 was performed on biopsy specimens, resection specimens (whole sections), as well as on the TMA. Results: The proportion of PD-L1-positive stainings were comparable between the resection specimens (48% and 19%), the biopsies (43% and 17%), and the TMAs (47% and 14%), using cutoffs of 1% and 50%, respectively (P > .39 all comparisons). When the resection specimens were considered as reference, PD-L1 status differed in 16%/5% for biopsies and in 9%/9% for TMAs (1%/50% cutoff). The sensitivity of the biopsy analysis was 79%/82% and the specificity was 90%/98% at the 1%/50% cutoff. The Cohens kappa value for the agreement between biopsy and tumor. was 0.70 at the 1% cutoff and 0.83 at the 50% cutoff. Conclusion: The results indicate a moderate concordance between the analysis of biopsy and whole tumor tissue, resulting in misclassification of samples in particular when the lower 1% cutoff was used. Clinicians should be aware of this uncertainty when interpreting PD-L1 reports for treatment decisions.

  • 14.
    Eriksson, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Engholm, Ebbe
    Univ Copenhagen, Chem Biol, Dept Chem, DK-1871 Frederiksberg C, Denmark.
    Blixt, Ola
    Univ Copenhagen, Chem Biol, Dept Chem, DK-1871 Frederiksberg C, Denmark.
    Waldenstrom, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, SE-39231 Kalmar, Sweden.
    Munster, Vincent
    NIAID, Lab Virol, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olsen, Bjorn
    Uppsala Univ, Zoonosis Sci Ctr, Dept Med Sci, SE-75123 Uppsala, Sweden.
    Jourdain, Elsa
    INRA, EPIA, VetAgro Sup, UMR0346, FR-63122 St Genes Champanelle, France.
    Ellstrom, Patrik
    Uppsala Univ, Zoonosis Sci Ctr, Dept Med Sci, SE-75123 Uppsala, Sweden.
    Characterization of avian influenza virus attachment patterns to human and pig tissues2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12215Article in journal (Refereed)
    Abstract [en]

    Wild birds of Anseriformes and Charadriiformes are natural reservoirs of influenza A viruses (IAVs). Occasionally, IAVs transmit and adapt to mammalian hosts, and are maintained as epidemic strains in their new hosts. Viral adaptions to mammalian hosts include altered receptor preference of host epithelial sialylated oligosaccharides from terminal alpha 2,3-linked sialic acid (SA) towards alpha 2,6-linked SA. However, alpha 2,3-linked SA has been found in human respiratory tract epithelium, and human infections by avian IAVs (AIVs) have been reported. To further explore the attachment properties of AIVs, four AIVs of different subtypes were investigated on human and pig tissues using virus histochemistry. Additionally, glycan array analysis was performed for further characterization of IAVs' receptor structure tropism. Generally, AIV attachment was more abundant to human tissues than to pig tissues. The attachment pattern was very strong to human conjunctiva and upper respiratory tract, but variable to the lower respiratory tract. AIVs mainly attached to alpha 2,3-linked SA, but also to combinations of alpha 2,3-and alpha 2,6-linked SA. The low attachment of these AIV isolates to pig tissues, but high attachment to human tissues, addresses the question whether AIVs in general require passage through pigs to obtain adaptions towards mammalian receptor structures.

  • 15.
    Eriksson, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Lorente-Leal, Victor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Waldenström, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden.
    González-Acuna, Daniel
    Univ Concepcion, Fac Ciencias Vet, Chillan, Chile.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Jourdain, Elsa
    INRA, UMR0346 EPIA, VetAgro Sup, St Genes Champanelle, France.
    Ellström, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Attachment Patterns of Human and Avian Influenza Viruses to Trachea and Colon of 26 Bird Species: Support for the Community Concept2019In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 10, article id 815Article in journal (Refereed)
    Abstract [en]

    Avian influenza A viruses (AIVs) have a broad host range, but are most intimately associated with waterfowl (Anseriformes) and, in the case of the H13 and H16 subtypes, gulls (Charadriiformes). Host associations are multifactorial, but a key factor is the ability of the virus to bind host cell receptors and thereby initiate infection. The current study aims at investigating the tissue attachment pattern of a panel of AIVs, comprising H3N2, H6N1, H12N5, and H16N3, to avian trachea and colon tissue samples obtained from host species of different orders. Virus attachment was not restricted to the bird species or order from which the virus was isolated. Instead, extensive virus attachment was observed to several distantly related avian species. In general, more virus attachment and receptor expression were observed in trachea than in colon samples. Additionally, a human seasonal H3N2 virus was studied. Unlike the studied AIVs, this virus mainly attached to tracheae from Charadriiformes and a very limited set of avian cola. In conclusion, the reported results highlight the importance of AIV attachment to trachea in many avian species. Finally, the importance of chickens and mallards in AIVs dynamics was illustrated by the abundant AIV attachment observed.

  • 16. Fagerberg, Linn
    et al.
    Hallström, Björn M
    Oksvold, Per
    Kampf, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Djureinovic, Dijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Odeberg, Jacob
    Habuka, Masato
    Tahmasebpoor, Simin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Danielsson, Angelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sjöstedt, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lundberg, Emma
    Szigyarto, Cristina Al-Khalili
    Skogs, Marie
    Takanen, Jenny Ottosson
    Berling, Holger
    Tegel, Hanna
    Mulder, Jan
    Nilsson, Peter
    Schwenk, Jochen M
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Danielsson, Frida
    Mardinoglu, Adil
    Sivertsson, Asa
    von Feilitzen, Kalle
    Forsberg, Mattias
    Zwahlen, Martin
    Olsson, IngMarie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Navani, Sanjay
    Huss, Mikael
    Nielsen, Jens
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Uhlén, Mathias
    Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics2014In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 13, no 2, p. 397-406Article in journal (Refereed)
    Abstract [en]

    Global classification of the human proteins with regards to spatial expression patterns across organs and tissues is important for studies of human biology and disease. Here, we used a quantitative transcriptomics analysis (RNA-Seq) to classify the tissue-specific expression of genes across a representative set of all major human organs and tissues and combined this analysis with antibody-based profiling of the same tissues. To present the data, we launch a new version of the Human Protein Atlas that integrates RNA and protein expression data corresponding to ∼80% of the human protein-coding genes with access to the primary data for both the RNA and the protein analysis on an individual gene level. We present a classification of all human protein-coding genes with regards to tissue-specificity and spatial expression pattern. The integrative human expression map can be used as a starting point to explore the molecular constituents of the human body.

  • 17.
    Guo, Jingtao
    et al.
    Univ Utah, Howard Hughes Med Inst, Sch Med, Dept Oncol Sci, Salt Lake City, UT 84112 USA;Univ Utah, Howard Hughes Med Inst, Huntsman Canc Inst, Sch Med, Salt Lake City, UT 84112 USA;Univ Utah, Hlth Sci Ctr, Ctr Reconstruct Urol & Mens Hlth, Dept Surg Androl Urol, Salt Lake City, UT 84122 USA.
    Grow, Edward J.
    Univ Utah, Howard Hughes Med Inst, Sch Med, Dept Oncol Sci, Salt Lake City, UT 84112 USA;Univ Utah, Howard Hughes Med Inst, Huntsman Canc Inst, Sch Med, Salt Lake City, UT 84112 USA.
    Mlcochova, Hana
    Univ Oxford, MRC Weatherall Inst Mol Med, Radcliffe Dept Med, Oxford OX3 9DS, England.
    Maher, Geoffrey J.
    Univ Oxford, MRC Weatherall Inst Mol Med, Radcliffe Dept Med, Oxford OX3 9DS, England.
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Nie, Xichen
    Univ Utah, Howard Hughes Med Inst, Sch Med, Dept Oncol Sci, Salt Lake City, UT 84112 USA;Univ Utah, Howard Hughes Med Inst, Huntsman Canc Inst, Sch Med, Salt Lake City, UT 84112 USA.
    Guo, Yixuan
    Univ Utah, Howard Hughes Med Inst, Sch Med, Dept Oncol Sci, Salt Lake City, UT 84112 USA;Univ Utah, Howard Hughes Med Inst, Huntsman Canc Inst, Sch Med, Salt Lake City, UT 84112 USA.
    Takei, Yodai
    CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
    Yun, Jina
    CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
    Cai, Long
    CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA.
    Kim, Robin
    Univ Utah, Sch Med, Dept Surg, Sect Transplantat, Salt Lake City, UT 84132 USA.
    Carrell, Douglas T.
    Univ Utah, Hlth Sci Ctr, Ctr Reconstruct Urol & Mens Hlth, Dept Surg Androl Urol, Salt Lake City, UT 84122 USA.
    Goriely, Anne
    Univ Oxford, MRC Weatherall Inst Mol Med, Radcliffe Dept Med, Oxford OX3 9DS, England.
    Hotaling, James M.
    Univ Utah, Hlth Sci Ctr, Ctr Reconstruct Urol & Mens Hlth, Dept Surg Androl Urol, Salt Lake City, UT 84122 USA.
    Cairns, Bradley R.
    Univ Utah, Howard Hughes Med Inst, Sch Med, Dept Oncol Sci, Salt Lake City, UT 84112 USA;Univ Utah, Howard Hughes Med Inst, Huntsman Canc Inst, Sch Med, Salt Lake City, UT 84112 USA.
    The adult human testis transcriptional cell atlas2018In: Cell Research, ISSN 1001-0602, E-ISSN 1748-7838, Vol. 28, p. 1141-1157Article in journal (Refereed)
    Abstract [en]

    Human adult spermatogenesis balances spermatogonial stem cell (SSC) self-renewal and differentiation, alongside complex germ cell-niche interactions, to ensure long-term fertility and faithful genome propagation. Here, we performed single-cell RNA sequencing of similar to 6500 testicular cells from young adults. We found five niche/somatic cell types (Leydig, myoid, Sertoli, endothelial, macrophage), and observed germline-niche interactions and key human-mouse differences. Spermatogenesis, including meiosis, was reconstructed computationally, revealing sequential coding, non-coding, and repeat-element transcriptional signatures. Interestingly, we identified five discrete transcriptional/developmental spermatogonial states, including a novel early SSC state, termed State 0. Epigenetic features and nascent transcription analyses suggested developmental plasticity within spermatogonial States. To understand the origin of State 0, we profiled testicular cells from infants, and identified distinct similarities between adult State 0 and infant SSCs. Overall, our datasets describe key transcriptional and epigenetic signatures of the normal adult human testis, and provide new insights into germ cell developmental transitions and plasticity.

  • 18.
    Guo, Jingtao
    et al.
    Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
    Grow, Edward J.
    Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
    Yi, Chongil
    Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
    Mlcochova, Hana
    Univ Oxford, Radcliffe Dept Med, MRC Weatherall Inst Mol Med, Oxford OX3 9DS, England..
    Maher, Geoffrey J.
    Univ Oxford, Radcliffe Dept Med, MRC Weatherall Inst Mol Med, Oxford OX3 9DS, England..
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Murphy, Patrick J.
    Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
    Wike, Candice L.
    Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
    Carrell, Douglas T.
    Univ Utah, Hlth Sci Ctr, Ctr Reconstruct Urol & Mens Hlth, Dept Surg Androl Urol, Salt Lake City, UT 84122 USA..
    Goriely, Anne
    Univ Oxford, Radcliffe Dept Med, MRC Weatherall Inst Mol Med, Oxford OX3 9DS, England..
    Hotaling, James M.
    Univ Utah, Hlth Sci Ctr, Ctr Reconstruct Urol & Mens Hlth, Dept Surg Androl Urol, Salt Lake City, UT 84122 USA..
    Cairns, Bradley R.
    Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
    Chromatin and Single-Cell RNA- Seq Profiling Reveal Dynamic Signaling and Metabolic Transitions during Human Spermatogonial Stem Cell Development2017In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 21, no 4, p. 533-546Article in journal (Refereed)
    Abstract [en]

    Human adult spermatogonial stem cells (hSSCs) must balance self-renewal and differentiation. To understand how this is achieved, we profiled DNA methylation and open chromatin (ATAC-seq) in SSEA4(+) hSSCs, analyzed bulk and single-cell RNA transcriptomes (RNA-seq) in SSEA4+ hSSCs and differentiating c-KIT+ spermatogonia, and performed validation studies via immunofluorescence. First, DNA hypomethylation at embryonic developmental genes supports their epigenetic "poising'' in hSSCs for future/embryonic expression, while core pluripotency genes (OCT4 and NANOG) were transcriptionally and epigenetically repressed. Interestingly, open chromatin in hSSCs was strikingly enriched in binding sites for pioneer factors (NFYA/B, DMRT1, and hormone receptors). Remarkably, single-cell RNA-seq clustering analysis identified four cellular/developmental states during hSSC differentiation, involving major transitions in cell-cycle and transcriptional regulators, splicing and signaling factors, and glucose/mitochondria regulators. Overall, our results outline the dynamic chromatin/transcription landscape operating in hSSCs and identify crucial molecular pathways that accompany the transition from quiescence to proliferation and differentiation.

  • 19. Haggmark, Anna
    et al.
    Hamsten, Carl
    Wiklundh, Emil
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mattsson, Cecilia
    Andersson, Eni
    Lundberg, Ingrid E.
    Gronlund, Hans
    Schwenk, Jochen M.
    Eklund, Anders
    Grunewald, Johan
    Nilsson, Peter
    Proteomic Profiling Reveals Autoimmune Targets in Sarcoidosis2015In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 191, no 5, p. 574-583Article in journal (Refereed)
    Abstract [en]

    Rationale: There is a need to further characterize the antibody repertoire in relation to sarcoidosis and potentially related autoantigens. Objectives: We investigated bronchoalveolar lavage (BAL) and serum samples from patients with sarcoidosis and healthy and diseased control subjects to discover sarcoidosis-associated autoantigens. Methods: Antigen microarrays built on 3,072 protein fragments were used to screen for IgG reactivity in 73 BAL samples from subjects with sarcoidosis, subjects with asthma, and healthy subjects. A set of 131 targets were selected for subsequent verification on suspension bead arrays using 272 additional BAL samples and 141 paired sera. Reactivity to four antigens was furthermore analyzed in 22 unprocessed BAL samples from patients with fibrosis and 269 plasma samples from patients diagnosed with myositis. Measurements and Main Results: Reactivity toward zinc finger protein 688 and mitochondrial ribosomal protein L43 were discovered with higher frequencies in patients with sarcoidosis, for mitochondrial ribosomal protein L43 especially in patients with non-Lofgren syndrome. Increased reactivity toward nuclear receptor coactivator 2 was also observed in patients with non-Lofgren syndrome as compared with patients with Lofgren syndrome. The antigen representing adenosine diphosphate-ribosylation factor GTPase activating protein 1 revealed high reactivity frequency in all sample groups but with significantly higher level of IgG reactivities in patients with sarcoidosis. Conclusions: Autoantigen reactivity was present in most BAL and serum samples analyzed, and the results revealed high interindividual heterogeneity, with most of the reactivities observed in single individuals only. Four proteins are here proposed as sarcoidosis-associated autoimmune targets and of interest for further validation in independent cohorts.

  • 20. Larsson, K.
    et al.
    Hofstrom, C.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Hansson, M.
    Angelidou, P.
    Hokfelt, T.
    Uhlen, M.
    Wernerus, H.
    Graslund, T.
    Hober, S.
    Novel antigen design for the generation of antibodies to G-protein-coupled receptors2011In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 370, no 1-2, p. 14-23Article in journal (Refereed)
    Abstract [en]

    Antibodies are important tools for the study of G-protein-coupled receptors, key proteins in cellular signaling. Due to their large hydrophobic membrane spanning regions and often very short loops exposed on the surface of the cells, generation of antibodies able to recognize the receptors in the endogenous environment has been difficult. Here, we describe an antigen-design method where the extracellular loops and N-terminus are combined to a single antigen for generation of antibodies specific to three selected GPCRs: NPY5R, B2ARN and GLP1R. The design strategy enabled straightforward antigen production and antibody generation. Binding of the antibodies to intact receptors was analyzed using flow cytometry and immunofluorescence based confocal microscopy on A-431 cells overexpressing the respective GPCR. The antibody-antigen interactions were characterized using epitope mapping, and the antibodies were applied in immunohistochemical staining of human tissues. Most of the antibodies showed specific binding to their respective overexpressing cell line but not to the non-transfected cells, thus indicating binding to their respective target receptor. The epitope mapping showed that sub-populations within the purified antibody pool recognized different regions of the antigen. Hence, the genetic combination of several different epitopes enables efficient generation of specific antibodies with potential use in several applications for the study of endogenous receptors.

  • 21.
    Lindskog Bergström, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Tissue Microarrays for Analysis of Expression Patterns2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Proteins are essential building blocks in every living cell, and since the complete human genome was sequenced in 2004, researchers have attempted to map the human proteome, which is the functional representation of the genome. One such initiative is the Human Protein Atlas programme (HPA), which generates monospecific antibodies towards all human proteins and uses these for high-throughput tissue profiling on tissue microarrays (TMAs). The results are publically available at the website www.proteinatlas.org.

    In this thesis, TMAs were used for analysis of expression patterns in various research areas. Different search queries in the HPA were tested and evaluated, and a number of potential biomarkers were identified, e.g. proteins exclusively expressed in islets of Langerhans, but not in exocrine glandular cells or other abdominal organs close to pancreas. The identified candidates were further analyzed on TMAs with pancreatic tissues from normal and diabetic individuals, and colocalization studies with insulin and glucagon revealed that several of the investigated proteins (DGCR2, GBF1, GPR44 and SerpinB10) appeared to be beta cell specific. Moreover, a set of proteins differentially expressed in lung cancer stroma was further analyzed on a clinical lung cancer cohort in the TMA format, and one protein (CD99) was significantly associated with survival. In addition, TMAs with tissue samples from different species were generated, e.g. for mapping of influenza virus attachment in various human and avian tissues. The results showed that the gull influenza virus H16N3 attached to human respiratory tract and eye, suggesting possible transmission of the virus between gull and human. TMAs were also used for analysis of protein expression differences between humans and other primates, and two proteins (TCF3 and SATB2) proved to be significantly differentially expressed on the human lineage at both the protein level and the RNA level.  

    In conclusion, this thesis exemplifies the potential of the TMA technology, which can be used for analysis of expression patterns in a large variety of research fields, such as biomarker discovery, influenza virus research or further understanding of human evolution.

  • 22.
    Lindskog Bergström, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Catrina, Anca
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Clin, Stockholm, Sweden..
    Nielsen, Soren
    Lund Univ, Dept Biochem & Struct Biol, Lund, Sweden..
    Rutzler, Michael
    Lund Univ, Dept Biochem & Struct Biol, Lund, Sweden.;Aalborg Univ, Inst Hlth Sci & Technol, Aalborg O, Denmark..
    A Systematic Characterization of Aquaporin-9 Expression in Human Normal and Pathological Tissues2016In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 64, no 5, p. 287-300Article in journal (Refereed)
    Abstract [en]

    AQP9 is known to facilitate hepatocyte glycerol uptake. Murine AQP9 protein expression has been verified in liver, skin, epididymis, epidermis and neuronal cells using knockout mice. Further expression sites have been reported in humans. We aimed to verify AQP9 expression in a large set of human normal organs, different cancer types, rheumatoid arthritis synovial biopsies as well as in cell lines and primary cells. Combining standardized immunohistochemistry with high-throughput mRNA sequencing, we found that AQP9 expression in normal tissues was limited, with high membranous expression only in hepatocytes. In cancer tissues, AQP9 expression was mainly found in hepatocellular carcinomas, suggesting no general contribution of AQP9 to carcinogenesis. AQP9 expression in a subset of rheumatoid arthritis synovial tissue samples was affected by Humira, thereby supporting a suggested role of TNF alpha in AQP9 regulation in this disease. Among cell lines and primary cells, LP-1 myeloma cells expressed high levels of AQP9, whereas low expression was observed in a few other lymphoid cell lines. AQP9 mRNA and protein expression was absent in HepG2 hepatocellular carcinoma cells. Overall, AQP9 expression in human tissues appears to be more selective than in mice.

  • 23.
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    The potential clinical impact of the tissue-based map of the human proteome2015In: Expert Review of Proteomics, ISSN 1478-9450, E-ISSN 1744-8387, Vol. 12, no 3, p. 213-215Article in journal (Other academic)
    Abstract [en]

    Since the first draft of the human genome sequence was published, several attempts have been made to map the human proteome, the functional representation of the genome. One such initiative is the Human Protein Atlas project, which recently released a tissue-based map of the human proteome. The Human Protein Atlas is based on the combination of transcriptomics and antibody-based proteomics for mapping the human proteome down to the single cell level. The comprehensive publicly available database contains more than 13 million unique immunohistochemistry images and provides an excellent resource for exploration and investigation of future drug targets and disease biomarkers.

  • 24.
    Lindskog, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Engkvist, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Antibody-based proteomics for discovery and exploration of proteins expressed in pancreatic islets2010In: Discovery Medicine, ISSN 1539-6509, E-ISSN 1944-7930, Vol. 9, no 49, p. 565-578Article in journal (Refereed)
    Abstract [en]

    Abnormal glucose tolerance and deviant blood glucose levels are late stage clinical parameters that signify diabetes mellitus. To be able to diagnose the disease at an earlier stage and develop new tools for beta cell imaging, new molecular markers are needed. In the present study, five proteins highly expressed in pancreatic islets with no expression in the surrounding exocrine glandular cells of pancreas, and one protein with the opposite expression pattern, were identified by searches in the Human Protein Atlas (www.proteinatlas.org). The proteins were analyzed immunohistochemically on a specially designed tissue microarray, containing isolated human islets and pancreatic tissues with different characteristics, and compared to the expression of previously known markers of endocrine and exocrine pancreatic cells. Of the five novel endocrine markers, tetraspanin-7 was identified as a membrane-bound protein with exclusive positivity in islet cells. Also beta-2-microglobulin and ubiquitin carboxyl-terminal hydrolase isozyme L1 were expressed in a majority of islet cells, whereas sad1/unc-84 domain-containing protein 1 and beta-1,3-glucuronyltransferase 1 were positive in a smaller subset of islet cells. The potential exocrine marker galectin-2 was expressed in both exocrine acinary cells and pancreatic ductal cells, with no or low positivity in islet cells. In conclusion, antibody-based proteomics and specially designed tissue microarrays enable identification and exploration of novel proteins with differential expression in pancreatic islets. Here we describe 5 candidate proteins for further investigation of their physiological role and potential involvement in the pathogenesis of diabetes. One of these proteins, tetraspanin-7, is expressed on the cell membrane and could thus be a potential candidate for future development of tracers for beta cell imaging.

  • 25.
    Lindskog, Cecilia
    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.
    Edlund, Karolina
    Mattsson, Johanna Sofia Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Immunohistochemistry-based prognostic biomarkers in NSCLC: novel findings on the road to clinical use?2015In: Expert Review of Molecular Diagnostics, ISSN 1473-7159, E-ISSN 1744-8352, Vol. 15, no 4, p. 471-490Article, review/survey (Refereed)
    Abstract [en]

    Prognostication of non-small cell lung cancer is principally based on stage, age and performance status. This review provides an overview of 342 potential prognostic biomarkers in non-small cell lung cancer described between January 2008 and June 2013, evaluating the association between immunohistochemical protein expression and survival endpoint. Numerous studies proposed prognostic biomarkers, but many were only evaluated in a single patient cohort, and a large number of biomarkers revealed inconclusive findings when analyzed in more than one study. Only 26 proteins first described after 2008 (ALDH1A1, ANXA1, BCAR1, CLDN1, EIF4E, EZH2, FOLR1, FOXM1, IL7R, IL12RB2, KIAA1524, CRMP1, LOX, MCM7, MTA1, MTDH, NCOA3, NDRG2, NEDD9, NES, PBK, PPM1D, SIRT1, SLC7A5, SQSTM1 and WNT1) demonstrated a consistent prognostic association in two or more independent patient cohorts, thus qualifying as promising candidates for diagnostic use. Raised quality standards for study design and antibody validation, and integration of preclinical findings with clinical needs are clearly warranted.

  • 26. Lindskog, Cecilia
    et al.
    Ellström, Patrik
    Olsen, Björn
    Pontén, Fredrik
    van Riel, Debby
    Munster, Vincent
    Gonzales-Acuna, Daniel
    Kuiken, Thijs
    Jourdain, Elsa
    H16 Gull Influenza Virus Attaches to the Human Respiratory Tract and EyeIn: Emerging Infectious Diseases, ISSN 1080-6059Article in journal (Other academic)
  • 27.
    Lindskog, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Fagerberg, Linn
    Hallstrom, Bjorn
    Edlund, Karolina
    Hellwig, Birte
    Rahnenfuhrer, Jorg
    Kampf, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Uhlen, Mathias
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    The lung-specific proteome defined by integration of transcriptomics and antibody-based profiling2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 12, p. 5184-5196Article in journal (Refereed)
    Abstract [en]

    The combined action of multiple cell types is essential for the physiological function of the lung, and increased awareness of the molecular constituents characterizing each cell type is likely to advance the understanding of lung biology and disease. In the current study, we used genome-wide RNA sequencing of normal lung parenchyma and 26 additional tissue types, combined with antibody-based protein profiling, to localize the expression to specific cell types. Altogether, 221 genes were found to be elevated in the lung compared with their expression in other analyzed tissues. Among the gene products were several well-known markers, but also several proteins previously not described in the context of the lung. To link the lung-specific molecular repertoire to human disease, survival associations of pneumocyte-specific genes were assessed by using transcriptomics data from 7 non-small-cell lung cancer (NSCLC) cohorts. Transcript levels of 10 genes (SFTPB, SFTPC, SFTPD, SLC34A2, LAMP3, CACNA2D2, AGER, EMP2, NKX2-1, and NAPSA) were significantly associated with survival in the adenocarcinoma subgroup, thus qualifying as promising biomarker candidates. In summary, based on an integrated omics approach, we identified genes with elevated expression in lung and localized corresponding protein expression to different cell types. As biomarker candidates, these proteins may represent intriguing starting points for further exploration in health and disease.

  • 28.
    Lindskog, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Jan W
    Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Danielsson, Angelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Novel pancreatic beta cell-specific proteins: Antibody-based proteomics for identification of new biomarker candidates2012In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 75, no 9, p. 2611-2620Article in journal (Refereed)
    Abstract [en]

    Beta cell-specific surface targets are required for non-invasive monitoring of beta cell mass, which could be used for evaluation of new diabetes treatments as well as to help unravel pathogenic mechanisms underlying beta cell dysfunction. By antibody-based proteomics, we have identified and explored a set of islet cell-specific proteins. A search algorithm in the Human Protein Atlas was set up for identification of islet-specific proteins that yielded 27 hits, of which twelve showed a clear membranous expression pattern or had predicted transmembrane regions. The specificity of the identified proteins was investigated by immunohistochemical staining of pancreas sections from diabetic and non-diabetic subjects. No expression of these antigens could be detected in the exocrine pancreas. Colocalization with insulin and glucagon was further determined by confocal microscopy using isolated human islets. All antibodies specifically stained human islets and colocalization analysis revealed that four proteins were exclusively expressed in beta cells. Importantly, these antibodies were negative in sections from subjects with long-standing type 1 diabetes. In the present study, we present four proteins; DGCR2, GBF1, GPR44 and SerpinB10, the expression of which has not previously been described in beta cells.

  • 29.
    Lindskog, Cecilia
    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.
    Kuhlwilm, Martin
    Davierwala, Armaity
    Fu, Ning
    Hedge, Geeta
    Uhlén, Mathias
    Navani, Sanjay
    Pääbo, Svante
    Pontén, Fredrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Analysis of Candidate Genes for Lineage-Specific Expression Changes in Humans and Primates2014In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, no 8, p. 3596-3606Article in journal (Refereed)
    Abstract [en]

    RUNX2, a gene involved in skeletal development, has previously been shown to be potentially affected by positive selection during recent human evolution. Here we have used antibody-based proteomics to characterize potential differences in expression patterns of RUNX2 interacting partners during primate evolution. Tissue microarrays consisting of a large set of normal tissues from human and macaque were used for protein profiling of 50 RUNX2 partners with immunohistochemistry. Eleven proteins (AR, CREBBP, EP300, FGF2, HDAC3, JUN, PRKD3, RUNX1, SATB2, TCF3, and YAP1) showed differences in expression between humans and macaques. These proteins were further profiled in tissues from chimpanzee, gorilla, and orangutan, and the corresponding genes were analyzed with regard to genomic features. Moreover, protein expression data were compared with previously obtained RNA sequencing data from six different organs. One gene (TCF3) showed significant expression differences between human and macaque at both the protein and RNA level, with higher expression in a subset of germ cells in human testis compared with macaque. In conclusion, normal tissues from macaque and human showed differences in expression of some RUNX2 partners that could be mapped to various defined cell types. The applied strategy appears advantageous to characterize the consequences of altered genes selected during evolution.

  • 30.
    Lindskog, Cecilia
    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.
    Linné, Jerker
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fagerberg, Linn
    Hallstrom, Bjorn M.
    Sundberg, Carl Johan
    Lindholm, Malene
    Huss, Mikael
    Kampf, Caroline
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Choi, Howard
    Liem, David A.
    Ping, Peipei
    Varemo, Leif
    Mardinoglu, Adil
    Nielsen, Jens
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Uhlen, Mathias
    The human cardiac and skeletal muscle proteomes defined by transcriptomics and antibody-based profiling2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 475Article in journal (Refereed)
    Abstract [en]

    Background: To understand cardiac and skeletal muscle function, it is important to define and explore their molecular constituents and also to identify similarities and differences in the gene expression in these two different striated muscle tissues. Here, we have investigated the genes and proteins with elevated expression in cardiac and skeletal muscle in relation to all other major human tissues and organs using a global transcriptomics analysis complemented with antibody-based profiling to localize the corresponding proteins on a single cell level. Results: Our study identified a comprehensive list of genes expressed in cardiac and skeletal muscle. The genes with elevated expression were further stratified according to their global expression pattern across the human body as well as their precise localization in the muscle tissues. The functions of the proteins encoded by the elevated genes are well in line with the physiological functions of cardiac and skeletal muscle, such as contraction, ion transport, regulation of membrane potential and actomyosin structure organization. A large fraction of the transcripts in both cardiac and skeletal muscle correspond to mitochondrial proteins involved in energy metabolism, which demonstrates the extreme specialization of these muscle tissues to provide energy for contraction. Conclusions: Our results provide a comprehensive list of genes and proteins elevated in striated muscles. A number of proteins not previously characterized in cardiac and skeletal muscle were identified and localized to specific cellular subcompartments. These proteins represent an interesting starting point for further functional analysis of their role in muscle biology and disease.

  • 31.
    Miyashita, Naoya
    et al.
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan.
    Horie, Masafumi
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan;Univ Southern Calif, Hastings Ctr Pulm Res, Div Pulm Crit Care & Sleep Med, Dept Med,Keck Sch Med, Los Angeles, CA USA;RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan.
    Suzuki, Hiroshi I.
    MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
    Yoshihara, Masahito
    RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan.
    Djureinovic, Dijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Persson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Brunnstrom, Hans
    Lund Univ, Lab Med Reg Skane, Dept Clin Sci Lund, Pathol, Lund, Sweden.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Elfving, Hedvig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Saito, Akira
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan;Univ Tokyo, Div Hlth Serv Promot, Tokyo, Japan.
    Nagase, Takahide
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan.
    An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1-Positive Lung Adenocarcinomas2018In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, no 11, p. 1676-1691Article in journal (Refereed)
    Abstract [en]

    Introduction: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute family bHLH transcription factor 1 (ASCL1), common to high-grade neuroendocrine tumors, small-cell lung cancer and large cell neuroendocrine carcinoma. Methods: The aim of this study was to characterize clinical and molecular features of ASCL1-positive lung adenocarcinoma by using recent transcriptome profiling in multiple patient cohorts and genome-wide epigenetic profiling including data from The Cancer Genome Atlas. Results: The ASCL1-positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor EGFR mutations. In transcriptome profiling, this subtype overlapped with the recently proposed proximal-proliferative molecular subtype. Gene expression profiling of ASCL1-positive cases suggested generally poor immune cell infiltration and none of the tumors were positive for programmed cell death ligand 1 protein expression. Genome-wide methylation analysis showed global DNA hypomethylation in ASCL1-positive cases. ASCL1 was associated with super-enhancers in ASCL1-positive lung adenocarcinoma cells, and ASCL1 silencing suppressed other super-enhancer-associated genes, suggesting thatASCL1 acts as a master transcriptional regulator. This was further reinforced by the essential roles of ASCL1 in cell proliferation, survival, and cell cycle control. Conclusions: These results suggest that ASCL1 defines a subgroup of lung adenocarcinoma with distinct molecular features by driving super-enhancer-mediated transcriptional programs.

  • 32.
    Morin, Eric
    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, Vascular Biology. Uppsala University.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Egevad, Lars
    Sandström, Per
    Hermenberg, Ulrika
    Claesson-Welsh, Lena
    Uppsala University, Science for Life Laboratory, SciLifeLab. 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 Immunology, Genetics and Pathology, Vascular Biology.
    Sjöberg, Elin
    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.
    Perivascular Neuropilin-1 expression is an independent marker of improved survival in renal cell carcinomaIn: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827Article in journal (Other academic)
    Abstract [en]

    Background: Considerable progress in renal cell carcinoma (RCC) treatment has been made in the last decade with the introduction of drugs targeting tumor angiogenesis. However, the 5-year survival of metastatic disease is still only 10-15%. Here, we explored the prognostic significance of compartment-specific expression of Neuropilin 1 (NRP1), a co-receptor for vascular endothelial growth factor (VEGF). NRP1 expression was analyzed in RCC tumor vessels, in perivascular tumor cells and generally in the tumor cells. Moreover, complex formation between NRP1 and the main VEGF receptor, VEGFR2, was determined.

    Methods: VEGFR2/NRP1 complex formation in cis (on the same cell) and trans (between cells) configurations was determined by in situ proximity ligation assay, and NRP1 protein expression in three compartments (endothelial cells, perivascular tumor cells and general tumor cell expression) was determined by immunofluorescent staining, in a cohort of 64 advanced renal cell carcinoma patients.

    Results: VEGFR2/NRP1 trans complexes were detected in 75% of the patient samples. The presence of trans VEGFR2/NRP1 complexes or perivascular NRP1 was associated with a reduced tumor vessel density. The presence of VEGFR2/NRP1 trans complexes, perivascular NRP1 and general tumor cell NRP1 expression correlated with improved survival, however, only VEGFR2/NRP1 trans complexes and perivascular NRP1 expression remained significant in multivariable analysis.

    Conclusion: Our work shows that VEGFR2/NRP1 complexes in trans, as well as perivascular NRP1 expression, are independent markers of improved survival in advanced renal cell carcinoma.

  • 33.
    Morin, Eric
    et al.
    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.
    Sjöberg, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Tjomsland, Vegard
    University of Oslo, Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Institute of Clinical Medicine, Oslo, Norway.
    Testini, Chiara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Franklin, Oskar
    Umeå University, Department of Surgery and Perioperative Sciences, Umeå, Sweden.
    Sund, Malin
    Umeå University, Department of Surgery and Perioperative Sciences, Umeå, Sweden.
    Öhlund, Daniel
    Umeå University, Department of Radiation Sciences, Umeå, Sweden ; Umeå University, Wallenberg Centre for Molecular Medicine, Umeå, Sweden.
    Kiflemariam, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sjöblom, Tobias
    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.
    Claesson-Welsh, Lena
    Uppsala University, Science for Life Laboratory, SciLifeLab. 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 Immunology, Genetics and Pathology, Vascular Biology.
    VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival2018In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, no 3, p. 311-322Article in journal (Refereed)
    Abstract [en]

    Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans-complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans-complex formation is an independent predictor of PDAC patient survival. 

  • 34.
    Månberg, Anna
    et al.
    KTH Royal Inst Technol, Dept Prot Sci, SciLifeLab, Affin Prote, Stockholm, Sweden.
    Bradley, Frideborg
    Karolinska Univ Hosp, Ctr Mol Med, Karolinska Inst, Dept Med Solna,Unit Infect Dis, Stockholm, Sweden.
    Qundos, Ulrika
    KTH Royal Inst Technol, Dept Prot Sci, SciLifeLab, Affin Prote, Stockholm, Sweden.
    Guthrie, Brandon L.
    Univ Washington, Dept Global Hlth, Washington, DC USA;Univ Washington, Dept Epidemiol Hlth, Washington, DC USA.
    Birse, Kenzie
    Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada;Publ Hlth Agcy Canada, JC Wilt Infect Dis Ctr, Natl HIV & Retrovirol Labs, Winnipeg, MB, Canada.
    Noel-Romas, Laura
    Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada;Publ Hlth Agcy Canada, JC Wilt Infect Dis Ctr, Natl HIV & Retrovirol Labs, Winnipeg, MB, Canada.
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Bosire, Rose
    Kenya Govt Med Res Ctr, Nairobi, Kenya.
    Kiarie, James
    Univ Nairobi, Dept Obstet & Gynecol, Nairobi, Kenya.
    Farquhar, Carey
    Univ Washington, Dept Med Global Hlth & Epidemiol, Seattle, WA 98195 USA.
    Burgener, Adam D.
    Karolinska Univ Hosp, Ctr Mol Med, Karolinska Inst, Dept Med Solna,Unit Infect Dis, Stockholm, Sweden;Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada;Publ Hlth Agcy Canada, JC Wilt Infect Dis Ctr, Natl HIV & Retrovirol Labs, Winnipeg, MB, Canada.
    Nilsson, Peter
    KTH Royal Inst Technol, Dept Prot Sci, SciLifeLab, Affin Prote, Stockholm, Sweden.
    Broliden, Kristina
    Karolinska Univ Hosp, Ctr Mol Med, Karolinska Inst, Dept Med Solna,Unit Infect Dis, Stockholm, Sweden.
    A High-throughput Bead-based Affinity Assay Enables Analysis of Genital Protein Signatures in Women At Risk of HIV Infection2019In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, no 3, p. 461-476Article in journal (Refereed)
    Abstract [en]

    Women at high risk of HIV infection, including sex workers and those with active genital inflammation, have molecular signatures of immune activation and epithelial barrier remodeling in samples of their genital mucosa. These alterations in the local immunological milieu are likely to impact HIV susceptibility. We here analyze host genital protein signatures in HIV uninfected women, with high frequency of condom use, living in HIV-serodiscordant relationships. Cervicovaginal secretions from women living in HIV-serodiscordant relationships (n = 62) were collected at three time points over 12 months. Women living in HIV-negative seroconcordant relationships (controls, n = 25) were sampled at one time point. All study subjects were examined for demographic parameters associated with susceptibility to HIV infection. The cervicovaginal samples were analyzed using a high-throughput bead-based affinity assay. Proteins involved in epithelial barrier function and inflammation were increased in HIV-serodiscordant women. By combining several methods of analysis, a total of five proteins (CAPG, KLK10, SPRR3, elafin/PI3, CSTB) were consistently associated with this study group. Proteins analyzed using the affinity set-up were further validated by label-free tandem mass spectrometry in a partially overlapping cohort with concordant results. Women living in HIV-serodiscordant relationships thus had elevated levels of proteins involved in epithelial barrier function and inflammation despite low prevalence of sexually transmitted infections and a high frequency of safe sex practices. The identified proteins are important markers to follow during assessment of mucosal HIV susceptibility factors and a high-throughput bead-based affinity set-up could be a suitable method for such evaluation.

  • 35.
    Nicholson, Anna M.
    et al.
    Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Robinson Way, Cambridge CB2 0RE, England.
    Olpe, Cora
    Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Robinson Way, Cambridge CB2 0RE, England;Cambridge Stem Cell Inst, Wellcome Trust Med Res Council, Cambridge, England.
    Hoyle, Alice
    Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Robinson Way, Cambridge CB2 0RE, England.
    Thorsen, Ann-Sofie
    Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Robinson Way, Cambridge CB2 0RE, England.
    Rus, Teja
    Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Robinson Way, Cambridge CB2 0RE, England.
    Colombe, Mathilde
    Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Robinson Way, Cambridge CB2 0RE, England.
    Brunton-Sim, Roxanne
    Norwich Res Pk BioRepository, James Watson Rd, Norwich NR4 7UQ, Norfolk, England.
    Kemp, Richard
    Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Robinson Way, Cambridge CB2 0RE, England.
    Marks, Kate
    St James Univ Hosp, Pathol & Tumour Biol, Level 4,Wellcome Trust Brenner Bldg,Beckett St, Leeds LS9 7TF, W Yorkshire, England.
    Quirke, Phil
    St James Univ Hosp, Pathol & Tumour Biol, Level 4,Wellcome Trust Brenner Bldg,Beckett St, Leeds LS9 7TF, W Yorkshire, England.
    Malhotra, Shalini
    CUHFT, Dept Histopathol, Box 235, Cambridge, England.
    ten Hoopen, Rogier
    CUHFT, Dept Histopathol, Box 235, Cambridge, England.
    Ibrahim, Ashraf
    CUHFT, Dept Histopathol, Box 235, Cambridge, England.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Myers, Meagan B.
    US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, HFT 120,3900 NCTR Rd, Jefferson, AR 72079 USA.
    Parsons, Barbara
    US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, HFT 120,3900 NCTR Rd, Jefferson, AR 72079 USA.
    Tavare, Simon
    Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Robinson Way, Cambridge CB2 0RE, England.
    Wilkinson, Mark
    Norwich Res Pk BioRepository, James Watson Rd, Norwich NR4 7UQ, Norfolk, England.
    Morrissey, Edward
    Univ Oxford, John Radcliffe Hosp, MRC Weatherall Inst Mol Med, Oxford OX3 9DS, England.
    Winton, Douglas J.
    Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Robinson Way, Cambridge CB2 0RE, England.
    Fixation and Spread of Somatic Mutations in Adult Human Colonic Epithelium2018In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 22, no 6, p. 909-918.e8Article in journal (Refereed)
    Abstract [en]

    We investigated the means and timing by which mutations become fixed in the human colonic epithelium by visualizing somatic clones and mathematical inference. Fixation requires two sequential steps. First, one of approximately seven active stem cells residing within each colonic crypt has to be mutated. Second, the mutated stem cell has to replace neighbors to populate the entire crypt in a process that takes several years. Subsequent clonal expansion due to crypt fission is infrequent for neutral mutations (around 0.7% of all crypts undergo fission in a single year). Pro-oncogenic mutations subvert both stem cell replacement to accelerate fixation and clonal expansion by crypt fission to achieve high mutant allele frequencies with age. The benchmarking of these behaviors allows the advantage associated with different gene-specific mutations to be compared irrespective of the cellular mechanisms by which they are conferred.

  • 36.
    Niinivirta, Marjut
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Department of Oncology, Uppsala University Hospital, Entrance 78, 751 85 Uppsala, Sweden.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Department of Oncology, Uppsala University Hospital, Entrance 78, 751 85 Uppsala, Sweden.
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Pontén, Fredrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Surgical Pathology, Uppsala University Hospital, 75185 Uppsala, Sweden.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Department of Oncology, Uppsala University Hospital, Entrance 78, 751 85 Uppsala, Sweden.
    Tumoral pyruvate kinase L/R as a predictive marker for the treatment of renal cancer patients with sunitinib and sorafenib2019In: Journal of Cancer, ISSN 1837-9664, Vol. 10, no 14, p. 3224-3231Article in journal (Other academic)
    Abstract [en]

    Background and aims: Treatment with tyrosine kinase inhibitors (TKI) like sunitinib and sorafenib has improved the prognosis of patients with metastatic renal cell cancer (mRCC). No predictive marker is available to select patients who will gain from these treatments. Tumoral pyruvate kinase L/R (PKLR) is a membrane protein with highly specific expression in the renal tubule. We have previously shown that the tumoral expression of cubilin (CUBN) is associated with progression free survival (PFS) in mRCC patients treated with sunitinib and sorafenib. The aim of the present study was to investigate if PKLR can predict response in these patients, alone and/or in combination with CUBN.

    Methods: A tissue microarray (TMA) was constructed of tumor samples from 139 mRCC patients. One hundred and thirty-six of these patients had been treated with sunitinib or sorafenib in the first or second-line setting. Thirty patients suffered from early severe toxicity leading to the termination of treatment. The remaining patients (n=106) were selected for the current study.

    Results: Fifty-five (52%) of the tumors expressed membranous PKLR. Patients with PKLR tumor expression experienced a significantly longer PFS compared to patients with no expression (eight versus five months, p = 0.019). Overall survival (OS) was also significantly better for patients with PKLR expression. In addition, the combined expression of PKLR and CUBN resulted in a higher predictive value than either marker alone.

    Conclusions: In this real world study we show that tumoral PKLR membrane expression is a positive predictive biomarker for sunitinib and sorafenib treatment in patients suffering from mRCC. Our results also indicate that the combined expression with cubilin more accurately than PKLR alone can select patients with no benefit from treatment.

  • 37.
    O'Hurley, Gillian
    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.
    Sjöstedt, Evelina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rahman, Arman
    Li, Bo
    Kampf, Caroline
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gallagher, William M.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Garbage in, garbage out: A critical evaluation of strategies used for validation of immunohistochemical biomarkers2014In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 8, no 4, p. 783-798Article, review/survey (Refereed)
    Abstract [en]

    The use of immunohistochemistry (IHC) in clinical cohorts is of paramount importance in determining the utility of a biomarker in clinical practice. A major bottleneck in translating a biomarker from bench-to-bedside is the lack of well characterized, specific antibodies suitable for IHC. Despite the widespread use of IHC as a biomarker validation tool, no universally accepted standardization guidelines have been developed to determine the applicability of particular antibodies for IHC prior to its use. In this review, we discuss the technical challenges faced by the use of immunohistochemical biomarkers and rigorously explore classical and emerging antibody validation technologies. Based on our review of these technologies, we provide strict criteria for the pragmatic validation of antibodies for use in immunohistochemical assays.

  • 38.
    Pozniak, Yair
    et al.
    Tel Aviv Univ, Sackler Fac Med, Dept Human Mol Genet & Biochem, IL-6997801 Tel Aviv, Israel..
    Balint-Lahat, Nora
    Inst Pathol, Sheba Med Ctr, IL-5265601 Tel Hashomer, Israel..
    Rudolph, Jan Daniel
    Tel Aviv Univ, Sackler Fac Med, Dept Human Mol Genet & Biochem, IL-6997801 Tel Aviv, Israel.;Tel Aviv Univ, Sch Comp Sci, IL-6997801 Tel Aviv, Israel..
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Katzir, Rotem
    Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA.;Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA..
    Avivi, Camilla
    Inst Pathol, Sheba Med Ctr, IL-5265601 Tel Hashomer, Israel..
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ruppin, Eytan
    Tel Aviv Univ, Sch Comp Sci, IL-6997801 Tel Aviv, Israel.;Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA.;Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA.;Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-6997801 Tel Aviv, Israel..
    Barshack, Iris
    Inst Pathol, Sheba Med Ctr, IL-5265601 Tel Hashomer, Israel.;Tel Aviv Univ, Sackler Fac Med, Dept Pathol, IL-6997801 Tel Aviv, Israel..
    Geiger, Tamar
    Tel Aviv Univ, Sackler Fac Med, Dept Human Mol Genet & Biochem, IL-6997801 Tel Aviv, Israel..
    System-wide Clinical Proteomics of Breast Cancer Reveals Global Remodeling of Tissue Homeostasis2016In: CELL SYSTEMS, ISSN 2405-4712, Vol. 2, no 3, p. 172-184Article in journal (Refereed)
    Abstract [en]

    The genomic and transcriptomic landscapes of breast cancer have been extensively studied, but the proteomes of breast tumors are far less characterized. Here, we use high-resolution, high-accuracy mass spectrometry to perform a deep analysis of luminal-type breast cancer progression using clinical breast samples from primary tumors, matched lymph node metastases, and healthy breast epithelia. We used a super-SILAC mix to quantify over 10,000 proteins with high accuracy, enabling us to identify key proteins and pathways associated with tumorigenesis and metastatic spread. We found high expression levels of proteins associated with protein synthesis and degradation in cancer tissues, accompanied by metabolic alterations that may facilitate energy production in cancer cells within their natural environment. In addition, we found proteomic differences between breast cancer stages and minor differences between primary tumors and their matched lymph node metastases. These results highlight the potential of proteomic technology in the elucidation of clinically relevant cancer signatures.

  • 39.
    Sjöstedt, Evelina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.
    Bollerslev, Jens
    Oslo Univ Hosp, Rikshosp, Dept Specialized Endocrinol, Oslo, Norway.; Univ Oslo, Fac Med, Oslo, Norway.
    Mulder, Jan
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Oslo Univ Hosp, Dept Pathol, Oslo, Norway.
    A specific antibody to detect transcription factor T-Pit: a reliable marker of corticotroph cell differentiation and a tool to improve the classification of pituitary neuroendocrine tumours2017In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 134, no 4, p. 675-677Article in journal (Other academic)
  • 40.
    Sjöstedt, Evelina
    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, Clinical and experimental pathology. KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, SE-17121 Stockholm, Sweden.
    Sivertsson, Åsa
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, SE-17121 Stockholm, Sweden.
    Noraddin, Feria Hikmet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Katona, Borbala
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Näsström, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vuu, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kesti, Dennis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Oksvold, Per
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, SE-17121 Stockholm, Sweden.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Ingmarie
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, SE-17121 Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Integration of Transcriptomics and Antibody-Based Proteomics for Exploration of Proteins Expressed in Specialized Tissues2018In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 17, no 12, p. 4127-4137Article in journal (Refereed)
    Abstract [en]

    A large portion of human proteins are referred to as missing proteins, defined as protein-coding genes that lack experimental data on the protein level due to factors such as temporal expression, expression in tissues that are difficult to sample, or they actually do not encode functional proteins. In the present investigation, an integrated omics approach was used for identification and exploration of missing proteins. Transcriptomics data from three different sources-the Human Protein Atlas (HPA), the GTEx consortium, and the FANTOM5 consortium-were used as a starting point to identify genes selectively expressed in specialized tissues. Complementing the analysis with profiling on more specific tissues based on immunohistochemistry allowed for further exploration of cell-type-specific expression patterns. More detailed tissue profiling was performed for >300 genes on complementing tissues. The analysis identified tissue-specific expression of nine proteins previously listed as missing proteins (POU4F1, FRMD1, ARHGEF33, GABRG1, KRTAP2-1, BHLHE22, SPRR4, AVPR1B, and DCLK3), as well as numerous proteins with evidence of existence on the protein level that previously lacked information on spatial resolution and cell-type-specific expression pattern. We here present a comprehensive strategy for identification of missing proteins by combining transcriptomics with antibody-based proteomics. The analyzed proteins provide interesting targets for organ-specific research in health and disease.

  • 41.
    Strakova, Katerina
    et al.
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic;Karolinska Inst, Biomedicum 6D, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, Tomtebodavagen 16, SE-17165 Stockholm, Sweden.
    Kowalski-Jahn, Maria
    Karolinska Inst, Biomedicum 6D, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, Tomtebodavagen 16, SE-17165 Stockholm, Sweden.
    Gybel, Tomas
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic.
    Valnohova, Jana
    Karolinska Inst, Biomedicum 6D, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, Tomtebodavagen 16, SE-17165 Stockholm, Sweden.
    Dhople, Vishnu M.
    Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Friedrich Ludwig Jahn Str 15, D-17487 Greifswald, Germany.
    Harnos, Jakub
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic.
    Bernatik, Ondrej
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic.
    Ganji, Ranjani Sri
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic;Masaryk Univ, Cent European Inst Technol, Kamenice 5, Brno 62500, Czech Republic.
    Zdrahal, Zbynek
    Masaryk Univ, Cent European Inst Technol, Kamenice 5, Brno 62500, Czech Republic.
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Sci Life Lab, Tomtebodavagen 16, S-17165 Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Bryja, Vitezslav
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic.
    Schulte, Gunnar
    Masaryk Univ, Fac Sci, Lab WNT Signaling, Inst Expt Biol, Kotlarska 2, CS-61137 Brno, Czech Republic;Karolinska Inst, Biomedicum 6D, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, Tomtebodavagen 16, SE-17165 Stockholm, Sweden.
    Dishevelled enables casein kinase 1-mediated phosphorylation of Frizzled 6 required for cell membrane localization2018In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 48, p. 18477-18493Article in journal (Refereed)
    Abstract [en]

    Frizzleds (FZDs) are receptors for secreted lipoglycoproteins of the Wingless/Int-1(WNT) family, initiating an important signal transduction network in multicellular organisms. FZDs are G protein-coupled receptors (GPCRs), which are well known to be regulated by phosphorylation, leading to specific downstream signaling or receptor desensitization. The role and underlying mechanisms of FZD phosphorylation remain largely unexplored. Here, we investigated the phosphorylation of human FZD(6). Using MS analysis and a phospho-state- and -site-specific antibody, we found that Ser-648, located in the FZD(6) C terminus, is efficiently phosphorylated by casein kinase 1 is an element of (CK1 is an element of) and that this phosphorylation requires the scaffolding protein Dishevelled (DVL). In an overexpression system, DVL1, -2, and -3 promoted CK1-mediated FZD(6) phosphorylation on Ser-648. This DVL activity required an intact DEP domain and FZD-mediated recruitment of this domain to the cell membrane. Substitution of the CK1 is an element of-targeted phosphomo-tif reduced FZD(6) surface expression, suggesting that Ser-648 phosphorylation controls membrane trafficking of FZD(6). Phos-pho-Ser-648 FZD(6) immunoreactivity in human fallopian tube epithelium was predominantly apical, associated with cilia in a subset of epithelial cells, compared with the total FZD(6) protein expression, suggesting that FZD(6) phosphorylation contributes to asymmetric localization of receptor function within the cell and to epithelial polarity. Given the key role of FZD(6) in planar cell polarity, our results raise the possibility that asymmetric phosphorylation of FZD(6) rather than asymmetric protein distribution accounts for polarized receptor signaling.

  • 42.
    Thul, Peter J.
    et al.
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    The human protein atlas: A spatial map of the human proteome2018In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 27, no 1, p. 233-244Article in journal (Refereed)
    Abstract [en]

    The correct spatial distribution of proteins is vital for their function and often mis-localization or ectopic expression leads to diseases. For more than a decade, the Human Protein Atlas (HPA) has constituted a valuable tool for researchers studying protein localization and expression in human tissues and cells. The centerpiece of the HPA is its unique antibody collection for mapping the entire human proteome by immunohistochemistry and immunocytochemistry. By these approaches, more than 10 million images showing protein expression patterns at a single-cell level were generated and are publicly available at . The antibody-based approach is combined with transcriptomics data for an overview of global expression profiles. The present article comprehensively describes the HPA database functions and how users can utilize it for their own research as well as discusses the future path of spatial proteomics.

  • 43.
    Thul, Peter J.
    et al.
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    åkesson, Lovisa
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Wiking, Mikaela
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Mahdessian, Diana
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Geladaki, Aikaterini
    Univ Cambridge, Dept Biochem, Cambridge Ctr Prote, Tennis Court Rd, Cambridge CB2 1QR, England.;Univ Cambridge, Dept Genet, Downing St, Cambridge CB2 3EH, England..
    Blal, Hammou Ait
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Alm, Tove
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bjork, Lars
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Breckels, Lisa M.
    Univ Cambridge, Dept Biochem, Cambridge Ctr Prote, Tennis Court Rd, Cambridge CB2 1QR, England.;Univ Cambridge, Dept Biochem, Computat Prote Unit, Tennis Court Rd, Cambridge CB2 1QR, England..
    Backstrom, Anna
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Danielsson, Frida
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Fagerberg, Linn
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Fall, Jenny
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Gatto, Laurent
    Univ Cambridge, Dept Biochem, Cambridge Ctr Prote, Tennis Court Rd, Cambridge CB2 1QR, England.;Univ Cambridge, Dept Biochem, Computat Prote Unit, Tennis Court Rd, Cambridge CB2 1QR, England..
    Gnann, Christian
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Hober, Sophia
    KTH Royal Inst Technol, Sch Biotechnol, Dept Prote, SE-10691 Stockholm, Sweden..
    Hjelmare, Martin
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Johansson, Fredric
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Lee, Sunjae
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Sci Life Lab, SE-17177 Stockholm, Sweden..
    Mulvey, Claire M.
    Univ Cambridge, Dept Biochem, Cambridge Ctr Prote, Tennis Court Rd, Cambridge CB2 1QR, England..
    Nilsson, Peter
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Oksvold, Per
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Rockberg, Johan
    KTH Royal Inst Technol, Sch Biotechnol, Dept Prote, SE-10691 Stockholm, Sweden..
    Schutten, Rutger
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Sivertsson, Asa
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Sjöstedt, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Skogs, Marie
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Stadler, Charlotte
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Sullivan, Devin P.
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Tegel, Hanna
    KTH Royal Inst Technol, Sch Biotechnol, Dept Prote, SE-10691 Stockholm, Sweden..
    Winsnes, Casper
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Zhang, Cheng
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Zwahlen, Martin
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Mardinoglu, Adil
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    von Feilitzen, Kalle
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Lilley, Kathryn S.
    Univ Cambridge, Dept Biochem, Cambridge Ctr Prote, Tennis Court Rd, Cambridge CB2 1QR, England..
    Uhlen, Mathias
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Lundberg, Emma
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    A subcellular map of the human proteome2017In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 356, no 6340, article id eaal332Article in journal (Refereed)
    Abstract [en]

    Resolving the spatial distribution of the human proteome at a subcellular level can greatly increase our understanding of human biology and disease. Here we present a comprehensive image-based map of subcellular protein distribution, the Cell Atlas, built by integrating transcriptomics and antibody-based immunofluorescence microscopy with validation by mass spectrometry. Mapping the in situ localization of 12,003 human proteins at a single-cell level to 30 subcellular structures enabled the definition of the proteomes of 13 major organelles. Exploration of the proteomes revealed single-cell variations in abundance or spatial distribution and localization of about half of the proteins to multiple compartments. This subcellular map can be used to refine existing protein-protein interaction networks and provides an important resource to deconvolute the highly complex architecture of the human cell.

  • 44. Uhlen, Mathias
    et al.
    Fagerberg, Linn
    Hallstroem, Bjoern M.
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Oksvold, Per
    Mardinoglu, Adil
    Sivertsson, Asa
    Kampf, Caroline
    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 and Morphological Pathology.
    Sjöstedt, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Asplund, Anna
    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 and Morphological Pathology.
    Olsson, IngMarie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Edlund, Karolina
    Lundberg, Emma
    Navani, Sanjay
    Szigyarto, Cristina Al-Khalili
    Odeberg, Jacob
    Djureinovic, Dijana
    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 and Morphological Pathology.
    Takanen, Jenny Ottosson
    Hober, Sophia
    Alm, Tove
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berling, Holger
    Tegel, Hanna
    Mulder, Jan
    Rockberg, Johan
    Nilsson, Peter
    Schwenk, Jochen M.
    Hamsten, Marica
    von Feilitzen, Kalle
    Forsberg, Mattias
    Persson, Lukas
    Johansson, Fredric
    Zwahlen, Martin
    von Heijne, Gunnar
    Nielsen, Jens
    Pontén, Fredrik
    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 and Morphological Pathology.
    Tissue-based map of the human proteome2015In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 347, no 6220, p. 394-+Article in journal (Refereed)
    Abstract [en]

    Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body.

  • 45.
    Uhlen, Mathias
    et al.
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.;KTH Royal Inst Technol, Dept Prote, Stockholm, Sweden.;Tech Univ Denmark, Novo Nordisk Fdn, Ctr Biosustainabil, Horsholm, Denmark..
    Hallstrom, Bjorn M.
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.;KTH Royal Inst Technol, Dept Prote, Stockholm, Sweden..
    Lindskog Bergström, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mardinoglu, Adil
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.;Chalmers, Dept Biol & Biol Engn, S-41296 Gothenburg, Sweden..
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nielsen, Jens
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.;Tech Univ Denmark, Novo Nordisk Fdn, Ctr Biosustainabil, Horsholm, Denmark.;Chalmers, Dept Biol & Biol Engn, S-41296 Gothenburg, Sweden..
    Transcriptomics resources of human tissues and organs2016In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 12, no 4, article id 862Article, review/survey (Refereed)
    Abstract [en]

    Quantifying the differential expression of genes in various human organs, tissues, and cell types is vital to understand human physiology and disease. Recently, several large-scale transcriptomics studies have analyzed the expression of protein-coding genes across tissues. These datasets provide a framework for defining the molecular constituents of the human body as well as for generating comprehensive lists of proteins expressed across tissues or in a tissue-restricted manner. Here, we review publicly available human transcriptome resources and discuss body-wide data from independent genome-wide transcriptome analyses of different tissues. Gene expression measurements from these independent datasets, generated using samples from fresh frozen surgical specimens and postmortem tissues, are consistent. Overall, the different genome-wide analyses support a distribution in which many proteins are found in all tissues and relatively few in a tissue-restricted manner. Moreover, we discuss the applications of publicly available omics data for building genome-scale metabolic models, used for analyzing cell and tissue functions both in physiological and in disease contexts.

  • 46.
    Uhlen, Mathias
    et al.
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.;Danish Tech Univ, Ctr Biosustainabil, Copenhagen, Denmark.;Royal Inst Technol, AlbaNova Univ Ctr, KTH, Sch Biotechnol, Stockholm, Sweden..
    Zhang, Cheng
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Lee, Sunjae
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Sjöstedt, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.
    Fagerberg, Linn
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Bidkhori, Gholamreza
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Benfeitas, Rui
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Arif, Muhammad
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Liu, Zhengtao
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Edfors, Fredrik
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Sanli, Kemal
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    von Feilitzen, Kalle
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Oksvold, Per
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Lundberg, Emma
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Hober, Sophia
    Royal Inst Technol, AlbaNova Univ Ctr, KTH, Sch Biotechnol, Stockholm, Sweden..
    Nilsson, Peter
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Mattsson, Johanna Sofia Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Schwenk, Jochen M.
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Brunnström, Hans
    Lund Univ, Skane Univ Hosp, Div Pathol, Lund, Sweden..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Djureinovic, Dijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Mardinoglu, Adil
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.;Royal Inst Technol, AlbaNova Univ Ctr, KTH, Sch Biotechnol, Stockholm, Sweden.;Chalmers, Dept Biol & Biol Engn, SE-41296 Gothenburg, Sweden..
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    A pathology atlas of the human cancer transcriptome2017In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 357, no 6352, article id eaan2507Article in journal (Refereed)
    Abstract [en]

    Cancer is one of the leading causes of death, and there is great interest in understanding the underlying molecular mechanisms involved in the pathogenesis and progression of individual tumors. We used systems-level approaches to analyze the genome-wide transcriptome of the protein-coding genes of 17 major cancer types with respect to clinical outcome. A general pattern emerged: Shorter patient survival was associated with up-regulation of genes involved in cell growth and with down-regulation of genes involved in cellular differentiation. Using genome-scale metabolic models, we show that cancer patients have widespread metabolic heterogeneity, highlighting the need for precise and personalized medicine for cancer treatment. All data are presented in an interactive open-access database (www.proteinatlas.org/pathology) to allow genome-wide exploration of the impact of individual proteins on clinical outcomes.

  • 47.
    Vandenbrouck, Yves
    et al.
    CEA, DRF, BIG, Lab Biol Grande Echelle, 17 Rue Martyrs, F-38054 Grenoble, France.;Inserm U1038, 17 Rue Martyrs, F-38054 Grenoble, France.;Univ Grenoble, F-38054 Grenoble, France..
    Lane, Lydie
    Univ Geneva, Dept Human Prot Sci, Fac Med, 1 Rue Michel Servet, CH-1211 Geneva 4, Switzerland.;CMU, SIB, CALIPHO Grp, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland..
    Carapito, Christine
    Univ Strasbourg, CNRS UMR7178, Lab Spectrometrie Masse BioOrgan LSMBO, 25 Rue Becquerel, F-67087 Strasbourg, France..
    Duek, Paula
    CMU, SIB, CALIPHO Grp, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland..
    Rondel, Karine
    Inserm U1085, Irset, Protim, Campus Beaulieu, F-35042 Rennes, France..
    Bruley, Christophe
    CEA, DRF, BIG, Lab Biol Grande Echelle, 17 Rue Martyrs, F-38054 Grenoble, France.;Inserm U1038, 17 Rue Martyrs, F-38054 Grenoble, France.;Univ Grenoble, F-38054 Grenoble, France..
    Macron, Charlotte
    Univ Strasbourg, CNRS UMR7178, Lab Spectrometrie Masse BioOrgan LSMBO, 25 Rue Becquerel, F-67087 Strasbourg, France..
    de Peredo, Anne Gonzalez
    Univ Toulouse, CNRS, UPS, Inst Pharmacol & Biol Struct, F-31062 Toulouse, France..
    Coute, Yohann
    CEA, DRF, BIG, Lab Biol Grande Echelle, 17 Rue Martyrs, F-38054 Grenoble, France.;Inserm U1038, 17 Rue Martyrs, F-38054 Grenoble, France.;Univ Grenoble, F-38054 Grenoble, France..
    Chaoui, Karima
    Univ Toulouse, CNRS, UPS, Inst Pharmacol & Biol Struct, F-31062 Toulouse, France..
    Com, Emmanuelle
    Inserm U1085, Irset, Protim, Campus Beaulieu, F-35042 Rennes, France..
    Gateau, Alain
    CMU, SIB, CALIPHO Grp, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland..
    Hesse, Anne-Marie
    CEA, DRF, BIG, Lab Biol Grande Echelle, 17 Rue Martyrs, F-38054 Grenoble, France.;Inserm U1038, 17 Rue Martyrs, F-38054 Grenoble, France.;Univ Grenoble, F-38054 Grenoble, France..
    Marcellin, Marlene
    Univ Toulouse, CNRS, UPS, Inst Pharmacol & Biol Struct, F-31062 Toulouse, France..
    Mear, Loren
    Inserm U1085, Irset, Protim, Campus Beaulieu, F-35042 Rennes, France..
    Mouton-Barbosa, Emmanuelle
    Univ Toulouse, CNRS, UPS, Inst Pharmacol & Biol Struct, F-31062 Toulouse, France..
    Robin, Thibault
    Ctr Univ Informat, Proteome Informat Grp, Route Drize 7, CH-1227 Carouge, Switzerland..
    Burlet-Schiltz, Odile
    Univ Toulouse, CNRS, UPS, Inst Pharmacol & Biol Struct, F-31062 Toulouse, France..
    Cianferani, Sarah
    Univ Strasbourg, CNRS UMR7178, Lab Spectrometrie Masse BioOrgan LSMBO, 25 Rue Becquerel, F-67087 Strasbourg, France..
    Ferro, Myriam
    CEA, DRF, BIG, Lab Biol Grande Echelle, 17 Rue Martyrs, F-38054 Grenoble, France.;Inserm U1038, 17 Rue Martyrs, F-38054 Grenoble, France.;Univ Grenoble, F-38054 Grenoble, France..
    Freour, Thomas
    CHU Nantes, Serv Med Reprod, 38 Blvd Jean Monnet, F-44093 Nantes, France.;INSERM UMR1064, F-44093 Nantes, France. Uppsala Univ, Sci Life Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Garin, Jerome
    CEA, DRF, BIG, Lab Biol Grande Echelle, 17 Rue Martyrs, F-38054 Grenoble, France.;Inserm U1038, 17 Rue Martyrs, F-38054 Grenoble, France.;Univ Grenoble, F-38054 Grenoble, France..
    Pineau, Charles
    Inserm U1085, Irset, Protim, Campus Beaulieu, F-35042 Rennes, France..
    Looking for Missing Proteins in the Proteome of Human Spermatozoa: An Update2016In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 15, no 11, p. 3998-4019Article in journal (Refereed)
    Abstract [en]

    The Chromosome-Centric Human Proteome Project (C-HPP) aims to identify "missing" proteins in the neXtProt knowledgebase. We present an in-depth proteomics analysis of the human sperm proteome to identify testis-enriched missing proteins. Using protein extraction procedures and LC-MS/MS analysis, we detected 235 proteins (PE2-PE4) for which no previous evidence of protein expression was annotated. Through LC-MS/MS and LC-PRM analysis, data mining, and immunohistochemistry, we confirmed the expression of 206 missing proteins (PE2-PE4) in line with current HPP guidelines (version 2.0). Parallel reaction monitoring acquisition and sythetic heavy labeled peptides targeted 36 "one-hit wonder" candidates selected based on prior peptide spectrum match assessment. 24 were validated with additional predicted and specifically targeted peptides. Evidence was found for 16 more missing proteins using immunohistochemistry on human testis sections. The expression pattern for some of these proteins was specific to the testis, and they could possibly be valuable markers with fertility assessment applications. Strong evidence was also found of four "uncertain" proteins (PE5); their status should be re-examined. We show how using a range of sample preparation techniques combined with MS-based analysis, expert knowledge, and complementary antibody-based techniques can produce data of interest to the community. All MS/MS data are available via ProteomeXchange under identifier PXD003947. In addition to contributing to the C-HPP, we hope these data will stimulate continued exploration of the sperm proteome.

1 - 47 of 47
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