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  • 301. Arlestig, Lisbeth
    et al.
    Brink, Mikael
    Hansson, Monika
    Jakobsson, Per Johan
    Holmdahl, Rikard
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klareskog, Lars
    Rantapaa-Dahlqvist, Solbritt M.
    Single Nucleotide Polymorphisms within the HLA-DRB1 Gene in Relation to Antibodies Against Citrullinated Peptides in Individuals Prior to the Development of Rheumatoid Arthritis2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no S10, p. S180-S180Article in journal (Other academic)
  • 302.
    Armand, Marine
    et al.
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Boudjoghra, Myriam
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Xochelli, Aliki
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Canioni, Danielle
    Univ Paris 05, Hop Necker, AP HP, Dept Pathol, Paris, France..
    Tavernier, Magali Le Garff
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Colombo, Monica
    Azienda Osped Univ AOU San Martino IST, IRCCS, Direz Sci, Genoa, Italy..
    Rabiega, Pascaline
    Univ Paris 06, INSERM, UMR S1136, Inst Pierre Louis Epidemiol & Sante Publ, Paris, France..
    Molina, Thierry
    Univ Paris 05, Hop Necker, AP HP, Dept Pathol, Paris, France..
    Charlotte, Frederic
    Univ Paris 06, Paris, France.;Hop La Pitie Salpetriere, Dept Pathol, Paris, France..
    Michot, Jean-Marie
    Inst Gustave Roussy, Dept Hematol & Drug Developmen, Villejuif, France..
    Lesty, Claude
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Carrat, Fabrice
    Univ Paris 06, INSERM, UMR S1136, Inst Pierre Louis Epidemiol & Sante Publ, Paris, France..
    Ferrarini, Manlio
    Azienda Osped Univ AOU San Martino IST, IRCCS, Direz Sci, Genoa, Italy..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Besson, Caroline
    Hop Bicetre, Dept Internal Med & Clin Immunol Biol Immunol & H, Le Kremlin Bicetre, France.;Univ Paris Sud, F-94275 Le Kremlin Bicetre, France..
    Hermine, Olivier
    Hop Necker Enfants Malad, Dept Adult Hematol, Paris, France.;Paris Descartes Univ, Paris, France..
    Davi, Frederic
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Auto-Immune Origin of B Cells from HCV-Associated Lymphoma2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 303.
    Armand, Philippe
    et al.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Murawski, Niels
    Univ Klinikum Saarlandes Innere Med I, Homburg, Germany..
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Zain, Jasmine
    City Hope Natl Med Ctr, Duarte, CA USA..
    Eichhorst, Barbara
    Univ Cologne, Cologne, Germany..
    Gulbas, Zafer
    Anadolu Med Ctr, Istanbul, Turkey..
    Hawkes, Eliza A.
    Austin Hlth, Olivia Newton John Canc Res Inst, Heidelberg, Vic, Australia..
    Pagel, John M.
    Swedish Canc Inst, Swedish Ctr Blood Disorders & Stem Cell Transplan, Seattle, WA USA..
    Phillips, Tycel
    Rogel Canc Ctr, Ann Arbor, MI USA..
    Ribrag, Vincent
    Inst Gustave Roussy, Villejuif, France..
    Svoboda, Jakub
    Univ Penn, Perelman Ctr Adv Med, Philadelphia, PA 19104 USA..
    Stathis, Anastasios
    Oncol Inst Southern Switzerland, Bellinzona, Switzerland..
    Chatterjee, Arkendu
    Merck & Co Inc, Kenilworth, NJ USA..
    Orlowski, Robert
    Merck & Co Inc, Kenilworth, NJ USA..
    Marinello, Patricia
    Merck & Co Inc, Kenilworth, NJ USA..
    Christian, Beth
    Ohio State Univ, James Canc Hosp, Columbus, OH 43210 USA.;Ohio State Univ, Solove Res Inst, Columbus, OH 43210 USA..
    Pembrolizumab in relapsed or refractory Richter syndrome2020In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 190, no 2, p. E117-E120Article in journal (Other academic)
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    fulltext
  • 304.
    Armand, Philippe
    et al.
    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.;Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA..
    Zinzani, Pier Luigi
    Azienda Osped Univ Bologna, Ist Ricovero & Cura Carattere Sci, Ist Ematol Seragnoli, Bologna, Italy.;Univ Bologna, Dipartimento Sci Med & Chirurg, Bologna, Italy..
    Lee, Hun Ju
    Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX USA..
    Johnson, Nathalie A.
    Jewish Gen Hosp, Dept Med, Montreal, PQ, Canada..
    Brice, Pauline
    Hop St Louis, Hematooncol, Paris, France..
    Radford, John
    Christie NHS Fdn Trust, Dept Med Oncol, NIHR Clin Res Facil, Manchester, England.;Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester, England..
    Ribrag, Vincent
    Gustave Roussy, Early Drug Dev Dept DITEP, Villejuif, France..
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Vassilakopoulos, Theodoros P.
    Natl & Kapodistrian Univ Athens, Laikon Gen Hosp, Dept Hematol & Bone Marrow Transplantat, Athens, Greece..
    Tomita, Akihiro
    Nagoya Univ, Grad Sch Med, Dept Hematol & Oncol, Nagoya, Japan..
    von Tresckow, Bastian
    Univ Cologne, Med Fac, Dept Internal Med 1, Cologne, Germany.;Univ Duisburg Essen, Univ Hosp Essen, West German Canc Ctr, Dept Hematol & Stem Cell Transplantat, Essen, Germany.;Univ Cologne, Univ Hosp Cologne, Cologne, Germany..
    Shipp, Margaret A.
    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA..
    Herrera, Alex F.
    City Hope Natl Med Ctr, Dept Hematol Hematopoiet Cell Transplantat, Duarte, CA USA..
    Lin, Jianxin
    Merck & Co Inc, Dept Med Oncol, Rahway, NJ USA..
    Kim, Eunhee
    Merck & Co Inc, Dept Med Oncol, Rahway, NJ USA..
    Chakraborty, Samhita
    Merck & Co Inc, Dept Med Oncol, Rahway, NJ USA..
    Marinello, Patricia
    Merck & Co Inc, Dept Med Oncol, Rahway, NJ USA..
    Moskowitz, Craig H.
    Univ Miami, Sylvester Comprehens Canc Ctr, Dept Med, Miami, FL USA..
    Five-year follow-up of KEYNOTE-087: pembrolizumab monotherapy for relapsed/refractory classical Hodgkin lymphoma2023In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 142, no 10, p. 878-886Article in journal (Refereed)
    Abstract [en]

    Previous analyses of the phase 2 KEYNOTE-087 (NCT02453594) trial of pembrolizumab monotherapy demonstrated effective antitumor activity with acceptable safety in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). However, long-term response durability and outcome of patients who receive a second course after treatment discontinuation after complete response (CR) remain of clinical interest. We present KEYNOTE-087 data after >5 years of median follow-up. Patients with R/R cHL and progressive disease (PD) after autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV; cohort 1), salvage chemotherapy and BV without ASCT (cohort 2), or ASCT without subsequent BV (cohort 3), received pembrolizumab for <= 2 years. Patients in CR who discontinued treatment and subsequently experienced PD were eligible for second-course pembrolizumab. Primary end points were the objective response rate (ORR) using blinded central review and safety. The median follow-up was 63.7 months. ORR was 71.4% (95% confidence interval [CI], 64.8-77.4; CR, 27.6%; partial response, 43.8%). Median duration of response (DOR) was 16.6 months; median progression-free survival was 13.7 months. A quarter of responders, including half of complete responders, maintained a response for >= 4 years. Median overall survival was not achieved. Among 20 patients receiving second-course pembrolizumab, ORR for 19 evaluable patients was 73.7% (95% CI, 48.8-90.8); median DOR was 15.2 months. Any-grade treatment-related adverse events occurred in 72.9% of patients and grade 3 or 4 adverse events occurred in 12.9% of patients; no treatment-related deaths occurred. Single-agent pembrolizumab can induce durable responses, particularly in patients achieving CR. Second-course pembrolizumab frequently reinduced sustained responses after relapse from initial CR.

  • 305. Arne, Kolstad
    et al.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Jerkeman, Mats
    Gronbaek, Kirsten
    Elonen, Erkki
    Raty, Riikka
    Pedersen, Lone Bredo
    Loft, Annika
    Bogsrud, Trond Velde
    Nordstrom, Marie
    Hansen, Per Boye
    Fagerli, Unn-Merete
    Nilsson-Ehle, Herman
    Lauritzsen, Grete Fossum
    Lehmann, Anne Kristine
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Karjalainen-Lindsberg, Marja-Liisa
    Ralfkiaer, Elisabeth
    Ehinger, Mats
    Delabie, Jan
    Bentzen, Hans
    Schildt, Jukka
    Kostova-Aherdan, Kamelia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Frederiksen, Henrik
    Brown, Peter de Nully
    Geisler, Christian H.
    Nordic MCL3 Study: Zevalin Combined with High-Dose Chemotherapy Followed by Autologous Stem Cell Support As Late Intensification for Mantle Cell Lymphoma (MCL) Patients < 66 Years Not in CR After Induction Chemoimmunotherapy: No Benefit of Zevalin2012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 21, p. 747-Article in journal (Refereed)
  • 306.
    Arngården, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Analysis of signaling pathway activity in single cells using the in situ Proximity Ligation Assay2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A cell that senses signals from its environment uses proteins for signal transduction via post translational modifications (PTMs) and protein- protein interactions (PPIs) from cell membrane into the nucleus where genes controlling cell proliferation, differentiation and apoptosis can be turned on or off, i.e. changing the phenotype or fate of the cell. Aberrations within such proteins are prone to cause diseases, such as cancer. Therefore, it is important so study aberrant signaling to be able to understand and treat diseases.

    In this thesis, signaling aberrations of PTMs and PPIs were analyzed with the use of the in situ proximity ligation assay (in situ PLA), and the thesis also contain method development of rolling circle amplification (RCA), which is the method used for signal amplification of in situ PLA reaction products.

    Paper I considers the integrity of RCA products. Here, the aim was to generate a smaller and more compact RCA product, for more accurate either visual or automated analysis. This was achieved with the use of an additional so called compaction oligonucleotide that during RCA was able to bind and pull segments of RCA products closer together. The compaction oligonucleotide served to increase the signal to noise ratio and decrease the number of false positive signals.

    The crosstalk between the Hippo and TGFβ signaling pathways were studied in paper II. Activity of the Hippo signaling pathway is regulated by cell density sensing and tissue control. We found differences in amounts and localization of interactions between the effector proteins of the two pathways depending on cell density and TGFβ stimulation.

    In paper III the NF-кB signaling pathway constitutively activated in chronic lymphocytic leukemia (CLL) was studied. A 4 base-pair frameshift deletion within the NFKBIE gene, which encodes the negative regulator IкBε, was found among 13 of a total 315 cases by the use of targeted deep sequencing. We found reduced levels of IкBε protein, decreased p65 inhibition, and increased phosphorylation, along with increased nuclear localization of p65 in NFKBIE deleted cases compared to healthy cases.

    Crosstalk between the Hippo and Wnt signaling pathway are studied within paper IV. Here, we found differences in cellular localization of TAZ/β-catenin interactions depending on colon cancer tumor stage and by further investigate Hippo/WNT crosstalk in cell line model systems we found an increase of complex formations involved in the crosstalk in sparse growing HEK293 cells compared to dense growing cells. Also, active WNT3a signaling was affected by cell density. Since cell density showed to have a big effect on Hippo/WNT crosstalk we continued to investigated the effect of E-cadherin, which has a function in cell junctions and maintenance of epithelial integrity on Hippo/WNT crosstalk. Interestingly, we found that E-cadherin is likely to regulate Hippo/WNT crosstalk.

    List of papers
    1. Compaction of rolling circle amplification products increases signal integrity and signal–to–noise ratio
    Open this publication in new window or tab >>Compaction of rolling circle amplification products increases signal integrity and signal–to–noise ratio
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    2015 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, p. 12317:1-10, article id 12317Article in journal (Refereed) Published
    National Category
    Medical Image Processing
    Research subject
    Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-260286 (URN)10.1038/srep12317 (DOI)000358358900001 ()26202090 (PubMedID)
    Funder
    EU, FP7, Seventh Framework Programme, 278568EU, FP7, Seventh Framework Programme, 259796Swedish Research Council
    Available from: 2015-07-23 Created: 2015-08-18 Last updated: 2022-09-15Bibliographically approved
    2. Crosstalk between Hippo and TGF beta: Subcellular Localization of YAP/TAZ/Smad Complexes
    Open this publication in new window or tab >>Crosstalk between Hippo and TGF beta: Subcellular Localization of YAP/TAZ/Smad Complexes
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    2015 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 427, no 21, p. 3407-3415Article in journal (Refereed) Published
    Abstract [en]

    The Hippo pathway plays a crucial role in growth control, proliferation and tumor suppression. Activity of the signaling pathway is associated with cell density sensing and tissue organization. Furthermore, the Hippo pathway helps to coordinate cellular processes through crosstalk with growth-factor-mediated signaling pathways such as TGF beta. Here we have examined the localization of interactions between proteins of the Hippo pathway (YAP/TAZ) and TGF beta (Smad2/3) signaling pathway by using in situ proximity ligation assays. We investigated the formation of protein complexes between YAP/TAZ and Smad2/3 and examined how these interactions were affected by TGF beta stimulation and cell density in HaCaT keratinocytes and in Smad4-deficient HT29 colon cancer cells. We demonstrate that TGF beta induces formation of YAP/TAZ-Smad2/3 complexes in HaCaT cells. Under sparse cell conditions, the complexes were detected to a higher degree and were predominantly located in the nucleus, while under dense culture conditions, the complexes were fewer and mainly located in the cytoplasm. Surprisingly, we could not detect any YAP/TAZ Smad2/3 complexes in HT29 cells. To examine if Smad4 deficiency was responsible for the absence of interactions, we treated HaCaT cells with siRNA targeting Smad4. However, we could still observe complex formation in the siRNA-treated cells, suggesting that Smad4 is not essential for the YAP Smad2/3 interaction. In conclusion, this study shows localized, density-dependent formation of YAP/TAZ Smad2/3 complexes in HaCaT cells and provides evidence supporting a crosstalk between the Hippo and the TGF beta signaling pathways.

    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-268434 (URN)10.1016/j.jmb.2015.04.015 (DOI)000363823200006 ()25937570 (PubMedID)
    Funder
    EU, FP7, Seventh Framework Programme, 278568Swedish Research Council
    Available from: 2015-12-04 Created: 2015-12-04 Last updated: 2017-12-01Bibliographically approved
    3. Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia
    Open this publication in new window or tab >>Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia
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    2015 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 212, no 6, p. 833-843Article in journal (Refereed) Published
    Abstract [en]

    NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.

    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-279237 (URN)10.1084/jem.20142009 (DOI)000355569300001 ()25987724 (PubMedID)
    Funder
    Swedish National Infrastructure for Computing (SNIC), b2011080Swedish Cancer SocietySwedish Research CouncilNIH (National Institute of Health), CA81554; CA081554EU, European Research Council, 259796EU, FP7, Seventh Framework Programme, 306242
    Available from: 2016-02-29 Created: 2016-02-29 Last updated: 2022-10-31Bibliographically approved
    4. Crosstalk between WNT and Hippo signaling pathways is affected by cell density and loss of or mutated E-cadherin protein, associated to HDGC.
    Open this publication in new window or tab >>Crosstalk between WNT and Hippo signaling pathways is affected by cell density and loss of or mutated E-cadherin protein, associated to HDGC.
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Research subject
    Molecular Medicine
    Identifiers
    urn:nbn:se:uu:diva-281714 (URN)
    Available from: 2016-03-29 Created: 2016-03-29 Last updated: 2016-05-12
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  • 307.
    Arngården, Linda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Crosstalk between WNT and Hippo signaling pathways changes upon colon cancer stage and is affected by cell density and loss of or mutated E-cadherin proteinManuscript (preprint) (Other academic)
  • 308.
    Arngården, Linda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Grannas, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Raykova, Doroteya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Zieba, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Grabek, Anaelle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Oelrich, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Figueiredo, Joana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Seruca, Raquel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Dahlin, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Crosstalk between WNT and Hippo signaling pathways is affected by cell density and loss of or mutated E-cadherin protein, associated to HDGC.Manuscript (preprint) (Other academic)
  • 309.
    Arnold, Hannah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Panara, Virginia
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gorniok, Beata Filipek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Skoczylas, Renae
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ranefall, Petter
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Gloger, Marleen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hogan, Benjamin M.
    Koltowska, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Mafba and  Mafbb Differentially Regulate Lymphatic Endothelial Cell Migration in Topographically Distinct Manners2021In: SSRN Electronic Journal, E-ISSN 1556-5068Article in journal (Refereed)
    Abstract [en]

    Lymphangiogenesis is the formation of lymphatic vessels from pre-existing vessels, a dynamic process that requires cell migration. Regardless of location, lymphatic endothelial cell (LEC) progenitors probe their surroundings while migrating to form the lymphatic network. Lymphatic development regulation depends on the transcription factor MAFB in different species. Zebrafish Mafba, expressed in LEC progenitors, is essential for their migration in the trunk. However, the transcriptional mechanism that orchestrate LEC migration in different lymphatic endothelial beds remains elusive. Here, we uncover topographically different requirements of the two paralogues, Mafba and Mafbb, for lymphatic cell migration. Both mafba and mafbb are necessary for facial lymphatic development, but mafbb is dispensable for trunk lymphatic development. On the molecular level, we demonstrate a regulatory network where Vegfc-Vegfd-SoxF-Mafba-Mafbb are essential in the facial lymphangiogenesis. We identify that mafba and mafbb fine-tune the directionality of LEC migration and vessel morphogenesis that is ultimately necessary for lymphatic function. 

  • 310.
    Arnold, Hannah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Panara, Virginia
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hussmann, Melina
    WWU Munster, Med Fac, Inst Cardiovasc Organogenesis & Regenerat, Munster, Germany..
    Gorniok, Beata Filipek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Skoczylas, Renae
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ranefall, Petter
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction.
    Gloger, Marleen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Allalou, Amin
    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. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction.
    Hogan, Benjamin M.
    Univ Melbourne, Dept Anat & Physiol, Melbourne, Vic 3000, Australia.;Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3000, Australia.;Peter MacCallum Canc Ctr, Organogenesis & Canc Program, Melbourne, Vic 3000, Australia..
    Schulte-Merker, Stefan
    WWU Munster, Med Fac, Inst Cardiovasc Organogenesis & Regenerat, Munster, Germany..
    Koltowska, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    mafba and mafbb differentially regulate lymphatic endothelial cell migration in topographically distinct manners2022In: Cell Reports, E-ISSN 2211-1247, Vol. 39, no 12, article id 110982Article in journal (Refereed)
    Abstract [en]

    Lymphangiogenesis, formation of lymphatic vessels from pre-existing vessels, is a dynamic process that requires cell migration. Regardless of location, migrating lymphatic endothelial cell (LEC) progenitors probe their surroundings to form the lymphatic network. Lymphatic-development regulation requires the transcription factor MAFB in different species. Zebrafish Mafba, expressed in LEC progenitors, is essential for their migration in the trunk. However, the transcriptional mechanism that orchestrates LEC migration in different lymphatic endothelial beds remains elusive. Here, we uncover topographically different requirements of the two paralogs, Mafba and Mafbb, for LEC migration. Both mafba and mafbb are necessary for facial lymphatic development, but mafbb is dispensable for trunk lymphatic development. On the molecular level, we demonstrate a regulatory network where Vegfc-Vegfd-SoxF-Mafba-Mafbb is essential in facial lymphangiogenesis. We identify that mafba and mafbb tune the directionality of LEC migration and vessel morphogenesis that is ultimately necessary for lymphatic function.

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  • 311.
    Artemenko, Konstantin A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Lind, Sara Bergström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Mayrhofer, Corina
    Zubarev, Roman A.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Optimization of immunoaffinity enrichment and detection: toward a comprehensive characterization of the phosphotyrosine proteome of K562 cells by liquid chromatography-mass spectrometry2011In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 136, no 9, p. 1971-1978Article in journal (Refereed)
    Abstract [en]

    Phosphorylation of protein tyrosine residues regulates many cell functions and has also been proved to be involved in oncogenesis. Thus, the identification of the phosphotyrosine (pTyr) proteome of cells is a very important task. Since tyrosine phosphorylation represents only around 1% of the total human phosphoproteome, the study of pTyr proteins is rather challenging. Here we report the optimization study of the phosphotyrosine proteome using K562 cells as a model system. A substantial segment of the phosphotyrosine proteome of K562 cells was characterized by immunoaffinity enrichment with 4G10 and PYKD1 antibodies followed by LC-MS/MS analysis. 480 non-redundant pTyr peptides corresponding to 342 pTyr proteins were found. 141 pTyr peptides were not described elsewhere. The mass spectrometry approach involving high-resolving FTMS analysis of precursor ions and subsequent detection of CID fragments in a linear ion trap was considered as optimal. For detection of low abundant pTyr peptides pooling of individual immunoaffinity enrichments for one LC-MS/MS analysis was crucial. The enrichment properties of the monoclonal PYKD1 antibody were presented for the first time, also in comparison to the 4G10 antibody. PYKD1 was found to be more effective for protein enrichment (1.2 and 5% efficiency at peptide and protein level correspondingly), while 4G10 showed better results when peptide enrichment was performed (15% efficiency versus 3.6% at protein level). Substantially different subsets of the phosphoproteome were enriched by these antibodies. This finding together with previous studies demonstrates that comprehensive pTyr proteome characterization by immunoprecipitation requires multiple antibodies to be used for the affinity enrichment.

  • 312. Arthur-Farraj, Peter J.
    et al.
    Latouche, Morwena
    Wilton, Daniel K.
    Quintes, Susanne
    Chabrol, Elodie
    Banerjee, Annbily
    Woodhoo, Ashwin
    Jenkins, Billy
    Rahman, Mary
    Turmaine, Mark
    Wicher, Grzegorz K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Mitter, Richard
    Greensmith, Linda
    Behrens, Axel
    Raivich, Gennadij
    Mirsky, Rhona
    Jessen, Kristjan R.
    c-Jun Reprograms Schwann Cells of Injured Nerves to Generate a Repair Cell Essential for Regeneration2012In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 75, no 4, p. 633-647Article in journal (Refereed)
    Abstract [en]

    The radical response of peripheral nerves to injury (Wallerian degeneration) is the cornerstone of nerve repair. We show that activation of the transcription factor c-Jun in Schwann cells is a global regulator of Wallerian degeneration. c-Jun governs major aspects of the injury response, determines the expression of trophic factors, adhesion molecules, the formation of regeneration tracks and myelin clearance and controls the distinctive regenerative potential of peripheral nerves. A key function of c-Jun is the activation of a repair program in Schwann cells and the creation of a cell specialized to support regeneration. We show that absence of c-Jun results in the formation of a dysfunctional repair cell, striking failure of functional recovery, and neuronal death. We conclude that a single glial transcription factor is essential for restoration of damaged nerves, acting to control the transdifferentiation of myelin and Remak Schwann cells to dedicated repair cells in damaged tissue.

  • 313. Arver, Brita
    et al.
    Isaksson, Karin
    Atterhem, Hans
    Baan, Annika
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Brandberg, Yvonne
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Emanuelsson, Monica
    Hellborg, Henrik
    Henriksson, Karin
    Karlsson, Per
    Loman, Niklas
    Lundberg, Jonas
    Ringberg, Anita
    Askmalm, Marie Stenmark
    Wickman, Marie
    Sandelin, Kerstin
    Bilateral Prophylactic Mastectomy in Swedish Women at High Risk of Breast Cancer: A National Survey2011In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140, Vol. 253, no 6, p. 1147-1154Article in journal (Refereed)
    Abstract [en]

    Background/Objective: This study attempted a national inventory of all bilateral prophylactic mastectomies performed in Sweden between 1995 and 2005 in high-risk women without a previous breast malignancy. The primary aim was to investigate the breast cancer incidence after surgery. Secondary aims were to describe the preoperative risk assessment, operation techniques, complications, histopathological findings, and regional differences. Methods: Geneticists, oncologists and surgeons performing prophylactic breast surgery were asked to identify all women eligible for inclusion in their region. The medical records were reviewed in each region and the data were analyzed centrally. The BOADICEA risk assessment model was used to calculate the number of expected/prevented breast cancers during the follow-up period. Results: A total of 223 women operated on in 8 hospitals were identified. During a mean follow-up of 6.6 years, no primary breast cancer was observed compared with 12 expected cases. However, 1 woman succumbed 9 years post mastectomy to widespread adenocarcinoma of uncertain origin. Median age at operation was 40 years. A total of 58% were BRCA1/2 mutation carriers. All but 3 women underwent breast reconstruction, 208 with implants and 12 with autologous tissue. Four small, unifocal, invasive cancers and 4 ductal carcinoma in situ were found in the mastectomy specimens. The incidence of nonbreast related complications was low(3%). Implant loss due to infection/necrosis occurred in 21 women (10%) but a majority received a new implant later. In total, 64% of the women underwent at least 1 unanticipated secondary operation.

  • 314.
    Arvidsson, Per I.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska institutet.
    Domeij, Bengt
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Hansson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lind, Anna-Sara
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Ullerås, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Öppenheten förstör chansen till patent2015In: Svenska dagbladet, ISSN 2001-3868Article in journal (Other (popular science, discussion, etc.))
  • 315.
    Arvidsson, Per I.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Drug Discovery & Development Platform & Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Sandberg, Kristian
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Open for collaboration: an academic platform for drug discovery and development at SciLifeLab2016In: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 21, no 10, p. 1690-1698Article, review/survey (Refereed)
    Abstract [en]

    The Science for Life Laboratory Drug Discovery and Development (SciLifeLab DDD) platform reaches out to Swedish academia with an industry-standard infrastructure for academic drug discovery, supported by earmarked funds from the Swedish government. In this review, we describe the build-up and operation of the platform, and reflect on our first two years of operation, with the ambition to share learnings and best practice with academic drug discovery centers globally. We also discuss how the Swedish Teacher Exemption Law, an internationally unique aspect of the innovation system, has shaped the operation. Furthermore, we address how this investment in infrastructure and expertise can be utilized to facilitate international collaboration between academia and industry in the best interest of those ultimately benefiting the most from translational pharmaceutical research - the patients.

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  • 316.
    Arvidsson, Sandra
    et al.
    Umea Univ, Dept Clin Physiol, Ctr Heart, Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Pilebro, Bjorn
    Umea Univ, Dept Cardiol, Ctr Heart, Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lindqvist, Per
    Umea Univ, Dept Clin Physiol, Ctr Heart, Umea, Sweden.;Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden..
    Suhr, Ole B.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 11, article id e0143456Article in journal (Refereed)
    Abstract [en]

    Purpose Transthyretin V30M (ATTR V30M) amyloidosis is a phenotypically diverse disease with symptoms ranging from predominant neuropathy to exclusive cardiac manifestations. The aims of this study were to determine the dispersion of the two types of fibrils found in Swedish ATTR V30M patients - Type A consisting of a mixture of truncated and full length ATTR fibrils and type B fibrils consisting of full length fibrils, and to estimate the severity of cardiac dysfunction in relation to fibril composition and sex. Material and Methods Echocardiographic data were analysed in 107 Swedish ATTR V30M patients with their fibril composition determined as either type A or type B. Measurements of left ventricular (LV) dimensions and evaluation of systolic and diastolic function including speckle tracking derived strain were performed. Patients were grouped according to fibril type and sex. Multivariate linear regression was utilised to determine factors of significant impact on LV thickness. Results There was no significant difference in proportions of the two types of fibrils between men and women. In patients with type A fibrils, women had significantly lower median septal (p = 0.007) and posterior wall thicknesses (p = 0.010), lower median LV mass indexed to height (p = 0.008), and higher septal strain (p = 0.037), as compared to males. These differences were not apparent in patients with type B fibrils. Multiple linear regression analysis revealed that fibril type, sex and age all had significant impact on LV septal thickness. Conclusion This study demonstrates a clear difference between sexes in the severity of amyloid heart disease in ATTR V30M amyloidosis patients. Even though type A fibrils were associated with more advanced amyloid heart disease compared to type B, women with type A fibrils generally developed less cardiac infiltration than men. The differences may explain the better outcome for liver transplanted late-onset female patients compared to males.

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  • 317. Arzberger, Thomas
    et al.
    Giese, Armin
    Edbauer, Dieter
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ferrer, Isidro
    Special Issue: Research on Brain Bank Material - From Ethical Issues to Biomolecular Studies2015In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 122, no 7, p. 933-936Article in journal (Other academic)
  • 318.
    Arzoo, Pakeeza Shaiq
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Klar, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Bergendal, Birgitta
    Norderyd, Johanna
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    WNT10A Mutations Account for 1/4 of Population- Based Isolated Oligodontia and Show Phenotypic Correlations2014In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 164, no 2, p. 353-359Article in journal (Refereed)
    Abstract [en]

    A large proportion (>50%) of patients with isolated oligodontia were recently reported with WNT10A mutations. We have analyzed a population-based cohort of 102 individuals diagnosed with non-syndromic oligodontia and a mean of 8.2 missing teeth. The cohort included 94 families and screening of WNT10A identified that 26 probands (27.7%) had at least one WNT10A variant. When we included the MSX1, PAX9, AXIN2, EDA, EDAR, and EDARADD genes, 38.3% of probands were positive for a mutation. Biallelic WNT10A mutations were strongly associated with a larger number of missing teeth (11.09) when compared to both monoallelic WNT10 mutations (6.82) and the group without mutations in WNT10A, MSX1, PAX9, AXIN2, EDA, EDAR, or EDARADD (7.77). Genotype-phenotype analysis of individuals with WNT10A mutations showed that premolars were the most common missing teeth. Furthermore, biallelic WNT10A mutations were associated with absence of maxillary and mandibular molars as well as mandibular central incisors. Maxillary central incisors were always present. Thus, our study indicates that WNT10A mutations are associated with both the type and numbers of missing teeth. Furthermore, we show that this population-based cohort of isolated oligodontia had a considerably lower frequency of mutated WNT10A alleles and a lower mean number of missing teeth when compared to patients recruited from dental specialist centers. (c) 2013 Wiley Periodicals, Inc.

  • 319. Asa, S L
    et al.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Chanson, P
    Delgrange, E
    Earls, P
    Ezzat, S
    Grossman, A
    Ikeda, H
    Inoshita, N
    Karavitaki, N
    Korbonits, M
    Laws, E R
    Lopes, M B
    Maartens, N
    McCutcheon, I E
    Mete, O
    Nishioka, H
    Raverot, G
    Roncaroli, F
    Saeger, W
    Syro, L V
    Vasiljevic, A
    Villa, C
    Wierinckx, A
    Trouillas, J
    From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal2017In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, no 4, p. C5-C8Article in journal (Refereed)
    Abstract [en]

    The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

  • 320. Asa, Sylvia L
    et al.
    Asioli, Sofia
    Bozkurt, Suheyla
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Chinezu, Laura
    Comunoglu, Nil
    Cossu, Giulia
    Cusimano, Michael
    Delgrange, Etienne
    Earls, Peter
    Ezzat, Shereen
    Gazioglu, Nurperi
    Grossman, Ashley
    Guaraldi, Federica
    Hickman, Richard A.
    Ikeda, Hidetoshi
    Jaffrain-Rea, Marie-Lise
    Karavitaki, Niki
    Kraljević, Ivana
    La Rosa, Stefano
    Manojlović-Gačić, Emilija
    Maartens, Niki
    McCutcheon, Ian E
    Messerer, Mahmoud
    Mete, Ozgur
    Nishioka, Hiroshi
    Oz, Buge
    Pakbaz, Sara
    Pekmezci, Melike
    Perry, Arie
    Reiniger, Lilla
    Roncaroli, Federico
    Saeger, Wolfgang
    Söylemezoğlu, Figen
    Tachibana, Osamu
    Trouillas, Jacqueline
    Turchini, John
    Uccella, Silvia
    Villa, Chiara
    Yamada, Shozo
    Yarman, Sema
    Pituitary neuroendocrine tumors (PitNETs): nomenclature evolution, not clinical revolution2020In: Pituitary, ISSN 1386-341X, E-ISSN 1573-7403, Vol. 23, no 3, p. 322-325Article in journal (Other academic)
  • 321.
    Asa, Sylvia L.
    et al.
    Case Western Reserve Univ, Univ Hosp Cleveland, Med Ctr, Dept Pathol, Cleveland, OH 44106 USA..
    Mete, Ozgur
    Univ Toronto, Univ Hlth Network, Dept Pathol, Toronto, ON, Canada..
    Cusimano, Michael D.
    Univ Toronto, Dept Neurosurg, St Michaels Hosp, Toronto, ON, Canada..
    McCutcheon, Ian E.
    Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA..
    Perry, Arie
    Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA..
    Yamada, Shozo
    Moriyama Neurol Ctr Hosp, Hypothalam & Pituitary Ctr, Tokyo, Japan..
    Nishioka, Hiroshi
    Toranomon Gen Hosp, Dept Hypothalam & Pituitary Surg, Tokyo, Japan..
    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.
    Uccella, Silvia
    Univ Insubria, Dept Pathol, Varese, Italy..
    La Rosa, Stefano
    Univ Hosp, Inst Pathol, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland..
    Grossman, Ashley B.
    Univ Oxford, Dept Endocrinol, London, England.;Royal Free London, London, England.;Barts & London Queen Marys Sch Med & Dent, London, England.;London Clin Ctr Endocrinol, London, England..
    Ezzat, Shereen
    Univ Toronto, Univ Hlth Network, Dept Med, Toronto, ON, Canada..
    Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification2021In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 34, no 9, p. 1634-1650Article, review/survey (Refereed)
    Abstract [en]

    The classification of adenohypophysial neoplasms as "pituitary neuroendocrine tumors" (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.

  • 322.
    Asawa, Kenta
    et al.
    Univ Tokyo, Sch Engn, Dept Bioengn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan..
    Ishihara, Kazuhiko
    Univ Tokyo, Sch Engn, Dept Mat Engn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan..
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, SE-39182 Kalmar, Sweden..
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Tokyo, Sch Engn, Dept Bioengn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan..
    Cell Surface Functionalization with Heparin-Conjugated Lipid to Suppress Blood Activation2021In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 31, no 11, article id 2008167Article in journal (Refereed)
    Abstract [en]

    Organ transplantation leads to damage of the endothelial glycocalyx of the transplanted organ, and the activated endothelial surface induces thromboinflammation. The result is dysfunction of the transplanted organ, known as ischemia reperfusion injury (IRI). Long-term graft survival strongly depends on the regulation of IRI. Here the aim is to reconstruct the glycocalyx to regulate blood activation during IRI. Heparin-conjugated lipid (fHep-lipid) is synthesized with 0.6, 1.8, 2.7, 4.5, or 8.0 fragmented heparins per lipid to compare their anticoagulation activity. First, liposome and cells are modified with each fHep-lipid and the surface properties are evaluated. Then the hemocompatibility of the modified human mesenchymal stem cells (hMSCs) is examined in a loop model using human blood. The antithrombin-binding capacity and anti-factor Xa activity of the fHep-lipids depend on the number of conjugated heparins, with efficacy increasing with increasing number of heparins. The modified liposomes are highly negatively charged and show strong anti-factor Xa activity. In addition, the cell surfaces of human erythrocytes and hMSCs can be uniformly modified with fHep-lipid. The whole blood studies reveal that fHep-lipid on hMSCs can prevent generation of thrombin-antithrombin complexes, coagulation markers, and platelet aggregation, whereas unmodified hMSCs trigger activation of the platelet and coagulation systems.

  • 323. Aschard, Hugues
    et al.
    Tobin, Martin D
    Hancock, Dana B
    Skurnik, David
    Sood, Akshay
    James, Alan
    Vernon Smith, Albert
    Manichaikul, Ani W
    Campbell, Archie
    Prins, Bram P
    Hayward, Caroline
    Loth, Daan W
    Porteous, David J
    Strachan, David P
    Zeggini, Eleftheria
    O'Connor, George T
    Brusselle, Guy G
    Boezen, H Marike
    Schulz, Holger
    Deary, Ian J
    Hall, Ian P
    Rudan, Igor
    Kaprio, Jaakko
    Wilson, James F
    Wilk, Jemma B
    Huffman, Jennifer E
    Hua Zhao, Jing
    de Jong, Kim
    Lyytikäinen, Leo-Pekka
    Wain, Louise V
    Jarvelin, Marjo-Riitta
    Kähönen, Mika
    Fornage, Myriam
    Polasek, Ozren
    Cassano, Patricia A
    Barr, R Graham
    Rawal, Rajesh
    Harris, Sarah E
    Gharib, Sina A
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heckbert, Susan R
    Lehtimäki, Terho
    Gyllensten, Ulf B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Society Scientific Group, Understanding
    Jackson, Victoria E
    Gudnason, Vilmundur
    Tang, Wenbo
    Dupuis, Josée
    Soler Artigas, María
    Joshi, Amit D
    London, Stephanie J
    Kraft, Peter
    Evidence for large-scale gene-by-smoking interaction effects on pulmonary function2017In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 46, no 3, p. 894-904Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking.

    METHODS: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia.

    RESULTS: We identified an interaction (βint = -0.036, 95% confidence interval, -0.040 to -0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV 1: /FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect.

    CONCLUSIONS: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.

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  • 324.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Regulation of thromboinflammation in therapeutic medicine: Special focus on surface coating strategies2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Biomaterials are an integral part of modern health care and offer potential treatment modalities to diseases and conditions otherwise intractable. However, the critical issue herein is incompatibility reactions.

    Our innate immune system is fundamental in protection against pathogens and foreign intruders and controls the discrimination between self and non-self. Biomaterials come in contact with blood upon implantation where they are sensed by innate immune mediators which through a cascade of complex, multifaceted reactions induce inflammation as well as thrombosis which may induce biomaterial dysfunction and rejection. This explains why patients undergoing haemodialysis therapy exhibit an increased incidence of whole-body inflammation and other thrombotic events. Similarly, therapeutic cells such as hepatocytes upon implantation initiate an instant blood mediated inflammatory reaction, responsible for cell damage and death via apoptosis.

    In order to achieve safer and more efficient therapeutic interventions,  engineering of materials and cells that can avoid these adverse reactions is essential. Fabrication of biomaterials consisting of  coating of bioinert polymers to avoid immune recognition and activation is a promising approach to modulate immune reactions.

    In this thesis, we have employed a PEG-lipid polymer coating, which intercalates in to biomembranes via hydrophobic interactions and thus shields from immune rejection. Treatment with PEG-lipid not only makes the surface “invisible” to immune cells but it also acts as a filter which prevents entry of immune cells without inducing cytotoxicity. Results from this thesis illustrate that fabrication of bio-surfaces by bio-inert PEG-lipid polymer is a harmless procedure which not  only attenuates thrombo-inflammation but also assist in design of self-tailored materials for a wide range of biomedical applications.

    List of papers
    1. Heparinization of cell surfaces with short pepetide-conjugated PEG-lipid regulates thromboinflammation in thransplantation of human MSCs and hepatocytes
    Open this publication in new window or tab >>Heparinization of cell surfaces with short pepetide-conjugated PEG-lipid regulates thromboinflammation in thransplantation of human MSCs and hepatocytes
    Show others...
    2016 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 35, p. 194-205Article in journal (Refereed) Published
    Abstract [en]

    Infusion of therapeutic cells into humans is associated with immune responses, including thromboinflammation, which result in a large loss of transplanted cells\ To address these problems, heparinization of the cell surfaces was achieved by a cell-surface modification technique using polyethylene glycol conjugated phospholipid (PEG-lipid) derivatives. A short heparin-binding peptide was conjugated to the PEG-lipid for immobilization of heparin conjugates on the surface of human mesenchymal stem cells (hMSCs) and human hepatocytes. Here three kinds of heparin-binding peptides were used for immobilizing heparin conjugates and examined for the antithrombogenic effects on the cell surface. The heparinized cells were incubated in human whole blood to evaluate their hemocompatibility by measuring blood parameters such as platelet count, coagulation markers, complement markers, and Factor Xa activity. We found that one of the heparin-binding peptides did not show cytotoxicity after the immobilization with heparin conjugates. The degree of binding of the heparin conjugates on the cell surface (analyzed by flow cytometer) depended on the ratio of the active peptide to control peptide. For both human MSCs and hepatocytes in whole-blood experiments, no platelet aggregation was seen in the heparin conjugate-immobilized cell group vs. the controls (non-coated cells or control peptide). Also, the levels of thrombin-antithrombin complex (TAT), C3a, and sC5b-9 were significantly lower than those of the controls, indicating a lower activation of coagulation and complement. Factor Xa analysis indicated that the heparin conjugate was still active on the cell surface at 24 h post-coating. It is possible to immobilize heparin conjugates onto hMSC and human hepatocyte surfaces and thereby protect the cell surfaces from damaging thromboinflammation. Statement of Signigficance We present a promising approach to enhance the biocompatibility of therapeutic cells. Here we used short peptide-conjugated PEG-lipid for cell surface modification and heparin conjugates for the coating of human hepatocytes and MSCs. We screened the short peptides to find higher affinity for heparinization of cell surface and performed hemocompatibility assay of heparinized human hepatocytes and human MSCs in human whole blood. Using heparin-binding peptide with higher affinity, not only coagulation activation but also complement activation was significantly suppressed. Thus, it was possible to protect human hepatocytes and human MSCs from the attack of thromboinflammatory activation, which can contribute to the improvement graft survival.

    Keywords
    Cell surface modification; Heparinization; Thromboinflammation; MSCs; Hepatocyte; Polyethylene glycol-conjugated phospholipid (PEG-lipid)
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-279420 (URN)10.1016/j.actbio.2016.02.018 (DOI)000375162200018 ()26876877 (PubMedID)
    Funder
    Swedish Research CouncilThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
    Available from: 2016-03-01 Created: 2016-03-01 Last updated: 2019-12-14Bibliographically approved
    2. Cell Adhesion Induced Using Surface Modification with Cell-Penetrating Peptide-Conjugated Poly(ethylene glycol)-Lipid: A New Cell Glue for 3D Cell-Based Structures
    Open this publication in new window or tab >>Cell Adhesion Induced Using Surface Modification with Cell-Penetrating Peptide-Conjugated Poly(ethylene glycol)-Lipid: A New Cell Glue for 3D Cell-Based Structures
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    2017 (English)In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 9, no 1, p. 244-254Article in journal (Refereed) Published
    Abstract [en]

    We synthesized a novel material, cell-penetrating peptide-conjugated poly(ethylene glycol)-lipid (CPP-PEG-lipid), that can induce the adhesion of floating cells. Firm cell adhesion with spreading could be induced by cell surface modification with the CPP-PEG-lipids. Cell adhesion was induced by CPPs but not by any other cationic short peptides we tested. Here, we demonstrated adherence using the floating cell line CCRF-CEM as well as primary human T cells, B cells, erythrocytes, and hepatocytes. As compared to cells grown in suspension, adherent cells were more rapidly induced to attach to substrates with the cell-surface modification. The critical factor for attachment was localization of CPPs at the cell membrane by PEG-lipids with PEG > 20 kDa. These cationic CPPs on PEG chains were able to interact with substrate surfaces such as polystyrene (PS) surfaces, glass surfaces, and PS microfibers that are negatively charged, inducing firm cell adhesion and cell spreading. Also, as opposed to normal cationic peptides that interact strongly with cell membranes, CPPs were less interactive with the cell surfaces because of their cell-penetrating property, making them more available for adhering cells to the substrate surface. No effects on cell viability or cell proliferation were observed after the induction of cell adhesion. With this technique, cells could be easily immobilized onto PS microfibers, an important step in fabricating 3D cell-based structures. Cells immobilized onto 3D PS microfibers were alive, and human hepatocytes showed normal production of urea and albumin on the microfibers. This method is novel in inducing firm cell adhesion via a one-step treatment.

    Keywords
    3D structure, cell adhesion, cell surface modification, cell-penetrating peptide (CPP), poly(ethylene glycol)-conjugated phospholipid (PEG−lipid)
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-373991 (URN)10.1021/acsami.6b14584 (DOI)000392037400031 ()27976850 (PubMedID)
    Funder
    The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
    Available from: 2019-01-17 Created: 2019-01-17 Last updated: 2019-12-14Bibliographically approved
    3. Validation of an MPC polymer coating to attenuate surface- induced cross-talk between the complement and coagulation systems in whole blood in in vitro and in vivo models
    Open this publication in new window or tab >>Validation of an MPC polymer coating to attenuate surface- induced cross-talk between the complement and coagulation systems in whole blood in in vitro and in vivo models
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    2019 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 19, no 5, article id 1800485Article in journal (Refereed) Published
    Abstract [en]

    Artificial surfaces that come into contact with blood induce an immediate activation of the cascade systems of the blood, leading to a thrombotic and/or inflammatory response that can eventually cause damage to the biomaterial or the patient, or to both. Heparin coating has been used to improve hemocompatibility, and another approach is 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer coatings. Here, the aim is to evaluate the hemocompatibility of MPC polymer coating by studying the interactions with coagulation and complement systems using human blood in vitro model and pig in vivo model. The stability of the coatings is investigated in vitro and MPC polymer-coated catheters are tested in vivo by insertion into the external jugular vein of pigs to monitor the catheters' antithrombotic properties. There is no significant activation of platelets or of the coagulation and complement systems in the MPC polymer-coated one, which was superior in hemocompatibility to non-coated matrix surfaces. The protective effect of the MPC polymer coat does not decline after incubation in human plasma for up to 2 weeks. With MPC polymer-coated catheters, it is possible to easily draw blood from pig for 4 days in contrast to the case for non-coated catheters, in which substantial clotting is seen.

    Place, publisher, year, edition, pages
    Wiley-VCH Verlagsgesellschaft, 2019
    Keywords
    blood compatibility, blood model systems, coagulation system, complement system, heparin coat, MPC polymer coat
    National Category
    Clinical Laboratory Medicine Biomaterials Science
    Identifiers
    urn:nbn:se:uu:diva-374785 (URN)10.1002/mabi.201800485 (DOI)000471340300015 ()30786149 (PubMedID)
    Funder
    Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
    Note

    Kazuhiko Ishihara har tillkommit som författare sedan posten lades in som manuskript.

    Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-12-14Bibliographically approved
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  • 325.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Asawa, Kenta
    Department of Bioengineering, The University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo, 113–8656 Japan.
    Yuuki, Inoue
    Department of Bioengineering, The University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo, 113–8656 Japan.
    Ishihara, Kazuhiko
    Department of Bioengineering, The University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo, 113–8656 Japan.
    Lindell, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Holmgren, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ryden, Anneli
    Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Almas Allé 8, 750 07 Uppsala, Sweden.
    Jensen-Waern, Marianne
    Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Almas Allé 8, 750 07 Uppsala, Sweden.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Department of Bioengineering, The University of Tokyo, Tokyo, Japan.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.
    Validation of an MPC polymer coating to attenuate surface- induced cross-talk between the complement and coagulation systems in whole blood in in vitro and in vivo models2019In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 19, no 5, article id 1800485Article in journal (Refereed)
    Abstract [en]

    Artificial surfaces that come into contact with blood induce an immediate activation of the cascade systems of the blood, leading to a thrombotic and/or inflammatory response that can eventually cause damage to the biomaterial or the patient, or to both. Heparin coating has been used to improve hemocompatibility, and another approach is 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer coatings. Here, the aim is to evaluate the hemocompatibility of MPC polymer coating by studying the interactions with coagulation and complement systems using human blood in vitro model and pig in vivo model. The stability of the coatings is investigated in vitro and MPC polymer-coated catheters are tested in vivo by insertion into the external jugular vein of pigs to monitor the catheters' antithrombotic properties. There is no significant activation of platelets or of the coagulation and complement systems in the MPC polymer-coated one, which was superior in hemocompatibility to non-coated matrix surfaces. The protective effect of the MPC polymer coat does not decline after incubation in human plasma for up to 2 weeks. With MPC polymer-coated catheters, it is possible to easily draw blood from pig for 4 days in contrast to the case for non-coated catheters, in which substantial clotting is seen.

  • 326.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Asawa, Kenta
    Yuuki, Inoue
    Kazuhiko, Ishihara2
    Lindell, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Holmgren, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ryden, Anneli
    Wearn, Marinne Jensen
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Validation of an MPC polymer coating to reduce surface-induced cascade system activation in whole blood in in vitroand in vivo modelsManuscript (preprint) (Other academic)
    Abstract [en]

    ABSTRACT

    Background: Artificial surfaces that come into contact with blood (e.g., when used in various forms of biomedical device) induce an immediate activation of the cascade systems of the blood, the coagulation and complement systems. These reactions may lead to a thrombotic and/or inflammatory response that can eventually cause damage to the biomaterial or the patient, or to both. Multiple strategies to dampen these reactions have been employed, with heparin conjugation to the material surface being the most successfulthus far. Another approach to improving hemocompatibility is to use 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer coatings.

    Experimental: In the present study, we evaluated the effectiveness of MPC polymer coating and compared it to a commercially available heparin coating in various in vitromodels using fresh human blood with the aim to replace the costly heparin-coated equipment with the more economic MPC. We then investigated the stability of the various coatings in human plasma in vitrofor 2 weeks. Finally, we inserted MPC polymer-coated catheters into the external jugular vein of pigs and monitored the catheters’ antithrombotic properties for 4 days.

    Results: 1) There was no significant activation of platelets and of the coagulation and complement systems on the MPC polymer-coated or the commercially available heparin surface. 2) Both coats were superior in hemocompatibility to non-coated matrix surfaces. 3) The protective effect of the MPC polymer coat did not decline after incubation in plasma for up to 2 weeks. 4) With MPC polymer-coated catheters, it was possible to easily draw blood from experimental animals for 4 days, in contrast to the case for heparin-flushed commercially available non-coated catheters, in which substantial clotting was seen.

  • 327.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnæus Center of Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden.
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gustafson, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Barbu, Andreea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Le Bland, Katarina
    Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institute, and Hematology and Regenerat ive Medicine Centre at Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Department of Bioengineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
    Heparinization of cell surfaces with short pepetide-conjugated PEG-lipid regulates thromboinflammation in thransplantation of human MSCs and hepatocytes2016In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 35, p. 194-205Article in journal (Refereed)
    Abstract [en]

    Infusion of therapeutic cells into humans is associated with immune responses, including thromboinflammation, which result in a large loss of transplanted cells\ To address these problems, heparinization of the cell surfaces was achieved by a cell-surface modification technique using polyethylene glycol conjugated phospholipid (PEG-lipid) derivatives. A short heparin-binding peptide was conjugated to the PEG-lipid for immobilization of heparin conjugates on the surface of human mesenchymal stem cells (hMSCs) and human hepatocytes. Here three kinds of heparin-binding peptides were used for immobilizing heparin conjugates and examined for the antithrombogenic effects on the cell surface. The heparinized cells were incubated in human whole blood to evaluate their hemocompatibility by measuring blood parameters such as platelet count, coagulation markers, complement markers, and Factor Xa activity. We found that one of the heparin-binding peptides did not show cytotoxicity after the immobilization with heparin conjugates. The degree of binding of the heparin conjugates on the cell surface (analyzed by flow cytometer) depended on the ratio of the active peptide to control peptide. For both human MSCs and hepatocytes in whole-blood experiments, no platelet aggregation was seen in the heparin conjugate-immobilized cell group vs. the controls (non-coated cells or control peptide). Also, the levels of thrombin-antithrombin complex (TAT), C3a, and sC5b-9 were significantly lower than those of the controls, indicating a lower activation of coagulation and complement. Factor Xa analysis indicated that the heparin conjugate was still active on the cell surface at 24 h post-coating. It is possible to immobilize heparin conjugates onto hMSC and human hepatocyte surfaces and thereby protect the cell surfaces from damaging thromboinflammation. Statement of Signigficance We present a promising approach to enhance the biocompatibility of therapeutic cells. Here we used short peptide-conjugated PEG-lipid for cell surface modification and heparin conjugates for the coating of human hepatocytes and MSCs. We screened the short peptides to find higher affinity for heparinization of cell surface and performed hemocompatibility assay of heparinized human hepatocytes and human MSCs in human whole blood. Using heparin-binding peptide with higher affinity, not only coagulation activation but also complement activation was significantly suppressed. Thus, it was possible to protect human hepatocytes and human MSCs from the attack of thromboinflammatory activation, which can contribute to the improvement graft survival.

  • 328.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Nordström, Johan
    Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Brandhorst, Heide
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jorns, Carl
    Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nowak, Greg
    Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Theisinger, Sonja
    Novaliq GmbH, Heidelberg, Germany.
    Hoeger, Simone
    Department of Nephrology, Endocrinology and Rheumatology, University Medical Center Mannheim, Mannheim, Germany.
    Wennberg, Lars
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Oxygen-charged HTK-F6H8 emulsion reduces ischemia: reperfusion injury in kidneys from brain-dead pigs2012In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 178, no 2, p. 959-967Article in journal (Refereed)
    Abstract [en]

    Background:

    Prolonged cold ischemia is frequently associated with a greater risk of delayed graft function and enhanced graft failure. We hypothesized that media, combining a high oxygen-dissolving capacity with specific qualities of organ preservation solutions, would be more efficient in reducing immediate ischemia-reperfusion injury from organs stored long term compared with standard preservation media.

    Methods:

    Kidneys retrieved from brain-dead pigs were flushed using either cold histidine-tryptophan-ketoglutarate (HTK) or oxygen-precharged emulsion composed of 75% HTK and 25% perfluorohexyloctane. After 18 h of cold ischemia the kidneys were transplanted into allogeneic recipients and assessed for adenosine triphosphate content, morphology, and expression of genes related to hypoxia, environmental stress, inflammation, and apoptosis.

    Results:

    Compared with HTK-flushed kidneys, organs preserved using oxygen-precharged HTK-perfluorohexyloctane emulsion had increased elevated adenosine triphosphate content and a significantly lower gene expression of hypoxia inducible factor-1 alpha, vascular endothelial growth factor, interleukin-1 alpha, tumor necrosis factor-alpha, interferon-alpha, JNK-1, p38, cytochrome-c, Bax, caspase-8, and caspase-3 at all time points assessed. In contrast, the mRNA expression of Bcl-2 was significantly increased.

    Conclusions:

    The present study has demonstrated that in brain-dead pigs the perfusion of kidneys with oxygen-precharged HTK-perfluorohexyloctane emulsion results in significantly reduced inflammation, hypoxic injury, and apoptosis and cellular integrity and energy content are well maintained. Histologic examination revealed less tubular, vascular, and glomerular changes in the emulsion-perfused tissue compared with the HTK-perfused counterparts. The concept of perfusing organs with oxygen-precharged emulsion based on organ preservation media represents an efficient alternative for improved organ preservation.

  • 329.
    Asleh, Karama
    et al.
    Univ British Columbia, Genet Pathol Evaluat Ctr, Dept Pathol & Lab Med, Vancouver, BC, Canada.;Univ British Columbia, Interdisciplinary Oncol Program, Fac Med, Vancouver, BC, Canada..
    Brauer, Heather Ann
    NanoString Technol Inc, Seattle, WA USA..
    Sullivan, Amy
    NanoString Technol Inc, Seattle, WA USA..
    Lauttia, Susanna
    Univ Helsinki, Biomed Helsinki, Lab Mol Oncol, Helsinki, Finland..
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Nielsen, Torsten O.
    Univ British Columbia, Genet Pathol Evaluat Ctr, Dept Pathol & Lab Med, Vancouver, BC, Canada..
    Joensuu, Heikki
    Univ Helsinki, Biomed Helsinki, Lab Mol Oncol, Helsinki, Finland.;Univ Helsinki, Comprehens Canc Ctr, Helsinki Univ Hosp, Helsinki, Finland.;Univ Helsinki, Dept Oncol, Helsinki, Finland..
    Thompson, E. Aubrey
    Mayo Clin, Ctr Comprehens Canc, Dept Canc Biol, Jacksonville, FL 32224 USA..
    Chumsri, Saranya
    Mayo Clin, Robert & Monica Jacoby Ctr Breast Hlth, Jacksonville, FL 32224 USA..
    Predictive Biomarkers for Adjuvant Capecitabine Benefit in Early-Stage Triple-Negative Breast Cancer in the FinXX Clinical Trial2020In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 26, no 11, p. 2603-2614Article in journal (Refereed)
    Abstract [en]

    Purpose: Recent studies have demonstrated a benefit of adjuvant capecitabine in early breast cancer, particularly in patients with triple-negative breast cancer (TNBC). However, TNBC is heterogeneous and more precise predictive biomarkers are needed. Experimental Design: Tumor tissues collected from TNBC patients in the FinXX trial, randomized to adjuvant anthracycline-taxane-based chemotherapy with or without capecitabine, were analyzed using a 770-gene panel targeting multiple biological mechanisms and additional 30-custom genes related to capecitabine metabolism. Hypothesis-generating exploratory analyses were performed to assess biomarker expression in relation to treatment effect using the Cox regression model and interaction tests adjusted for multiplicity. Results: One hundred eleven TNBC samples were evaluable (57 without capecitabine and 54 with capecitabine). The median follow-up was 10.2 years. Multivariate analysis showed significant improvement in recurrence-free survival (RFS) favoring capecitabine in four biologically important genes and metagenes, including cytotoxic cells [hazard ratio (HR) = 0.38; 95% confidence intervals (CI), 0.16-0.86, P-interaction = 0.01], endothelial (HR = 0.67; 95% CI, 0.20-2.22, P-interaction = 0.02), mast cells (HR = 0.78; 95% CI, 0.49-1.27, P-interaction = 0.04), and PDL2 (HR = 0.31; 95% CI, 0.12- 0.81, P- interaction = 0.03). Furthermore, we identified 38 single genes that were significantly associated with capecitabine benefit, and these were dominated by immune response pathway and enzymes involved in activating capecitabine to fluorouracil, including TYMP. However, these results were not significant when adjusted for multiple testing. Conclusions: Genes and metagenes related to antitumor immunity, immune response, and capecitabine activation could identify TNBC patients who are more likely to benefit from adjuvant capecitabine. Given the reduced power to observe significant findings when correcting for multiplicity, our findings provide the basis for future hypothesis- testing validation studies on larger clinical trials.

  • 330.
    Aspelund, Aleksanteri
    et al.
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Robciuc, Marius R.
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Karaman, Sinem
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Alitalo, Kari
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Lymphatic System in Cardiovascular Medicine2016In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 118, no 3, p. 515-530Article, review/survey (Refereed)
    Abstract [en]

    The mammalian circulatory system comprises both the cardiovascular system and the lymphatic system. In contrast to the blood vascular circulation, the lymphatic system forms a unidirectional transit pathway from the extracellular space to the venous system. It actively regulates tissue fluid homeostasis, absorption of gastrointestinal lipids, and trafficking of antigen-presenting cells and lymphocytes to lymphoid organs and on to the systemic circulation. The cardinal manifestation of lymphatic malfunction is lymphedema. Recent research has implicated the lymphatic system in the pathogenesis of cardiovascular diseases including obesity and metabolic disease, dyslipidemia, inflammation, atherosclerosis, hypertension, and myocardial infarction. Here, we review the most recent advances in the field of lymphatic vascular biology, with a focus on cardiovascular disease.

  • 331. Aspelund, Aleksanteri
    et al.
    Tammela, Tuomas
    Antila, Salli
    Nurmi, Harri
    Leppanen, Veli-Matti
    Zarkada, Georgia
    Stanczuk, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Francois, Mathias
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Saharinen, Pipsa
    Immonen, Ilkka
    Alitalo, Kari
    The Schlemm's canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel2014In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 9, p. 3975-3986Article in journal (Refereed)
    Abstract [en]

    In glaucoma, aqueous outflow into the Schlemm's canal (SC) is obstructed. Despite striking structural and functional similarities with the lymphatic vascular, system, it is unknown whether the SC is a blood or lymphatic vessel. Here, we demonstrated the expression of lymphatic endothelial cell markers by the SC in murine and zebrafish models as well as in human eye tissue. The initial stages of SC development involved induction of the transcription factor PROX1 and the lymphangiogenic receptor tyrosine kinase VEGFR-3 in venous endothelial cells in postnatal mice. Using gene deletion and function-blocking antibodies in mice, we determined that the lymphangiogenic growth factor VEGF-C and its receptor, VEGFR-3, are essential for SC development. Delivery of VEGF-C into the adult eye resulted in sprouting, proliferation, and growth of SC endothelial cells, whereas VEGF-A obliterated the aqueous outflow system. Furthermore, a single injection of recombinant VEGF-C induced SC growth and was associated with trend toward a sustained decrease in intraocular pressure in adult mice. These results reveal the evolutionary conservation of the lymphatic-like phenotype of the SC, implicate VEGF-C and VEGFR-3 as critical regulators of SC lymphangiogenesis, and provide a basis for further studies on therapeutic manipulation of the SC with VEGF-C in glaucoma treatment.

  • 332. Aspelund, Aleksanteri
    et al.
    Tammela, Tuomas
    Antila, Salli
    Nurmi, Harri
    Leppanen, Veli-Matti
    Zarkada, Georgia
    Stanczuk, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Francois, Mathias
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Saharinen, Pipsa
    Immonen, Ilkka
    Alitalo, Kari
    Therapeutic Insights to Lymphangiogenic Growth Factors2015In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 52, no S1, p. 19-19Article in journal (Other academic)
  • 333.
    Aspenström, Pontus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Activated Rho GTPases in Cancer-The Beginning of a New Paradigm2018In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 19, no 12, article id 3949Article, review/survey (Refereed)
    Abstract [en]

    Involvement of Rho GTPases in cancer has been a matter of debate since the identification of the first members of this branch of the Ras superfamily of small GTPases. The Rho GTPases were ascribed important roles in the cell, although these were restricted to regulation of cytoskeletal dynamics, cell morphogenesis, and cell locomotion, with initially no clear indications of direct involvement in cancer progression. This paradigm has been challenged by numerous observations that Rho-regulated pathways are often dysregulated in cancers. More recently, identification of point mutants in the Rho GTPases Rac1, RhoA, and Cdc42 in human tumors has finally given rise to a new paradigm, and we can now state with confidence that Rho GTPases serve as oncogenes in several human cancers. This article provides an expose of current knowledge of the roles of activated Rho GTPases in cancers.

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  • 334.
    Aspenström, Pontus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    The Intrinsic GDP/GTP Exchange Activities of Cdc42 and Rac1 Are A Critical Determinants for Their Specific Effects on Mobilization of the Actin Filament System2019In: Cells, E-ISSN 2073-4409, Vol. 8, no 7, article id 759Article in journal (Refereed)
    Abstract [en]

    The Rho GTPases comprise a subfamily of the Ras superfamily of small GTPases. Their importance in regulation of cell morphology and cell migration is well characterized. According to the prevailing paradigm, Cdc42 regulates the formation of filopodia, Rac1 regulates the formation of lamellipodia, and RhoA triggers the assembly of focal adhesions. However, this scheme is clearly an oversimplification, as the Rho subfamily encompasses 20 members with diverse effects on a number of vital cellular processes, including cytoskeletal dynamics and cell proliferation, migration, and invasion. This article highlights the importance of the catalytic activities of the classical Rho GTPases Cdc42 and Rac1, in terms of their specific effects on the dynamic reorganization of the actin filament system. GTPase-deficient mutants of Cdc42 and Rac1 trigger the formation of broad lamellipodia and stress fibers, and fast-cycling mutations trigger filopodia formation and stress fiber dissolution. The filopodia response requires the involvement of the formin family of actin nucleation promotors. In contrast, the formation of broad lamellipodia induced by GTPase-deficient Cdc42 and Rac1 is mediated through Arp2/3-dependent actin nucleation.

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  • 335.
    Aspenström, Pontus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    The Role of Fast-Cycling Atypical RHO GTPases in Cancer2022In: Cancers, ISSN 2072-6694, Vol. 14, no 8, article id 1961Article, review/survey (Refereed)
    Abstract [en]

    For many years, cancer-associated mutations in RHO GTPases were not identified and observations suggesting roles for RHO GTPases in cancer were sparse. Instead, RHO GTPases were considered primarily to regulate cell morphology and cell migration, processes that rely on the dynamic behavior of the cytoskeleton. This notion is in contrast to the RAS proteins, which are famous oncogenes and found to be mutated at high incidence in human cancers. Recent advancements in the tools for large-scale genome analysis have resulted in a paradigm shift and RHO GTPases are today found altered in many cancer types. This review article deals with the recent views on the roles of RHO GTPases in cancer, with a focus on the so-called fast-cycling RHO GTPases. The RHO GTPases comprise a subfamily within the RAS superfamily of small GTP-hydrolyzing enzymes and have primarily been ascribed roles in regulation of cytoskeletal dynamics in eukaryotic cells. An oncogenic role for the RHO GTPases has been disregarded, as no activating point mutations were found for genes encoding RHO GTPases. Instead, dysregulated expression of RHO GTPases and their regulators have been identified in cancer, often in the context of increased tumor cell migration and invasion. In the new landscape of cancer genomics, activating point mutations in members of the RHO GTPases have been identified, in particular in RAC1, RHOA, and CDC42, which has suggested that RHO GTPases can indeed serve as oncogenes in certain cancer types. This review describes the current knowledge of these cancer-associated mutant RHO GTPases, with a focus on how their altered kinetics can contribute to cancer progression.

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  • 336. Asplund, A. C.
    et al.
    Falk, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Moens, Lotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kumar, Y.
    Bauser, C.
    Bernatowska, E.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Smith, C. I. E.
    Large-scale mutation analysis of primary immunodeficiency patients by next-generation sequencing2012In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 32, no Suppl 1, p. 227-228Article in journal (Other academic)
  • 337.
    Asplund, Anna
    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.
    Edqvist, Per-Henrik D
    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.
    Schwenk, Jochen 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.
    Antibodies for profiling the human proteome: The Human Protein Atlas as a resource for cancer research2012In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 12, no 13, p. 2067-2077Article, review/survey (Refereed)
    Abstract [en]

    In this review, we present an update on the progress of the Human Protein Atlas, with an emphasis on strategies for validating immunohistochemistry-based protein expression patterns and on the possibilities to extend the map of protein expression patterns for cancer research projects. The objectives underlying the Human Protein Atlas include (i) the generation of validated antibodies toward a major isoform of all proteins encoded by the human genome, (ii) creating an information database of protein expression patterns in normal human tissues, in cells, and in cancer, and (iii) utilizing generated antibodies and protein expression data as tools to identify clinically useful biomarkers. The success of such an effort is dependent on the validity of antibodies as specific binders of intended targets in applications used to map protein expression patterns. The development of strategies to support specific target binding is crucial and remains a challenge as a large fraction of proteins encoded by the human genome is poorly characterized, including the approximately one-third of all proteins lacking evidence of existence. Conceivable methods for validation include the use of paired antibodies, i.e. two independent antibodies targeting different and nonoverlapping epitopes on the same protein as well as comparative analysis of mRNA expression patterns with corresponding proteins.

  • 338.
    Asplund, Olof
    et al.
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Storm, Petter
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden.;Wallenberg Neurosci Ctr, Dept Expt Med Sci Dev & Regenerat Neurobiol, Lund, Sweden..
    Chandra, Vikash
    Univ Helsinki, Fac Med, Stem Cells & Metab Res Program, Helsinki, Finland..
    Hatem, Gad
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Ottosson-Laakso, Emilia
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Mansour-Aly, Dina
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Krus, Ulrika
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Ibrahim, Hazem
    Univ Helsinki, Fac Med, Stem Cells & Metab Res Program, Helsinki, Finland..
    Ahlqvist, Emma
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Tuomi, Tiinamaija
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden.;Helsinki Univ Hosp, Abdominal Ctr, Folkhalsan Res Ctr, Dept Endocrinol, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Renström, Erik
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. , Sweden.;Univ Gothenburg, Inst Biomed, Dept Clin Chem & Transfus Med, Gothenburg, Sweden..
    Wierup, Nils
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Ibberson, Mark
    SIB Swiss Inst Bioinformat, Vital IT Grp, Lausanne, Switzerland..
    Solimena, Michele
    Tech Univ Dresden, Paul Langerhans Inst Dresden, Munich Univ Hosp Carl Gustav Carus, Helmholtz Ctr, Dresden, Germany.;Tech Univ Dresden, Fac Med, Dresden, Germany.;German Ctr Diabet Res DZD, Munich, Germany.;Max Planck Inst Mol Cell Biol & Genet, MPI CBG, Dresden, Germany..
    Marchetti, Piero
    Univ Pisa, Cisanello Univ Hosp, Dept Clin & Expt Med, Pisa, Italy..
    Wollheim, Claes
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden.;Univ Geneva, Fac Med, Dept Cell Physiol & Metab, Geneva, Switzerland..
    Artner, Isabella
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Mulder, Hindrik
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Hansson, Ola
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Otonkoski, Timo
    Univ Helsinki, Fac Med, Stem Cells & Metab Res Program, Helsinki, Finland.;Helsinki Univ Hosp, Childrens Hosp, Helsinki, Finland..
    Groop, Leif
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Prasad, Rashmi B.
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Lund Univ, Human Tissue Lab, Diabet Ctr, Lund, Sweden..
    Islet Gene View-a tool to facilitate islet research2022In: Life Science Alliance, E-ISSN 2575-1077, Vol. 5, no 12, article id e202201376Article in journal (Refereed)
    Abstract [en]

    Characterization of gene expression in pancreatic islets and its alteration in type 2 diabetes (T2D) are vital in understanding islet function and T2D pathogenesis. We leveraged RNA sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. Expression data were related to islet phenotypes, diabetes status, other islet-expressed genes, islet hormone-encoding genes and for expression in insulin target tissues. The IGW web application produces output graphs for a particular gene of interest. In IGW, 284 differentially expressed genes (DEGs) were identified in T2D donor islets compared with controls. Forty percent of DEGs showed cell-type enrichment and a large proportion significantly co-expressed with islet hormone-encoding genes; glucagon (GCG, 56%), amylin (IAPP, 52%), insulin (INS, 44%), and somatostatin (SST, 24%). Inhibition of two DEGs, UNC5D and SERPINE2, impaired glucose-stimulated insulin secretion and impacted cell survival in a human beta-cell model. The exploratory use of IGW could help designing more comprehensive functional follow-up studies and serve to identify therapeutic targets in T2D.

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  • 339.
    Astradsson, Thorsteinn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Sellberg, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Tiblom Ehrsson, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Systemic Inflammatory Reaction in Patients With Head and Neck Cancer-An Explorative Study2019In: Frontiers in Oncology, E-ISSN 2234-943X, Vol. 9, article id 1177Article in journal (Refereed)
    Abstract [en]

    Aim: To assess the longitudinal pattern of pro-inflammatory cytokines and growth factors in serum up to 1 year following treatment for head and neck cancer. Materials and Methods: Patients with newly diagnosed, curable head and neck cancer were included (n = 30). The most common subsite was oropharynx (n = 13) followed by oral cavity (n = 9). Blood was drawn from all patients at regular intervals (before treatment, 7 weeks after the start of the treatment, and at 3 months and 1 year after termination of treatment) and analyzed for cytokines (Il-1 beta, Il-2, Il-4, Il-5, Il-6, Il-8, Il-10, GM-CSF, TNF-alpha, and IFN-gamma) and growth factors (G-CSF, FGF-2, EGF, and VEGF). Results: The time point of the peak level of pro-inflammatory cytokines was 7 weeks after start of treatment which corresponded for the majority of patients with termination of radiotherapy or chemoradiotherapy. Patients undergoing chemoradiotherapy exhibited a significant increase of IL-1 beta, IL-6, and IL-10 at 7 weeks as compared to pre-treatment levels. At 1 year after termination of treatment four patients experienced recurrence of disease while 26 patients were considered disease-free. The patients with recurrence had significantly higher levels of IL-1 beta, IL-6, IL-8, and IL-10 at 7 weeks after the start of treatment than patients without recurrence. Correlated with T stadium patients with T3-T4 had higher levels of IL-1 beta and IL-8 than patients with T1-T2 7 weeks after the start of treatment. Conclusions: The observed immune response in this explorative study demonstrates that chemoradiotherapy may induce not only a local treatment effect on the immune system but also effects far outside the irradiated field. The result of the study indicates that analysis of a pro-inflammatory panel of cytokines in serum at 7 weeks after the start of treatment could be of prognostic value in patients with head and neck cancer. Further study of a larger cohort could help identify patients at larger risk for recurrent disease with measurements of pro-inflammatory cytokines under and after treatment.

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  • 340.
    Astradsson, Thorsteinn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Sellberg, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ehrsson, Ylva Tiblom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Sandström, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Serum Proteomics in Patients with Head and Neck Cancer: Peripheral Blood Immune Response to Treatment2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 11, article id 6304Article in journal (Refereed)
    Abstract [en]

    In this real-world study, the aims were to prospectively evaluate the expression of inflammatory proteins in serum collected from head and neck cancer patients before and after treatment, and to assess whether there were differences in expression associated with treatment modalities. The mixed study cohort consisted of 180 patients with head and neck cancer. The most common tumor sites were the oropharynx (n = 81), the oral cavity (n = 53), and the larynx (n = 22). Blood tests for proteomics analysis were carried out before treatment, 7 weeks after the start of treatment, and 3 and 12 months after the termination of treatment. Sera were analyzed for 83 proteins using an immuno-oncology biomarker panel (Olink, Uppsala, Sweden). Patients were divided into four treatment groups: surgery alone (Surg group, n = 24), radiotherapy with or without surgery (RT group, n = 94), radiotherapy with concomitant cisplatin (CRT group, n = 47), and radiotherapy with concomitant targeted therapy (RT Cetux group, n = 15). For the overall cohort, the expression levels of 15 of the 83 proteins changed significantly between the pretreatment sample and the sample taken 7 weeks after the start of treatment. At 7 weeks after the start of treatment, 13 proteins showed lower expression in the CRT group compared to the RT group. The majority of the inflammatory proteins had returned to their pretreatment levels after 12 months. It was clearly demonstrated that cisplatin-based chemoradiation has immunological effects in patients with head and neck cancer. This analysis draws attention to several inflammatory proteins that are of interest for further studies.

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  • 341.
    Atefyekta, Saba
    et al.
    Chalmers Univ Technol, Dept Chem & Chem Engn, SE-41296 Gothenburg, Sweden.
    Blomstrand, Edvin
    Chalmers Univ Technol, Dept Chem & Chem Engn, SE-41296 Gothenburg, Sweden.
    Rajasekharan, Anand K.
    Chalmers Univ Technol, Dept Chem & Chem Engn, SE-41296 Gothenburg, Sweden.
    Svensson, Sara
    Univ Gothenburg, Dept Biomat, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden.
    Trobos, Margarita
    Univ Gothenburg, Dept Biomat, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden; Univ Gothenburg, Ctr Antibiot Resistance Res CARe, SE-40530 Gothenburg, Sweden.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Webster, Thomas J.
    Northeastern Univ, Dept Chem Engn, Boston, MA 02115 USA.
    Thomsen, Peter
    Univ Gothenburg, Dept Biomat, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden.
    Andersson, Martin
    Chalmers Univ Technol, Dept Chem & Chem Engn, SE-41296 Gothenburg, Sweden.
    Antimicrobial Peptide-Functionalized Mesoporous Hydrogels2021In: ACS Biomaterials Science & Engineering, E-ISSN 2373-9878, Vol. 7, no 4, p. 1693-1702Article in journal (Refereed)
    Abstract [en]

    Antimicrobial peptides (AMPs) are seen as a promising replacement to conventional antibiotics for the prevention of skin wound infections. However, due to the short half-life of AMPs in biological environments, such as blood, their use in clinical applications has been limited. The covalent immobilization of AMPs onto suitable substrates is an effective solution to create contact-killing surfaces with increased long-term stability. In this work, an antimicrobial peptide, RRPRPRPRPWWWW-NH2 (RRP9W4N), was covalently attached to amphiphilic and ordered mesoporous Pluronic F127 hydrogels made of cross-linked lyotropic liquid crystals through 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) chemistry. The AMP-hydrogels showed high antibacterial activity against Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa, methicillin-resistant S. aureus (MRSA), and multidrug-resistant Escherichia coli for up to 24 h. Furthermore, the AMP-hydrogels did not present any toxicity to human fibroblasts. The AMPs retained their antimicrobial activity up to 48 h in human blood serum, which is a significant increase in stability compared to when used in dissolved state. A pilot in vivo rat model showed 10–100× less viable counts of S. aureus on AMP-hydrogels compared with control hydrogels during the first 3 days of infection. Studies performed on human whole blood showed that blood coagulated more readily in the presence of AMP-hydrogels as compared to hydrogels without AMPs, indicating potential hemostatic activity. Overall, the results suggest that the combination of amphiphilic hydrogels with covalently bonded AMPs has potential to be used as antibacterial wound dressing material to reduce infections and promote hemostatic activity as an alternative to antibiotics or other antimicrobial agents, whose use should be restricted.

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  • 342.
    Atienza Párraga, Alba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Nylund, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Diamanti, Klev
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Garrido-Zabala, Berta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Vasquez, Louella
    Department of Laboratory Medicine, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Lund University, Lund, Sweden..
    Pyl, Paul Theodor
    Department of Clinical Sciences, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory Lund University, Lund, Sweden..
    Raykova, Doroteya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Skaftason, Aron
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Ma, Anqi
    Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA..
    Jin, Jian
    Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA..
    Martín-Subero, José Ignacio
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Department of Pathology, Hematopathology Section, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona..
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Komorowski, Jan
    Institute of Computer Science, Polish Academy of Sciences, Warsaw, Poland.
    Jernberg Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Kalushkova, Antonia
    Dual DNMT/EZH2 inhibition synergistically re-configures the epigenome and promotes anti-tumour effects in multiple myelomaManuscript (preprint) (Other academic)
  • 343. Attarha, Sanaz
    et al.
    Roy, Ananya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, SE-75007 Uppsala, Sweden..
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Mast cells modulate proliferation, migration and sternness of glioma cells through downregulation of GSK3 beta expression and inhibition of STAT3 activation2017In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 37, p. 81-92Article in journal (Refereed)
    Abstract [en]

    Glioblastoma (GBM) heterogeneity is the main obstacle to efficient treatment due to the existence of sub population of cells with increased tumorigenicity and network of tumor associated parenchymal cells in the tumor microenvironment. We previously demonstrated that mast cells (MCs) infiltrate mouse and human gliomas in response to variety of signals in a glioma grade-dependent manner. However, the role of MCs in glioma development and the mechanisms behind MCs-glioma cells interaction remain unidentified. In the present study, we show that MCs upon activation by glioma cells produce soluble factors including IL-6, which are documented to be involved in cancer-related activities. We observe 'tumor educated' MCs decrease glioma cell proliferation and migration, reduce self-renewal capacity and expression of stemness markers but in turn promote glioma cell differentiation. 'Tumor educated' MC derived mediators exert these effects via inactivation of STAT3 signaling pathway through GSK3 beta down-regulation. We identified 'tumor educated' MC derived IL-6 as one of the contributors among the complex mixture of MCs mediators, to be partially involved in the observed MC induced biological effect on glioma cells. Thus, MC mediated abolition of STAT3 signaling hampers glioma cell proliferation and migration by suppressing their stemness and inducing differentiation via down-regulation of GSK3 beta expression. Targeting newly identified inflammatory MC-STAT3 axis could contribute to patient tailored therapy and unveil potential future therapeutic opportunities for patients.

  • 344.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Jonsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Soluble ligands as drug targets2020In: Nature reviews. Drug discovery, ISSN 1474-1776, E-ISSN 1474-1784, Vol. 19, no 10, p. 695-710Article, review/survey (Refereed)
    Abstract [en]

    Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters. However, owing largely to the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. In this Review, we analyse drugs targeting ligands that have reached clinical development at some point since 1992. We identify 291 drugs that target 99 unique ligands, and we discuss trends in the characteristics of the ligands, drugs and indications for which they have been tested. In the last 5 years, the number of ligand-targeting drugs approved by the FDA has doubled to 34, while the number of clinically validated ligand targets has doubled to 22. Cytokines and growth factors are the predominant types of targeted ligands (70%), and inflammation and autoimmune disorders, cancer and ophthalmological diseases are the top therapeutic areas for both approved agents and agents in clinical studies, reflecting the central role of cytokine and/or growth factor pathways in such diseases. With the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. This Review analyses drugs targeting ligands that have reached clinical development in the past three decades and discusses strategic issues such as the pros and cons of different ligand-targeting therapeutic modalities.

  • 345.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Orphan Drugs and Their Impact on Pharmaceutical Development2018In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 39, no 6, p. 525-535Article, review/survey (Refereed)
    Abstract [en]

    High levels of productivity, with an increasing number of approvals for new molecular entities (NMEs) by the FDA during the past decade, have coincided with the emergence of innovative drugs for treatments of rare diseases that have utilized the FDA orphan drug program. Since 2000, NMEs with orphan designation encompass a significant portion of approved drugs and constitute about 80% of the approved drugs that have established novel human genome-encoded products in recent years. Biological approvals are also expanding, with 40% of the approved biological agents having orphan designation. This trend illustrates a pivot within the pharmaceutical industry: from research programs that focus on canonical blockbuster indications and targets, towards the establishment of new treatments for rare and difficult to treat diseases.

  • 346.
    Aughton, Karen
    et al.
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Elander, Nils O.
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England.;Linköping Univ, Dept Oncol, SE-58183 Linköping, Sweden..
    Evans, Anthony
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Jackson, Richard
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Campbell, Fiona
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Costello, Eithne
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Halloran, Christopher M.
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Mackey, John R.
    Univ Alberta, Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada..
    Scarfe, Andrew G.
    Univ Alberta, Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada..
    Valle, Juan W.
    Univ Manchester, Christie NHS Fdn Trust, Manchester M20 4BX, Lancs, England..
    Carter, Ross
    Glasgow Royal Infirm, Glasgow G4 0SF, Lanark, Scotland..
    Cunningham, David
    Royal Marsden Natl Hlth Serv NHS Fdn Trust, London SW3 6JJ, England..
    Tebbutt, Niall C.
    Austin Hlth, Melbourne, Vic 3084, Australia..
    Goldstein, David
    Univ New South Wales, Prince Wales Hosp & Clin Sch, Sydney, NSW 2052, Australia..
    Shannon, Jennifer
    Univ Sydney, Nepean Canc Ctr, Sydney, NSW 2747, Australia..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hackert, Thilo
    Heidelberg Univ, Dept Surg, D-69047 Heidelberg, Germany..
    Charnley, Richard M.
    Freeman Rd Hosp, Newcastle Upon Tyne NE7 7DN, Tyne & Wear, England..
    Anthoney, Alan
    St James Univ Hosp, Leeds LS9 7TF, W Yorkshire, England..
    Lerch, Markus M.
    Univ Med Greifswald, Dept Med A, D-17489 Greifswald, Germany..
    Mayerle, Julia
    Univ Med Greifswald, Dept Med A, D-17489 Greifswald, Germany.;Klinikum LMU Munchen Grosshadern, Med Klin & Poliklin 2, D-81377 Munich, Germany..
    Palmer, Daniel H.
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Büchler, Markus W.
    Heidelberg Univ, Dept Surg, D-69047 Heidelberg, Germany..
    Ghaneh, Paula
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    Neoptolemos, John P.
    Heidelberg Univ, Dept Surg, D-69047 Heidelberg, Germany..
    Greenhalf, William
    Univ Liverpool, Liverpool Expt Canc Med Ctr, 2nd Floor Sherrington Bldg,Ashton St, Liverpool L69 3GE, Merseyside, England..
    hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA2021In: Cancers, ISSN 2072-6694, Vol. 13, no 22, article id 5758Article in journal (Refereed)
    Abstract [en]

    Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine; median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm; 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine; 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.

    Simple Summary:

    Recent clinical trials suggest that combination therapies that include either gemcitabine or 5-fluorouracil (5-FU) both give significant survival benefits for pancreatic cancer patients. The tumor level of the nucleoside transporter hENT1 is prognostic in patients treated with adjuvant gemcitabine but not adjuvant 5-FU. This work shows for the first time that hENT1 is only predictive of benefit from gemcitabine over 5-FU in patients with low levels of CDA transcript. A choice between adjuvant 5-FU based combination therapies (such as FOLFIRINOX) and gemcitabine-based therapy (e.g., GemCap) could be made based on a combination of hENT1 protein and CDA mRNA measured in a resected tumor.

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  • 347.
    Auvinen, Marja-Kaisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Zhao, Jingcheng
    Karolinska Inst, Dept Med, Clin Epidemiol Div, Stockholm, Sweden..
    Lassen, Ewa
    Umeå Univ Hosp, Dept Clin Immunol & Transfus Med, Umeå, Sweden..
    Lubenow, Norbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Seger Mollen, Agneta
    Linköping Univ, Dept Clin Immunol & Transfus Med, Linköping, Sweden.;Linköping Univ, Dept Biomed & Clin Sci, Linköping, Sweden..
    Watz, Emma
    Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden.;Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden..
    Wikman, Agneta
    Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden.;Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden..
    Edgren, Gustaf
    Karolinska Inst, Dept Med, Clin Epidemiol Div, Stockholm, Sweden.;Soder Sjukhuset, Dept Cardiol, Stockholm, Sweden..
    Patterns of blood use in Sweden from 2008 to 2017: A nationwide cohort study2020In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 60, no 11, p. 2529-2536Article in journal (Refereed)
    Abstract [en]

    Background Transfusion patterns in Sweden have not been characterized on a nationwide level. Study Design and Methods We conducted a nationwide descriptive cohort study in Sweden from 2008 to 2017. Data on blood donors, donations, component manufacture, transfusions, and transfused patients were extracted from Swedish portion of the Scandinavian Donations and Transfusions (SCANDAT3-S) database. Results A total of 708 436 patients received 5 587 684 red cell, plasma, or platelet transfusions during the study period. The age-standardized transfusion rate decreased markedly during the study period for red cell units (from 53 to 39 units/1000 persons) and plasma units (from 11 to 4.9 units/1000 persons), but remained relatively constant for platelet concentrates. The transfusion rate was 30%-40% higher in males than in females in the first year of life, and higher in males over 45 years than in females. Between age 20 and 45, the majority of red cells were transfused to female patients with obstetric indications, whereas trauma was the predominant indication for male contemporaries. In females over 80 years, the largest proportion of red cells were administered due to trauma. Overall, hematological patients received 36% of all platelet units. There were large regional differences in transfusion rates for red cell units, ranging from less than 30 to greater than 60/1000 persons. Conclusion Transfusion rates in Sweden remain high but have decreased strikingly during the study period - with the exception of platelet transfusions. Based on the available data, it is difficult to draw firm conclusions about whether transfusion rates can be further reduced.

  • 348.
    Avenel, Christophe
    et al.
    CADESS Med AB, Uppsala, Sweden.
    Tolf, Anna
    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. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden..
    Carlbom, Ingrid
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. CADESS Med AB, Uppsala, Sweden.
    Glandular Segmentation of Prostate Cancer: An Illustration of How the Choice of Histopathological Stain Is One Key to Success for Computational Pathology2019In: Frontiers in Bioengineering and Biotechnology, E-ISSN 2296-4185, Vol. 7, article id 125Article in journal (Refereed)
    Abstract [en]

    Digital pathology offers the potential for computer-aided diagnosis, significantly reducing the pathologists' workload and paving the way for accurate prognostication with reduced inter-and intra-observer variations. But successful computer-based analysis requires careful tissue preparation and image acquisition to keep color and intensity variations to a minimum. While the human eye may recognize prostate glands with significant color and intensity variations, a computer algorithm may fail under such conditions. Since malignancy grading of prostate tissue according to Gleason or to the International Society of Urological Pathology (ISUP) grading system is based on architectural growth patterns of prostatic carcinoma, automatic methods must rely on accurate identification of the prostate glands. But due to poor color differentiation between stroma and epithelium from the common stain hematoxylin-eosin, no method is yet able to segment all types of glands, making automatic prognostication hard to attain. We address the effect of tissue preparation on glandular segmentation with an alternative stain, Picrosirius red-hematoxylin, which clearly delineates the stromal boundaries, and couple this stain with a color decomposition that removes intensity variation. In this paper we propose a segmentation algorithm that uses image analysis techniques based on mathematical morphology and that can successfully determine the glandular boundaries. Accurate determination of the stromal and glandular morphology enables the identification of the architectural pattern that determine the malignancy grade and classify each gland into its appropriate Gleason grade or ISUP Grade Group. Segmentation of prostate tissue with the new stain and decomposition method has been successfully tested on more than 11000 objects including well-formed glands (Gleason grade 3), cribriform and fine caliber glands (grade 4), and single cells (grade 5) glands.

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  • 349. Ax, Anna-Karin
    et al.
    Husberg, Magnus
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Healthcare Sciences and e-Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Demmelmaier, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness. Department of Sport Science and Physical Education, University of Agder, Kristiansand, Norway.
    Berntsen, Sveinung
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Sjövall, Katarina
    Börjeson, Sussanne
    Nordin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Davidson, Thomas
    Cost-effectiveness of different exercise intensities during oncological treatment in the Phys-Can RCT2023In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 62, no 4, p. 414-421Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cost-effectiveness is important in the prioritisation between interventions in health care. Exercise is cost-effective compared to usual care during oncological treatment; however, the significance of exercise intensity to the cost-effectiveness is unclear. In the present study, we aimed to evaluate the long-term cost-effectiveness of the randomised controlled trial Phys-Can, a six-month exercise programme of high (HI) or low-to-moderate intensity (LMI) during (neo)adjuvant oncological treatment.

    METHODS: A cost-effectiveness analysis was performed, based on 189 participants with breast, colorectal, or prostate cancer (HI: n = 99 and LMI: n = 90) from the Phys-Can RCT in Sweden. Costs were estimated from a societal perspective, and included cost of the exercise intervention, health care utilisation and productivity loss. Health outcomes were assessed as quality-adjusted life-years (QALYs), using EQ-5D-5L at baseline, post intervention and 12 months after the completion of the intervention.

    RESULTS: At 12-month follow-up after the intervention, the total cost per participant did not differ significantly between HI (€27,314) and LMI exercise (€29,788). There was no significant difference in health outcome between the intensity groups. On average HI generated 1.190 QALYs and LMI 1.185 QALYs. The mean incremental cost-effectiveness ratio indicated that HI was cost effective compared with LMI, but the uncertainty was large.

    CONCLUSIONS: We conclude that HI and LMI exercise have similar costs and effects during oncological treatment. Hence, based on cost-effectiveness, we suggest that decision makers and clinicians can consider implementing both HI and LMI exercise programmes and recommend either intensity to the patients with cancer during oncological treatment to facilitate improvement of health.

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  • 350.
    Ax, Anna-Karin
    et al.
    Department of Oncology, Linköping University, Linköping, Sweden; Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
    Husberg, Magnus
    Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Demmelmaier, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness. Department of Sport Science and Physical Education, University of Agder, Kristiansand, Norway.
    Berntsen, Sveinung
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Sjövall, Katarina
    Department of Oncology, Faculty of Health Sciences, Kristianstad University, Kristianstad, Sweden.
    Börjeson, Sussanne
    Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
    Nordin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Davidson, Thomas
    Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
    Long-term resource utilisation and associated costs of exercise during (neo)adjuvant oncological treatment: the Phys-Can project2022In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 61, no 7, p. 888-896Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Exercise during oncological treatment is beneficial to patient health and can counteract the side effects of treatment. Knowledge of the societal costs associated with an exercise intervention, however, is limited. The aims of the present study were to evaluate the long-term resource utilisation and societal costs of an exercise intervention conducted during (neo)adjuvant oncological treatment in a randomised control trial (RCT) versus usual care (UC), and to compare high-intensity (HI) versus low-to-moderate intensity (LMI) exercise in the RCT.

    METHODS: We used data from the Physical Training and Cancer (Phys-Can) project. In the RCT, 577 participants were randomised to HI or to LMI of combined endurance and resistance training for 6 months, during oncological treatment. The project also included 89 participants with UC in a longitudinal observational study. We measured at baseline and after 18 months. Resource utilisation and costs of the exercise intervention, health care, and productivity loss were compared using analyses of covariance (RCT vs. UC) and t test (HI vs. LMI).

    RESULTS: Complete data were available for 619 participants (RCT HI: n = 269, LMI: n = 265, and UC: n = 85). We found no difference in total societal costs between the exercise intervention groups in the RCT and UC. However, participants in the RCT had lower rates of disability pension days (p < .001), corresponding costs (p = .001), and pharmacy costs (p = .018) than the UC group. Nor did we find differences in resource utilisation or costs between HI and LMI exercise int the RCT.

    CONCLUSION: Our study showed no difference in total societal costs between the comprehensive exercise intervention and UC or between the exercise intensities. This suggests that exercise, with its well-documented health benefits during oncological treatment, produces neither additional costs nor savings.

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