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  • 51.
    Acharya, Shikha
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Odontol, Dept Oral Microbiol & Immunol, PO 450, S-40530 Gothenburg, Sweden.
    Jin, Chunsheng
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Med Biochem & Cell Biol, Gothenburg, Sweden.
    Bylund, Johan
    Univ Gothenburg, Sahlgrenska Acad, Inst Odontol, Dept Oral Microbiol & Immunol, PO 450, S-40530 Gothenburg, Sweden.
    Shen, Qiujin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jontell, Mats
    Univ Gothenburg, Sahlgrenska Acad, Inst Odontol, Dept Oral Med & Pathol, Gothenburg, Sweden.
    Carlen, Anette
    Univ Gothenburg, Sahlgrenska Acad, Inst Odontol, Dept Oral Microbiol & Immunol, PO 450, S-40530 Gothenburg, Sweden.
    Karlsson, Niclas G.
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Med Biochem & Cell Biol, Gothenburg, Sweden.
    Reduced sialyl-Lewis(x) on salivary MUC7 from patients with burning mouth syndrome2019In: Molecular Omics, E-ISSN 2515-4184, Vol. 15, no 5, p. 331-339Article in journal (Refereed)
    Abstract [en]

    We analysed and compared MUC7 O-glycosylation and inflammatory biomarkers in saliva from female patients with burning mouth syndrome (BMS) and gender/age-matched controls. Oligosaccharides from salivary MUC7 from BMS and controls were released. Inflammatory mediators were measured by multiplex proximity extension assay. Presence of sialyl-Lewis(x) (Si-Le(x)) epitope on MUC7 was confirmed using Western blot. MUC7 O-glycans and measured inflammatory biomarkers were found to be similar between BMS and controls. However, oligosaccharides sialyl-Lewis(x) (Si-Le(x)) was found to be reduced in samples from BMS patients. Positive correlation (combined patients and controls) was found between levels of C-C motif chemokine 19 (CCL-19) and the amount of core-2 oligosaccharides on MUC7 as well as fractalkine (CX3CL1) and level of sialylation. Patients with BMS were shown to represent a heterogeneous group in terms of inflammatory biomarkers. This indicates that BMS patients could be further stratified on the basis of low-level inflammation. The results furthermore indicate that reduced sialylation of MUC7, particularly Si-Le(x), may be an important feature in patients with BMS. However, the functional aspects and potential involvement in immune regulation of Si-Le(x) remains unclear. Our data suggests a chemokine driven alteration of MUC7 glycosylation.

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  • 52. Achen, M G
    et al.
    Roufail, S
    Domagala, T
    Catimel, B
    Nice, E C
    Geleick, D M
    Murphy, R
    Scott, A M
    Caesar, C
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Alitalo, K
    Stacker, S A
    Monoclonal antibodies to vascular endothelial growth factor-D block its interactions with both VEGF receptor-2 and VEGF receptor-3.2000In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 267, no 9Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor-D (VEGF-D), the most recently discovered mammalian member of the VEGF family, is an angiogenic protein that activates VEGF receptor-2 (VEGFR-2/Flk1/KDR) and VEGFR-3 (Flt4). These receptor tyrosine kinases, localized on vascular and lymphatic endothelial cells, signal for angiogenesis and lymphangiogenesis. VEGF-D consists of a central receptor-binding VEGF homology domain (VHD) and N-terminal and C-terminal propeptides that are cleaved from the VHD to generate a mature, bioactive form consisting of dimers of the VHD. Here we report characterization of mAbs raised to the VHD of human VEGF-D in order to generate VEGF-D antagonists. The mAbs bind the fully processed VHD with high affinity and also bind unprocessed VEGF-D. We demonstrate, using bioassays for the binding and cross-linking of VEGFR-2 and VEGFR-3 and biosensor analysis with immobilized receptors, that one of the mAbs, designated VD1, is able to compete potently with mature VEGF-D for binding to both VEGFR-2 and VEGFR-3 for binding to mature VEGF-D. This indicates that the binding epitopes on VEGF-D for these two receptors may be in close proximity. Furthermore, VD1 blocks the mitogenic response of human microvascular endothelial cells to VEGF-D. The anti-(VEGF-D) mAbs raised to the bioactive region of this growth factor will be powerful tools for analysis of the biological functions of VEGF-D.

  • 53. Adam, A
    et al.
    Robison, J
    Lu, J
    Jose, R
    Badran, N
    Vivas-Buitrago, T
    Rigamonti, D
    Sattar, A
    Omoush, O
    Hammad, M
    Dawood, M
    Maghaslah, M
    Belcher, T
    Carson, K
    Hoffberger, J
    Jusué Torres, I
    Foley, S
    Yasar, S
    Thai, Q A
    Wemmer, J
    Klinge, P
    Al-Mutawa, L
    Al-Ghamdi, H
    Carson, K A
    Asgari, M
    de Zélicourt, D
    Kurtcuoglu, V
    Garnotel, S
    Salmon, S
    Balédent, O
    Lokossou, A
    Page, G
    Balardy, L
    Czosnyka, Z
    Payoux, P
    Schmidt, E A
    Zitoun, M
    Sevestre, M A
    Alperin, N
    Baudracco, I
    Craven, C
    Matloob, S
    Thompson, S
    Haylock Vize, P
    Thorne, L
    Watkins, L D
    Toma, A K
    Bechter, Karl
    Pong, A C
    Jugé, L
    Bilston, L E
    Cheng, S
    Bradley, W
    Hakim, F
    Ramón, J F
    Cárdenas, M F
    Davidson, J S
    García, C
    González, D
    Bermúdez, S
    Useche, N
    Mejía, J A
    Mayorga, P
    Cruz, F
    Martinez, C
    Matiz, M C
    Vallejo, M
    Ghotme, K
    Soto, H A
    Riveros, D
    Buitrago, A
    Mora, M
    Murcia, L
    Bermudez, S
    Cohen, D
    Dasgupta, D
    Curtis, C
    Domínguez, L
    Remolina, A J
    Grijalba, M A
    Whitehouse, K J
    Edwards, R J
    Eleftheriou, A
    Lundin, F
    Fountas, K N
    Kapsalaki, E Z
    Smisson, H F
    Robinson, J S
    Fritsch, M J
    Arouk, W
    Garzon, M
    Kang, M
    Sandhu, K
    Baghawatti, D
    Aquilina, K
    James, G
    Thompson, D
    Gehlen, M
    Schmid Daners, M
    Eklund, A
    Malm, J
    Gomez, D
    Guerra, M
    Jara, M
    Flores, M
    Vío, K
    Moreno, I
    Rodríguez, S
    Ortega, E
    Rodríguez, E M
    McAllister, J P
    Guerra, M M
    Morales, D M
    Sival, D
    Jimenez, A
    Limbrick, D D
    Ishikawa, M
    Yamada, S
    Yamamoto, K
    Junkkari, A
    Häyrinen, A
    Rauramaa, T
    Sintonen, H
    Nerg, O
    Koivisto, A M
    Roine, R P
    Viinamäki, H
    Soininen, H
    Luikku, A
    Jääskeläinen, J E
    Leinonen, V
    Kehler, U
    Lilja-Lund, O
    Kockum, K
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Riklund, K
    Söderström, L
    Hellström, P
    Laurell, K
    Kojoukhova, M
    Sutela, A
    Vanninen, R
    Vanha, K I
    Timonen, M
    Rummukainen, J
    Korhonen, V
    Helisalmi, S
    Solje, E
    Remes, A M
    Huovinen, J
    Paananen, J
    Hiltunen, M
    Kurki, M
    Martin, B
    Loth, F
    Luciano, M
    Luikku, A J
    Hall, A
    Herukka, S K
    Mattila, J
    Lötjönen, J
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Jurjević, I
    Miyajima, M
    Nakajima, M
    Murai, H
    Shin, T
    Kawaguchi, D
    Akiba, C
    Ogino, I
    Karagiozov, K
    Arai, H
    Reis, R C
    Teixeira, M J
    Valêncio, C G
    da Vigua, D
    Almeida-Lopes, L
    Mancini, M W
    Pinto, F C G
    Maykot, R H
    Calia, G
    Tornai, J
    Silvestre, S S S
    Mendes, G
    Sousa, V
    Bezerra, B
    Dutra, P
    Modesto, P
    Oliveira, M F
    Petitto, C E
    Pulhorn, H
    Chandran, A
    McMahon, C
    Rao, A S
    Jumaly, M
    Solomon, D
    Moghekar, A
    Relkin, N
    Hamilton, M
    Katzen, H
    Williams, M
    Bach, T
    Zuspan, S
    Holubkov, R
    Rigamonti, A
    Clemens, G
    Sharkey, P
    Sanyal, A
    Sankey, E
    Rigamonti, K
    Naqvi, S
    Hung, A
    Schmidt, E
    Ory-Magne, F
    Gantet, P
    Guenego, A
    Januel, A C
    Tall, P
    Fabre, N
    Mahieu, L
    Cognard, C
    Gray, L
    Buttner-Ennever, J A
    Takagi, K
    Onouchi, K
    Thompson, S D
    Thorne, L D
    Tully, H M
    Wenger, T L
    Kukull, W A
    Doherty, D
    Dobyns, W B
    Moran, D
    Vakili, S
    Patel, M A
    Elder, B
    Goodwin, C R
    Crawford, J A
    Pletnikov, M V
    Xu, J
    Blitz, A
    Herzka, D A
    Guerrero-Cazares, H
    Quiñones-Hinojosa, A
    Mori, S
    Saavedra, P
    Treviño, H
    Maitani, K
    Ziai, W C
    Eslami, V
    Nekoovaght-Tak, S
    Dlugash, R
    Yenokyan, G
    McBee, N
    Hanley, D F
    Abstracts from Hydrocephalus 2016.2017In: Fluids and Barriers of the CNS, E-ISSN 2045-8118, Vol. 14, no Suppl 1, article id 15Article in journal (Refereed)
  • 54.
    Adamson, L.
    et al.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden..
    Andersson, B.
    Gothenburg Univ, Immunol, Gothenburg, Sweden..
    Kiessling, R.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden..
    Nasman-Glaser, B.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden..
    Karlsson-Parra, Alex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    GMP-production of an allogenic DC-based cancer vaccine (INTUVAX) for treatment of patients with metastatic kidney-or primary liver cancer. Comparison of two production platforms for DC-generation2016In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 46, p. 946-947Article in journal (Other academic)
  • 55. Adamson, R. E.
    et al.
    Frazier, A. A.
    Evans, H.
    Chambers, K. F.
    Schenk, E.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Birnie, R.
    Mitry, R. R.
    Dhawan, A.
    Maitland, N. J.
    In Vitro Primary Cell Culture as a Physiologically Relevant Method for Preclinical Testing of Human Oncolytic Adenovirus2012In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 23, no 2, p. 218-230Article in journal (Refereed)
    Abstract [en]

    Ad[I/PPT-E1A] is an oncolytic adenovirus that specifically kills prostate cells via restricted replication by a prostate-specific regulatory element. Off-target replication of oncolytic adenoviruses would have serious clinical consequences. As a proposed ex vivo test, we describe the assessment of the specificity of Ad[I/PPT-E1A] viral cytotoxicity and replication in human nonprostate primary cells. Four primary nonprostate cell types were selected to mimic the effects of potential in vivo exposure to Ad[I/PPT-E1A] virus: bronchial epithelial cells, urothelial cells, vascular endothelial cells, and hepatocytes. Primary cells were analyzed for Ad[I/PPT-E1A] viral cytotoxicity in MTS assays, and viral replication was determined by hexon titer immunostaining assays to quantify viral hexon protein. The results revealed that at an extreme multiplicity of infection of 500, unlikely to be achieved in vivo, Ad[I/PPT-E1A] virus showed no significant cytotoxic effects in the nonprostate primary cell types apart from the hepatocytes. Transmission electron microscopy studies revealed high levels of Ad[I/PPT-E1A] sequestered in the cytoplasm of these cells. Adenoviral green fluorescent protein reporter studies showed no evidence for nuclear localization, suggesting that the cytotoxic effects of Ad[I/PPT-E1A] in human primary hepatocytes are related to viral sequestration. Also, hepatocytes had increased amounts of coxsackie adenovirus receptor surface protein. Active viral replication was only observed in the permissive primary prostate cells and LNCaP prostate cell line, and was not evident in any of the other nonprostate cells types tested, confirming the specificity of Ad[I/PPT-E1A]. Thus, using a relevant panel of primary human cells provides a convenient and alternative preclinical assay for examining the specificity of conditionally replicating oncolytic adenoviruses in vivo.

  • 56.
    Adhikari, Subash
    et al.
    Macquarie Univ, Dept Biomed Sci, Fac Med Hlth & Human Sci, N Ryde, NSW 2109, Australia..
    Nice, Edouard C.
    Macquarie Univ, Dept Biomed Sci, Fac Med Hlth & Human Sci, N Ryde, NSW 2109, Australia.;Monash Univ, Dept Biochem & Mol Biol, Fac Med Nursing & Hlth Sci, Melbourne, Vic 3800, Australia..
    Deutsch, Eric W.
    Inst Syst Biol, 401 Terry Ave North, Seattle, WA 98109 USA..
    Lane, Lydie
    Univ Geneva, SIB Swiss Inst Bioinformat, Fac Med, CMU, Michel Servet 1, CH-1211 Geneva, Switzerland.;Univ Geneva, Dept Microbiol & Mol Med, Fac Med, CMU, Michel Servet 1, CH-1211 Geneva, Switzerland..
    Omenn, Gilbert S.
    Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Pennington, Stephen R.
    Univ Coll Dublin, UCD Conway Inst Biomol & Biomed Res, Sch Med, Dublin, Ireland..
    Paik, Young-Ki
    Yonsei Proteome Res Ctr, Sudaemoon Ku, 50 Yonsei ro, Seoul 120749, South Korea..
    Overall, Christopher M.
    Univ British Columbia, Fac Dent, Vancouver, BC, Canada..
    Corrales, Fernando J.
    Ctr Nacl Biotecnol CSIC, Funct Prote Lab, Proteored ISCIII, Madrid 28049, Spain..
    Cristea, Ileana M.
    Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA..
    Van Eyk, Jennifer E.
    Smidt Heart Inst, Cedars Sinai Med Ctr, Adv Clin Biosyst Res Inst, Los Angeles, CA 90048 USA..
    Uhlen, Mathias
    KTH Royal Inst Technol, Sch Engn Sci Chem, Sci Life Lab Biotechnol & Hlth, S-17121 Solna, Sweden..
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Chan, Daniel W.
    Johns Hopkins Univ, Dept Pathol & Oncol, Sch Med, Baltimore, MD 21224 USA..
    Bairoch, Amos
    Arizona State Univ, Biodesign Inst, Tempe, AZ USA..
    Waddington, James C.
    Justice, Joshua L.
    Arizona State Univ, Biodesign Inst, Tempe, AZ USA..
    LaBaer, Joshua
    Rodriguez, Henry
    NCI, Off Canc Clin Prote Res, NIH, Bethesda, MD 20892 USA..
    He, Fuchu
    Beijing Inst Life, Beijing Proteome Res Ctr, Natl Ctr Prot Sci Beijing, State Key Lab Prote, Beijing 102206, Peoples R China..
    Kostrzewa, Markus
    Bruker Daltonik GmbH, Microbiol & Diagnost, Fahrenheitstr, D-428359 Bremen, Germany..
    Ping, Peipei
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Cardiac Prote & Signaling Lab, Los Angeles, CA USA..
    Gundry, Rebekah L.
    Univ Nebraska Med Ctr, Div Cardiovasc Med, Cardiom Program, Ctr Heart & Vasc Res, Omaha, NE 68198 USA.;Univ Nebraska Med Ctr, Dept Cellular & Integrat Physiol, Cardiom Program, Ctr Heart & Vasc Res, Omaha, NE 68198 USA..
    Stewart, Peter
    Royal Prince Alfred Hosp, Dept Chem Pathol, Camperdown, NSW, Australia..
    Srivastava, Sanjeeva
    Indian Inst Technol, Powai 400076, Maharashtra, India..
    Srivastava, Sudhir
    Natl Canc Inst, Natl Inst Hlth, Canc Biomarkers Res Branch, Med Ctr Dr, Suite 5E136, Rockville, MD 20852 USA.;Fed Univ Rio Janeiro, Inst Chem, Lab Prote, Athos da Silveria Ramos,149, BR-21941909 Rio De Janeiro, RJ, Brazil..
    Nogueira, Fabio C. S.
    Fed Univ Rio Janeiro, Inst Chem, Prote Unit, Athos da Silveria Ramos,149, BR-21941909 Rio De Janeiro, RJ, Brazil.;Univ Grenoble Alpes, INSERM, CEA, IRIG BGE,U1038, F-38000 Grenoble, France..
    Domont, Gilberto B.
    Univ Grenoble Alpes, INSERM, CEA, IRIG BGE,U1038, F-38000 Grenoble, France..
    Vandenbrouck, Yves
    Univ Colorado, Dept Med Cardiol, Anschutz Med Campus, Aurora, CO USA.;Univ Colorado, Dept Biochem, Anschutz Med Campus, Aurora, CO USA.;Univ Colorado, Dept Mol Genet, Anschutz Med Campus, Aurora, CO USA..
    Lam, Maggie P. Y.
    Univ Colorado, Dept Med, Div Cardiol, Anschutz Med Campus, Aurora, CO USA.;European Bioinformat Inst, Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England..
    Wennersten, Sara
    Univ New South Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia..
    Vizcaino, Juan Antonio
    Univ Calif San Diego, Dept Comp Sci & Engn, 9500 Gilman Dr,Mail Code 0404, San Diego, CA 92093 USA..
    Wilkins, Marc
    Lund Univ, Dept Biomed Engn, Lund, Sweden..
    Schwenk, Jochen M.
    Lundberg, Emma
    Bandeira, Nuno
    Univ Texas Hlth Sci Ctr San Antonio, UT Hlth, Dept Biochem & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA..
    Marko-Varga, Gyorgy
    Univ Rennes, INSERM, EHESP, IREST,UMR S 1085, F-35042 Rennes, France..
    Weintraub, Susan T.
    Leiden Univ, Med Ctr, NL-2333 Leiden, Netherlands..
    Pineau, Charles
    Stanford Sch Med, Dept Genet, Stanford, CA 94305 USA..
    Kusebauch, Ulrike
    Moritz, Robert L.
    Ahn, Seong Beom
    Palmblad, Magnus
    Univ Rennes, INSERM, EHESP, IREST,UMR S 1085, F-35042 Rennes, France..
    Snyder, Michael P.
    Leiden Univ, Med Ctr, NL-2333 Leiden, Netherlands..
    Aebersold, Ruedi
    Stanford Sch Med, Dept Genet, Stanford, CA 94305 USA..
    Baker, Mark S.
    Macquarie Univ, Dept Biomed Sci, Fac Med Hlth & Human Sci, N Ryde, NSW 2109, Australia.;Leiden Univ, Med Ctr, NL-2333 Leiden, Netherlands.;Univ Zurich, Fac Sci, Zurich, Switzerland..
    A high-stringency blueprint of the human proteome2020In: Nature Communications, E-ISSN 2041-1723, Vol. 11, no 1, article id 5301Article in journal (Refereed)
    Abstract [en]

    The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP's tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases. The Human Proteome Project (HPP) was launched in 2010 to enhance accurate annotation of the genome-encoded proteome. Ten years later, the HPP releases its first blueprint of the human proteome, annotating 90% of all known proteins at high-stringency and discussing the implications of proteomics for precision medicine.

    Download full text (pdf)
    FULLTEXT01
  • 57.
    Adjeiwaah, Mary
    et al.
    Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden..
    Bylund, Mikael
    Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden..
    Lundman, Josef A.
    Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden..
    Karlsson, Camilla Thellenberg
    Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden..
    Jonsson, Joakim H.
    Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden..
    Nyholm, Tufve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden.
    Quantifying the Effect of 3T Magnetic Resonance Imaging Residual System Distortions and Patient-Induced Susceptibility Distortions on Radiation Therapy Treatment Planning for Prostate Cancer2018In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 100, no 2, p. 317-324Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate the effect of magnetic resonance system-and patient-induced susceptibility distortions from a 3T scanner on dose distributions for prostate cancers.

    Methods and Materials: Combined displacement fields from the residual system and patient-induced susceptibility distortions were used to distort 17 prostate patient CT images. VMAT dose plans were initially optimized on distorted CT images and the plan parameters transferred to the original patient CT images to calculate a new dose distribution.

    Results: Maximum residual mean distortions of 3.19 mm at a radial distance of 25 cm and maximum mean patient-induced susceptibility shifts of 5.8 mm were found using the lowest bandwidth of 122 Hz per pixel. There was a dose difference of <0.5% between distorted and undistorted treatment plans. The 90% confidence intervals of the mean difference between the dCT and CT treatment plans were all within an equivalence interval of (-0.5, 0.5) for all investigated plan quality measures.

    Conclusions: Patient-induced susceptibility distortions at high field strengths in closed bore magnetic resonance scanners are larger than residual system distortions after using vendor-supplied 3-dimensional correction for the delineated regions studied. However, errors in dose due to disturbed patient outline and shifts caused by patient-induced susceptibility effects are below 0.5%.

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    fulltext
  • 58.
    Adler, Anna
    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 Immunology, Genetics and Pathology, Vascular Biology.
    Initiation of alternative pathway of complement, and development of novel liposomal coatings2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The complement system is a central part of the innate immune system, and is an essential part in recognizing and clearing non/altered-self surfaces in the body. This thesis comprises of projects in which the initiation of the alternative pathway (AP) of complement in the fluid phase as well on various artificial and lipid surfaces has been studied. We have also synthesized and evaluated polymer-lipids as liposome coatings to suppress innate immune activation with focus on complement regulation.

    In paper I we investigated how “C3b-like” C3(H2O) is in regards to form an initial fluid phase AP C3 convertase. Even though C3(H2O) could form a C3 convertase, it was much slower in comparison to the convertase generated by C3b. 

    In paper II the contact activation of C3 on various artificial and lipid surfaces as a potential targeted AP activation pathway was explored. C3 bound selectively to lipid surfaces with negatively charged phospholipids and cholesterol, activated platelets and apoptotic cells. Thus, AP was initiated without prior proteolytic cleavage of C3 nor by preformed C3(H2O) on specific surfaces in a selective manner.

    In paper III and IV, synthetic phosphatidylcholine inspired polymer-lipids consisting of poly(2-methacryloyloxyethyl phosphorylcholine)-conjugated lipids (PMPC-lipids) with different degrees of MPC polymerization were synthesized. The protein adsorption, with focus on complement proteins onto the PMPC-lipids were evaluated, indicating that PMPC-lipids with a longer polymer chain are better to suppress protein adsorption. 

    In paper V fragmented heparin-conjugated (fHep) lipids were investigated for their potential ability to recruit complement regulators to a lipid bilayer surface for complement regulation. This study indicated that fHep-liposomes could recruit the main fluid phase regulator of the AP, factor H, as well as the coagulation regulator antithrombin from human plasma. 

    To conclude, the results from this thesis indicates that C3(H2O) in the fluid phase is a poor initiator of the AP, however contact activated C3 could be targeting activation pathway for the AP. We could also successfully synthesize PMPC-lipids and fHep-lipids for protein suppression and potential complement regulation on coated liposomes. 

    List of papers
    1. Assessment of the Role of C3(H2O) in the Alternative Pathway
    Open this publication in new window or tab >>Assessment of the Role of C3(H2O) in the Alternative Pathway
    Show others...
    2020 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 11, article id 530Article in journal (Refereed) Published
    Abstract [en]

    In this study we investigate the hydrolysis of C3 to C3(H2O) and its ability to initiate activation via the alternative pathway (AP) of the complement system. The internal thioester bond within C3 is hydrolyzed by water in plasma because of its inherent lability. This results in the formation of non-proteolytically activated C3(H2O) which is believed have C3b-like properties and be able to form an active initial fluid phase C3 convertase together with Factor B (FB). The generation of C3(H2O) occurs at a low but constant rate in blood, but the formation can be greatly accelerated by the interaction with various surfaces or nucleophilic and chaotropic agents. In order to more specifically elucidate the relevance of the C3(H2O) for AP activation, formation was induced in solution by repeated freeze/thawing, methylamine or KCSN treatment and named C3(x) where the x can be any of the reactive nucleophilic or chaotropic agents. Isolation and characterization of C3(x) showed that it exists in several forms with varying attributes, where some have more C3b-like properties and can be cleaved by Factor I in the presence of Factor H. However, in common for all these variants is that they are less active partners in initial formation of the AP convertase compared with the corresponding activity of C3b. These observations support the idea that formation of C3(x) in the fluid phase is not a strong initiator of the AP. It is rather likely that the AP mainly acts as an amplification mechanism of complement activation that is triggered by deposition of target-bound C3b molecules generated by other means.

    Place, publisher, year, edition, pages
    FRONTIERS MEDIA SA, 2020
    Keywords
    complement, C3, C3(H2O), C3b, alternative pathway, C3 convertase
    National Category
    Immunology
    Identifiers
    urn:nbn:se:uu:diva-410958 (URN)10.3389/fimmu.2020.00530 (DOI)000526750400001 ()32296436 (PubMedID)
    Funder
    Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519
    Available from: 2020-05-28 Created: 2020-05-28 Last updated: 2024-01-17Bibliographically approved
    2. A targeted binding and activation of native C3 without proteolytic cleavage induced by contact with biosurfaces
    Open this publication in new window or tab >>A targeted binding and activation of native C3 without proteolytic cleavage induced by contact with biosurfaces
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    complement, alternative pathway, contact activated C3, thioester, biosurfaces
    National Category
    Immunology in the medical area
    Research subject
    Immunology; Immunology
    Identifiers
    urn:nbn:se:uu:diva-499228 (URN)
    Available from: 2023-03-24 Created: 2023-03-24 Last updated: 2023-03-28
    3. Synthesis of poly(2-methacryloyloxyethyl phosphorylcholine)-conjugated lipids and their characterization and surface properties of modified liposomes for protein interactions
    Open this publication in new window or tab >>Synthesis of poly(2-methacryloyloxyethyl phosphorylcholine)-conjugated lipids and their characterization and surface properties of modified liposomes for protein interactions
    Show others...
    2021 (English)In: Biomaterials Science, ISSN 2047-4830, E-ISSN 2047-4849, Vol. 9, no 17, p. 5854-5867Article in journal (Refereed) Published
    Abstract [en]

    Poly(ethylene glycol) (PEG) is frequently used for liposomal surface modification. However, as PEGylated liposomes are cleared rapidly from circulation upon repeated injections, substitutes of PEG are being sought. We focused on a water-soluble polymer composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) units, and synthesized poly(MPC) (PMPC)-conjugated lipid (PMPC-lipid) with degrees of MPC polymerization ranging from 10 to 100 (calculated molecular weight: 3 to 30 kDa). In addition, lipids with three different alkyl chains, myristoyl, palmitoyl, and stearoyl, were applied for liposomal surface coating. We studied the interactions of PMPC-lipids with plasma albumin, human complement protein C3 and fibrinogen using a quartz crystal microbalance with energy dissipation, and found that adsorption of albumin, C3 and fibrinogen could be suppressed by coating with PMPC-lipids. In particular, the effect was more pronounced for PMPC chains with higher molecular weight. We evaluated the size, polydispersity index, surface charge, and membrane fluidity of the PMPC-lipid-modified liposomes. We found that the effect of the coating on the dispersion stability was maintained over a long period (98 days). Furthermore, we also demonstrated that the anti-PEG antibody did not interact with PMPC-lipids. Thus, our findings suggest that PMPC-lipids can be used for liposomal coating.

    Place, publisher, year, edition, pages
    Royal Society of ChemistryRoyal Society of Chemistry (RSC), 2021
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-469709 (URN)10.1039/d1bm00570g (DOI)000674760600001 ()34286724 (PubMedID)
    Funder
    Swedish Research Council, 2018-04199Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)VinnovaEU, Horizon 2020
    Available from: 2022-03-14 Created: 2022-03-14 Last updated: 2024-01-15Bibliographically approved
    4. Effect of liposome surface modification with water-soluble phospholipid polymer chain-conjugated lipids on interaction with human plasma proteins
    Open this publication in new window or tab >>Effect of liposome surface modification with water-soluble phospholipid polymer chain-conjugated lipids on interaction with human plasma proteins
    Show others...
    2022 (English)In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 10, no 14, p. 2512-2522Article in journal (Refereed) Published
    Abstract [en]

    Alternative liposome surface coatings for PEGylation to evade the immune system, particularly the complement system, have garnered significant interest. We previously reported poly(2-methacryloyloxyethyl phosphorylcholine) (MPC)-based lipids (PMPC-lipids) and investigated the surface modification of liposomes. In this study, we synthesize PMPC-lipids with polymerization degrees of 10 (MPC10-lipid), 20 (MPC20-lipid), 50 (MPC50-lipid), and 100 (MPC100-lipid), and coated liposomes with 1, 5, or 10 mol% PMPC-lipids (PMPC-liposomes). Non-modified and PEGylated liposomes are used as controls. We investigate the liposome size, surface charge, polydispersity index, and adsorption of plasma proteins to the liposomes post incubation in human plasma containing N,N,N ',N '-ethylenediamine tetraacetic acid (EDTA) or lepirudin by some methods such as sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), western blotting, and automated capillary western blot, with emphasis on the binding of complement protein C3. It is shown that the coating of liposome PMPC-lipids can suppress protein adsorption more effectively with an increase in the molecular weight and molar ratio (1-10 mol%). Apolipoprotein A-I is detected on PMPC-liposomes with a higher molecular weight and higher molar ratio of PMPC-lipids, whereas alpha(2)-macroglobulin is detected on non-modified, PEGylated, and PMPC-liposomes with a shorter polymer chain. In addition, a correlation is shown among the PMPC molecular weight, molar ratio, and C3 binding. The MPC10-lipid cannot inhibit C3 binding efficiently, whereas surface modifications with 10 mol% MPC20-lipid and 5 mol% and 10 mol% MPC50-lipid suppress both total protein and C3 binding. Hence, liposome modification with PMPC-lipids can be a possible strategy for avoiding complement activation.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry (RSC), 2022
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-478350 (URN)10.1039/d1tb01485d (DOI)000704923100001 ()34617092 (PubMedID)
    Funder
    Swedish Research Council, 2018-04199Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519EU, Horizon 2020Vinnova
    Available from: 2022-06-23 Created: 2022-06-23 Last updated: 2023-03-28Bibliographically approved
    5. Regulation of the innate immune system by fragmented heparin-conjugated lipids on lipid bilayered membranes in vitro
    Open this publication in new window or tab >>Regulation of the innate immune system by fragmented heparin-conjugated lipids on lipid bilayered membranes in vitro
    Show others...
    2023 (English)In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 11, no 46, p. 11121-11134Article in journal (Refereed) Published
    Abstract [en]

    Surface modification with heparin is a powerful biomaterial coating strategy that protects against innate immunity activation since heparin is a part of the proteoglycan heparan sulfate on cell surfaces in the body. We studied the heparinization of cellular and material surfaces via lipid conjugation to a heparin-binding peptide. In the present study, we synthesized fragmented heparin (fHep)-conjugated phospholipids and studied their regulation of the innate immune system on a lipid bilayered surface using liposomes. Liposomes have versatile applications, such as drug-delivery systems, due to their ability to carry a wide range of molecules. Owing to their morphological similarity to cell membranes, they can also be used to mimic a simple cell-membrane to study protein–lipid interactions. We investigated the interaction of complement-regulators, factor H and C4b-binding protein (C4BP), as well as the coagulation inhibitor antithrombin (AT), with fHep-lipids on the liposomal surface. Herein, we studied the ability of fHep-lipids to recruit factor H, C4BP, and AT using a quartz crystal microbalance with dissipation monitoring. With dynamic light scattering, we demonstrated that liposomes could be modified with fHep-lipids and were stable up to 60 days at 4 °C. Using a capillary western blot-based method (Wes), we showed that fHep-liposomes could recruit factor H in a model system using purified proteins and assist in the degradation of the active complement protein C3b to iC3b. Furthermore, we found that fHep-liposomes could recruit factor H and AT from human plasma. Therefore, the use of fHep-lipids could be a potential coating for liposomes and cell surfaces to regulate the immune system on the lipid surface.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry, 2023
    National Category
    Immunology in the medical area Biochemistry and Molecular Biology Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-499229 (URN)10.1039/D3TB01721D (DOI)001103685900001 ()37953734 (PubMedID)
    Funder
    The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)Swedish Research Council, 2018-04199EU, Horizon 2020Vinnova
    Note

    Title in the list of papers of Anna Adler's thesis: Regulation of innate immune system by fragmented heparin-conjugated lipids on lipid bilayer membranes

    Available from: 2023-03-24 Created: 2023-03-24 Last updated: 2024-02-08Bibliographically approved
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  • 59.
    Adler, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Fritsch, Marlene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Leneweit, Gero
    Carl Gustav Carus-Institute, Association for the Promotion of Cancer Therapy, Niefern-Öschelbronn, Germany.
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Linnaeus Center of Biomaterials Chemistry, Linnaeus University, SE-391 82 Kalmar, Sweden.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Cellular and Molecular Biotechnology Research Institute (CMB), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central Fifth, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan; Master's/Doctoral Program in Life Science Innovation (T-LSI), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
    Regulation of the innate immune system by fragmented heparin-conjugated lipids on lipid bilayered membranes in vitro2023In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 11, no 46, p. 11121-11134Article in journal (Refereed)
    Abstract [en]

    Surface modification with heparin is a powerful biomaterial coating strategy that protects against innate immunity activation since heparin is a part of the proteoglycan heparan sulfate on cell surfaces in the body. We studied the heparinization of cellular and material surfaces via lipid conjugation to a heparin-binding peptide. In the present study, we synthesized fragmented heparin (fHep)-conjugated phospholipids and studied their regulation of the innate immune system on a lipid bilayered surface using liposomes. Liposomes have versatile applications, such as drug-delivery systems, due to their ability to carry a wide range of molecules. Owing to their morphological similarity to cell membranes, they can also be used to mimic a simple cell-membrane to study protein–lipid interactions. We investigated the interaction of complement-regulators, factor H and C4b-binding protein (C4BP), as well as the coagulation inhibitor antithrombin (AT), with fHep-lipids on the liposomal surface. Herein, we studied the ability of fHep-lipids to recruit factor H, C4BP, and AT using a quartz crystal microbalance with dissipation monitoring. With dynamic light scattering, we demonstrated that liposomes could be modified with fHep-lipids and were stable up to 60 days at 4 °C. Using a capillary western blot-based method (Wes), we showed that fHep-liposomes could recruit factor H in a model system using purified proteins and assist in the degradation of the active complement protein C3b to iC3b. Furthermore, we found that fHep-liposomes could recruit factor H and AT from human plasma. Therefore, the use of fHep-lipids could be a potential coating for liposomes and cell surfaces to regulate the immune system on the lipid surface.

    Download full text (pdf)
    fulltext
  • 60.
    Adler, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Inoue, Yuuki
    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..
    Baba, Teruhiko
    Natl Inst Adv Ind Sci & Technol, Cellular & Mol Biotechnol Res Inst CMB, AIST Tsukuba Cent 5,1-1-1 Higashi, Tsukuba, Ibaraki 3058565, Japan..
    Ishihara, Kazuhiko
    Univ Tokyo, Sch Engn, Dept Mat Engn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan..
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Natl Inst Adv Ind Sci & Technol, Cellular & Mol Biotechnol Res Inst CMB, AIST Tsukuba Cent 5,1-1-1 Higashi, Tsukuba, Ibaraki 3058565, Japan..
    Effect of liposome surface modification with water-soluble phospholipid polymer chain-conjugated lipids on interaction with human plasma proteins2022In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 10, no 14, p. 2512-2522Article in journal (Refereed)
    Abstract [en]

    Alternative liposome surface coatings for PEGylation to evade the immune system, particularly the complement system, have garnered significant interest. We previously reported poly(2-methacryloyloxyethyl phosphorylcholine) (MPC)-based lipids (PMPC-lipids) and investigated the surface modification of liposomes. In this study, we synthesize PMPC-lipids with polymerization degrees of 10 (MPC10-lipid), 20 (MPC20-lipid), 50 (MPC50-lipid), and 100 (MPC100-lipid), and coated liposomes with 1, 5, or 10 mol% PMPC-lipids (PMPC-liposomes). Non-modified and PEGylated liposomes are used as controls. We investigate the liposome size, surface charge, polydispersity index, and adsorption of plasma proteins to the liposomes post incubation in human plasma containing N,N,N ',N '-ethylenediamine tetraacetic acid (EDTA) or lepirudin by some methods such as sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), western blotting, and automated capillary western blot, with emphasis on the binding of complement protein C3. It is shown that the coating of liposome PMPC-lipids can suppress protein adsorption more effectively with an increase in the molecular weight and molar ratio (1-10 mol%). Apolipoprotein A-I is detected on PMPC-liposomes with a higher molecular weight and higher molar ratio of PMPC-lipids, whereas alpha(2)-macroglobulin is detected on non-modified, PEGylated, and PMPC-liposomes with a shorter polymer chain. In addition, a correlation is shown among the PMPC molecular weight, molar ratio, and C3 binding. The MPC10-lipid cannot inhibit C3 binding efficiently, whereas surface modifications with 10 mol% MPC20-lipid and 5 mol% and 10 mol% MPC50-lipid suppress both total protein and C3 binding. Hence, liposome modification with PMPC-lipids can be a possible strategy for avoiding complement activation.

  • 61.
    Adler, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Inoue, Yuuki
    Univ Tokyo, Sch Engn, Dept Mat Engn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan..
    Sato, Yuya
    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.;Natl Inst Adv Ind Sci & Technol, Cellular & Mol Biotechnol Res Inst CMB, Tsukuba Cent Fifth,1-1-1 Higashi, Tsukuba, Ibaraki 3058565, Japan..
    Synthesis of poly(2-methacryloyloxyethyl phosphorylcholine)-conjugated lipids and their characterization and surface properties of modified liposomes for protein interactions2021In: Biomaterials Science, ISSN 2047-4830, E-ISSN 2047-4849, Vol. 9, no 17, p. 5854-5867Article in journal (Refereed)
    Abstract [en]

    Poly(ethylene glycol) (PEG) is frequently used for liposomal surface modification. However, as PEGylated liposomes are cleared rapidly from circulation upon repeated injections, substitutes of PEG are being sought. We focused on a water-soluble polymer composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) units, and synthesized poly(MPC) (PMPC)-conjugated lipid (PMPC-lipid) with degrees of MPC polymerization ranging from 10 to 100 (calculated molecular weight: 3 to 30 kDa). In addition, lipids with three different alkyl chains, myristoyl, palmitoyl, and stearoyl, were applied for liposomal surface coating. We studied the interactions of PMPC-lipids with plasma albumin, human complement protein C3 and fibrinogen using a quartz crystal microbalance with energy dissipation, and found that adsorption of albumin, C3 and fibrinogen could be suppressed by coating with PMPC-lipids. In particular, the effect was more pronounced for PMPC chains with higher molecular weight. We evaluated the size, polydispersity index, surface charge, and membrane fluidity of the PMPC-lipid-modified liposomes. We found that the effect of the coating on the dispersion stability was maintained over a long period (98 days). Furthermore, we also demonstrated that the anti-PEG antibody did not interact with PMPC-lipids. Thus, our findings suggest that PMPC-lipids can be used for liposomal coating.

  • 62.
    Adler, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Manivel, Vivek Anand
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fromell, Karin
    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. Cellular & Mol Biotechnol Res Inst CMB, Natl Inst Adv Ind Sci andTechnol AIST, Tsukuba, 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, Kalmar, Sweden..
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    A Robust Method to Store Complement C3 With Superior Ability to Maintain the Native Structure and Function of the Protein2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 891994Article in journal (Refereed)
    Abstract [en]

    Complement components have a reputation to be very labile. One of the reasons for this is the spontaneous hydrolysis of the internal thioester that is found in both C3 and C4 (but not in C5). Despite the fact that approximate to 20,000 papers have been published on human C3 there is still no reliable method to store the protein without generating C3(H2O), a fact that may have affected studies of the conformation and function of C3, including recent studies on intracellular C3(H2O). The aim of this work was to define the conditions for storage of native C3 and to introduce a robust method that makes C3 almost resistant to the generation of C3(H2O). Here, we precipitated native C3 at the isoelectric point in low ionic strength buffer before freezing the protein at -80 degrees C. The formation of C3(H2O) was determined using cation exchange chromatography and the hemolytic activity of the different C3 preparations was determined using a hemolytic assay for the classical pathway. We show that freezing native C3 in the precipitated form is the best method to avoid loss of function and generation of C3(H2O). By contrast, the most efficient way to consistently generate C3(H2O) was to incubate native C3 in a buffer at pH 11.0. We conclude that we have defined the optimal storage conditions for storing and maintaining the function of native C3 without generating C3(H2O) and also the conditions for consistently generating C3(H2O).

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  • 63.
    Adler, Jeremy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Colour blindness: journals should enable image redisplay2021In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 599, no 7883, p. 32-32Article in journal (Other academic)
  • 64.
    Adler, Jeremy
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala Univ, Dept Immunol Genet & Pathol, BioVis, Uppsala, Sweden..
    Huang, Ainsley
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Med Biochem & Cell Biol, Gothenburg, Sweden..
    Parmryd, Ingela
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Med Biochem & Cell Biol, Gothenburg, Sweden..
    Find_plasma_membrane and measure_plasma_membrane: ImageJ macros for efficient identification of and measurements at and around the plasma membrane2023In: SoftwareX, E-ISSN 2352-7110, Vol. 24, article id 101570Article in journal (Refereed)
    Abstract [en]

    The plasma membrane that encloses cells is difficult to precisely delineate but this is often required for quantitation of fluorescence images. We have created an ImageJ macro that efficiently maps the plasma membrane based on a few imprecisely marked points as the user input, to generate a one-pixel-wide region of interest. A second macro makes measurements from the plasma membrane and optionally from additional regions of interest, offset both inwards and outwards from the plasma membrane. While we are interested in membrane order quantified by generalized polarization, any measurements from two or more channels could easily be implemented.

  • 65.
    Adler, Jeremy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Colocalization Analysis in Fluorescence Microscopy2012In: Cell Imaging Techniques: Methods and Protocols / [ed] Taatjes, Douglas J. & Roth, Jürgen, New York: Humana Press, 2012, p. 97-109Chapter in book (Refereed)
    Abstract [en]

    The measurement of colocalization requires images of two fluorophores that are aligned, with no cross talk, and that the intensities remain within the response range of the microscope. Quantitation depends upon differentiating between the presence and absence of fluorescence, and measurements should be made within biologically relevant regions of interest. Co-occurrence can be measured simply by area or with the M1 and M2 coefficients, and should be compared to random distributions. Correlation analysis should use the Pearson and Spearman coefficients, which need to be measured by replicate based noise corrected correlation to eliminate errors arising from differences in image quality. Ideally, both co-occurrence and correlation should be reported.

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    fulltext
  • 66.
    Adler, Jeremy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Quantification of Colocalisation; Co-Occurrence, Correlation, Empty Voxels, Regions of Interest and Thresholding2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 602A-602AArticle in journal (Other academic)
    Abstract [en]

    Measuring colocalisation is not straightforward with a plethora of coefficients that encapsulate different definitions. Measurements may also be implemented differently. Not only do measurements differ; interconversion is impossible making comparisons challenging. There is a need to cull coefficients and for clear definitions of what precisely is meant by colocalisation in individual studies. Colocalisation can be considered to have two components; co-occurrence which reports whether the fluorophores are found together and correlation which reports on the similarity in their patterns of intensity.

  • 67.
    Adler, Jeremy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Parmryd, Ingela
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Ingela Parmryd, Box 440, S-40530 Gothenburg, Sweden.
    Quantifying colocalization: the MOC is a hybrid coefficient - an uninformative mix of co-occurrence and correlation2019In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 132, no 1, article id UNSP jcs222455Article in journal (Other academic)
  • 68.
    Adler, Jeremy
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Quantifying colocalization: thresholding, void voxels and the H-coef2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 11, p. e111983-Article in journal (Refereed)
    Abstract [en]

    A critical step in the analysis of images is identifying the area of interest e.g. nuclei. When the nuclei are brighter than the remainder of the image an intensity can be chosen to identify the nuclei. Intensity thresholding is complicated by variations in the intensity of individual nuclei and their intensity relative to their surroundings. To compensate thresholds can be based on local rather than global intensities. By testing local thresholding methods we found that the local mean performed poorly while the Phansalkar method and a new method based on identifying the local background were superior. A new colocalization coefficient, the Hcoef, highlights a number of controversial issues. (i) Are molecular interactions measurable (ii) whether to include voxels without fluorophores in calculations, and (iii) the meaning of negative correlations. Negative correlations can arise biologically (a) because the two fluorophores are in different places or (b) when high intensities of one fluorophore coincide with low intensities of a second. The cases are distinct and we argue that it is only relevant to measure correlation using pixels that contain both fluorophores and, when the fluorophores are in different places, to just report the lack of co-occurrence and omit these uninformative negative correlation. The Hcoef could report molecular interactions in a homogenous medium. But biology is not homogenous and distributions also reflect physico-chemical properties, targeted delivery and retention. The Hcoef actually measures a mix of correlation and co-occurrence, which makes its interpretation problematic and in the absence of a convincing demonstration we advise caution, favouring separate measurements of correlation and of co-occurrence.

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  • 69.
    Adolphe, Christelle
    et al.
    Univ Queensland, Univ Queensland Diamantina Inst, Woolloongabba, Qld 4102, Australia..
    Millar, Amanda
    Univ Queensland, Univ Queensland Diamantina Inst, Woolloongabba, Qld 4102, Australia..
    Kojic, Marija
    Univ Queensland, Univ Queensland Diamantina Inst, Woolloongabba, Qld 4102, Australia..
    Barkauskas, Deborah S.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Sundström, Anders
    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.
    Swartling, Fredrik J.
    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.
    Hediyeh-Zadeh, Soroor
    Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic, Australia.;Univ Melbourne, Fac Med Dent & Hlth Sci, Dept Med Biol, Melbourne, Vic, Australia..
    Tan, Chin Wee
    Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic, Australia.;Univ Melbourne, Fac Med Dent & Hlth Sci, Dept Med Biol, Melbourne, Vic, Australia..
    Davis, Melissa J.
    Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic, Australia.;Univ Melbourne, Fac Med Dent & Hlth Sci, Dept Med Biol, Melbourne, Vic, Australia.;Univ Melbourne, Fac Med Dent & Hlth Sci, Dept Clin Pathol, Melbourne, Vic, Australia..
    Genovesi, Laura A.
    Univ Queensland, Univ Queensland Diamantina Inst, Woolloongabba, Qld 4102, Australia..
    Wainwright, Brandon J.
    Univ Queensland, Univ Queensland Diamantina Inst, Woolloongabba, Qld 4102, Australia..
    SOX9 Defines Distinct Populations of Cells in SHH Medulloblastoma but Is Not Required for Math1-Driven Tumor Formation2021In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 19, no 11, p. 1831-1839Article in journal (Refereed)
    Abstract [en]

    Medulloblastoma is the most common malignant pediatric brain tumor and there is an urgent need for molecularly targeted and subgroup-specific therapies. The stem cell factor SOX9, has been proposed as a potential therapeutic target for the treatment of Sonic Hedgehog medulloblastoma (SHH-MB) subgroup tumors, given its role as a downstream target of Hedgehog signaling and in functionally promoting SHH-MB metastasis and treatment resistance. However, the functional requirement for SOX9 in the genesis of medulloblastoma remains to be determined. Here we report a previously undocumented level of SOX9 expression exclusively in proliferating granule cell precursors ( GCP) of the postnatal mouse cerebellum, which function as the medulloblastoma-initiating cells of SHH-MBs. Wild-type GCPs express comparatively lower levels of SOX9 than neural stem cells and mature astroglia and SOX9(low) GCP-like tumor cells constitute the bulk of both infant (Math1Cre: Ptch1(lox/lox)) and adult (Ptch1(LacZ/+)) SHH-MB mouse models. Human medulloblastoma single-cell RNA data analyses reveal three distinct SOX9 populations present in SHH-MB and noticeably absent in other medulloblastoma subgroups: SOX9(+)MATH1(+) (GCP), SOX9(+)GFAP(+) (astrocytes) and SOX9(+)MATH1(+)GFAP(+) (potential tumor-derived astrocytes). To functionally address whether SOX9 is required as a downstream effector of Hedgehog signaling in medulloblastoma tumor cells, we ablated Sox9 using a Math1Cre model system. Surprisingly, targeted ablation of Sox9 in GCPs (Math1Cre:Sox9(lox/lox)) revealed no overt phenotype and loss of Sox9 in SHH-MB (Math1Cre:Ptch1(lox/lox);Sox9(lox/lox)) does not affect tumor formation.

  • 70.
    Adrian-Martinez, S.
    et al.
    Univ Politecn Valencia, Inst Invest Gestio Integrada Zones Costaneres IGI, C Paranimf 1, E-46730 Gandia, Spain..
    Albert, A.
    Univ Haute Alsace, GRPHE, Inst Univ Technol Colmar, 34 Rue Grillenbreit BP, F-50568 Colmar, France..
    Andre, M.
    Tech Univ Catalonia, Lab Appl Bioacoust, E-08800 Barcelona, Spain..
    Anton, G.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Ardid, M.
    Univ Politecn Valencia, Inst Invest Gestio Integrada Zones Costaneres IGI, C Paranimf 1, E-46730 Gandia, Spain..
    Aubert, J. -J
    Baret, B.
    Univ Paris Diderot, CNRS, IN2P3, Observ Paris,Sorbonne Paris Cite,CEA IRFU,APC, F-75205 Paris, France..
    Barrios-Marti, J.
    Univ Valencia, CSIC, IFIC Inst Fis Corpuscular, Edificios Invest Paterna, Apdo Correos 22085, E-46071 Valencia, Spain..
    Basa, S.
    LAM Lab Astrophys Marseille, Pole Etoile Site Chateau Gombert, Rue Frederic Joliot Curie 38, F-13388 Marseille, France..
    Bertin, V.
    Aix Marseille Univ, CNRS, IN2P3, CPPM UMR 7346, F-13288 Marseille, France..
    Biagi, S.
    Ist Nazl Fis Nucl, Lab Nazl Sud, Via S Sofia 62, I-95123 Catania, Italy..
    Bormuth, R.
    Nikhef, Sci Pk, Amsterdam, Netherlands.;Leiden Univ, Huygens Kamerlingh Onnes Lab, NL-2300 RA Leiden, Netherlands..
    Bouwhuis, M. C.
    Nikhef, Sci Pk, Amsterdam, Netherlands..
    Bruijn, R.
    Nikhef, Sci Pk, Amsterdam, Netherlands.;Univ Amsterdam, Inst Hoge Energie Fys, Sci Pk 105, NL-1098 XG Amsterdam, Netherlands..
    Brunner, J.
    Aix Marseille Univ, CNRS, IN2P3, CPPM UMR 7346, F-13288 Marseille, France..
    Busto, J.
    Aix Marseille Univ, CNRS, IN2P3, CPPM UMR 7346, F-13288 Marseille, France..
    Capone, A.
    Ist Nazl Fis Nucl, Sez Roma, Ple Aldo Moro 2, I-00185 Rome, Italy.;Univ Roma La Sapienza, Dipartimento Fis, Ple Aldo Moro 2, I-00185 Rome, Italy..
    Caramete, L.
    Inst Space Sci, RO-077125 Bucharest, Magurele, Romania..
    Carr, J.
    Aix Marseille Univ, CNRS, IN2P3, CPPM UMR 7346, F-13288 Marseille, France..
    Chiarusi, T.
    Ist Nazl Fis Nucl, Sez Bologna, Viale Berti Pichat 6-2, I-40127 Bologna, Italy..
    Circella, M.
    Ist Nazl Fis Nucl, Sez Bari, Via E Orabona 4, I-70126 Bari, Italy..
    Coniglione, R.
    Ist Nazl Fis Nucl, Lab Nazl Sud, Via S Sofia 62, I-95123 Catania, Italy..
    Costantini, H.
    Aix Marseille Univ, CNRS, IN2P3, CPPM UMR 7346, F-13288 Marseille, France..
    Coyle, P.
    Aix Marseille Univ, CNRS, IN2P3, CPPM UMR 7346, F-13288 Marseille, France..
    Creusot, A.
    Univ Paris Diderot, CNRS, IN2P3, Observ Paris,Sorbonne Paris Cite,CEA IRFU,APC, F-75205 Paris, France..
    Dekeyser, I.
    Aix Marseille Univ, Mediterranean Inst Oceanog, F-13288 Marseille 9, France.;Univ Sud Toulon Var, CNRS INSU IRD 110, F-83957 La Garde, France..
    Deschamps, A.
    Univ Nice Sophia Antipolis, Geoazur, CNRS, Observ Cote Azur,IRD, Sophia Antipolis, France..
    De Bonis, G.
    Ist Nazl Fis Nucl, Sez Roma, Ple Aldo Moro 2, I-00185 Rome, Italy.;Univ Roma La Sapienza, Dipartimento Fis, Ple Aldo Moro 2, I-00185 Rome, Italy..
    Distefano, C.
    Ist Nazl Fis Nucl, Lab Nazl Sud, Via S Sofia 62, I-95123 Catania, Italy..
    Donzaud, C.
    Univ Paris Diderot, CNRS, IN2P3, Observ Paris,Sorbonne Paris Cite,CEA IRFU,APC, F-75205 Paris, France.;Univ Paris 11, F-91405 Orsay, France..
    Dornic, D.
    Aix Marseille Univ, CNRS, IN2P3, CPPM UMR 7346, F-13288 Marseille, France..
    Drouhin, D.
    Univ Haute Alsace, GRPHE, Inst Univ Technol Colmar, 34 Rue Grillenbreit BP, F-50568 Colmar, France..
    Dumas, A.
    Univ Clermont Ferrand, Univ Blaise Pascal, CNRS, Phys Corpusculaire Lab,IN2P3, BP 10448, F-63000 Clermont Ferrand, France..
    Eberl, T.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Elsaesser, D.
    Univ Wurzburg, Inst Theoret Phys & Astrophys, Emil Fischer Str 31, D-97074 Wrzburg, Germany..
    Enzenhoefer, A.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Fehn, K.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Felis, I.
    Univ Politecn Valencia, Inst Invest Gestio Integrada Zones Costaneres IGI, C Paranimf 1, E-46730 Gandia, Spain..
    Fermani, P.
    Ist Nazl Fis Nucl, Sez Roma, Ple Aldo Moro 2, I-00185 Rome, Italy.;Univ Roma La Sapienza, Dipartimento Fis, Ple Aldo Moro 2, I-00185 Rome, Italy..
    Folger, F.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Fusco, L. A.
    Ist Nazl Fis Nucl, Sez Bologna, Viale Berti Pichat 6-2, I-40127 Bologna, Italy.;Univ Bologna, Dipartimento Fis & Astron, Viale Berti Pichat 6-2, I-40127 Bologna, Italy..
    Galata, S.
    Univ Paris Diderot, CNRS, IN2P3, Observ Paris,Sorbonne Paris Cite,CEA IRFU,APC, F-75205 Paris, France..
    Gay, P.
    Univ Clermont Ferrand, Univ Blaise Pascal, CNRS, Phys Corpusculaire Lab,IN2P3, BP 10448, F-63000 Clermont Ferrand, France..
    Geisselsoeder, S.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Geyer, K.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Giordano, V.
    Ist Nazl Fis Nucl, Sez Catania, Viale Andrea Doria 6, I-95125 Catania, Italy..
    Gleixner, A.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Gracia-Ruiz, R.
    Univ Paris Diderot, CNRS, IN2P3, Observ Paris,Sorbonne Paris Cite,CEA IRFU,APC, F-75205 Paris, France..
    Graf, K.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Hallmann, S.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    van Haren, H.
    Royal Netherlands Inst Sea Res NIOZ, Landsdiep 4, NL-1797 SZ Texel, Netherlands..
    Heijboer, A. J.
    Nikhef, Sci Pk, Amsterdam, Netherlands..
    Hello, Y.
    Univ Nice Sophia Antipolis, Geoazur, CNRS, Observ Cote Azur,IRD, Sophia Antipolis, France..
    Hernandez-Rey, J. J.
    Univ Valencia, CSIC, IFIC Inst Fis Corpuscular, Edificios Invest Paterna, Apdo Correos 22085, E-46071 Valencia, Spain..
    Hoessl, J.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Hofestaedt, J.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Hugon, C.
    Ist Nazl Fis Nucl, Sez Genova, Via Dodecaneso 33, I-16146 Genoa, Italy.;Univ Genoa, Dipartimento Fis, Via Dodecaneso 33, I-16146 Genoa, Italy..
    James, C. W.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    de Jong, M.
    Nikhef, Sci Pk, Amsterdam, Netherlands.;Leiden Univ, Huygens Kamerlingh Onnes Lab, NL-2300 RA Leiden, Netherlands..
    Kadler, M.
    Univ Wurzburg, Inst Theoret Phys & Astrophys, Emil Fischer Str 31, D-97074 Wrzburg, Germany..
    Kalekin, O.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Katz, U.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Kiessling, D.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Kooijman, P.
    Nikhef, Sci Pk, Amsterdam, Netherlands.;Univ Amsterdam, Inst Hoge Energie Fys, Sci Pk 105, NL-1098 XG Amsterdam, Netherlands.;Univ Utrecht, Fac Betawetenschappen, Princetonplein 5, NL-3584 CC Utrecht, Netherlands..
    Kouchner, A.
    Univ Paris Diderot, CNRS, IN2P3, Observ Paris,Sorbonne Paris Cite,CEA IRFU,APC, F-75205 Paris, France..
    Kreter, M.
    Univ Wurzburg, Inst Theoret Phys & Astrophys, Emil Fischer Str 31, D-97074 Wrzburg, Germany..
    Kreykenbohm, I.
    Univ Erlangen Nurnberg, Dr Remeis Sternwarte, Sternwartstr 7, D-96049 Bamberg, Germany.;Univ Erlangen Nurnberg, ECAP, Sternwartstr 7, D-96049 Bamberg, Germany..
    Kulikovskiy, V.
    Ist Nazl Fis Nucl, Lab Nazl Sud, Via S Sofia 62, I-95123 Catania, Italy.;Moscow MV Lomonosov State Univ, Skobeltsyn Inst Nucl Phys, Moscow 119991, Russia..
    Lahmann, R.
    Lefevre, D.
    Aix Marseille Univ, Mediterranean Inst Oceanog, F-13288 Marseille 9, France.;Univ Sud Toulon Var, CNRS INSU IRD 110, F-83957 La Garde, France..
    Leonora, E.
    Ist Nazl Fis Nucl, Sez Catania, Viale Andrea Doria 6, I-95125 Catania, Italy.;Univ Catania, Dipartimento Fis & Astron, Viale Andrea Doria 6, I-95125 Catania, Italy..
    Loucatos, S.
    CEA Saclay, Serv Phys Particules, Inst Rech Fondament Univers, Direct Sci Matiere, F-91191 Gif Sur Yvette, France..
    Marcelin, M.
    LAM Lab Astrophys Marseille, Pole Etoile Site Chateau Gombert, Rue Frederic Joliot Curie 38, F-13388 Marseille, France..
    Margiotta, A.
    Ist Nazl Fis Nucl, Sez Bologna, Viale Berti Pichat 6-2, I-40127 Bologna, Italy.;Univ Bologna, Dipartimento Fis & Astron, Viale Berti Pichat 6-2, I-40127 Bologna, Italy..
    Marinelli, A.
    Ist Nazl Fis Nucl, Sez Pisa, Largo B Pontecorvo 3, I-56127 Pisa, Italy.;Univ Pisa, Dipartimento Fis, Largo B Pontecorvo 3, I-56127 Pisa, Italy..
    Martinez-Mora, J. A.
    Univ Politecn Valencia, Inst Invest Gestio Integrada Zones Costaneres IGI, C Paranimf 1, E-46730 Gandia, Spain..
    Mathieu, A.
    Aix Marseille Univ, CNRS, IN2P3, CPPM UMR 7346, F-13288 Marseille, France..
    Michael, T.
    Nikhef, Sci Pk, Amsterdam, Netherlands..
    Migliozzi, P.
    Ist Nazl Fis Nucl, Sez Napoli, Via Cintia, I-80126 Naples, Italy..
    Moussa, A.
    Univ Mohammed 1, Lab Phys Matter & Radiat, BP 717, Oujda 6000, Morocco..
    Mueller, C.
    Univ Wurzburg, Inst Theoret Phys & Astrophys, Emil Fischer Str 31, D-97074 Wrzburg, Germany..
    Nezri, E.
    LAM Lab Astrophys Marseille, Pole Etoile Site Chateau Gombert, Rue Frederic Joliot Curie 38, F-13388 Marseille, France..
    Pavalas, G. E.
    Inst Space Sci, RO-077125 Bucharest, Magurele, Romania..
    Pellegrino, C.
    Ist Nazl Fis Nucl, Sez Bologna, Viale Berti Pichat 6-2, I-40127 Bologna, Italy.;Univ Bologna, Dipartimento Fis & Astron, Viale Berti Pichat 6-2, I-40127 Bologna, Italy..
    Perrina, C.
    Ist Nazl Fis Nucl, Sez Roma, Ple Aldo Moro 2, I-00185 Rome, Italy.;Univ Roma La Sapienza, Dipartimento Fis, Ple Aldo Moro 2, I-00185 Rome, Italy..
    Piattelli, P.
    Ist Nazl Fis Nucl, Lab Nazl Sud, Via S Sofia 62, I-95123 Catania, Italy..
    Popa, V.
    Inst Space Sci, RO-077125 Bucharest, Magurele, Romania..
    Pradier, T.
    Univ Strasbourg, IPHC, 23 Rue Loess, F-67037 Strasbourg, France.;CNRS, UMR7178, F-67037 Strasbourg, France..
    Racca, C.
    Univ Haute Alsace, GRPHE, Inst Univ Technol Colmar, 34 Rue Grillenbreit BP, F-50568 Colmar, France..
    Riccobene, G.
    Ist Nazl Fis Nucl, Lab Nazl Sud, Via S Sofia 62, I-95123 Catania, Italy..
    Richter, R.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Roensch, K.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Saldana, M.
    Univ Politecn Valencia, Inst Invest Gestio Integrada Zones Costaneres IGI, C Paranimf 1, E-46730 Gandia, Spain..
    Samtleben, D. F. E.
    Nikhef, Sci Pk, Amsterdam, Netherlands.;Leiden Univ, Huygens Kamerlingh Onnes Lab, NL-2300 RA Leiden, Netherlands..
    Sanchez-Losa, A.
    Univ Valencia, CSIC, IFIC Inst Fis Corpuscular, Edificios Invest Paterna, Apdo Correos 22085, E-46071 Valencia, Spain..
    Sanguineti, M.
    Ist Nazl Fis Nucl, Sez Genova, Via Dodecaneso 33, I-16146 Genoa, Italy.;Univ Genoa, Dipartimento Fis, Via Dodecaneso 33, I-16146 Genoa, Italy..
    Sapienza, P.
    Ist Nazl Fis Nucl, Lab Nazl Sud, Via S Sofia 62, I-95123 Catania, Italy..
    Schmid, J.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Schnabel, J.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Schussler, F.
    CEA Saclay, Serv Phys Particules, Inst Rech Fondament Univers, Direct Sci Matiere, F-91191 Gif Sur Yvette, France..
    Seitz, T.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Sieger, C.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Spurio, M.
    Ist Nazl Fis Nucl, Sez Bologna, Viale Berti Pichat 6-2, I-40127 Bologna, Italy.;Univ Bologna, Dipartimento Fis & Astron, Viale Berti Pichat 6-2, I-40127 Bologna, Italy..
    Steijger, J. J. M.
    Nikhef, Sci Pk, Amsterdam, Netherlands..
    Stolarczyk, Th.
    CEA Saclay, Serv Phys Particules, Inst Rech Fondament Univers, Direct Sci Matiere, F-91191 Gif Sur Yvette, France..
    Taiuti, M.
    Ist Nazl Fis Nucl, Sez Genova, Via Dodecaneso 33, I-16146 Genoa, Italy.;Univ Genoa, Dipartimento Fis, Via Dodecaneso 33, I-16146 Genoa, Italy..
    Tamburini, C.
    Aix Marseille Univ, Mediterranean Inst Oceanog, F-13288 Marseille 9, France.;Univ Sud Toulon Var, CNRS INSU IRD 110, F-83957 La Garde, France..
    Trovato, A.
    Ist Nazl Fis Nucl, Lab Nazl Sud, Via S Sofia 62, I-95123 Catania, Italy..
    Tselengidou, M.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany.;Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, D-91058 Erlangen, Germany..
    Tonnis, C.
    Univ Valencia, CSIC, IFIC Inst Fis Corpuscular, Edificios Invest Paterna, Apdo Correos 22085, E-46071 Valencia, Spain..
    Vallage, B.
    CEA Saclay, Serv Phys Particules, Inst Rech Fondament Univers, Direct Sci Matiere, F-91191 Gif Sur Yvette, France..
    Vallee, C.
    Aix Marseille Univ, CNRS, IN2P3, CPPM UMR 7346, F-13288 Marseille, France..
    Van Elewyck, V.
    Univ Paris Diderot, CNRS, IN2P3, Observ Paris,Sorbonne Paris Cite,CEA IRFU,APC, F-75205 Paris, France..
    Visser, E.
    Nikhef, Sci Pk, Amsterdam, Netherlands..
    Vivolo, D.
    Ist Nazl Fis Nucl, Sez Napoli, Via Cintia, I-80126 Naples, Italy.;Univ Naples Federico II, Dipartimento Fis, Via Cintia, I-80126 Naples, Italy..
    Wagner, S.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, Erwin Rommel Str 1, D-91058 Erlangen, Germany..
    Wilms, J.
    Univ Erlangen Nurnberg, Dr Remeis Sternwarte, Sternwartstr 7, D-96049 Bamberg, Germany.;Univ Erlangen Nurnberg, ECAP, Sternwartstr 7, D-96049 Bamberg, Germany..
    Zornoza, J. D.
    Univ Valencia, CSIC, IFIC Inst Fis Corpuscular, Edificios Invest Paterna, Apdo Correos 22085, E-46071 Valencia, Spain..
    Zuniga, J.
    Univ Valencia, CSIC, IFIC Inst Fis Corpuscular, Edificios Invest Paterna, Apdo Correos 22085, E-46071 Valencia, Spain..
    Aartsen, M. G.
    Univ Adelaide, Dept Phys, Adelaide, SA 5005, Australia..
    Abraham, K.
    Tech Univ Munich, D-85748 Garching, Germany..
    Ackermann, M.
    DESY, D-15735 Zeuthen, Germany..
    Adams, J.
    Univ Canterbury, Dept Phys & Astron, Private Bag 4800, Christchurch, New Zealand..
    Aguilar, J. A.
    Univ Libre Bruxelles, Sci Fac CP230, B-1050 Brussels, Belgium..
    Ahlers, M.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Ahrens, M.
    Stockholm Univ, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.;Stockholm Univ, Dept Phys, SE-10691 Stockholm, Sweden..
    Altmann, D.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, D-91058 Erlangen, Germany..
    Anderson, T.
    Penn State Univ, Dept Phys, 104 Davey Lab, University Pk, PA 16802 USA..
    Ansseau, I.
    Univ Libre Bruxelles, Sci Fac CP230, B-1050 Brussels, Belgium..
    Archinger, M.
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Arguelles, C.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Arlen, T. C.
    Penn State Univ, Dept Phys, 104 Davey Lab, University Pk, PA 16802 USA..
    Auffenberg, J.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Bai, X.
    South Dakota Sch Mines & Technol, Dept Phys, Rapid City, SD 57701 USA..
    Barwick, S. W.
    Univ Calif Irvine, Dept Phys & Astron, Irvine, CA 92697 USA..
    Baum, V.
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Bay, R.
    Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA..
    Beatty, J. J.
    Ohio State Univ, Dept Phys, 174 W 18th Ave, Columbus, OH 43210 USA.;Ohio State Univ, Ctr Cosmol & Astroparticle Phys, Columbus, OH 43210 USA.;Ohio State Univ, Dept Astron, 174 W 18th Ave, Columbus, OH 43210 USA..
    Tjus, J. Becker
    Ruhr Univ Bochum, Fak Phys & Astron, D-44780 Bochum, Germany..
    Becker, K. -H
    Beiser, E.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Berghaus, P.
    DESY, D-15735 Zeuthen, Germany..
    Berley, D.
    Univ Maryland, Dept Phys, College Pk, MD 20742 USA..
    Bernardini, E.
    Tech Univ Munich, D-85748 Garching, Germany.;DESY, D-15735 Zeuthen, Germany..
    Bernhard, A.
    Besson, D. Z.
    Univ Kansas, Dept Phys & Astron, Lawrence, KS 66045 USA..
    Binder, G.
    Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.;Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA..
    Bindig, D.
    Univ Wuppertal, Dept Phys, D-42119 Wuppertal, Germany..
    Bissok, M.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Blaufuss, E.
    Univ Maryland, Dept Phys, College Pk, MD 20742 USA..
    Blumenthal, J.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Boersma, David J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Bohm, C.
    Stockholm Univ, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.;Stockholm Univ, Dept Phys, SE-10691 Stockholm, Sweden..
    Boerner, M.
    Tech Univ Dortmund, Dept Phys, D-44221 Dortmund, Germany..
    Bos, F.
    Ruhr Univ Bochum, Fak Phys & Astron, D-44780 Bochum, Germany..
    Bose, D.
    Sungkyunkwan Univ, Dept Phys, Suwon 440746, South Korea..
    Boeser, S.
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Botner, Olga
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Braun, J.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Brayeur, L.
    Vrije Univ Brussel, Dienst ELEM, B-1050 Brussels, Belgium..
    Bretz, H. -P
    Buzinsky, N.
    Univ Alberta, Dept Phys, Edmonton, AB T6G 2E1, Canada..
    Casey, J.
    Georgia Inst Technol, Sch Phys, Atlanta, GA 30332 USA.;Georgia Inst Technol, Ctr Relativist Astrophys, Atlanta, GA 30332 USA..
    Casier, M.
    Vrije Univ Brussel, Dienst ELEM, B-1050 Brussels, Belgium..
    Cheung, E.
    Univ Maryland, Dept Phys, College Pk, MD 20742 USA..
    Chirkin, D.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Christov, A.
    Univ Geneva, Dept Phys Nucl & Corpusculaire, CH-1211 Geneva, Switzerland..
    Clark, K.
    Univ Toronto, Dept Phys, 60 St George St, Toronto, ON M5S 1A7, Canada..
    Classen, L.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, D-91058 Erlangen, Germany..
    Coenders, S.
    Tech Univ Munich, D-85748 Garching, Germany..
    Cowen, D. F.
    Penn State Univ, Dept Phys, 104 Davey Lab, University Pk, PA 16802 USA.;Penn State Univ, Dept Astron & Astrophys, 525 Davey Lab, University Pk, PA 16802 USA..
    Silva, A. H. Cruz
    DESY, D-15735 Zeuthen, Germany..
    Daughhetee, J.
    Georgia Inst Technol, Sch Phys, Atlanta, GA 30332 USA.;Georgia Inst Technol, Ctr Relativist Astrophys, Atlanta, GA 30332 USA..
    Davis, J. C.
    Ohio State Univ, Dept Phys, 174 W 18th Ave, Columbus, OH 43210 USA.;Ohio State Univ, Ctr Cosmol & Astroparticle Phys, Columbus, OH 43210 USA..
    Day, M.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    de Andre, J. P. A. M.
    Michigan State Univ, Dept Phys & Astron, E Lansing, MI 48824 USA..
    De Clercq, C.
    Vrije Univ Brussel, Dienst ELEM, B-1050 Brussels, Belgium..
    Rosendo, E. del Pino
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Dembinski, H.
    Univ Delaware, Bartol Res Inst, Newark, DE 19716 USA.;Univ Delaware, Dept Phys & Astron, Newark, DE 19716 USA..
    De Ridder, S.
    Univ Ghent, Dept Phys & Astron, B-9000 Ghent, Belgium..
    Desiati, P.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    de Vries, K. D.
    Vrije Univ Brussel, Dienst ELEM, B-1050 Brussels, Belgium..
    de Wasseige, G.
    Vrije Univ Brussel, Dienst ELEM, B-1050 Brussels, Belgium..
    de With, M.
    Humboldt Univ, Inst Phys, D-12489 Berlin, Germany..
    De Young, T.
    Michigan State Univ, Dept Phys & Astron, E Lansing, MI 48824 USA..
    Diaz-Velez, J. C.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    di Lorenzo, V.
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Dumm, J. P.
    Stockholm Univ, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.;Stockholm Univ, Dept Phys, SE-10691 Stockholm, Sweden..
    Dunkman, M.
    Penn State Univ, Dept Phys, 104 Davey Lab, University Pk, PA 16802 USA..
    Eberhardt, B.
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Ehrhardt, T.
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Eichmann, B.
    Ruhr Univ Bochum, Fak Phys & Astron, D-44780 Bochum, Germany..
    Euler, Sebastian
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Evenson, P. A.
    Univ Delaware, Bartol Res Inst, Newark, DE 19716 USA.;Univ Delaware, Dept Phys & Astron, Newark, DE 19716 USA..
    Fahey, S.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Fazely, A. R.
    Southern Univ, Dept Phys, Baton Rouge, LA 70813 USA..
    Feintzeig, J.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Felde, J.
    Univ Maryland, Dept Phys, College Pk, MD 20742 USA..
    Filimonov, K.
    Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA..
    Finley, C.
    Stockholm Univ, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.;Stockholm Univ, Dept Phys, SE-10691 Stockholm, Sweden..
    Fischer-Wasels, T.
    Univ Wuppertal, Dept Phys, D-42119 Wuppertal, Germany..
    Flis, S.
    Stockholm Univ, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.;Stockholm Univ, Dept Phys, SE-10691 Stockholm, Sweden..
    Foesig, C. -C
    Fuchs, T.
    Tech Univ Dortmund, Dept Phys, D-44221 Dortmund, Germany..
    Gaisser, T. K.
    Univ Delaware, Bartol Res Inst, Newark, DE 19716 USA.;Univ Delaware, Dept Phys & Astron, Newark, DE 19716 USA..
    Gaior, R.
    Chiba Univ, Dept Phys, Chiba 2638522, Japan..
    Gallagher, J.
    Univ Wisconsin, Dept Astron, Madison, WI 53706 USA..
    Gerhardt, L.
    Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.;Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA..
    Ghorbani, K.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Gier, D.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Gladstone, L.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Glagla, M.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Gluesenkamp, T.
    DESY, D-15735 Zeuthen, Germany..
    Goldschmidt, A.
    Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA.;Georgia Inst Technol, Ctr Relativist Astrophys, Atlanta, GA 30332 USA..
    Golup, G.
    Vrije Univ Brussel, Dienst ELEM, B-1050 Brussels, Belgium..
    Gonzalez, J. G.
    Univ Delaware, Bartol Res Inst, Newark, DE 19716 USA.;Univ Delaware, Dept Phys & Astron, Newark, DE 19716 USA..
    Gora, D.
    DESY, D-15735 Zeuthen, Germany..
    Grant, D.
    Univ Alberta, Dept Phys, Edmonton, AB T6G 2E1, Canada..
    Griffith, Z.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Gross, A.
    Tech Univ Munich, D-85748 Garching, Germany..
    Ha, C.
    Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.;Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA..
    Haack, C.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Ismail, A. Haj
    Univ Ghent, Dept Phys & Astron, B-9000 Ghent, Belgium..
    Hallgren, Allan
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Halzen, F.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Hansen, E.
    Univ Copenhagen, Niels Bohr Inst, Blegdamsvej 17, DK-2100 Copenhagen, Denmark..
    Hansmann, B.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Hanson, K.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Hebecker, D.
    Humboldt Univ, Inst Phys, D-12489 Berlin, Germany..
    Heereman, D.
    Univ Libre Bruxelles, Sci Fac CP230, B-1050 Brussels, Belgium..
    Helbing, K.
    Univ Wuppertal, Dept Phys, D-42119 Wuppertal, Germany..
    Hellauer, R.
    Univ Maryland, Dept Phys, College Pk, MD 20742 USA..
    Hickford, S.
    Hignight, J.
    Michigan State Univ, Dept Phys & Astron, E Lansing, MI 48824 USA..
    Hill, G. C.
    Univ Adelaide, Dept Phys, Adelaide, SA 5005, Australia..
    Hoffman, K. D.
    Univ Maryland, Dept Phys, College Pk, MD 20742 USA..
    Hoffmann, R.
    Univ Wuppertal, Dept Phys, D-42119 Wuppertal, Germany..
    Holzapfel, K.
    Tech Univ Munich, D-85748 Garching, Germany..
    Homeier, A.
    Univ Bonn, Inst Phys, Nussallee 12, D-53115 Bonn, Germany..
    Hoshina, K.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA.;Univ Tokyo, Earthquake Res Inst, Bunkyo Ku, Tokyo 1130032, Japan..
    Huang, F.
    Penn State Univ, Dept Phys, 104 Davey Lab, University Pk, PA 16802 USA..
    Huber, M.
    Tech Univ Munich, D-85748 Garching, Germany..
    Huelsnitz, W.
    Univ Maryland, Dept Phys, College Pk, MD 20742 USA..
    Hulth, P. O.
    Stockholm Univ, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.;Stockholm Univ, Dept Phys, SE-10691 Stockholm, Sweden..
    Hultqvist, K.
    Stockholm Univ, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.;Stockholm Univ, Dept Phys, SE-10691 Stockholm, Sweden..
    In, S.
    Sungkyunkwan Univ, Dept Phys, Suwon 440746, South Korea..
    Ishihara, A.
    Chiba Univ, Dept Phys, Chiba 2638522, Japan..
    Jacobi, E.
    DESY, D-15735 Zeuthen, Germany..
    Japaridze, G. S.
    Clark Atlanta Univ, CTSPS, Atlanta, GA 30314 USA..
    Jeong, M.
    Sungkyunkwan Univ, Dept Phys, Suwon 440746, South Korea..
    Jero, K.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Jurkovic, M.
    Tech Univ Munich, D-85748 Garching, Germany..
    Kappes, A.
    Univ Erlangen Nurnberg, Erlangen Ctr Astroparticle Phys, D-91058 Erlangen, Germany..
    Karg, T.
    DESY, D-15735 Zeuthen, Germany..
    Karle, A.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Kauer, M.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA.;Yale Univ, Dept Phys, New Haven, CT 06520 USA..
    Keivani, A.
    Penn State Univ, Dept Phys, 104 Davey Lab, University Pk, PA 16802 USA..
    Kelley, J. L.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Kemp, J.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Kheirandish, A.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Kiryluk, J.
    SUNY Stony Brook, Dept Phys & Astron, Stony Brook, NY 11794 USA..
    Klaes, J.
    Univ Wuppertal, Dept Phys, D-42119 Wuppertal, Germany..
    Klein, S. R.
    Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.;Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA..
    Kohnen, G.
    Univ Mons, B-7000 Mons, Belgium..
    Koirala, R.
    Univ Delaware, Bartol Res Inst, Newark, DE 19716 USA.;Univ Delaware, Dept Phys & Astron, Newark, DE 19716 USA..
    Kolanoski, H.
    Humboldt Univ, Inst Phys, D-12489 Berlin, Germany..
    Konietz, R.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Koepke, L.
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Kopper, C.
    Univ Alberta, Dept Phys, Edmonton, AB T6G 2E1, Canada..
    Kopper, S.
    Univ Wuppertal, Dept Phys, D-42119 Wuppertal, Germany..
    Koskinen, D. J.
    Univ Copenhagen, Niels Bohr Inst, Blegdamsvej 17, DK-2100 Copenhagen, Denmark..
    Kowalski, M.
    DESY, D-15735 Zeuthen, Germany.;Humboldt Univ, Inst Phys, D-12489 Berlin, Germany..
    Krings, K.
    Tech Univ Munich, D-85748 Garching, Germany..
    Kroll, G.
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Kroll, M.
    Ruhr Univ Bochum, Fak Phys & Astron, D-44780 Bochum, Germany..
    Krueckl, G.
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Kunnen, J.
    Vrije Univ Brussel, Dienst ELEM, B-1050 Brussels, Belgium..
    Kurahashi, N.
    Drexel Univ, Dept Phys, 3141 Chestnut St, Philadelphia, PA 19104 USA..
    Kuwabara, T.
    Chiba Univ, Dept Phys, Chiba 2638522, Japan..
    Labare, M.
    Univ Ghent, Dept Phys & Astron, B-9000 Ghent, Belgium..
    Lanfranchi, J. L.
    Penn State Univ, Dept Phys, 104 Davey Lab, University Pk, PA 16802 USA..
    Larson, M. J.
    Univ Copenhagen, Niels Bohr Inst, Blegdamsvej 17, DK-2100 Copenhagen, Denmark..
    Lesiak-Bzdak, M.
    SUNY Stony Brook, Dept Phys & Astron, Stony Brook, NY 11794 USA..
    Leuermann, M.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Leuner, J.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Lu, L.
    Chiba Univ, Dept Phys, Chiba 2638522, Japan..
    Lunemann, J.
    Vrije Univ Brussel, Dienst ELEM, B-1050 Brussels, Belgium..
    Madsen, J.
    Univ Wisconsin, Dept Phys, River Falls, WI 54022 USA..
    Maggi, G.
    Vrije Univ Brussel, Dienst ELEM, B-1050 Brussels, Belgium..
    Mahn, K. B. M.
    Michigan State Univ, Dept Phys & Astron, E Lansing, MI 48824 USA..
    Mandelartz, M.
    Ruhr Univ Bochum, Fak Phys & Astron, D-44780 Bochum, Germany..
    Maruyama, R.
    Yale Univ, Dept Phys, New Haven, CT 06520 USA..
    Mase, K.
    Chiba Univ, Dept Phys, Chiba 2638522, Japan..
    Matis, H. S.
    Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA..
    Maunu, R.
    Univ Maryland, Dept Phys, College Pk, MD 20742 USA..
    McNally, F.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Meagher, K.
    Univ Libre Bruxelles, Sci Fac CP230, B-1050 Brussels, Belgium..
    Medici, M.
    Univ Copenhagen, Niels Bohr Inst, Blegdamsvej 17, DK-2100 Copenhagen, Denmark..
    Meli, A.
    Univ Ghent, Dept Phys & Astron, B-9000 Ghent, Belgium..
    Menne, T.
    Tech Univ Dortmund, Dept Phys, D-44221 Dortmund, Germany..
    Merino, G.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Meures, T.
    Univ Libre Bruxelles, Sci Fac CP230, B-1050 Brussels, Belgium..
    Miarecki, S.
    Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA.;Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA..
    Middell, E.
    DESY, D-15735 Zeuthen, Germany..
    Mohrmann, L.
    DESY, D-15735 Zeuthen, Germany..
    Montaruli, T.
    Univ Geneva, Dept Phys Nucl & Corpusculaire, CH-1211 Geneva, Switzerland..
    Morse, R.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Nahnhauer, R.
    DESY, D-15735 Zeuthen, Germany..
    Naumann, U.
    Univ Wuppertal, Dept Phys, D-42119 Wuppertal, Germany..
    Neer, G.
    Michigan State Univ, Dept Phys & Astron, E Lansing, MI 48824 USA..
    Niederhausen, H.
    SUNY Stony Brook, Dept Phys & Astron, Stony Brook, NY 11794 USA..
    Nowicki, S. C.
    Univ Alberta, Dept Phys, Edmonton, AB T6G 2E1, Canada..
    Nygren, D. R.
    Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA..
    Pollmann, A. Obertacke
    Univ Wuppertal, Dept Phys, D-42119 Wuppertal, Germany..
    Olivas, A.
    Univ Maryland, Dept Phys, College Pk, MD 20742 USA..
    Omairat, A.
    Univ Wuppertal, Dept Phys, D-42119 Wuppertal, Germany..
    O'Murchadha, A.
    Univ Libre Bruxelles, Sci Fac CP230, B-1050 Brussels, Belgium..
    Palczewski, T.
    Univ Alabama, Dept Phys & Astron, Tuscaloosa, AL 35487 USA..
    Pandya, H.
    Univ Delaware, Bartol Res Inst, Newark, DE 19716 USA.;Univ Delaware, Dept Phys & Astron, Newark, DE 19716 USA..
    Pankova, D. V.
    Penn State Univ, Dept Phys, 104 Davey Lab, University Pk, PA 16802 USA..
    Paul, L.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Pepper, J. A.
    Univ Alabama, Dept Phys & Astron, Tuscaloosa, AL 35487 USA..
    de los Heros, Carlos Perez
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Pfendner, C.
    Ohio State Univ, Dept Phys, 174 W 18th Ave, Columbus, OH 43210 USA.;Ohio State Univ, Ctr Cosmol & Astroparticle Phys, Columbus, OH 43210 USA..
    Pieloth, D.
    Tech Univ Dortmund, Dept Phys, D-44221 Dortmund, Germany..
    Pinat, E.
    Univ Libre Bruxelles, Sci Fac CP230, B-1050 Brussels, Belgium..
    Posselt, J.
    Univ Wuppertal, Dept Phys, D-42119 Wuppertal, Germany..
    Price, P. B.
    Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA..
    Przybylski, G. T.
    Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA..
    Puetz, J.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Quinnan, M.
    Penn State Univ, Dept Phys, 104 Davey Lab, University Pk, PA 16802 USA..
    Raab, C.
    Univ Libre Bruxelles, Sci Fac CP230, B-1050 Brussels, Belgium..
    Raedel, L.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Rameez, M.
    Univ Geneva, Dept Phys Nucl & Corpusculaire, CH-1211 Geneva, Switzerland..
    Rawlins, K.
    Univ Alaska Anchorage, Dept Phys & Astron, 3211 Providence Dr, Anchorage, AK 99508 USA..
    Reimann, R.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Relich, M.
    Chiba Univ, Dept Phys, Chiba 2638522, Japan..
    Resconi, E.
    Tech Univ Munich, D-85748 Garching, Germany..
    Rhode, W.
    Tech Univ Dortmund, Dept Phys, D-44221 Dortmund, Germany..
    Richman, M.
    Drexel Univ, Dept Phys, 3141 Chestnut St, Philadelphia, PA 19104 USA..
    Richter, S.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Riedel, B.
    Univ Alberta, Dept Phys, Edmonton, AB T6G 2E1, Canada..
    Robertson, S.
    Univ Adelaide, Dept Phys, Adelaide, SA 5005, Australia..
    Rongen, M.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Rott, C.
    Sungkyunkwan Univ, Dept Phys, Suwon 440746, South Korea..
    Ruhe, T.
    Tech Univ Dortmund, Dept Phys, D-44221 Dortmund, Germany..
    Ryckbosch, D.
    Univ Ghent, Dept Phys & Astron, B-9000 Ghent, Belgium..
    Sabbatini, L.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Sander, H. -G
    Sandrock, A.
    Tech Univ Dortmund, Dept Phys, D-44221 Dortmund, Germany..
    Sandroos, J.
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Sarkar, S.
    Univ Copenhagen, Niels Bohr Inst, Blegdamsvej 17, DK-2100 Copenhagen, Denmark.;Univ Oxford, Dept Phys, 1 Keble Rd, Oxford OX1 3NP, England..
    Schatto, K.
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Scheriau, F.
    Tech Univ Dortmund, Dept Phys, D-44221 Dortmund, Germany..
    Schimp, M.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Schmidt, T.
    Univ Maryland, Dept Phys, College Pk, MD 20742 USA..
    Schmitz, M.
    Tech Univ Dortmund, Dept Phys, D-44221 Dortmund, Germany..
    Schoenen, S.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Schoeneberg, S.
    Ruhr Univ Bochum, Fak Phys & Astron, D-44780 Bochum, Germany..
    Schoenwald, A.
    DESY, D-15735 Zeuthen, Germany..
    Schulte, L.
    Univ Bonn, Inst Phys, Nussallee 12, D-53115 Bonn, Germany..
    Schumacher, L.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Seckel, D.
    Univ Delaware, Bartol Res Inst, Newark, DE 19716 USA.;Univ Delaware, Dept Phys & Astron, Newark, DE 19716 USA..
    Seunarine, S.
    Univ Wisconsin, Dept Phys, River Falls, WI 54022 USA..
    Soldin, D.
    Univ Wuppertal, Dept Phys, D-42119 Wuppertal, Germany..
    Song, M.
    Univ Maryland, Dept Phys, College Pk, MD 20742 USA..
    Spiczak, G. M.
    Univ Wisconsin, Dept Phys, River Falls, WI 54022 USA..
    Spiering, C.
    DESY, D-15735 Zeuthen, Germany..
    Stahlberg, M.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Stamatikos, M.
    Ohio State Univ, Dept Phys, 174 W 18th Ave, Columbus, OH 43210 USA.;Ohio State Univ, Ctr Cosmol & Astroparticle Phys, Columbus, OH 43210 USA.;NASA, Goddard Space Flight Ctr, Greenbelt, MD 20771 USA..
    Stanev, T.
    Univ Delaware, Bartol Res Inst, Newark, DE 19716 USA.;Univ Delaware, Dept Phys & Astron, Newark, DE 19716 USA..
    Stasik, A.
    DESY, D-15735 Zeuthen, Germany..
    Steuer, A.
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Stezelberger, T.
    Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA..
    Stokstad, R. G.
    Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA..
    Stoessl, A.
    DESY, D-15735 Zeuthen, Germany..
    Ström, Rickard
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Strotjohann, N. L.
    DESY, D-15735 Zeuthen, Germany..
    Sullivan, G. W.
    Univ Maryland, Dept Phys, College Pk, MD 20742 USA..
    Sutherland, M.
    Ohio State Univ, Dept Astron, 174 W 18th Ave, Columbus, OH 43210 USA..
    Taavola, Henric
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Taboada, I.
    Georgia Inst Technol, Sch Phys, Atlanta, GA 30332 USA.;Georgia Inst Technol, Ctr Relativist Astrophys, Atlanta, GA 30332 USA..
    Tatar, J.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics. Ohio State Univ, Dept Phys, 174 W 18th Ave, Columbus, OH 43210 USA.;Ohio State Univ, Ctr Cosmol & Astroparticle Phys, Columbus, OH 43210 USA..
    Ter-Antonyan, S.
    Southern Univ, Dept Phys, Baton Rouge, LA 70813 USA..
    Terliuk, A.
    DESY, D-15735 Zeuthen, Germany..
    Tesic, G.
    Penn State Univ, Dept Phys, 104 Davey Lab, University Pk, PA 16802 USA..
    Tilav, S.
    Univ Delaware, Bartol Res Inst, Newark, DE 19716 USA.;Univ Delaware, Dept Phys & Astron, Newark, DE 19716 USA..
    Toale, P. A.
    Univ Wisconsin, Dept Phys, River Falls, WI 54022 USA..
    Tobin, M. N.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Toscano, S.
    Vrije Univ Brussel, Dienst ELEM, B-1050 Brussels, Belgium..
    Tosi, D.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Turcati, A.
    Tech Univ Munich, D-85748 Garching, Germany..
    Unger, Lisa E.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Usner, M.
    DESY, D-15735 Zeuthen, Germany..
    Vallecorsa, S.
    Univ Geneva, Dept Phys Nucl & Corpusculaire, CH-1211 Geneva, Switzerland..
    Vandenbroucke, J.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    van Eijndhoven, N.
    Vrije Univ Brussel, Dienst ELEM, B-1050 Brussels, Belgium..
    Vanheule, S.
    Univ Ghent, Dept Phys & Astron, B-9000 Ghent, Belgium..
    van Santen, J.
    DESY, D-15735 Zeuthen, Germany..
    Veenkamp, J.
    Tech Univ Munich, D-85748 Garching, Germany..
    Vehring, M.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Voge, M.
    Univ Bonn, Inst Phys, Nussallee 12, D-53115 Bonn, Germany..
    Vraeghe, M.
    Univ Ghent, Dept Phys & Astron, B-9000 Ghent, Belgium..
    Walck, C.
    Stockholm Univ, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.;Stockholm Univ, Dept Phys, SE-10691 Stockholm, Sweden..
    Wallace, A.
    Univ Adelaide, Dept Phys, Adelaide, SA 5005, Australia..
    Wallraff, M.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Wandkowsky, N.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Weaver, Ch.
    Univ Alberta, Dept Phys, Edmonton, AB T6G 2E1, Canada..
    Wendt, C.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Westerhoff, S.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Whelan, B. J.
    Univ Adelaide, Dept Phys, Adelaide, SA 5005, Australia..
    Wiebe, K.
    Johannes Gutenberg Univ Mainz, Inst Phys, Staudinger Weg 7, D-55099 Mainz, Germany..
    Wiebusch, C. H.
    Rhein Westfal TH Aachen, Inst Phys 3, D-52056 Aachen, Germany..
    Wille, L.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA..
    Williams, D. R.
    Univ Wisconsin, Dept Phys, River Falls, WI 54022 USA..
    Wissing, H.
    Univ Maryland, Dept Phys, College Pk, MD 20742 USA..
    Wolf, M.
    Stockholm Univ, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.;Stockholm Univ, Dept Phys, SE-10691 Stockholm, Sweden..
    Wood, T. R.
    Univ Alberta, Dept Phys, Edmonton, AB T6G 2E1, Canada..
    Woschnagg, K.
    Univ Calif Berkeley, Dept Phys, Berkeley, CA 94720 USA..
    Xu, D. L.
    Univ Wisconsin, Dept Phys, 1150 Univ Ave, Madison, WI 53706 USA.;Univ Wisconsin, Wisconsin IceCube Particle Astrophys Ctr, Madison, WI 53706 USA..
    Xu, X. W.
    Southern Univ, Dept Phys, Baton Rouge, LA 70813 USA..
    Xu, Y.
    SUNY Stony Brook, Dept Phys & Astron, Stony Brook, NY 11794 USA..
    Yanez, J. P.
    DESY, D-15735 Zeuthen, Germany..
    Yodh, G.
    Univ Calif Irvine, Dept Phys & Astron, Irvine, CA 92697 USA..
    Yoshida, S.
    Chiba Univ, Dept Phys, Chiba 2638522, Japan..
    Zoll, M.
    Stockholm Univ, Oskar Klein Ctr, SE-10691 Stockholm, Sweden.;Stockholm Univ, Dept Phys, SE-10691 Stockholm, Sweden..
    The First Combined Search For Neutrino Point-Sources In The Southern Hemisphere With The Antares And Icecube Neutrino Telescopes2016In: Astrophysical Journal, ISSN 0004-637X, E-ISSN 1538-4357, Vol. 823, no 1, article id 65Article in journal (Refereed)
    Abstract [en]

    We present the results of searches for point-like sources of neutrinos based on the first combined analysis of data from both the ANTARES and IceCube neutrino telescopes. The combination of both detectors, which differ in size and location, forms a window in the southern sky where the sensitivity to point sources improves by up to a factor of 2 compared with individual analyses. Using data recorded by ANTARES from 2007 to 2012, and by IceCube from 2008 to 2011, we search for sources of neutrino emission both across the southern sky and from a preselected list of candidate objects. No significant excess over background has been found in these searches, and flux upper limits for the candidate sources are presented for E-2.5 and E-2 power-law spectra with different energy cut-offs.

  • 71.
    Adrian-Martinez, S.
    et al.
    Univ Politecn Valencia, Inst Invest Gestio Integrada Zones Costaneres IGI, C Paranimf 1, Gandia 46730, Spain.
    Boersma, David J.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Botner, Olga
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Euler, Sebastian
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Hallgren, Allan
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Perez de los Heros, Carlos
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ström, Rickard
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Zweizig, J.
    CALTECH, LIGO, Pasadena, CA 91125 USA.
    High-energy neutrino follow-up search of gravitational wave event GW150914 with ANTARES and IceCube2016In: PHYSICAL REVIEW D, ISSN 2470-0010, Vol. 93, no 12, article id 122010Article in journal (Refereed)
    Abstract [en]

    We present the high-energy-neutrino follow-up observations of the first gravitational wave transient GW150914 observed by the Advanced LIGO detectors on September 14, 2015. We search for coincident neutrino candidates within the data recorded by the IceCube and ANTARES neutrino detectors. A possible joint detection could be used in targeted electromagnetic follow-up observations, given the significantly better angular resolution of neutrino events compared to gravitational waves. We find no neutrino candidates in both temporal and spatial coincidence with the gravitational wave event. Within +/- 500 s of the gravitational wave event, the number of neutrino candidates detected by IceCube and ANTARES were three and zero, respectively. This is consistent with the expected atmospheric background, and none of the neutrino candidates were directionally coincident with GW150914. We use this nondetection to constrain neutrino emission from the gravitational-wave event.

  • 72. Adrianto, Indra
    et al.
    Wen, Feng
    Templeton, Amanda
    Wiley, Graham
    King, Jarrod B.
    Lessard, Christopher J.
    Bates, Jared S.
    Hu, Yanqing
    Kelly, Jennifer A.
    Kaufman, Kenneth M.
    Guthridge, Joel M.
    Alarcon-Riquelme, Marta E.
    Anaya, Juan-Manuel
    Bae, Sang-Cheol
    Bang, So-Young
    Boackle, Susan A.
    Brown, Elizabeth E.
    Petri, Michelle A.
    Gallant, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Ramsey-Goldman, Rosalind
    Reveille, John D.
    Vila, Luis M.
    Criswell, Lindsey A.
    Edberg, Jeffrey C.
    Freedman, Barry I.
    Gregersen, Peter K.
    Gilkeson, Gary S.
    Jacob, Chaim O.
    James, Judith A.
    Kamen, Diane L.
    Kimberly, Robert P.
    Martin, Javier
    Merrill, Joan T.
    Niewold, Timothy B.
    Park, So-Yeon
    Pons-Estel, Bernardo A.
    Scofield, R. Hal
    Stevens, Anne M.
    Tsao, Betty P.
    Vyse, Timothy J.
    Langefeld, Carl D.
    Harley, John B.
    Moser, Kathy L.
    Webb, Carol F.
    Humphrey, Mary Beth
    Montgomery, Courtney Gray
    Gaffney, Patrick M.
    Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus2011In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, no 3, p. 253-258Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 x 10(-8), odds ratio = 1.70) and Korean (P = 8.33 x 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-kappa B subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.

  • 73. Aeinehband, Shahin
    et al.
    Lindblom, Rickard P F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Al Nimer, Faiez
    Vijayaraghavan, Swetha
    Sandholm, Kerstin
    Khademi, Mohsen
    Olsson, Tomas
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Kristina Ekdahl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Darreh-Shori, Taher
    Piehl, Fredrik
    Complement Component C3 and Butyrylcholinesterase Activity Are Associated with Neurodegeneration and Clinical Disability in Multiple Sclerosis2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 4Article in journal (Refereed)
    Abstract [en]

    Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genomewide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with >= 9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

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  • 74.
    Agarwal, Prasoon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Regulation of Gene Expression in Multiple Myeloma Cells and Normal Fibroblasts: Integrative Bioinformatic and Experimental Approaches2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work presented in this thesis applies integrative genomic and experimental approaches to investigate mechanisms involved in regulation of gene expression in the context of disease and normal cell biology.

    In papers I and II, we have explored the role of epigenetic regulation of gene expression in multiple myeloma (MM). By using a bioinformatic approach we identified the Polycomb repressive complex 2 (PRC2) to be a common denominator for the underexpressed gene signature in MM. By using inhibitors of the PRC2 we showed an activation of the genes silenced by H3K27me3 and a reduction in the tumor load and increased overall survival in the in vivo 5TMM model. Using ChIP-sequencing we defined the distribution of H3K27me3 and H3K4me3 marks in MM patients cells. In an integrated bioinformatic approach, the H3K27me3-associated genes significantly correlated to under-expression in patients with less favorable survival. Thus, our data indicates the presence of a common under-expressed gene profile and provides a rationale for implementing new therapies focusing on epigenetic alterations in MM.

    In paper III we address the existence of a small cell population in MM presenting with differential tumorigenic properties in the 5T33MM murine model. We report that the predominant population of CD138+ cells had higher engraftment potential, higher clonogenic growth, whereas the CD138- MM cells presented with less mature phenotype and higher drug resistance. Our findings suggest that while designing treatment regimes for MM, both the cellpopulations must be targeted.

    In paper IV we have studied the general mechanism of differential gene expression regulation by CGGBP1 in response to growth signals in normal human fibroblasts. We found that CGGBP1 binding affects global gene expression by RNA Polymerase II. This is mediated by Alu RNAdependentinhibition of RNA Polymerase II. In presence of growth signals CGGBP1 is retained in the nuclei and exhibits enhanced Alu binding thus inhibiting RNA Polymerase III binding on Alus. Hence we suggest a mechanism by which CGGBP1 orchestrates Alu RNA-mediated regulation of RNA Polymerase II. This thesis provides new insights for using integrative bioinformatic approaches to decipher gene expression regulation mechanisms in MM and in normal cells.

    List of papers
    1. Polycomb target genes are silenced in multiple myeloma
    Open this publication in new window or tab >>Polycomb target genes are silenced in multiple myeloma
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    2010 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 5, no 7, p. e11483-Article in journal (Refereed) Published
    Abstract [en]

    Multiple myeloma (MM) is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG) proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP) assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep) and the histone deacetylase inhibitor LBH589 (Panobinostat), reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies.

    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-133207 (URN)10.1371/journal.pone.0011483 (DOI)000279715300003 ()20634887 (PubMedID)
    Available from: 2010-11-03 Created: 2010-11-03 Last updated: 2021-06-14Bibliographically approved
    2. The epigenomic map of multiple myeloma reveals the importance of Polycomb gene silencing for the malignancy
    Open this publication in new window or tab >>The epigenomic map of multiple myeloma reveals the importance of Polycomb gene silencing for the malignancy
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Multiple myeloma (MM) is characterized by accumulation of post-germinal center, isotype switched, long-living plasma cells with retained proliferation capacity within the bone marrow. MM is highly heterogeneous and remains fatal. This heterogeneity has hampered identification of a common underlying mechanism for disease establishment and the development of targeted therapy. We recently provided proof-of-principle that gene silencing associated with H3K27me3 contributes to the malignancy of MM. Here we present the first epigenomic map of MM for H3K27me3 and H3K4me3 derived by ChIP- and RNA sequencing from freshly-isolated bone marrow plasma cells from four patients. We compile lists of targets common among the patients as well as unique to MM when compared with PBMCs. Indicating the clinical relevance of our findings, we find increased silencing of H3K27me3 targets with disease progression and in patients presenting with a poor prognosis. Bivalent genes further significantly correlated to under-expressed genes in MM and were unique to MM when compared to PBMCs. Furthermore, bivalent genes, unlike H3K27me3 targets, significantly associated with transcriptional activation upon Polycomb inhibition indicating a potential for drug targeting. Thus, we suggest that gene silencing by Polycomb plays an important role in the development of the malignant phenotype of the MM cell during tumor progression.

    National Category
    Cell and Molecular Biology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-199492 (URN)
    Available from: 2013-05-06 Created: 2013-05-06 Last updated: 2018-01-11Bibliographically approved
    3. Tumor-initiating capacity of CD138- and CD138+ tumor cells in the 5T33 multiple myeloma model
    Open this publication in new window or tab >>Tumor-initiating capacity of CD138- and CD138+ tumor cells in the 5T33 multiple myeloma model
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    2012 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, no 6, p. 1436-1439Article in journal, Letter (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-177948 (URN)10.1038/leu.2011.373 (DOI)000305081000040 ()22289925 (PubMedID)
    Available from: 2012-07-25 Created: 2012-07-20 Last updated: 2017-12-07Bibliographically approved
    4. Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs
    Open this publication in new window or tab >>Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs
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    2016 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 15, no 12, p. 1558-1571Article in journal (Refereed) Published
    Abstract [en]

    CGGBP1 (CGG triplet repeat-binding protein 1) regulates cell proliferation, stress response,cytokinesis, telomeric integrity and transcription. It could affect these processes by modulatingtarget gene expression under different conditions. Identification of CGGBP1-target genes andtheir regulation could reveal how a transcription regulator affects such diverse cellular processes.Here we describe the mechanisms of differential gene expression regulation by CGGBP1 inquiescent or growing cells. By studying global gene expression patterns and genome-wide DNAbindingpatterns of CGGBP1, we show that a possible mechanism through which it affects theexpression of RNA Pol II-transcribed genes in trans depends on Alu RNA. We also show that itregulates Alu transcription in cis by binding to Alu promoter. Our results also indicate thatpotential phosphorylation of CGGBP1 upon growth stimulation facilitates its nuclear retention,Alu-binding and dislodging of RNA Pol III therefrom. These findings provide insights into howAlu transcription is regulated in response to growth signals.

    Keywords
    Alu-SINEs; CGGBP1; ChIP-seq; growth signals; RNA Pol III; transcription; tyrosine phosphorylation
    National Category
    Cell Biology
    Research subject
    Bioinformatics; Biology
    Identifiers
    urn:nbn:se:uu:diva-230959 (URN)10.4161/15384101.2014.967094 (DOI)000379743800011 ()25483050 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research Council
    Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2017-12-05Bibliographically approved
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  • 75.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Alzrigat, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Párraga, Alba Atienza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Singh, Umashankar
    Ungerstedt, Johanna
    Österborg, Anders
    Brown, Peter J
    Ma, Anqi
    Jin, Jian
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.2016In: Oncotarget, E-ISSN 1949-2553, Vol. 7, no 6, p. 6809-6923Article in journal (Refereed)
    Abstract [en]

    Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

  • 76.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Collier, Paul
    Fritz, Markus Hsi-Yang
    Benes, Vladimir
    Wiklund, Helena Jernberg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    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.
    Singh, Umashankar
    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.
    CGGBP1 mitigates cytosine methylation at repetitive DNA sequences2015In: BMC Genomics, E-ISSN 1471-2164, Vol. 16, article id 390Article in journal (Refereed)
    Abstract [en]

    Background: CGGBP1 is a repetitive DNA-binding transcription regulator with target sites at CpG-rich sequences such as CGG repeats and Alu-SINEs and L1-LINEs. The role of CGGBP1 as a possible mediator of CpG methylation however remains unknown. At CpG-rich sequences cytosine methylation is a major mechanism of transcriptional repression. Concordantly, gene-rich regions typically carry lower levels of CpG methylation than the repetitive elements. It is well known that at interspersed repeats Alu-SINEs and L1-LINEs high levels of CpG methylation constitute a transcriptional silencing and retrotransposon inactivating mechanism. Results: Here, we have studied genome-wide CpG methylation with or without CGGBP1-depletion. By high throughput sequencing of bisulfite-treated genomic DNA we have identified CGGBP1 to be a negative regulator of CpG methylation at repetitive DNA sequences. In addition, we have studied CpG methylation alterations on Alu and L1 retrotransposons in CGGBP1-depleted cells using a novel bisulfite-treatment and high throughput sequencing approach. Conclusions: The results clearly show that CGGBP1 is a possible bidirectional regulator of CpG methylation at Alus, and acts as a repressor of methylation at L1 retrotransposons.

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  • 77.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Teichmann, Martin
    Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux 2, rue , Robert Escarpit, 33607 Pessac, France..
    Jernberg Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Smit, Arian
    Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Singh, Umashankar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs2016In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 15, no 12, p. 1558-1571Article in journal (Refereed)
    Abstract [en]

    CGGBP1 (CGG triplet repeat-binding protein 1) regulates cell proliferation, stress response,cytokinesis, telomeric integrity and transcription. It could affect these processes by modulatingtarget gene expression under different conditions. Identification of CGGBP1-target genes andtheir regulation could reveal how a transcription regulator affects such diverse cellular processes.Here we describe the mechanisms of differential gene expression regulation by CGGBP1 inquiescent or growing cells. By studying global gene expression patterns and genome-wide DNAbindingpatterns of CGGBP1, we show that a possible mechanism through which it affects theexpression of RNA Pol II-transcribed genes in trans depends on Alu RNA. We also show that itregulates Alu transcription in cis by binding to Alu promoter. Our results also indicate thatpotential phosphorylation of CGGBP1 upon growth stimulation facilitates its nuclear retention,Alu-binding and dislodging of RNA Pol III therefrom. These findings provide insights into howAlu transcription is regulated in response to growth signals.

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    fulltext
  • 78.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Alzrigat, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Osterborg, Anders
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    An Epigenomic Map of Multiple Myeloma Reveals the Importance of Polycomb Gene Silencing for the Malignancy2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 79.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Österborg, Anders
    Department of Hematology, Karolinska University Hospital Solna.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Jernberg Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    The epigenomic map of multiple myeloma reveals the importance of Polycomb gene silencing for the malignancyManuscript (preprint) (Other academic)
    Abstract [en]

    Multiple myeloma (MM) is characterized by accumulation of post-germinal center, isotype switched, long-living plasma cells with retained proliferation capacity within the bone marrow. MM is highly heterogeneous and remains fatal. This heterogeneity has hampered identification of a common underlying mechanism for disease establishment and the development of targeted therapy. We recently provided proof-of-principle that gene silencing associated with H3K27me3 contributes to the malignancy of MM. Here we present the first epigenomic map of MM for H3K27me3 and H3K4me3 derived by ChIP- and RNA sequencing from freshly-isolated bone marrow plasma cells from four patients. We compile lists of targets common among the patients as well as unique to MM when compared with PBMCs. Indicating the clinical relevance of our findings, we find increased silencing of H3K27me3 targets with disease progression and in patients presenting with a poor prognosis. Bivalent genes further significantly correlated to under-expressed genes in MM and were unique to MM when compared to PBMCs. Furthermore, bivalent genes, unlike H3K27me3 targets, significantly associated with transcriptional activation upon Polycomb inhibition indicating a potential for drug targeting. Thus, we suggest that gene silencing by Polycomb plays an important role in the development of the malignant phenotype of the MM cell during tumor progression.

  • 80.
    Agathangelidis, A.
    et al.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Bystry, V.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Hadzidimitriou, A.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Sutton, L. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Minga, E.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Kienle, D.
    Univ Ulm, Dept Internal Med 3, D-89069 Ulm, Germany..
    Davis, Z.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Yan, X. J.
    North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA..
    Shanafelt, T.
    Mayo Clin, Dept Med, Dept Hematol, Rochester, MN USA..
    Boudjogra, M.
    Univ Paris 06, Hop Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Hop Pitie Salpetriere, Paris, France..
    Plevova, K.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Gounari, M.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Xochelli, A.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Navarro, A.
    Univ Barcelona, IDIBAPS, Unidad Hematopatol, Serv Anat Patol, Barcelona, Spain..
    Chatzouli, M.
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Pedersen, L. B.
    Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Scarfo, L.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Rossi, D.
    Amedeo Avogadro Univ Eastern Piedmont, Dept Hematol, Novara, Italy..
    Veronese, S.
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Niguarda Canc Ctr, Dept Hematol, Milan, Italy..
    Facco, M.
    Univ Padua, Sch Med, Hematol & Clin Immunol Branch, Dept Med, Padua, Italy..
    Bikos, V.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Karan-Djurasevic, T.
    Univ Belgrade, Inst Mol Genet & Genet Engn, Belgrade, Serbia..
    Pavlovic, S.
    Univ Kragujevac, Kragujevac, Serbia..
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Poiron, C.
    Univ Montpellier, IMGT, LIGM, IGH, Montpellier, France..
    Chu, C. C.
    North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA..
    Stalika, E.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Giudicelli, V.
    Univ Montpellier, IMGT, LIGM, IGH, Montpellier, France..
    Panagiotidis, P.
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Sudarikov, A.
    Natl Hematol Res Ctr, Dept Mol Hematol, Moscow, Russia..
    Anagnostopoulos, A.
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Trentin, L.
    Univ Padua, Sch Med, Hematol & Clin Immunol Branch, Dept Med, Padua, Italy..
    Catherwood, M.
    Belfast City Hosp, Dept Hematooncol, Belfast BT9 7AD, Antrim, North Ireland..
    Montillo, M.
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Niguarda Canc Ctr, Dept Hematol, Milan, Italy..
    Gaidano, G.
    Amedeo Avogadro Univ Eastern Piedmont, Dept Hematol, Novara, Italy..
    Campo, E.
    Univ Barcelona, IDIBAPS, Unidad Hematopatol, Serv Anat Patol, Barcelona, Spain..
    Geisler, C. H.
    Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Langerak, A. W.
    Erasmus MC, Univ Med Ctr, Dept Immunol, Rotterdam, Netherlands..
    Pospisilova, S.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Lefranc, M. P.
    Univ Montpellier, IMGT, LIGM, IGH, Montpellier, France..
    Chiorazzi, N.
    North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA..
    Oscier, D.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Jelinek, D. F.
    Mayo Clin, Dept Immunol, Rochester, MN USA..
    Stilgenbauer, S.
    Univ Ulm, Dept Internal Med 3, D-89069 Ulm, Germany..
    Belessi, C.
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Davi, F.
    Univ Paris 06, Hop Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Hop Pitie Salpetriere, Paris, France..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ghia, P.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Darzentas, N.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. CERTH, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    HIGHER-ORDER IMMUNOGLOBULIN SEQUENCE RELATIONS FOR MAJOR SUBSETS OF CHRONIC LYMPHOCYTIC LEUKEMIA: UNIQUENESS VERSUS EQUIVALENCE2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 47-48Article in journal (Other academic)
  • 81.
    Agathangelidis, Andreas
    et al.
    Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermis, Thessaloniki 57001, Greece..
    Chatzidimitriou, Anastasia
    Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermis, Thessaloniki 57001, Greece.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Gemenetzi, Katerina
    Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermis, Thessaloniki 57001, Greece.;Democritus Univ Thrace, Dept Mol Biol & Genet, Alexandroupolis, Greece..
    Giudicelli, Veronique
    Univ Montpellier, Ctr Natl Rech Sci CNRS, Inst Genet Humaine IGH, Unite Mixte Rech UMR, Montpellier, France..
    Karypidou, Maria
    Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermis, Thessaloniki 57001, Greece..
    Plevova, Karla
    Masaryk Univ, Fac Med, Dept Internal Med Hematol & Oncol, Univ Hosp Brno, Brno, Czech Republic.;Masaryk Univ, Ctr Mol Med, Cent European Inst Technol, Brno, Czech Republic..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Yan, Xiao-Jie
    Feinstein Inst Med Res, Northwell Hlth, Manhasset, NY USA..
    Jeromin, Sabine
    MLL Munich Leukemia Lab, Munich, Germany..
    Schneider, Christof
    Univ Hosp Med Ctr, Ulm, Germany..
    Pedersen, Lone Bredo
    Copenhagen Univ Hosp, Rigshosp, Dept Hematol, Copenhagen, Denmark..
    Tschumper, Renee C.
    Mayo Clin, Dept Immunol, Rochester, MN USA..
    Sutton, Lesley-Ann
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Baliakas, Panagiotis
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Scarfo, Lydia
    Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Strateg Res Program CLL,Ist Ricovero & Cura Carat, Milan, Italy..
    van Gastel, Ellen J.
    Univ Med Ctr UMC, Dept Immunol, Lab Med Immunol, Erasmus MC, Rotterdam, Netherlands..
    Armand, Marine
    Sorbonne Univ, Ctr Rech Cordeliers, Dept Biol Hematol, Hop Pitie Salpetriere,AP HP,UMR S 1138, Paris, France..
    Tausch, Eugen
    Ulm Univ, Dept Internal Med 3, Ulm, Germany..
    Biderman, Bella
    Natl Res Ctr Hematol, Moscow, Russia..
    Baer, Constance
    MLL Munich Leukemia Lab, Munich, Germany..
    Bagnara, Davide
    Univ Genoa, Dept Expt Med, Genoa, Italy..
    Navarro, Alba
    Ctr Invest Biomed Red Oncol CIBERONC, Madrid, Spain.;Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain..
    de Septenville, Anne Langlois
    Sorbonne Univ, Ctr Rech Cordeliers, Dept Biol Hematol, Hop Pitie Salpetriere,AP HP,UMR S 1138, Paris, France..
    Guido, Valentina
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Haematol Dept, Mol Pathol Unit, Milan, Italy..
    Mitterbauer-Hohendanner, Gerlinde
    Med Univ Vienna, Dept Lab Med, Vienna, Austria..
    Dimovski, Aleksandar
    Ss Cyril & Methodius Univ Skopje, Fac Pharm, Skopje, North Macedonia..
    Brieghel, Christian
    Copenhagen Univ Hosp, Rigshosp, Dept Hematol, Copenhagen, Denmark..
    Lawless, Sarah
    Belfast City Hosp, Clin Haematol, Belfast Hlth & Social Care Trust, Belfast, Antrim, North Ireland..
    Meggendorfer, Manja
    MLL Munich Leukemia Lab, Munich, Germany..
    Brazdilova, Kamila
    Masaryk Univ, Fac Med, Dept Internal Med Hematol & Oncol, Univ Hosp Brno, Brno, Czech Republic.;Masaryk Univ, Ctr Mol Med, Cent European Inst Technol, Brno, Czech Republic..
    Ritgen, Matthias
    Univ Hosp Schleswig Holstein, Med Dept 2, Campus Kiel, Kiel, Germany..
    Facco, Monica
    Univ Padua, Dept Med DIMED, Hematol & Clin Immunol Unit, Padua, Italy.;Veneto Inst Mol Med, Padua, Italy..
    Tresoldi, Cristina
    Ist Sci San Raffaele, Div Immunol Transplantat & Infect Dis, IRCCS, Milan, Italy..
    Visentin, Andrea
    Univ Padua, Dept Med DIMED, Hematol & Clin Immunol Unit, Padua, Italy.;Veneto Inst Mol Med, Padua, Italy..
    Patriarca, Andrea
    Univ Eastern Piedmont Osped Maggiore Carita, Dept Translat Med, Div Hematol, Novara, Italy..
    Catherwood, Mark
    Belfast City Hosp, Clin Haematol, Belfast Hlth & Social Care Trust, Belfast, Antrim, North Ireland..
    Bonello, Lisa
    Azienda Osped Univ AOU, City Hlth & Sci Turin, Gen Anatomopathol & Mol Oncogenet, Turin, Italy..
    Sudarikov, Andrey
    Natl Res Ctr Hematol, Moscow, Russia..
    Vanura, Katrina
    Med Univ Vienna, Dept Lab Med, Vienna, Austria..
    Roumelioti, Maria
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Francova, Hana Skuhrova
    Masaryk Univ, Fac Med, Dept Internal Med Hematol & Oncol, Univ Hosp Brno, Brno, Czech Republic..
    Moysiadis, Theodoros
    Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermis, Thessaloniki 57001, Greece..
    Veronese, Silvio
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Haematol Dept, Mol Pathol Unit, Milan, Italy..
    Giannopoulos, Krzysztof
    Med Univ Lublin, Expt Hematooncol Dept, Lublin, Poland..
    Mansouri, Larry
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Karan-Djurasevic, Teodora
    Univ Belgrade, Inst Mol Genet & Genet Engn, Belgrade, Serbia..
    Sandaltzopoulos, Raphael
    Democritus Univ Thrace, Dept Mol Biol & Genet, Alexandroupolis, Greece..
    Bodor, Csaba
    Semmelweis Univ, Dept Pathol & Expt Canc Res 1, MTA SE Momentum Mol Oncohematol Res Grp, Budapest, Hungary..
    Fais, Franco
    Univ Genoa, Dept Expt Med, Genoa, Italy.;IRCCS Osped Policlin San Martino, UO Mol Pathol, Genoa, Italy..
    Kater, Arnon
    Univ Amsterdam, Amsterdam UMC, Amsterdam Infect & Immun Inst, Dept Hematol,Canc Ctr Amsterdam, Amsterdam, Netherlands..
    Panovska, Irina
    Ss Cyril & Methodius Univ Skopje, Fac Med, Dept Hematol, Skopje, North Macedonia..
    Rossi, Davide
    Inst Southern Switzerland, Div Hematol Oncol, Bellinzona, Switzerland..
    Alshemmari, Salem
    Kuwait Univ, Fac Med, Dept Med, Kuwait, Kuwait..
    Panagiotidis, Panagiotis
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Costeas, Paul
    Ctr Study Haematol Malignancies, Nicosia, Cyprus.;Karaiskakio Fdn, Nicosia, Cyprus..
    Espinet, Blanca
    Hosp Mar, Serv Patol & Serv Hematol, Lab Citogenet Mol, Lab Citol Hematol, Barcelona, Spain..
    Antic, Darko
    Clin Ctr Serbia, Clin Hematol, Belgrade, Serbia..
    Foroni, Letizia
    Hammersmith Hosp, London, England..
    Montillo, Marco
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Haematol Dept, Mol Pathol Unit, Milan, Italy..
    Trentin, Livio
    Univ Padua, Dept Med DIMED, Hematol & Clin Immunol Unit, Padua, Italy.;Veneto Inst Mol Med, Padua, Italy..
    Stavroyianni, Niki
    G Papanicolaou Hosp, Hematol Dept, Hematocrit HCT Unit, Thessaloniki, Greece..
    Gaidano, Gianluca
    Univ Eastern Piedmont Osped Maggiore Carita, Dept Translat Med, Div Hematol, Novara, Italy..
    di Celle, Paola Francia
    Azienda Osped Univ AOU, City Hlth & Sci Turin, Gen Anatomopathol & Mol Oncogenet, Turin, Italy..
    Niemann, Carsten
    Copenhagen Univ Hosp, Rigshosp, Dept Hematol, Copenhagen, Denmark..
    Campo, Elias
    Ctr Invest Biomed Red Oncol CIBERONC, Madrid, Spain.;Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain.;Univ Barcelona, Hosp Clin Barcelona, Barcelona, Spain..
    Anagnostopoulos, Achilles
    Hammersmith Hosp, London, England..
    Pott, Christiane
    Univ Hosp Schleswig Holstein, Med Dept 2, Campus Kiel, Kiel, Germany..
    Fischer, Kirsten
    Univ Hosp Cologne, Cologne, Germany..
    Hallek, Michael
    Univ Cologne, Dept & Internal Med, Cologne, Germany..
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Stilgenbauer, Stephan
    Ulm Univ, Dept Internal Med 3, Ulm, Germany..
    Haferlach, Claudia
    MLL Munich Leukemia Lab, Munich, Germany..
    Jelinek, Diane
    Mayo Clin, Dept Immunol, Scottsdale, AZ USA..
    Chiorazzi, Nicholas
    Feinstein Inst Med Res, Northwell Hlth, Manhasset, NY USA..
    Pospisilova, Sarka
    Masaryk Univ, Fac Med, Dept Internal Med Hematol & Oncol, Univ Hosp Brno, Brno, Czech Republic.;Masaryk Univ, Ctr Mol Med, Cent European Inst Technol, Brno, Czech Republic..
    Lefranc, Marie-Paule
    Univ Montpellier, Ctr Natl Rech Sci CNRS, Inst Genet Humaine IGH, Unite Mixte Rech UMR, Montpellier, France..
    Kossida, Sofia
    Univ Montpellier, Ctr Natl Rech Sci CNRS, Inst Genet Humaine IGH, Unite Mixte Rech UMR, Montpellier, France..
    Langerak, Anton W.
    Univ Med Ctr UMC, Dept Immunol, Lab Med Immunol, Erasmus MC, Rotterdam, Netherlands..
    Belessi, Chrysoula
    Nikea Gen Hosp, Hematol Dept, Piraeus, Greece..
    Davi, Frederic
    Univ Med Ctr UMC, Dept Immunol, Lab Med Immunol, Erasmus MC, Rotterdam, Netherlands..
    Rosenquist, Richard
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Karolinska Univ Lab, Clin Genet, Stockholm, Sweden..
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Strateg Res Program CLL,Ist Ricovero & Cura Carat, Milan, Italy..
    Stamatopoulos, Kostas
    Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermis, Thessaloniki 57001, Greece.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL2021In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 137, no 10, p. 1365-1376Article in journal (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed "satellites," were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.

  • 82. Agathangelidis, Andreas
    et al.
    Darzentas, Nikos
    Hadzidimitriou, Anastasia
    Brochet, Xavier
    Murray, Fiona
    Yan, Xiao-Jie
    Davis, Zadie
    van Gastel-Mol, Ellen J.
    Tresoldi, Cristina
    Chu, Charles C.
    Cahill, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Giudicelli, Veronique
    Tichy, Boris
    Pedersen, Lone Bredo
    Foroni, Letizia
    Bonello, Lisa
    Janus, Agnieszka
    Smedby, Karin
    Anagnostopoulos, Achilles
    Merle-Beral, Helene
    Laoutaris, Nikolaos
    Juliusson, Gunnar
    di Celle, Paola Francia
    Pospisilova, Sarka
    Jurlander, Jesper
    Geisler, Christian
    Tsaftaris, Athanasios
    Lefranc, Marie-Paule
    Langerak, Anton W.
    Oscier, David Graham
    Chiorazzi, Nicholas
    Belessi, Chrysoula
    Davi, Frederic
    Rosenquist Brandell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Ghia, Paolo
    Stamatopoulos, Kostas
    Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies2012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 119, no 19, p. 4467-4475Article in journal (Refereed)
    Abstract [en]

    Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1: 2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.

  • 83. Agathangelidis, Andreas
    et al.
    Hadzidimitriou, Anastasia
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Stamatopoulos, Kostas
    Unlocking the secrets of immunoglobulin receptors in mantle cell lymphoma: Implications for the origin and selection of the malignant cells2011In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 21, no 5, p. 299-307Article, review/survey (Refereed)
    Abstract [en]

    Immunogenetic analysis of mantle cell lymphoma (MCL) has offered important evidence helping to decipher the immune pathways leading to its development and also prompting a reappraisal of the views about its ontogeny. In particular, older and more recent studies have demonstrated that MCL is characterized by a highly distinctive immunoglobulin gene repertoire with remarkable predominance of the IGHV3-21 and IGHV4-34 genes; restricted associations of IGHV,IGHD and IGHJ genes, culminating in the creation of quasi-identical ("stereotyped") heavy complementarity-determining region 3 sequences in roughly 10% of cases; and, very precisely targeted and, probably, functionally driven somatic hypermutation, ranging from minimal (in most cases) to pronounced. Furthermore, comparison to other entities, in particular CLL, revealed that several of these immunogenetic features are "MCL-biased". On these grounds, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases.

  • 84.
    Agathangelidis, Andreas
    et al.
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Ljungström, Viktor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Scarfo, Lydia
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Fazi, Claudia
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Gounari, Maria
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy;Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Pandzic, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stamatopoulos, Kostas
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Tonon, Giovanni
    IRCCS Ist Sci San Raffaele, Funct Genom Canc Unit, Div Expt Oncol, Milan, Italy.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 5, p. 865-873Article in journal (Refereed)
    Abstract [en]

    Despite the recent discovery of recurrent driver mutations in chronic lymphocytic leukemia, the genetic factors involved in disease onset remain largely unknown. To address this issue, we per-formed whole-genome sequencing in 11 individuals with monoclonal B-cell lymphocytosis, both of the low-count and high-count subtypes, and 5 patients with ultra-stable chronic lymphocytic leukemia (>10 years without progression from initial diagnosis). All three entities were indistinguishable at the genomic level exhibiting low genomic complexity and similar types of somatic mutations. Exonic mutations were not frequently identified in putative chronic lymphocytic leukemia driver genes in all settings, including low-count monoclonal B-cell lymphocytosis. To corroborate these findings, we also performed deep sequencing in 11 known frequently mutated genes in an extended cohort of 28 monoclonal B-cell lym phocytosis/chronic lymphocytic leukemia cases. Interestingly, shared mutations were detected between clonal B cells and paired polymorphonuclear cells, strengthening the notion that at least a fraction of somatic mutations may occur before disease onset, likely at the hematopoietic stem cell level. Finally, we identified previously unreported non-coding variants targeting pathways relevant to B-cell and chronic lymphocytic leukemia development, likely associated with the acquisition of the characteristic neoplastic phenotype typical of both monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.

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  • 85.
    Agathangelidis, Andreas
    et al.
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Sutton, Lesley Ann
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Hadzidimitriou, Anastasia
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Tresoldi, Cristina
    IRCCS San Raffaele Sci Inst, Div Immunol Transplantat & Infect, Milan, Italy.
    Langerak, Anton W.
    Erasmus Univ, Med Ctr, Lab Med Immunol, Dept Immunol, Rotterdam, Netherlands.
    Belessi, Chrysoula
    Nikea Gen Hosp, Hematol Dept, Piraeus, Greece.
    Davi, Frederic
    Hop La Pitie Salpetriere, AP HP, Dept Hematol, Paris, France;UPMC Univ Paris 06, UMRS 1138, Paris, France.
    Rosenquist, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Stamatopoulos, Kostas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Ghia, Paolo
    IRCCS Ist Scientifico San Raffaele, Div Expt Oncol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation2018In: Journal of Visualized Experiments, E-ISSN 1940-087X, no 141, article id e57787Article in journal (Refereed)
    Abstract [en]

    During B cell maturation, the complex process of immunoglobulin (IG) gene V(D)J recombination coupled with somatic hypermutation (SHM) gives rise to a unique DNA sequence within each individual B cell. Since B cell malignancies result from the clonal expansion of a single cell, IG genes represent a unique molecular signature common to all the malignant cells within an individual patient; thus, IG gene rearrangements can be used as clonal markers. In addition to serving as an important clonal identifier, the IG gene sequence can act as a 'molecular timeline' since it is associated with specific developmental stages and hence reflects the history of the B cell involved in the neoplastic transformation. Moreover, for certain malignancies, in particular chronic lymphocytic leukemia (CLL), the IG gene sequence holds prognostic and potentially predictive capabilities. That said, extrapolating meaningful conclusions from IG gene sequence analysis would be impossible if robust methods and tools were not available to aid in their analysis. This article, drawing on the vast experience of the European Research Initiative on CLL (ERIC), details the technical aspects and essential requirements necessary to ensure reliable and reproducible IG gene sequence analysis in CLL, a test that is now recommended for all CLL patients prior to treatment. More specifically, the various analytical stages are described ranging from the identification of the clonotypic IG gene rearrangement and the determination of the nucleotide sequence to the accurate clinical interpretation of the IG gene sequence data.

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  • 86. Agathangelidis, Andreas
    et al.
    Vardi, Anna
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Stereotyped B-cell receptors in chronic lymphocytic leukemia2014In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 55, no 10, p. 2252-2261Article, review/survey (Refereed)
    Abstract [en]

    Over the last decade, immunogenetic analysis of B-cell receptor immunoglobulins (BcR IGs) has proved to be a particularly fruitful field in chronic lymphocytic leukemia (CLL), not only for understanding disease pathogenesis but also for discriminating clinical subgroups with markedly distinct course and outcome. Of utmost importance was the identification of quasi-identical BcR IGs among unrelated patients with CLL, fittingly coined as "stereotypy," that set the wheels in motion for unraveling the role of antigen(s) in the selection and expansion of the leukemic clones. The categorization of CLL clones into "subsets" according to shared BcR IG structural characteristics provided a compartmentalized view of this otherwise heterogeneous disease, which eventually led to defining strikingly homogeneous groups of patients in terms of: (i) functional properties of the clonal BcR IGs, e. g. BcR reactivity and signaling; (ii) clonal genetic landscape, e. g. genomic aberrations, gene expression/methylation profiles, microRNA signatures; and (iii) clinical course and outcome. The remarkable restriction of the CLL IG gene repertoire, resulting to a great degree from the high impact of BcR IG stereotypy, may also prompt speculations regarding CLL ontogenesis. Overall, the BcR IG molecule justifiably lies at the heart of CLL clinical research, holding the promise of subset-tailored therapies.

  • 87.
    Agathangelidis, Andreas
    et al.
    Inst Appl Biosci, Ctr Res & Technol Hellas, Thessaloniki, Greece.;Natl & Kapodistrian Univ Athens, Sch Sci, Dept Biol, Athens, Greece..
    Vlachonikola, Elisavet
    Inst Appl Biosci, Ctr Res & Technol Hellas, Thessaloniki, Greece.;Aristotle Univ Thessaloniki, Fac Biol, Dept Genet & Mol Biol, Thessaloniki, Greece..
    Davi, Frederic
    Hop La Pitie Salpetriere, APHP, Dept Hematol, Paris, France.;Sorbonne Univ, Paris, France..
    Langerak, Anton W.
    Erasmus MC, Dept Immunol, Lab Med Immunol, Rotterdam, Netherlands..
    Chatzidimitriou, Anastasia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Inst Appl Biosci, Ctr Res & Technol Hellas, Thessaloniki, Greece.
    High-Throughput immunogenetics for precision medicine in cancer2022In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 84, p. 80-88Article in journal (Refereed)
    Abstract [en]

    Cancer is characterized by an extremely complex biological background, which hinders personalized therapeutic interventions. Precision medicine promises to overcome this obstacle through integrating information from different 'subsystems', including the host, the external environment, the tumor itself and the tumor microenvironment. Immunogenetics is an essential tool that allows dissecting both lymphoid cancer ontogeny at both a cell-intrinsic and a cell-extrinsic level, i.e. through characterizing micro-environmental interactions, with a view to precision medicine. This is particularly thanks to the introduction of powerful, high-throughput approaches i.e. next generation sequencing, which allow the comprehensive characterization of immune repertoires. Indeed, NGS immunogenetic analysis (Immune-seq) has emerged as key to both understanding cancer pathogenesis and improving the accuracy of clinical decision making in oncology. Immune-seq has applications in lymphoid malignancies, assisting in the diagnosis e.g. through differentiating from reactive conditions, as well as in disease monitoring through accurate assessment of minimal residual disease. Moreover, Immune-seq facilitates the study of T cell receptor clonal dynamics in critical clinical contexts, including transplantation as well as innovative immunotherapy for solid cancers. The clinical utility of Immune-seq represents the focus of the present contribution, where we highlight what can be achieved but also what must be addressed in order to maximally realize the promise of Immune-seq in precision medicine in cancer.

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  • 88. Agmon-Levin, Nancy
    et al.
    Damoiseaux, Jan
    Kallenberg, Cees
    Sack, Ulrich
    Witte, Torsten
    Herold, Manfred
    Bossuyt, Xavier
    Musset, Lucille
    Cervera, Ricard
    Plaza-Lopez, Aresio
    Dias, Carlos
    Sousa, Maria Jose
    Radice, Antonella
    Eriksson, Catharina
    Hultgren, Olof
    Viander, Markku
    Khamashta, Munther
    Regenass, Stephan
    Coelho Andrade, Luis Eduardo
    Wiik, Allan
    Tincani, Angela
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bloch, Donald B.
    Fritzler, Marvin J.
    Chan, Edward K. L.
    Garcia-De la Torre, I.
    Konstantinov, Konstantin N.
    Lahita, Robert
    Wilson, Merlin
    Vainio, Olli
    Fabien, Nicole
    Sinico, Renato Alberto
    Meroni, Pierluigi
    Shoenfeld, Yehuda
    International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no 1, p. 17-23Article in journal (Refereed)
    Abstract [en]

    Anti-nuclear antibodies (ANA) are fundamental for the diagnosis of autoimmune diseases, and have been determined by indirect immunofluorescence assay (IIFA) for decades. As the demand for ANA testing increased, alternative techniques were developed challenging the classic IIFA. These alternative platforms differ in their antigen profiles, sensitivity and specificity, raising uncertainties regarding standardisation and interpretation of incongruent results. Therefore, an international group of experts has created recommendations for ANA testing by different methods. Two groups of experts participated in this initiative. The European autoimmunity standardization initiative representing 15 European countries and the International Union of Immunologic Societies/World Health Organization/Arthritis Foundation/Centers for Disease Control and Prevention autoantibody standardising committee. A three-step process followed by a Delphi exercise with closed voting was applied. Twenty-five recommendations for determining ANA (1-13), anti-double stranded DNA antibodies (14-18), specific antibodies (19-23) and validation of methods (24-25) were created. Significant differences between experts were observed regarding recommendations 24-25 (p<0.03). Here, we formulated recommendations for the assessment and interpretation of ANA and associated antibodies. Notably, the roles of IIFA as a reference method, and the importance of defining nuclear and cytoplasmic staining, were emphasised, while the need to incorporate alternative automated methods was acknowledged. Various approaches to overcome discrepancies between methods were suggested of which an improved bench-to-bedside communication is of the utmost importance. These recommendations are based on current knowledge and can enable harmonisation of local algorithms for testing and evaluation of ANA and related autoantibodies. Last but not least, new more appropriate terminologies have been suggested.

  • 89.
    Agnarsdóttir, Margrét
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Biomarker Discovery in Cutaneous Malignant Melanoma: A Study Based on Tissue Microarrays and Immunohistochemistry2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The incidence of cutaneous malignant melanoma has increased dramatically in Caucasians the last few decades, an increase that is partly explained by altered sun exposure habits. For the individual patient, with a localized disease, the tumor thickness of the excised lesion is the most important prognostic factor. However, there is a need to identify characteristics that can place patients in certain risk groups.

    In this study, the protein expression of multiple proteins in malignant melanoma tumors was studied, with the aim of identifying potential new candidate biomarkers. Representative samples from melanoma tissues were assembled in a tissue microarray format and protein expression was detected using immunohistochemistry. Multiple cohorts were used and for a subset of proteins the expression was also analyzed in melanocytes in normal skin and in benign nevi. The immunohistochemical staining was evaluated manually and for part of the proteins also with an automated algorithm.

    The protein expression of STX7 was described for the first time in tumors of the melanocytic lineage. Stronger expression of STX7 and SOX10 was seen in superficial spreading melanomas compared with nodular malignant melanomas. An inverse relationship between STX7 expression and T-stage was seen and between SOX10 expression and T-stage and Ki-67, respectively. In a population-based cohort the expression of MITF was analyzed and found to be associated with prognosis. Twenty-one potential biomarkers were analyzed using bioinformatics tools and a protein signature was identified which had a prognostic value independent of T-stage. The protein driving this signature was RBM3, a protein not previously described in malignant melanoma. Other markers included in the signature were MITF, SOX10 and Ki-67.

    In conclusion, the protein expression of numerous potential biomarkers was extensively studied and a new prognostic protein panel was identified which can be of value for risk stratification.

    List of papers
    1. Selective expression of Syntaxin-7 protein in benign melanocytes and malignant melanoma
    Open this publication in new window or tab >>Selective expression of Syntaxin-7 protein in benign melanocytes and malignant melanoma
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    2009 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 8, no 4, p. 1639-1646Article in journal (Refereed) Published
    Abstract [en]

    To search for proteins expressed in human melanocytes and melanoma, we employed an antibody-based proteomics strategy to screen for protein expression in tissue microarrays containing normal tissues, cancer tissues and cell lines. Syntaxin-7 (STX7) was identified as a novel protein, not previously characterized in cells of melanocytic lineage, displaying a cell type-specific protein expression pattern. In tumor tissues, STX7 was expressed in malignant melanoma and lymphoma. The protein was further characterized regarding subcellular localization, specificity, tissue distribution pattern and potential as a diagnostic and prognostic marker using cell lines and tissue microarrays containing normal skin, melanocytic nevi and primary and metastatic melanoma. STX7 was expressed in normal melanocytes, various benign melanocytic nevi, atypical nevi and malignant melanoma. Analysis in two independent melanoma cohorts demonstrated STX7 expression in nearly all investigated tumors, although at varying levels (>90% positive tumors). The expression level of STX7 protein was inversely correlated to tumor stage, suggesting that decreased expression of STX7 is associated with more aggressive tumors. In conclusion, we present protein profiling data for a novel protein showing high sensitivity and specificity for cells of the melanocytic lineage. The presented antibody-based proteomics approach can be used as an effective strategy to identify novel tumor markers and evaluate their potential clinical relevance.

    Keywords
    malignant melanoma, melanocytes, antibody proteomics, tissue microarray, Syntaxin-7
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-105503 (URN)10.1021/pr800745e (DOI)000264928200004 ()19173671 (PubMedID)
    Available from: 2009-06-04 Created: 2009-06-04 Last updated: 2022-01-28Bibliographically approved
    2. SOX10 expression in superficial spreading and nodular malignant melanomas
    Open this publication in new window or tab >>SOX10 expression in superficial spreading and nodular malignant melanomas
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    2010 (English)In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 20, no 6, p. 468-478Article in journal (Refereed) Published
    Abstract [en]

    SOX10 is a transcription factor expressed in nerve cells and melanocytes. The aim of this study was to investigate the protein expression pattern of SOX10 in malignant melanoma tumors and to analyze whether the results correlated with clinical parameters and the proliferation marker Ki-67. Furthermore, proliferation and migration were analyzed in three different cell lines employing SOX10 small interfering RNA-mediated silencing. Expression patterns were determined in 106 primary tumors and 39 metastases in addition to 16 normal skin samples and six benign nevi employing immunohistochemistry and tissue microarrays. The immunohistochemical staining was evaluated manually and with an automated algorithm. SOX10 was strongly expressed in the benign tissues, but for the malignant tumors superficial spreading melanomas stained stronger than nodular malignant melanomas (P=0.008). The staining intensity was also inversely correlated with T-stage (Spearman's ρ=-0.261, P=0.008). Overall survival and time to recurrence were significantly correlated with SOX10 intensity, but not in multivariate analysis including T-stage. With the automated algorithm there was an inverse correlation between the SOX10 staining intensity and the proliferation marker, Ki-67 (ρ=-0.173, P=0.02) and a significant difference in the intensity signal between the benign tissues, the primary tumors and the metastases where the metastases stained the weakest (P≤0.001). SOX10 downregulation resulted in variable effects on proliferation and migration rates in the melanoma cell lines. In conclusion, the SOX10 intensity level differed depending on the tissue studied and SOX10 might have a role in survival. No conclusion regarding the role of SOX10 for in-vitro proliferation and migration could be drawn.

    Keywords
    Immunohistochemistry, malignant melanoma, small interfering RNA, SOX10
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-133423 (URN)10.1097/CMR.0b013e3283403ccd (DOI)000283744100005 ()20890226 (PubMedID)
    Available from: 2010-11-10 Created: 2010-11-10 Last updated: 2022-01-28Bibliographically approved
    3. MITF as a Prognostic Marker in Cutaneous Malignant Melanoma
    Open this publication in new window or tab >>MITF as a Prognostic Marker in Cutaneous Malignant Melanoma
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Microphthalmia associated transcription factor (MITF) protein has a central role in the differentiation and survival of melanocytes. The aim of the study was to investigate whether MITF can be employed as a prognostic marker in patients operated on for cutaneous malignant melanoma.

    Methods: A cohort study design based on information collected from population-based registers. For included patients tissue microarrays and immunohistochemistry were employed to study the protein expression of MITF in the primary malignant melanoma tumors by estimating the fraction of positive tumor cells and the staining intensity.

    Results: The vast majority of tumors expressed MITF in >25% of the tumor cells with a strong staining intensity and looking at these factors individually these patients had a better prognosis. When cell fraction and intensity were combined a high-risk group dying of malignant melanoma was identified as those with 25% -75% of tumor cells staining with weak intensity and those with <25% of tumor cells staining with strong intensity. However, the majority of the deaths occurred in the lower risk groups.

    Conclusions: Although a high-risk group for death in malignant melanoma was identified we conclude that MITF is not useful as a prognostic marker because of the distribution of that particular expression in the population.

    Impact: Our results indicate a bi-phasic pattern of MITF expression and although not useful as a prognostic marker these results are in line with other experimental studies and are relevant to explore further.

     

    Keywords
    MITF, prognosis, survival, immunohistochemistry, tissue microarray
    National Category
    Cell and Molecular Biology
    Research subject
    Cancer Epidemiology; Pathology
    Identifiers
    urn:nbn:se:uu:diva-143436 (URN)
    Available from: 2011-02-16 Created: 2011-01-20 Last updated: 2018-01-12
    4. Protein Biomarkers in Malignant Melanoma: An Image Analysis-Based Study on Melanoma Markers of Potential Clinical Relevance
    Open this publication in new window or tab >>Protein Biomarkers in Malignant Melanoma: An Image Analysis-Based Study on Melanoma Markers of Potential Clinical Relevance
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The thickness of a primary malignant melanoma tumor is the most important prognostic indicator for a patient with primary cutaneous malignant melanoma. To optimize the management and treatment of melanoma patients there is an unmet need to identify characteristics that can further stratify melanoma patients into high or low risk for progressive disease. Despite numerous studies no single marker has yet been shown to add significant prognostic information. An algorithmic approach, combining data from several markers provides an attractive model to identify patients of increased risk of dying from malignant melanoma. The primary aim of the present study was to analyze the correlation between clinical outcome and protein expression patterns of multiple proteins in malignant melanoma tumors using immunohistochemistry and tissue microarrays. Candidate proteins were identified based on a selective and differential expression pattern in melanoma tumors and tested in a cohort of 143 melanoma patients. Protein expression was analyzed using both manual scoring and automated image analysis-based algorithms. We found no single marker of prognosis that was independent of tumor thickness. When combining potential prognostic markers we could define a prognostic index, based on RBM3, MITF, SOX10 and Ki-67, that was independent of tumor thickness in multivariate analysis. Our findings suggest that a good prognosis signature can be identified in melanoma patients with tumors showing a low fraction of Ki-67 positive tumor cells and a high fraction of RBM3 positive tumor cells combined with low intensity levels of SOX10 and MITF.

     

    Keywords
    malignant melanoma, immunohistochemistry, tissue microarray, protein expression, automated analysis, RBM3, SOX10, MITF, Ki-67
    National Category
    Cell and Molecular Biology
    Research subject
    Pathology; Bioinformatics
    Identifiers
    urn:nbn:se:uu:diva-144108 (URN)
    Available from: 2011-02-16 Created: 2011-01-27 Last updated: 2018-01-12
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  • 90.
    Agnarsdóttir, Margrét
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Department of Clinical Pathology, Akademiska University Hospital.
    Popova, Svetlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Department of Clinical Pathology, Akademiska University Hospital.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Department of Clinical Pathology, Akademiska University Hospital.
    Expression of CMV protein pp65 in cutaneous malignant melanoma2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 10, article id e0223854Article in journal (Refereed)
    Abstract [en]

    Human cytomegalovirus (CVM) has been detected by immunohistochemistry (IHC) in brain tumours; however, whether CMV antigen is seen in melanomas has not yet been elucidated. Applying IHC, melanoma tissue was assessed for the expression of pp65, a tegument protein of CMV. Two cohorts were available, cohort-I and II, the latter included also related metastasis. In addition to IHC, in situ hybridisation (ISH) was carried out to assess whether CMV related genetic sequences were detectable in a subset of cases. Seventy per cent of the 142 cases in cohort-I and 50% of the 37 cases in cohort-II displayed immunoreactivity (IR). In both cohorts, the IHC outcome correlated with T-stage (Cohort I: Spearman 0.22, p = 0.01, Cohort II: Fisher exact text 0.04). In 30 of cohort-II cases, when IHC staining was carried out on both the primary tumour and the corresponding metastasis, no change in IR was noted in 53%; in 20%, the IR was lower and in 27% higher in the metastasis when compared with the primary tumour. These results were significant (Fisher exact test 0.03). Applying ISH technique on four tumour cases with detectable pp65 protein, CMV related genetic sequence was not detected. Here, we demonstrate, congruent with observations published for brain tumours, that the protein pp65 is indeed observed in substantial number of melanoma cases with IHC; however, no signal was detected with ISH technique. These findings are in line with previously reported studies, demonstrating that the role of CMV in tumours is still debatable.

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  • 91.
    Agnarsdóttir, Margrét
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Päären, Helen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Vassilaki, Ismini
    The impact of standardized care pathway on reporting time for invasive melanoma: results from one pathology department in Sweden2019In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 124, no 4, p. 260-264Article in journal (Refereed)
    Abstract [en]

    Background: Standardized care pathway (SCP) was introduced by the Swedish health authorities to eliminate unwanted delay in the diagnostics of cancer patients; for melanoma, SCP started in 2016. The aim of this study was to investigate the impact of SCP on reporting time for invasive melanomas.

    Materials and methods: Information on reporting time was collected on all samples handled according to the SCP and on all invasive melanomas diagnosed in 2016–2018 at the Department of Clinical Pathology, Akademiska University Hospital, Uppsala, Sweden.

    Results: During the study period, 205 samples were handled according to the SCP, resulting in 53 cases (26%) diagnosed with invasive melanomas. A total of 301 invasive melanomas from 286 patients were diagnosed during the study period; 67 (22%) were submitted as SCP, 36 (12%) as a general priority case, and 198 (66%) as non-priority. The reporting time for the SCP cases was 8 days, for general priority cases 6 days, and for non-priority cases it was 24 days. The reporting time increased from 18 to 31 days for the non-priority cases and from 15 to 25 days for all cases with invasive melanomas during the study period.

    Conclusion: This study demonstrates prolonged reporting times for invasive melanomas since the implementation of SCP. This is probably caused by the crowd-out effect of the SCP samples, limited personnel resources, and inaccuracy of the clinical diagnosis. SCP might therefore be a suboptimal method to shorten reporting times for invasive melanomas.

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  • 92.
    Agnarsdóttir, Margrét
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Rexhepaj, Elton
    UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Ireland.
    Magnusson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Patil, Tushar
    Lab Surgpath, Mumbai, India.
    Johansson, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Jirström, Karin
    Center for Molecular Pathology, Department of Laboratory Medicine, Skåne University Hospital, Lund University, Malmö, Sweden .
    Uhlen, Mathias
    Department of Proteomics, School of Biotechnology, AlbaNova University Center, KTH-Royal Institute of Technology, SE-10691 Stockholm, Sweden .
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Gallagher, William
    UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Ireland. .
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Protein Biomarkers in Malignant Melanoma: An Image Analysis-Based Study on Melanoma Markers of Potential Clinical RelevanceManuscript (preprint) (Other academic)
    Abstract [en]

    The thickness of a primary malignant melanoma tumor is the most important prognostic indicator for a patient with primary cutaneous malignant melanoma. To optimize the management and treatment of melanoma patients there is an unmet need to identify characteristics that can further stratify melanoma patients into high or low risk for progressive disease. Despite numerous studies no single marker has yet been shown to add significant prognostic information. An algorithmic approach, combining data from several markers provides an attractive model to identify patients of increased risk of dying from malignant melanoma. The primary aim of the present study was to analyze the correlation between clinical outcome and protein expression patterns of multiple proteins in malignant melanoma tumors using immunohistochemistry and tissue microarrays. Candidate proteins were identified based on a selective and differential expression pattern in melanoma tumors and tested in a cohort of 143 melanoma patients. Protein expression was analyzed using both manual scoring and automated image analysis-based algorithms. We found no single marker of prognosis that was independent of tumor thickness. When combining potential prognostic markers we could define a prognostic index, based on RBM3, MITF, SOX10 and Ki-67, that was independent of tumor thickness in multivariate analysis. Our findings suggest that a good prognosis signature can be identified in melanoma patients with tumors showing a low fraction of Ki-67 positive tumor cells and a high fraction of RBM3 positive tumor cells combined with low intensity levels of SOX10 and MITF.

     

  • 93. Agren, Rasmus
    et al.
    Mardinoglu, Adil
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Kampf, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Uhlen, Mathias
    Nielsen, Jens
    Identification of anticancer drugs for hepatocellular carcinoma through personalized genome-scale metabolic modeling2014In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 10, no 3Article in journal (Refereed)
    Abstract [en]

    Synopsis image Personalized GEMs for six hepatocellular carcinoma patients are reconstructed using proteomics data and a task-driven model reconstruction algorithm. These GEMs are used to predict antimetabolites preventing tumor growth in all patients or in individual patients. The presence of proteins encoded by 15,841 genes in tumors from 27 HCC patients is evaluated by immunohistochemistry. Personalized GEMs for six HCC patients and GEMs for 83 healthy cell types are reconstructed based on HMR 2.0 and the tINIT algorithm for task-driven model reconstruction. 101 antimetabolites are predicted to inhibit tumor growth in all patients. Antimetabolite toxicity is tested using the 83 cell type-specific GEMs. An l-carnitine analog inhibits the proliferation of HepG2 cells. Abstract Genome-scale metabolic models (GEMs) have proven useful as scaffolds for the integration of omics data for understanding the genotype-phenotype relationship in a mechanistic manner. Here, we evaluated the presence/absence of proteins encoded by 15,841 genes in 27 hepatocellular carcinoma (HCC) patients using immunohistochemistry. We used this information to reconstruct personalized GEMs for six HCC patients based on the proteomics data, HMR 2.0, and a task-driven model reconstruction algorithm (tINIT). The personalized GEMs were employed to identify anticancer drugs using the concept of antimetabolites; i.e., drugs that are structural analogs to metabolites. The toxicity of each antimetabolite was predicted by assessing the in silico functionality of 83 healthy cell type-specific GEMs, which were also reconstructed with the tINIT algorithm. We predicted 101 antimetabolites that could be effective in preventing tumor growth in all HCC patients, and 46 antimetabolites which were specific to individual patients. Twenty-two of the 101 predicted antimetabolites have already been used in different cancer treatment strategies, while the remaining antimetabolites represent new potential drugs. Finally, one of the identified targets was validated experimentally, and it was confirmed to attenuate growth of the HepG2 cell line.

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  • 94.
    Ahlgren, Kerstin M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grimelius, Lars
    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.
    von Euler, Henrik
    Sundberg, Katarina
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedhammar, Åke
    Andersson, Göran
    Hansson-Hamlin, Helene
    Lernmark, Åke
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 8, p. e105473-Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS:

    Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.

    METHODS:

    Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.

    RESULTS:

    None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.

    CONCLUSIONS/INTERPRETATIONS:

    Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.

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  • 95.
    Ahlgren, Kerstin M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Moretti, Silvia
    Lundgren, Brita Ardesjö
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, Iulia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åhlin, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Norling, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hallgren, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Perheentupa, Jaakko
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Crewther, Pauline E.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bensing, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Scott, Hamish S.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Romani, Luigina
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model2011In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 41, no 1, p. 235-245Article in journal (Refereed)
    Abstract [en]

    Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal failure are hallmarks of the disease. The critical mechanisms causing chronic mucocutaneous candidiasis in APS-1 patients have not been identified although autoantibodies to cytokines are implicated in the pathogenesis. To investigate whether the Th reactivity to Candida albicans (C. albicans) and other stimuli was altered, we isolated PBMC from APS-1 patients and matched healthy controls. The Th17 pathway was upregulated in response to C. albicans in APS-1 patients, whereas the IL-22 secretion was reduced. Autoantibodies against IL-22, IL-17A and IL-17F were detected in sera from APS-1 patients by immunoprecipitation. In addition, Aire-deficient (Aire(0/0) ) mice were much more susceptible than Aire(+/+) mice to mucosal candidiasis and C. albicans-induced Th17- and Th1-cell responses were increased in Aire(0/0) mice. Thus an excessive IL-17A reactivity towards C. albicans was observed in APS-1 patients and Aire(0/0) mice.

  • 96.
    Ahlgren, Sara
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Fondell, Amelie
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Swedish Radiat Safety Author, Res Unit, Solna Strandvag 96, SE-17116 Stockholm, Sweden.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    EGF-targeting lipodisks for specific delivery of poorly water-soluble anticancer agents to tumour cells2017In: RSC Advances, E-ISSN 2046-2069, Vol. 7, no 36, p. 22178-22186Article in journal (Refereed)
    Abstract [en]

    Concerns regarding poor aqueous solubility, high toxicity and lack of specificity impede the translation of many hydrophobic anticancer agents into safe and effective anticancer drugs. The application of colloidal drug delivery systems, and in particular the use of lipid-based nanocarriers, has been identified as a promising means to overcome these issues. PEG-stabilized lipid nanodisks (lipodisks) have lately emerged as a novel type of biocompatible, nontoxic and adaptable drug nanocarrier. In this study we have explored the potential of lipodisks as a platform for formulation and tumour targeted delivery of hydrophobic anticancer agents. Using curcumin as a model compound, we show that lipodisks can be loaded with substantial amounts of hydrophobic drugs (curcumin/lipid molar ratio 0.15). We demonstrate moreover that by deliberate choice of preparation protocols the lipodisks can be provided with relevant amounts of targeting proteins, such as epidermal growth factor (EGF). Data from in vitro cell studies verify that such EGF-decorated curcumin-loaded lipodisks are capable of EGF-receptor specific targeting of human A-431 tumour cells, and strongly suggest that the interaction between the lipodisks and the tumour cells results in receptor-mediated internalization of the disks and their cargo.

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  • 97.
    Ahlin, Cecilia
    et al.
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Lundgren, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Embretsen-Varro, Elin
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Jirstrom, Karin
    Lund Univ, Dept Pathol & Oncol, Lund, Sweden..
    Blomqvist, Carl
    Orebro Univ, Dept Oncol, Orebro, Sweden.;Univ Helsinki, Dept Oncol, Helsinki, Finland..
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers2017In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 164, no 3, p. 667-678Article in journal (Refereed)
    Abstract [en]

    Cyclin D1 has a central role in cell cycle control and is an important component of estrogen regulation of cell cycle progression. We have previously shown that high cyclin D expression is related to aggressive features of ER-positive but not ER-negative breast cancer. The aims of the present study were to validate this differential ER-related effect and furthermore explore the relationship between cyclin D overexpression and CCND1 gene amplification status in a node-negative breast cancer case-control study. Immunohistochemical nuclear expression of cyclin D1 (n = 364) and amplification of the gene CCND1 by fluorescent in situ hybridization (n = 255) was performed on tissue microarray sections from patients with T1-2N0M0 breast cancer. Patients given adjuvant chemotherapy were excluded. The primary event was defined as breast cancer death. Breast cancer-specific survival was analyzed in univariate and multivariable models using conditional logistic regression. Expression of cyclin D1 above the median (61.7%) in ER breast cancer was associated with an increased risk for breast cancer death (OR 3.2 95% CI 1.5-6.8) also when adjusted for tumor size and grade (OR 3.1). No significant prognostic impact of cyclin D1 expression was found among ER-negative cases. Cyclin D1 overexpression was significantly associated to high expression of the proliferation markers cyclins A (rho 0.19, p = 0.006) and B (rho 0.18, p = 0.003) in ER-positive tumors, but not in ER-negative cases. There was a significant association between CCND1 amplification and cyclin D1 expression (p = 0.003), but CCND1 amplification was not statistically significantly prognostic (HR 1.4, 95% CI 0.4-4.4). We confirmed our previous observation that high cyclin D1 expression is associated to high proliferation and a threefold higher risk of death from breast cancer in ER-positive breast cancer.

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  • 98.
    Ahmad, Awais
    et al.
    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 Vi3.
    Cajander, Åsa
    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 Vi3.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ehrsson, Ylva Tiblom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Langegård, Ulrica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Designing for Human Well-Being: A Case Study with Informal Caregivers of Individuals with Cancer2022In: Studies in Health Technology and Informatics, ISSN 0926-9630, E-ISSN 1879-8365, Vol. 294, p. 214-218Article in journal (Refereed)
    Abstract [en]

    Informal Caregivers such as a spouse, other close relatives or friends of cancer patients can play an essential role in home-based treatment and care. However, the informal caregivers might not be prepared for this responsibility, and they might have several unmet requirements for taking care of patients in the home environment. The informal caregivers’ physical, social and psychological health is also profoundly affected due to the health conditions of their relatives. We propose a User-centred Positive Design as a hybrid framework by merging the traditional User-cantered design and positive design frameworks to enhance the informal caregivers’ subjective well-being. Our ongoing project (Carer-eSupport) will be used as a case study, and its main objective is to co-create and evaluate a web-based support system for informal caregivers of people with cancer. The proposed framework can be used for the design and development of health information systems with a special focus on users’ wellbeing and positive emotions.

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  • 99.
    Ahmad, Awais
    et al.
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect, Clin Immunol & Transfus Med, SE-58183 Linköping, Sweden..
    Dahle, Charlotte
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect, Clin Immunol & Transfus Med, SE-58183 Linköping, Sweden..
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sjowall, Christopher
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect Rheumatol, SE-58183 Linköping, Sweden..
    Kechagias, Stergios
    Linköping Univ, Dept Hlth Med & Caring Sci, Div Diagnost & Specialist Med Gastroenterol & Hep, SE-58183 Linköping, Sweden..
    Autoantibodies Associated with Autoimmune Liver Diseases in a Healthy Population: Evaluation of a Commercial Immunoblot Test2022In: Diagnostics, ISSN 2075-4418, Vol. 12, no 7, article id 1572Article in journal (Refereed)
    Abstract [en]

    Autoantibodies constitute important tools for diagnosing the autoimmune liver diseases (AILD) autoimmune hepatitis and primary biliary cholangitis. The EUROLINE immunoblot assay, detecting multiple specificities, is widely used, but the clinical importance of weakly positive findings is unclear. The manufacturer's recommended cut-off was evaluated by investigating AILD-associated autoantibodies in 825 blood donors and 60 confirmed AILD cases. Positive findings were followed up with immunofluorescence microscopy on rat tissue, anti-M2-ELISA, alternative immunoblot assay, and liver function tests. Thirty-six (4.4%) blood donors were positive with EUROLINE. The most common specificities were LC-1 (1.6%), gp210 (1.3%), and AMA-M2 (1.1%). In general, the positive results were higher in patients than in blood donors, whereas anti-LC-1 was higher in blood donors. The liver function tests were slightly elevated in 2 of the 36 immunoblot positive blood donors. The majority of the positive EUROLINE findings could not be confirmed with the follow-up tests. The EUROLINE-Autoimmune Liver Diseases-(IgG) immunoblot detected autoantibodies in 4.4% of blood donors without signs of AILD. Our findings indicate that the recommended cut-off can be raised for most specificities without loss of diagnostic sensitivity. The prevalence of anti-LC-1 among blood donors indicates a problem with the antigen source.

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  • 100.
    Ahmad, Awais
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division Vi3.
    Premanandan, Shweta
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Informatics and Media.
    Langegård, Ulrica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Cajander, Åsa
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division Vi3.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Healthcare Sciences and e-Health.
    Carlsson, Maria E.
    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.
    Ehrsson, Ylva Tiblom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Positive Design Framework for Carer-eSupport: A Qualitative Study to Support Informal Caregivers of Patients with Head and Neck Cancer in Sweden2023In: JMIR Cancer, E-ISSN 2369-1999, Vol. 9, article id e45748Article in journal (Refereed)
    Abstract [en]

    Background: Informal caregivers of patients with head and neck cancer (HNC), such as the patient’s spouse, other close relatives, or friends, can play an important role in home-based treatment and health care. Research shows that informal caregivers are usually unprepared for this responsibility and need support with taking care of patients and other daily life activities. These circumstances place them in a vulnerable position, and their well-being may be compromised. This study is part of our ongoing project Carer eSupport, which aims to develop a web-based intervention to facilitate informal caregivers in the home environment.

    Objective: This study aimed to explore the situation and context of informal caregivers of patients with HNC and their needs for designing and developing a web-based intervention (Carer eSupport). In addition, we proposed a novel framework for the development of a web-based intervention aimed at promoting the well-being of informal caregivers. Methods: Focus groups were conducted with 15 informal caregivers and 13 healthcare professionals. Both informal caregivers and healthcare professionals were recruited from 3 university hospitals in Sweden. We adopted a thematic data analysis process to analyze the data.

    Results: We investigated informal caregivers’ needs, critical factors for adoption, and desired functionalities of Carer eSupport.A total of 4 major themes, including information, web-based forum, virtual meeting place, and chatbot, emerged and were discussed by informal caregivers and health care professionals for Carer eSupport. However, most study participants did not like the idea of a chatbot for asking questions and retrieving information and expressed their concerns such as a lack of trust in robotic technologies and missing human contact while communicating with chatbots. The results from the focus groups were discussed through the lens of positive design research approaches.

    Conclusions: This study provided an in-depth understanding of informal caregivers’ contexts and their preferred functions for a web-based intervention (Carer eSupport). Using the theoretical foundation of designing for well-being and positive design in the informal caregiving context, we proposed a positive design framework to support informal caregivers’ well-being. Our proposed framework might be helpful for human-computer interaction and user experience researchers to design meaningful health interventions with a clear focus on users’ well-being and positive emotions, especially for informal caregivers of patients with HNC.

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