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  • 301.
    Berglund, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Enblad, G
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Flordal, E
    Lui, WO
    Backlin, C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Thunberg, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sundstrom, C
    Department of Genetics and Pathology.
    Roos, G
    Allander, SV
    Erlanson, M
    Rosenquist, R
    Department of Genetics and Pathology.
    Larsson, C
    Lagercrantz, S
    Chromosomal imbalances in diffuse large B-cell lymphoma detected bycomparative genomic hybridization.2002In: Mod Pathol, Vol. 15, p. 807-Article in journal (Refereed)
  • 302.
    Berglund, Mattias
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Amini, Rose-Marie
    Department of Genetics and Pathology.
    Book, Majlis
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rosenquist, Richard
    Department of Genetics and Pathology.
    Roos, Göran
    Thunberg, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Subtype preference of the BCL6397G/C polymorphism in germinal-center and non-germinal-center subtypes of diffuse large B-cell lymphoma.2006In: Blood, ISSN 0006-4971, Vol. 108, no 10, p. 3623-4Article in journal (Refereed)
  • 303.
    Berglund, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Roos, Göran
    Erlanson, Martin
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Larsson, Catharina
    Lagercrantz, Svetlana
    Genomic imbalances during transformation from follicular lymphoma to diffuse large B-cell lymphoma2007In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 20, no 1, p. 63-75Article in journal (Refereed)
    Abstract [en]

    Follicular lymphoma is commonly transformed to a more aggressive diffuse large B-cell lymphoma (DLBCL). In order to molecularely characterize this histiological and clinical transformation, comparative genomic hybridization was applied on 23 follicular lymphoma and 35 transformed DLBCL tumors from a total of 30 patients. The results were also compared with our published findings in de novo DLBCL. Copy number changes were detected in 70% of follicular lymphoma and in 97% of transformed DLBCL. In follicular lymphoma, the most common alterations were +18q21 (33%), +Xq25–26 (28%), +1q31–32 (23%), and -17p (23%), whereas transformed DLBCL most frequently exhibited +Xq25–26 (36%), +12q15 (29%), +7pter-q22 (25%), +8q21 (21%), and -6q16–21(25%). Transformed DLBCL showed significantly more alterations as compared to follicular lymphoma (P=0.0001), and the alterations -6q16–21 and +7pter-q22 were only found in transformed DLBCL but not in follicular lymphoma (P=0.02). Alterations involving +13q22 were significantly less frequent, whereas -4q13–21 was more common in transformed as compared to de novo DLBCL (P=0.01 and P=0.02, respectively). Clinical progression from follicular lymphoma to transformed DLBCL is on the genetic level associated with acquirement of increasing number of genomic copy number changes, with non-random involvement of specific target regions. The findings support diverse genetic background between transformed and de novo DLBCL.

  • 304.
    Berglund, Mattias
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Thunberg, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Amini, Rose-Marie
    Department of Genetics and Pathology.
    Book, Majlis
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Roos, Göran
    Erlanson, Martin
    Linderoth, Johan
    Dictor, Michael
    Jerkeman, Mats
    Cavallin-Ståhl, Eva
    Sundström, Christer
    Department of Genetics and Pathology.
    Rehn-Eriksson, Suzanne
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Backlin, Carin
    Department of Genetics and Pathology.
    Hagberg, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rosenquist, Richard
    Department of Genetics and Pathology.
    Enblad, Gunilla
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Evaluation of immunophenotype in diffuse large B-cell lymphoma and its impact on prognosis.2005In: Mod Pathol, ISSN 0893-3952, Vol. 18, no 8, p. 1113-20Article in journal (Other scientific)
  • 305.
    Berglund, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Fridberg, Marie
    Wingren, Anette Gjörloff
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Leuchowius, Karl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lagercrantz, Svetlana
    Horvat, Andrea
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Establishment of a cell line from a chemotherapy resistant diffuse large B-cell lymphoma2007In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 48, no 5, p. 1038-1041Article in journal (Refereed)
  • 306.
    Berglund, Mattias
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Thunberg, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Roos, Göran
    Rosenquist, Richard
    Department of Genetics and Pathology.
    Enblad, Gunilla
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    The interleukin-10 gene promoter polymorphism (-1082) does not correlate with clinical outcome in diffuse large B-cell lymphoma.2005In: Blood, ISSN 0006-4971, Vol. 105, no 12, p. 4894-5; author reply 4895Article in journal (Other scientific)
  • 307. Bergqvist, Jenny
    et al.
    Elmberger, Goran
    Ohd, John
    Linderholm, Barbro
    Bjohle, Judith
    Hellborg, Henrik
    Nordgren, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Borg, Anna-Lena
    Skoog, Lambert
    Bergh, Jonas
    Activated ERK1/2 and phosphorylated oestrogen receptor alpha are associated with improved breast cancer survival in women treated with tamoxifen.2006In: Eur J Cancer, ISSN 0959-8049, Vol. 42, no 8, p. 1104-12Article in journal (Refereed)
  • 308. Bergsteinsdottir, K
    et al.
    Yang, HT
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Pettersson, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Holmdahl, R
    Evidence for common autoimmune disease genes controlling onset, severity,and chronicity based on experimental models for multiple sclerosis andrheumatoid arthritis.2000In: J Immunol, Vol. 164, p. 1564-Article in journal (Refereed)
  • 309. Bergsteinsdottir, Kristin
    et al.
    Yang, Hai-Tao
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Holmdahl, Rikard
    Pettersson, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Evidence for common autoimmune disease genes controlling onset, severity and chronicity based on experimental models for multiple sclerosis and rheumatoid arthritis1999In: The Journal of ImmunologyArticle, book review (Other scientific)
  • 310.
    Bergstrom, Daniel
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Hermansson, Annika
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Diaz de Stahl, Teresita
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Heldin, Nils-Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Non-autocrine, constitutive activation of Met in human thyroid carcinoma cells in culture.1999In: Br. J. Cancer, Vol. 80, p. 650-Article in journal (Refereed)
  • 311.
    Bergstrom, Daniel
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Nilsson, Mikael
    Heldin, Nils-Erik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Impaired response to hepatocyte growth factor in FRTL-5 rat thyroid cells expressing a functional hepatocyte growth factor2000In: Thyroid, Vol. 10, p. 631-Article in journal (Refereed)
  • 312.
    Bergstrom, Joakim
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Murphy, Charles
    Eulitz, Manfred
    Weiss, Deborah T
    Westermark, Gunilla T
    Solomon, Alan
    Westermark, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Co-deposition of apolipoprotein A-IV and transthyretin in senile systemic (ATTR) amyloidosis2001In: Biochem. Biophys. Res. Commun., Vol. 285, p. 903-Article in journal (Refereed)
  • 313.
    Bergstrom, TF
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Engkvist, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Erlandsson, R
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Josefsson, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Mack, SJ
    Erlich, HA
    Gyllensten, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Tracing the origin of HLA-DRB1 alleles by microsatellite polymorphism.1999In: Am. J. Hum. Genet., Vol. 64, p. 1709-Article in journal (Refereed)
  • 314.
    Bergstrom, TF
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Erlandsson, R
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Engkvist, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Josefsson, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Erlich, HA
    Gyllensten, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Phylogenetic history of hominoid DRB loci and alleles inferred from intronsequences.1999In: Immunol Rev, Vol. 167, p. 351-Article in journal (Refereed)
  • 315.
    Bergström, Daniel
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Growth factor receptor signalling in thyrocytes of normal and neoplastic origin2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cellular growth and function are controlled by stimulatory and inhibitory factors actingthrough specific receptors. The present thesis focuses on the role of growth factors, theirreceptors and signalling pathways in normal and neoplastic thyroid epithelial cell biology.

    Decreased sensitivity towards the growth inhibitory transforming growth factor-β(TGF-β) has been described in various types of carcinomas. This is thought to bemediated by inactivation of TGF-β receptors or the downstream signalling Smad proteins.Effects of TGF-β were evaluated in six anaplastic thyroid carcinoma cell lines andcompared to normal thyrocytes. One tumour cell line did not respond to TGF-β.Interestingly, this was not a result of loss or downregulation of TGF-β receptors or Smadmolecules.

    Hepatocyte and epidermal growth factors (HGF and EGF) are potent mitogens forthyroid epithelial ceils. FRTL-5 cells, commonly used as a model system of normalthyrocytes, were found unresponsive to HGF despite the expression of functional HGFreceptors (Met) and a seemingly normal intracellular signal transduction. Met was foundoverexpressed and constitutively activated in a ligand independent fashion in a majority ofthe investigated anaplastic thyroid carcinoma cell lines. The same cell lines showed a basalactivation of the EGF receptor (EGFR), perhaps as a result of concomitant expression of transforming growth factor-α, one of the EGFR ligands. Upon inhibition of EGFRsignalling Met was downregulated and its tyrosine phosphorylation was diminished,suggesting a cross talk between the two receptors. Furthermore, inhibition of EGFR signalling decreased tumour cell proliferation.

    In summary, evidence of a novel mechanism for TGF-β insensitivity in anaplasticthyroid carcinoma cells is presented. The results also indicate that FRTL-5 cells are oflimited use for studies of normal thyrocyte biology. Moreover, anaplastic thyroidcarcinoma cells have the capacity to overexpress constitutively activated Met, which maybe due to aberrant activation of the EGFR signalling system.

  • 316.
    Bergström, J
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Murphy, CL
    Eulitz, M
    Weiss, DT
    Westermark, GT
    Solomon, A
    Westermark, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Apolipoprotein A-IV codeposited with transthyretin in senile systemic amyloidosis2001Chapter in book (Other scientific)
  • 317.
    Bergström, J.Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Epidermal growth factor receptor signaling activates Met in human anaplastic thyroid carcinoma cells2000In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 259, no 1, p. 293-299Article in journal (Refereed)
    Abstract [en]

    Overexpression of Met is a common finding in thyroid carcinomas. Recently, we reported on overexpression and ligand-independent constitutive activation of Met in anaplastic thyroid carcinoma cells. In the present study we have investigated a putative mechanism for this phenomenon. Cell lines with constitutively activated Met expressed both TGF-alpha mRNA and protein. Western blot analysis revealed expression of receptors for epidermal growth factor (EGFR) in all carcinoma cell lines; in tumor cells with elevated levels of TGF-alpha mRNA there was a constitutive tyrosine phosphorylation of the EGFRs. Preincubation of carcinoma cells with suramin decreased EGFR activation and downregulated Met expression as well as the ligand-independent phosphorylation of Met. Similar results were obtained with a EGFR tyrosine kinase inhibitor, AG 1478. The MEK inhibitor U0126 had an even more pronounced effect compared to AG 1478, indicating a Ras/MAPK-mediated signal in the regulation of Met expression and activation. Inhibition of EGFR signaling also decreased proliferation of the anaplastic thyroid carcinoma cells. Thus, aberrant activation of EGFRs may lead to an overexpression and activation of Met, which may be of importance for the malignant phenotype of anaplastic thyroid carcinomas.

  • 318.
    Bergström, Joakim
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Apolipoprotein A-IV and Transthyretin in Swedish Forms of Systemic Amyloidosis2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Over 20 different plasma proteins have been shown to have the capacity to undergo conformational changes and self-assemble into highly stable and insoluble amyloid fibrils.

    One, transthyretin (TTR), consists of 127 amino acid residues arranged in eight β-strands (named A to H) and is involved in two different clinical forms of amyloidosis. In familial amyloidotic polyneuropathy (FAP), mutated TTR is found in the amyloid deposits while in senile systemic amyloidosis (SSA) only wild type TTR is present in the amyloid deposits.

    In this study, we have identified a novel form of amyloidosis that is caused by the deposition of an N-terminal fragment of apolipoprotein A-IV (apoA-IV). Interestingly, apoA-IV amyloid was found deposited in a patient that also suffered from SSA. Thus, this patient had two biochemically distinct and concurrent forms of amyloidosis that were derived from apoA-IV and TTR.

    We have also discovered that two different morphological deposition patterns (identified as patterns A and B) exist in TTR-derived amyloidosis. Pattern A, observed in all SSA patients studied and in half of the FAP patients examined contained large homogenous deposits that were composed of short randomly oriented fibrils. In contrast, pattern B was observed in the remaining FAP patients and was represented by smaller-sized deposits that consisted of longer fibrils that were arranged in parallel bundles. The predominant TTR component deposited also differed between the two amyloid patterns. Amyloid pattern A contained mainly C-terminal TTR fragments while pattern B amyloid consisted of full-length TTR. Our findings suggest that two different mechanisms of fibril formation may exist in TTR-derived amyloidosis.

    We have found two epitopes, corresponding to strand C and H that are surface-exposed in TTR-derived amyloid fibrils but hidden and part of the hydrophobic core in the native molecular structure. This indicates that TTR undergoes partial unfolding during fibril formation.

    List of papers
    1. Codeposition of apolipoprotein A-IV and transthyretin in senile systemic (ATTR) amyloidosis
    Open this publication in new window or tab >>Codeposition of apolipoprotein A-IV and transthyretin in senile systemic (ATTR) amyloidosis
    Show others...
    2001 In: Biochemical and Biophysical Research Communications, Vol. 285, p. 903-908Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92104 (URN)
    Available from: 2004-09-10 Created: 2004-09-10Bibliographically approved
    2. Two different types of amyloid deposits-apolipoprotein A-IV and transthyretin-in a patient with systemic amyloidosis
    Open this publication in new window or tab >>Two different types of amyloid deposits-apolipoprotein A-IV and transthyretin-in a patient with systemic amyloidosis
    Show others...
    2004 In: Laboratory Investigation, Vol. 84, p. 981-988Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92105 (URN)
    Available from: 2004-09-10 Created: 2004-09-10Bibliographically approved
    3. Amyloid deposits in transthyretin derived amyloidosis: Cleaved transthyretin is associated with distinct amyloid morphology
    Open this publication in new window or tab >>Amyloid deposits in transthyretin derived amyloidosis: Cleaved transthyretin is associated with distinct amyloid morphology
    Show others...
    2005 (English)In: The Internet Journal of Pathology, ISSN 1528-8307, Vol. 206, no 2, p. 224-232Article in journal (Refereed) Published
    Abstract [en]

    The pathological fibrillar deposits found in the heart and other organs of patients with senile systemic amyloidosis (SSA) and Swedish familial amyloidotic polyneuropathy (FAP) contain wild-type (wt) and a mutant form of transthyretin (TTR), respectively. Previously, it was reported that these two forms of amyloid have different molecular features and it was thus postulated that the mechanism responsible for TTR fibrillogenesis in SSA and FAP may differ. To document further the nature of the amyloid in these entities, detailed morphological, histochemical, immunological, and structural analyses of specimens obtained from 14 individuals with SSA and 11 Swedish FAP patients have been performed. Two distinct patterns of amyloid deposition (designated A and B) were evident. In pattern A, found in all SSA and five of 11 FAP cases, the amyloid had a homogeneous but patchy distribution within the sub-endocardium, sub-epicardium, and myocardium; exhibited weak congophilia and green birefringence; and was composed of tightly packed, short, unorientated fibrils. This material contained mainly approximately 79-residue C-terminal fragments of the amyloidogenic precursor protein. In pattern B, seen in the six other FAP patients, the amyloid appeared as thin streaks throughout the cardiac tissue; often surrounded individual muscle cells; was strongly congophilic and birefringent; had long fibrils arranged in parallel bundles, often penetrating into myocytes; and was composed of virtually intact TTR molecules. These findings provide substantive evidence for the morphological and structural heterogeneity of TTR fibrils and suggest that the two types of deposition may reflect fundamental differences in the pathogenesis of the TTR-associated amyloidoses.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-92106 (URN)10.1002/path.1759 (DOI)15810051 (PubMedID)
    Available from: 2004-09-10 Created: 2004-09-10 Last updated: 2017-12-14Bibliographically approved
    4. Structure of in vivo formed transtyretin amyloid fibrils
    Open this publication in new window or tab >>Structure of in vivo formed transtyretin amyloid fibrils
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-92107 (URN)
    Available from: 2004-09-10 Created: 2004-09-10 Last updated: 2010-01-13Bibliographically approved
    Download full text (pdf)
    FULLTEXT01
  • 319.
    Bergström, Joakim
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Engström, Ulla
    Westermark, Per
    Structure of in vivo formed transtyretin amyloid fibrilsManuscript (Other academic)
  • 320.
    Bergström, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Engström, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Yamashita, Taro
    Ando, Yukio
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Surface exposed epitopes and structural heterogeneity of in vivo formed transthyretin amyloid fibrils2006In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 348, no 2, p. 532-539Article in journal (Refereed)
    Abstract [en]

    We have investigated the structure of in vivo formed transthyretin (TTR) amyloid deposits by using antisera raised against short linear sequences of the TTR molecule. In immunohistochemistry, antisera anti-TTR41-50 and anti-TTR115-124-a reacted specifically with both wildtype ATTR and ATTR V30M material, whereas only anti-TTR41-50 recognized ATTR Y114C material. Similar results were obtained by ELISA analysis of ATTR V30M and ATTR Y114C vitreous amyloid, where the anti-TTR115-124-a antiserum failed to react with ATTR Y114C material. Moreover, neither of the antisera recognized natively structured TTR present in pancreatic alpha cells. Our results strongly indicate that the TTR molecule undergoes structural changes during fibrillogenesis in vivo. The finding of a structural difference between wildtype ATTR and ATTR V30M material on one hand and ATTR Y114C material on the other suggests that the fibril formation pathway of these ATTR variants may differ in vivo.

  • 321.
    Bergström, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gustavsson, Åsa
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Sletten, Knut
    Murphy, Charles
    Weiss, Deborah
    Solomon, Alan
    Olofsson, Bert-Ove
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Amyloid deposits in transthyretin derived amyloidosis: Cleaved transthyretin is associated with distinct amyloid morphology2005In: The Internet Journal of Pathology, ISSN 1528-8307, Vol. 206, no 2, p. 224-232Article in journal (Refereed)
    Abstract [en]

    The pathological fibrillar deposits found in the heart and other organs of patients with senile systemic amyloidosis (SSA) and Swedish familial amyloidotic polyneuropathy (FAP) contain wild-type (wt) and a mutant form of transthyretin (TTR), respectively. Previously, it was reported that these two forms of amyloid have different molecular features and it was thus postulated that the mechanism responsible for TTR fibrillogenesis in SSA and FAP may differ. To document further the nature of the amyloid in these entities, detailed morphological, histochemical, immunological, and structural analyses of specimens obtained from 14 individuals with SSA and 11 Swedish FAP patients have been performed. Two distinct patterns of amyloid deposition (designated A and B) were evident. In pattern A, found in all SSA and five of 11 FAP cases, the amyloid had a homogeneous but patchy distribution within the sub-endocardium, sub-epicardium, and myocardium; exhibited weak congophilia and green birefringence; and was composed of tightly packed, short, unorientated fibrils. This material contained mainly approximately 79-residue C-terminal fragments of the amyloidogenic precursor protein. In pattern B, seen in the six other FAP patients, the amyloid appeared as thin streaks throughout the cardiac tissue; often surrounded individual muscle cells; was strongly congophilic and birefringent; had long fibrils arranged in parallel bundles, often penetrating into myocytes; and was composed of virtually intact TTR molecules. These findings provide substantive evidence for the morphological and structural heterogeneity of TTR fibrils and suggest that the two types of deposition may reflect fundamental differences in the pathogenesis of the TTR-associated amyloidoses.

  • 322.
    Bergström, Joakim
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Murphy, Charles
    Eulitz, Manfred
    Weiss, Deborah
    Westermark, Gunilla
    Solomon, Alan
    Westermark, Per
    Weiss, Deborah Tyra
    Codeposition of apolipoprotein A-IV and transthyretin in senile systemic (ATTR) amyloidosis2001In: Biochemical and Biophysical Research Communications, Vol. 285, p. 903-908Article in journal (Refereed)
  • 323.
    Bergström, Joakim
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Murphy, Charles L.
    Weiss, Deborah T.
    Solomon, Alan
    Sletten, Knut
    Hellman, Ulf
    Ludwiginstitutet för Cancerforskning.
    Westermark, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Two different types of amyloid deposits - apolipoprotein A-IV and transthyretin - in a patient with systemic amyloidosis2004In: Lab. Invest., Vol. 84, p. 981-988Article in journal (Refereed)
    Abstract [en]

    Certain forms of systemic amyloidosis have been associated with the pathologic deposition as fibrils of three different apolipoprotein-related proteins--apolipoprotein A-I, apolipoprotein A-II, and serum amyloid A. We have previously reported (Bergstrom et al, Biochem Biophys Res Commun 2001;285:903-908) that amyloid fibrils extracted from the heart of an elderly male with senile systemic amyloidosis contained, in addition to wild-type transthyretin-related molecules, an N-terminal fragment of yet a fourth apolipoprotein--apolipoprotein A-IV (apoA-IV). We now provide the results of our studies that have established the complete amino-acid sequence of this approximately 70-residue component and, additionally, have shown this protein to be the product of an unmutated apoA-IV gene. Notably, the apoA-IV and transthyretin fibrils were not codeposited but, rather, had anatomically distinct patterns of distribution within the heart and other organs, as evidenced immunohistochemically, by variation in the ultra structural morphology and by differences in the intensity of Congo red birefringence. These findings provide the first conclusive evidence that two separate forms of amyloid, each derived from a wild-type amyloidogenic precursor protein, were present in a patient with systemic amyloidosis.

  • 324.
    Bergström, Joakim
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Murphy, Charles
    Weiss, Deborah
    Solomon, Alan
    Sletten, Knut
    Hellman, Ulf
    Westermark, Per
    Two different types of amyloid deposits-apolipoprotein A-IV and transthyretin-in a patient with systemic amyloidosis2004In: Laboratory Investigation, Vol. 84, p. 981-988Article in journal (Refereed)
  • 325.
    Bergström Lind, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Molin, Magnus
    Savitski, Mikhail M.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Emilsson, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Åström, Jonas
    Uppsala BIO.
    Hedberg, Ludwig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Adams, Chris
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Nielsen, Michael
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Andersson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zubarev, Roman
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Immunoaffinity Enrichments Followed by Mass Spectrometric Detection for Studying Global Protein Tyrosine Phosphorylation2008In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 7, no 7, p. 2897-2910Article in journal (Refereed)
    Abstract [en]

    Phosphorylation of protein tyrosine residues regulates important cell functions and is, when dysregulated, often crucially involved in oncogenesis. It is therefore important to develop and evaluate methods for identifying and studying tyrosine phosphorylated (P-Tyr) proteins. P-Tyr proteins are present at very low concentrations within cells, requiring highly selective enrichment methods to be detected. In this study, we applied immunoaffinity as enrichment step for P-Tyr proteins. Five selected anti-phosphotyrosine antibodies (monoclonal antibodies 4G10, PY100, PYKD1, 13F9 and one polyclonal antiserum) were evaluated with respect to their capability to enrich P-Tyr proteins from cell extracts of the K562 leukemia cell line. The enrichment resulted in the detection of a group of proteins that potentially were tyrosine-phosphorylated (putative P-Tyr proteins). High accuracy identification of actual P-Tyr sites were performed using a highly selective and sensitive liquid chromatography Fourier transform mass spectrometer (LC-FTMS) setup with complementary collision activated dissociation (CAD) and electron capture dissociation (ECD) fragmentations. 4G10 and PY100 antibodies recognized the greatest number of putative P-Tyr proteins in initial screening experiments and were therefore further evaluated and compared in immunoaffinity enrichment of both P-Tyr proteins and peptides. Using the 4G10 antibody for enrichment of proteins, we identified 459 putative P-Tyr proteins by MS. Out of these proteins, 12 were directly verified as P-Tyr proteins by MS analysis of the actual site. Using the PY100 antibody for enrichment of peptides, we detected 67 P-Tyr peptides (sites) and 89 putative P-Tyr proteins. Generally, enrichment at the peptide level made it difficult to reliably determine the identity of the proteins. In contrast, protein identification following immunoaffinity enrichment at the protein level gave greater sequence coverage and thus a higher confidence in the protein identification. By combining all available information, 40 proteins were identified as true P-Tyr proteins from the K562 cell line. In conclusion, this study showed that a combination of immunoaffinity enrichment using multiple antibodies of both intact and digested proteins in parallel experiments is required for best possible coverage of all possible P-Tyr proteins in a sample.

  • 326.
    Bergström, T
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Josefsson, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Erlich, H
    Gyllensten, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Recent origin of HLA-DRB1 alleles and implications for human evolution.1998In: Nature Genetics, Vol. 18, p. 237-Article in journal (Refereed)
  • 327.
    Bergström, Tomas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Raser och Gener2005In: Vetenskap eller villfarelse, Leopard förlag , 2005Chapter in book (Other (popular scientific, debate etc.))
  • 328.
    Bergström, Tomas
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Engkvist, Hans
    Erlandsson, Rickard
    Josefsson, Agneta
    Mack, Steve
    Erlich, Henry
    Gyllensten, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Tracing the origin of HLA-DRB1 alleles by microsatellite polymorphism.1999In: Am J Hum Genet, ISSN 0002-9297, Vol. 64, no 6, p. 1709-18Article in journal (Refereed)
    Abstract [en]

    We analyzed the origin of allelic diversity at the class II HLA-DRB1 locus, using a complex microsatellite located in intron 2, close to the polymorphic second exon. A phylogenetic analysis of human, gorilla, and chimpanzee DRB1 sequences indicated that the structure of the microsatellite has evolved, primarily by point mutations, from a putative ancestral (GT)x(GA)y-complex-dinucleotide repeat. In all contemporary DRB1 allelic lineages, with the exception of the human *04 and the gorilla *08 lineages, the (GA)y repeat is interrupted, often by a G-->C substitution. In general, the length of the 3' (GA)y repeat correlates with the allelic lineage and thus evolves more slowly than a middle (GA)z repeat, whose length correlates with specific alleles within the lineage. Comparison of the microsatellite sequence from 30 human DRB1 alleles showed the longer 5' (GT)x to be more variable than the shorter middle (GA)z and 3' (GA)y repeats. Analysis of multiple samples with the same exon sequence, derived from different continents, showed that the 5' (GT)x repeat evolves more rapidly than the middle (GA)z and the 3' (GA)y repeats, which is consistent with findings of a higher mutation rate for longer tracts. The microsatellite-repeat-length variation was used to trace the origin of new DRB1 alleles, such as the new *08 alleles found in the Cayapa people of Ecuador and the Ticuna people of Brazil.

  • 329.
    Bergström, Tomas
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Erlandsson, Rickard
    Engkvist, Hans
    Josefsson, Agneta
    Erlich, Henry
    Gyllensten, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Phylogenetic history of hominoid DRB loci and alleles inferred from intron sequences.1999In: Immunol Rev, ISSN 0105-2896, Vol. 167, p. 351-65Article in journal (Refereed)
    Abstract [en]

    The evolutionary relationships among the MHC class II DRB4, DRB5 and DRB6 loci as well as the allelic lineages and alleles of the DRB1 locus were studied based on intron 1 and intron 2 sequences from humans, chimpanzee (Pan troglodytes), bonobo (Pan paniscus) and gorilla (Gorilla gorilla). The phylogenetic trees for these sequences indicate that most of the DRB1 allelic lineages predate the separation of the hominoid species studied, consistent with previous analysis of the coding sequences of these lineages. However, the intron sequence variation among alleles within DRB1 allelic lineages is very limited, consistent with the notion that the majority of the contemporary alleles have been generated within the last 250,000 years. The clustering of the DRB1 allelic lineages *08 and *12 with *03 supports a common ancestry for the DR8 and DR52 haplotypes. Similarly, the clustering of DRB1 allelic lineages *15 and *01 with the DRB3 locus is consistent with a common ancestry for the DR1 and DR51 haplotypes. Two cases of recombination around the second exon were observed: 1) the HLA-DRB6 locus appears to have been generated through a recombination between a DRB5 allele and an ancestral DRB6 allele, and 2) the gorilla sequence Gogo-DRB1 *03 appears to have been generated through a recombination between the DRB3 locus and an allele from the DRB1 *03 allelic lineage. The nucleotide substitution rate of DRB introns was estimated to 0.85-1.63 x 10(-9) per site per year, based on comparisons between the most closely related sequences from different hominoid species. This estimate is similar to the substitution rate for other intronic regions of the primate genome.

  • 330.
    Bergström, Tomas
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Josefsson, Agneta
    Erlich, Henry
    Gyllensten, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Recent origin of HLA-DRB1 alleles and implications for human evolution.1998In: Nat Genet, ISSN 1061-4036, Vol. 18, no 3, p. 237-42Article in journal (Refereed)
    Abstract [en]

    The HLA class I and class II loci are the most highly polymorphic coding regions in the human genome. Based on the similarity of the coding sequences of alleles between species, it has been claimed that the HLA polymorphism is ancient and predates the separation of human (Homo) and chimpanzee (Pan), 4-7.4 Myr ago. Analysis of intron sequences, however, provides support for a more recent origin and for rapid generation of alleles at the HLA class II DRB1 locus. The human DRB1 alleles can be divided into groups (allelic lineages); most of these lineages have diverged from each other before the separation of Homo and Pan. Alleles within such a lineage, however, appear to be, on average, 250,000 years old, implying that the vast majority (greater than 90%) of the more than 135 contemporary human DRB1 alleles have been generated after the separation of Homo and Pan. The coalescence time of alleles within allelic lineages indicates that the effective population size (Ne) for early hominids (over the last 1 Myr) was approximately 10(4) individuals, similar to estimates based on other nuclear loci and mitochondrial DNA. With a single exception, the genetic mechanisms (gene conversion and point mutation) that have diversified the exon-2 sequences do not appear to extend into the adjacent intron sequences. The part of exon 2 encoding the beta-sheet evolves in concert with the surrounding introns, while the alpha-helix appears to have been subjected to gene conversion-like events, suggesting that such exchange events are highly localised and occur over extremely short sequence tracts.

  • 331.
    Berne, B
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Ponten, J
    Department of Genetics and Pathology.
    Ponten, F
    Decreased p53 expression in chronically sunexposed human skin after topical photoprotection.1998In: Photodermatology, Photoimmunology & Photomedicine, Vol. 14, p. 148-Article in journal (Refereed)
  • 332. Berrington de Gonzales, A
    et al.
    Ekbom, A
    Glass, AG
    Galanti, MR
    Grimelius, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Allison, MJ
    Inskip, PD
    Comparison of documented and recalled histories of exposure to diagnostic x-rays i case-control studies of thyroid cancer2003In: Am. J. Epidemiol., Vol. 157, p. 652-Article in journal (Refereed)
  • 333.
    Berstrom, T
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    U, Gyllensten
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Evolution of Mhc Class II polymorphism: The rise and fall of class II gene function in primates.1995In: Ann. Rev. Immunology,, Vol. 143, p. 13-Article in journal (Refereed)
  • 334.
    Bersztel, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Wanders, A
    Department of Genetics and Pathology.
    Wadstrom, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Ekberg, H
    Olausson, M
    Tufveson, G
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Gannedahl, G
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Deoxyspergualin is synergistic with cyclosporin A, but not with FK506 in a rat heart allograft transplantation model.1995In: Transplant Proc, Vol. 27, p. 3547Other (Other scientific)
  • 335.
    Beskow, AH
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Josefsson, AM
    Gyllensten, UB
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    HLA class II alleles associated with infection by HPV16 in cervical cancerin situ.2001In: Int J Cancer, Vol. 93, p. 817-Article in journal (Refereed)
  • 336.
    Beskow, Anna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Genetic Risk Factors for Cervical Carcinoma in situ2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Oncogenic human papillomaviruses (HPVs) are implicated in 99.7 % of cervical cancer cases but require the co-operation of other factors. To investigate potential genetic risk factors we have typed the HLA class II DRB1 and DQB1 loci in 478 women diagnosed with cervical carcinoma in situ and in 608 age-matched controls. Quantitative measurements of HPV 16, HPV 18/45 and HPV 31 were obtained. The DRB1*1501 and DQB1*0602 alleles were found to increase the risk of HPV 16 infection. Carriers of DRB1*1501 and DQB1*0602 were also shown to have an increased risk of a higher viral load compared to non-carriers. The DRB1*1301 and DQB1*0603 alleles were found to protect from HPV 18/45 and 31 infections as well as resulting in a lower viral load in carriers compared to non-carriers. Women with a high HPV 16, 18/45 or 31 viral load were more prone to long-term infections and women with a low HPV 16 viral load were more prone to short-term infections. Carriers of DRB1*1501 and DQB1*0602 alleles were also shown to have an increased risk of long-term infections compared to short-term infections. We also tested if an HPV susceptibility locus found for epidermodysplasia verruciformis (EV) was also linked to HPV susceptibility in cervical cancer. We did not find any linkage to this locus in a set of 77 families, each with at least three cases diagnosed with cervical carcinoma in situ. Other potential risk factors tested were HPV 16 E6 variants together with a p53 codon 72 polymorphism and HLA class II alleles. We found an association between the E6 L83V variant and the HLA DR4-DQ3 haplotype, as well as an increased frequency of Arg homozygosity of p53 in women infected with the L83V variant. These results show that alleles at HLA class II loci represents risk factors for persistent HPV infection and thereby also contribute to the risk of development of cervical carcinoma in situ.

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  • 337.
    Beskow, Anna
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Gyllensten, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Host genetic control of HPV 16 titer in carcinoma in situ of the cervix uteri.2002In: Int J Cancer. , Vol. 101, p. 526-Article in journal (Refereed)
  • 338.
    Beskow, Anna H.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    cDNA Sequencing of Nuclear NADH Dehydrogenase Subunit Genes in Complex I Deficient Myopathic Patients2000In: Gene Funct. Dis., Vol. 1Other (Other scientific)
  • 339.
    Beskow, Anna H.
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Engelmark, Malin T.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Magnusson, Jessica J.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Gyllensten, Ulf B.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Interaction of host and viral risk factors for development of cervical carcinoma in situ2005In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 117, no 4, p. 690-692Article in journal (Other academic)
    Abstract [en]

    Infection by oncogenic human papillomavirus (HPV) is a necessary but not sufficient cause of cervical carcinoma. Several host genetic and viral factors have been reported to increase the risk of carcinoma development given an HPV infection. In our study, we have analysed the contribution of HPV 16 E6 sequence subtype and allelic variation at human leukocyte antigen (HLA) class II loci to the risk of developing cervical carcinoma in situ. Non-European-like HPV 16 E6 sequence subtypes were not found to be associated with an increased risk of cervical carcinoma, as compared to European-like variants. However, an association was found between the HPV 16 E6 L83V variant and the DR*04-DQ*03 haplotype. This association has been observed in several independent studies and shows that both the host HLA class II genotype and viral subtype will affect the risk of an infection progressing into cervical carcinoma.

  • 340. Beskow, Anna H
    et al.
    Moberg, Martin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Gyllensten, Ulf B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri.2005In: Int J Cancer, ISSN 0020-7136, Vol. 117, no 3, p. 510-4Article in journal (Refereed)
  • 341. Beskow, Anna
    et al.
    Moberg, Martin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Gyllensten, Ulf
    HLA class II allele control of HPV load in carcinoma in situ of the cervix uteriManuscript (Other academic)
  • 342.
    Beskow, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rönnholm, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Magnusson, Patrik K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gyllensten, Ulf B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Susceptibility locus for epidermodysplasia verruciformis not linked to cervical cancer in situ2001In: Hereditas, ISSN 0018-0661, E-ISSN 1601-5223, Vol. 135, no 1, p. 61-63Article in journal (Refereed)
    Abstract [en]

    Cervical cancer is strongly associated with infection by oncogenic forms of human papillomavirus (HPV), mainly HPV 16 and HPV 18. The aim of this study was to test if a locus previously mapped to a region on chromosome 17 qter in patients with epidermodysplasia verucciformis (EV) and psoriasis and considered to be responsible for an increased susceptibility to HPV 5, also is linked to increased HPV susceptibility in cervical cancer in situ. We also wanted to test whether HPV 16 positivity cluster in families with cervical cancer. DNA was extracted from formalin fixed biopsies of 224 affected from 77 families diagnosed with cervical cancer in situ. Two microsatellite markers (D17S939 and D17S802) containing the locus were genotyped and linkage analysis was performed. No linkage was found to any of the two markers, neither when considering all cancer cases as affected nor when only considering HPV 16 infected cancer cases as affected in the analysis. We conclude that the susceptibility locus for HPV 5 infections associated with EV and psoriasis does not seem to affect susceptibility to HPV 16, frequently detected in cervical cancer. Also, positivity for HPV 16 did not show a significant clustering in families.

  • 343. Bhattacharya, Resham
    et al.
    Kwon, Junhye
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wang, Enfeng
    Patra, Sujata
    Bida, John Paul
    Bajzer, Zeljko
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mukhopadhyay, Debabrata
    Distinct role of PLC{beta}3 in VEGF-mediated directional migration and vascular sprouting2009In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 122, no 7, p. 1025-1034Article in journal (Refereed)
    Abstract [en]

    Endothelial cell proliferation and migration is essential to angiogenesis. Typically, proliferation and chemotaxis of endothelial cells is driven by growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). VEGF activates phospholipases (PLCs) - specifically PLCgamma1 - that are important for tubulogenesis, differentiation and DNA synthesis. However, we show here that VEGF, specifically through VEGFR2, induces phosphorylation of two serine residues on PLCbeta3, and this was confirmed in an ex vivo embryoid body model. Knockdown of PLCbeta3 in HUVEC cells affects IP3 production, actin reorganization, migration and proliferation; whereas migration is inhibited, proliferation is enhanced. Our data suggest that enhanced proliferation is precipitated by an accelerated cell cycle, and decreased migration by an inability to activate CDC42. Given that PLCbeta3 is typically known as an effector of heterotrimeric G-proteins, our data demonstrate a unique crosstalk between the G-protein and receptor tyrosine kinase (RTK) axes and reveal a novel molecular mechanism of VEGF signaling and, thus, angiogenesis.

  • 344.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Filén, Frej
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Ruutu, Mirja
    Garmo, Hans
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nordling, Stig
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Andersson, Swen-Olof
    Bratell, Stefan
    Spångberg, Anders
    Palmgren, Juni
    Adami, Hans-Olov
    Johansson, Jan-Erik
    Lindeborg, T.
    Einarsson, G.
    Ekman, P.
    Wijkström, H.
    Karlberg, L.
    Hagberg, G.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    de la Torre, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hamberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lindgren, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mavadati, E.
    Gobén, B.
    Pettersson, I.
    Damber, J.E.
    Lindgren, A.
    Varenhorst, E.
    Norlén, B.J.
    Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial2008In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 100, no 16, p. 1144-54Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The benefit of radical prostatectomy in patients with early prostate cancer has been assessed in only one randomized trial. In 2005, we reported that radical prostatectomy improved prostate cancer survival compared with watchful waiting after a median of 8.2 years of follow-up. We now report results after 3 more years of follow-up. METHODS: From October 1, 1989, through February 28, 1999, 695 men with clinically localized prostate cancer were randomly assigned to radical prostatectomy (n = 347) or watchful waiting (n = 348). Follow-up was complete through December 31, 2006, with histopathologic review and blinded evaluation of causes of death. Relative risks (RRs) were estimated using the Cox proportional hazards model. Statistical tests were two-sided. RESULTS: During a median of 10.8 years of follow-up (range = 3 weeks to 17.2 years), 137 men in the surgery group and 156 in the watchful waiting group died (P = .09). For 47 of the 347 men (13.5%) who were randomly assigned to surgery and 68 of the 348 men (19.5%) who were not, death was due to prostate cancer. The difference in cumulative incidence of death due to prostate cancer remained stable after about 10 years of follow-up. At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% confidence interval [CI] = 0.2 to 11.1%), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03). The difference in cumulative incidence of distant metastases did not increase beyond 10 years of follow-up. At 12 years, 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2%), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). Among men who underwent radical prostatectomy, those with extracapsular tumor growth had 14 times the risk of prostate cancer death as those without it (RR = 14.2, 95% CI = 3.3 to 61.8; P < .001). CONCLUSION: Radical prostatectomy reduces prostate cancer mortality and risk of metastases with little or no further increase in benefit 10 or more years after surgery.

  • 345.
    Bill-Axelson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ruutu, Mirja
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Andersson, Sven-Olof
    Bratell, Stefan
    Spångberg, Anders
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nordling, Stig
    Garmo, Hans
    Palmgren, J
    Adami, HO
    Norlén, Bo Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Johansson, JE
    Radical prostatectomy versus watchful waiting in early prostate cancer2005In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 352, no 19, p. 1977-1944Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    In 2002, we reported the initial results of a trial comparing radical prostatectomy with watchful waiting in the management of early prostate cancer. After three more years of follow-up, we report estimated 10-year results.

    METHODS:

    From October 1989 through February 1999, 695 men with early prostate cancer (mean age, 64.7 years) were randomly assigned to radical prostatectomy (347 men) or watchful waiting (348 men). The follow-up was complete through 2003, with blinded evaluation of the causes of death. The primary end point was death due to prostate cancer; the secondary end points were death from any cause, metastasis, and local progression.

    RESULTS:

    During a median of 8.2 years of follow-up, 83 men in the surgery group and 106 men in the watchful-waiting group died (P=0.04). In 30 of the 347 men assigned to surgery (8.6 percent) and 50 of the 348 men assigned to watchful waiting (14.4 percent), death was due to prostate cancer. The difference in the cumulative incidence of death due to prostate cancer increased from 2.0 percentage points after 5 years to 5.3 percentage points after 10 years, for a relative risk of 0.56 (95 percent confidence interval, 0.36 to 0.88; P=0.01 by Gray's test). For distant metastasis, the corresponding increase was from 1.7 to 10.2 percentage points, for a relative risk in the surgery group of 0.60 (95 percent confidence interval, 0.42 to 0.86; P=0.004 by Gray's test), and for local progression, the increase was from 19.1 to 25.1 percentage points, for a relative risk of 0.33 (95 percent confidence interval, 0.25 to 0.44; P<0.001 by Gray's test).

    CONCLUSIONS:

    Radical prostatectomy reduces disease-specific mortality, overall mortality, and the risks of metastasis and local progression. The absolute reduction in the risk of death after 10 years is small, but the reductions in the risks of metastasis and local tumor progression are substantial.

  • 346.
    Bin Kaderi, Mohamed Arifin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the GNAS1, BCL2 and MDM2 genes and the RNA expression levels of the LPL, ZAP70, TCL1, CLLU1 and MCL1 genes were suggested as novel prognostic markers in CLL.

    In papers I-III, we performed genotyping analyses of the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL.

    In paper IV, we measured the RNA expression levels of LPL, ZAP70, TCL1, CLLU1 and MCL1 in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except MCL1, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for LPL and CLLU1 expression. Among the RNA-based markers, multivariate analysis revealed LPL expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results.

    In summary, data from papers I-III could not verify the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that LPL expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize LPL quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.

    List of papers
    1. The GNAS1 T393C polymorphism and lack of clinical prognostic value in chronic lymphocytic leukemia
    Open this publication in new window or tab >>The GNAS1 T393C polymorphism and lack of clinical prognostic value in chronic lymphocytic leukemia
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    2008 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 32, no 6, p. 984-987Article in journal (Refereed) Published
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with no known single predisposing genetic factor shown in all cases. Recently, a single nucleotide polymorphism (SNP) T393C in the GNAS1 gene has been reported to have a clinical impact on CLL progression and overall survival. In order to further investigate the T393C SNP in CLL, we have genotyped 279 CLL cases and correlated the genotypes to clinical outcome and other known prognostic factors such as the immunoglobulin heavy chain variable (IGHV) gene mutation status and CD38 expression. In the present study, no difference in overall survival or time to treatment was observed in the CLL patients with the different genotypes in contrast to the previous report. Furthermore, no correlation was observed with the T393C genotypes and IGHV mutational status, Binet stage or CD38 in this cohort. In summary, our data does not support the use of the T393C GNAS SNP as a clinical prognostic factor in CLL.

    Keywords
    GNAS1 T393C single nucleotide polymorphism, chronic lymphocytic leukemia prognosis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-13005 (URN)10.1016/j.leukres.2007.10.003 (DOI)000255269100021 ()18006055 (PubMedID)
    Available from: 2008-01-20 Created: 2008-01-20 Last updated: 2017-12-11Bibliographically approved
    2. The BCL-2 promoter (-938C>A) polymorphism does not predict clinical outcome in chronic lymphocytic leukemia
    Open this publication in new window or tab >>The BCL-2 promoter (-938C>A) polymorphism does not predict clinical outcome in chronic lymphocytic leukemia
    Show others...
    2008 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 22, no 2, p. 339-343Article in journal (Refereed) Published
    Abstract [en]

    The (-938C>A) polymorphism in the promoter region of the BCL-2 gene was recently associated with inferior time to treatment and overall survival in B-cell chronic lymphocytic leukemia (CLL) patients displaying the -938A/A genotype and may thus serve as an unfavorable genetic marker in CLL. Furthermore, the -938A/A genotype was associated with increased expression of Bcl-2. To investigate this further, we analyzed the -938 genotypes of the BCL-2 gene in 268 CLL patients and correlated data with treatment status, overall survival and known prognostic factors, for example, Binet stage, immunoglobulin heavy-chain variable (IGHV) mutational status and CD38 expression. In contrast to the recent report, the current cohort of CLL patients showed no differences either in time to treatment or overall survival in relation to usage of a particular genotype. In addition, no correlation was evident between the (-938C>A) genotypes and IGHV mutational status, Binet stage or CD38. Furthermore, the polymorphism did not appear to affect the Bcl-2 expression at the RNA level. Taken together, our data do not support the use of the (-938C>A) BCL-2 polymorphism as a prognostic marker in CLL and argue against its postulated role in modulating Bcl-2 levels.

    Keywords
    chronic lymphocytic leukemia, BCL-2 promoter polymorphism, immunoglobulin heavy-chain variable gene mutation status, Binet stage, CD38, prognosis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-13004 (URN)10.1038/sj.leu.2405042 (DOI)000253166900015 ()18046447 (PubMedID)
    Available from: 2008-01-20 Created: 2009-01-12 Last updated: 2017-12-11Bibliographically approved
    3. Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia
    Open this publication in new window or tab >>Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia
    Show others...
    2010 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 34, no 3, p. 335-339Article in journal (Refereed) Published
    Abstract [en]

    The 309T>G polymorphism in the promoter region of the MDM2gene, known as SNP309, has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. To investigate this further, we analyzed the MDM2 SNP309 genotypes in 418 CLL patients and correlated the results with established CLL prognostic factors, time to treatment and overall survival. In this Swedish cohort, no association existed between any particular MDM2 SNP309 genotype, overall survival and time to treatment. Furthermore, no correlation was shown between the MDM2 SNP309 genotypes and Binet stage, IGHV mutational status and recurrent genomic aberrations. In summary, this study argues against the use of the MDM2 SNP309 as a prognostic marker in CLL.

    Keywords
    MDM2 SNP309, Chronic lymphocytic leukemia, Binet stage, IGHV mutational status, Genomic aberrations, Prognostic markers
    National Category
    Medical and Health Sciences
    Research subject
    Clinical Genetics; Medicine; Oncology; Medical Genetics; Molecular Genetics
    Identifiers
    urn:nbn:se:uu:diva-111075 (URN)10.1016/j.leukres.2009.06.006 (DOI)000274529600013 ()19573916 (PubMedID)
    Available from: 2009-12-02 Created: 2009-12-02 Last updated: 2017-12-12Bibliographically approved
    4. LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia
    Open this publication in new window or tab >>LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia
    Show others...
    2011 (English)In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 96, no 8, p. 1153-1160Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    The expression levels of LPL, ZAP70, TCL1A, CLLU1 and MCL1 have recently been proposed as prognostic factors in chronic lymphocytic leukemia. However, few studies have systematically compared these different RNA-based markers.

    DESIGN AND METHODS:

    Using real-time quantitative PCR, we measured the mRNA expression levels of these genes in unsorted samples from 252 newly diagnosed chronic lymphocytic leukemia patients and correlated our data with established prognostic markers (for example Binet stage, CD38, IGHV gene mutational status and genomic aberrations) and clinical outcome.

    RESULTS:

    High expression levels of all RNA-based markers, except MCL1, predicted shorter overall survival and time to treatment, with LPL being the most significant. In multivariate analysis including the RNA-based markers, LPL expression was the only independent prognostic marker for overall survival and time to treatment. When studying LPL expression and the established markers, LPL expression retained its independent prognostic strength for overall survival. All of the RNA-based markers, albeit with varying ability, added prognostic information to established markers, with LPL expression giving the most significant results. Notably, high LPL expression predicted a worse outcome in good-prognosis subgroups, such as patients with mutated IGHV genes, Binet stage A, CD38 negativity or favorable cytogenetics. In particular, the combination of LPL expression and CD38 could further stratify Binet stage A patients.

    CONCLUSIONS:

    LPL expression is the strongest RNA-based prognostic marker in chronic lymphocytic leukemia that could potentially be applied to predict outcome in the clinical setting, particularly in the large group of patients with favorable prognosis.

    National Category
    Medical and Health Sciences Medical Genetics Cancer and Oncology
    Research subject
    Clinical Genetics; Medical Genetics; Oncology
    Identifiers
    urn:nbn:se:uu:diva-111078 (URN)10.3324/haematol.2010.039396 (DOI)000294722700013 ()21508119 (PubMedID)
    Available from: 2009-12-02 Created: 2009-12-02 Last updated: 2018-01-12Bibliographically approved
    Download full text (pdf)
    FULLTEXT01
  • 347.
    Bindra, Amarinder
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Muradrasoli, Shaman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Kisekka, Robinah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Search for DNA of exogenous mouse mammary tumor virus-related virus in human breast cancer samples2007In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 88, p. 1806-1809Article in journal (Refereed)
    Abstract [en]

    Earlier reports of a human exogenous retrovirus (HMTV) related closely to mouse mammary tumor virus (MMTV) led us to search for these viral sequences in breast cancer tissues and normal tissues. A real-time PCR was developed based on MMTV and published HMTV envelope sequences. The real-time PCR method can detect one to ten copies of MMTV target DNA. Tissue samples were collected prospectively from 18 breast cancer patients and 11 non-malignant control cases, as well as peripheral blood leukocytes from the same women. Despite the high sensitivity of the real-time PCR method used, none of the samples were positive for HMTV DNA or RNA. The absence of HMTV DNA in both breast cancer samples and controls indicates either that the concentration of putative HMTV DNA in the breast cancers was too low for detection or that it did not exist there.

  • 348.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dahl, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Evaluation of beta globin mRNA as an early marker of haemoglobin response to epoetin treatment2007In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 24, no 3, p. 318-322Article in journal (Refereed)
    Abstract [en]

    Approximately 60% of anaemic cancer patients respond to epoetin treatment. An early marker of response would be valuable in order to avoid ineffective treatment. We have previously shown that beta globin mRNA increases rapidly after epoetin beta treatment of healthy controls. In the present study we have evaluated whether a change of this marker during the first 2 weeks of epoetin treatment could predict later Hb response in anaemic cancer patients. Twenty cancer patients with Hb <11 g/dl received epoetin beta (NeoRecormon®) 10,000 IU three times weekly during 6 weeks. Hb, reticulocytes and β-globin mRNA were followed. The latter was measured quantitatively using PCR via the 5′ nuclease assay. Eleven patients responded with a Hb increase of >1 g/dl, nine were nonresponders. All responders increased in β-globin mRNA within 2 weeks, mean 7.7× base-line. With a cut-off of an increase of 3× base-line value, we obtained a specificity of 45% and a sensitivity of 91% for the prediction of a later increase of Hb >1 g/dl. With a cut-off of 4× base-line, the specificity increased to 66%, but the sensitivity decreased to 82%. Beta globin mRNA increases before Hb in all responding patients. However, some non-responding patients also show an increase, and there is a trade-off between specificity and sensitivity as the cut-off level is set at different levels. Compared to reticulocyte count, β-globin mRNA is more reliable in the individual patient, but the clinical usefulness of the assay needs to be evaluated in further studies.

     

  • 349. Birney, Ewan
    et al.
    Hudson, Thomas J.
    Green, Eric D.
    Gunter, Chris
    Eddy, Sean
    Rogers, Jane
    Harris, Jennifer R.
    Ehrlich, S. Dusko
    Apweiler, Rolf
    Austin, Christopher P.
    Berglund, Lisa
    Bobrow, Martin
    Bountra, Chas
    Brookes, Anthony J.
    Cambon-Thomsen, Anne
    Carter, Nigel P.
    Chisholm, Rex L.
    Contreras, Jorge L.
    Cooke, Robert M.
    Crosby, William L.
    Dewar, Ken
    Durbin, Richard
    Dyke, Stephanie O. M.
    Ecker, Joseph R.
    El Emam, Khaled
    Feuk, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gabriel, Stacey B.
    Gallacher, John
    Gelbart, William M.
    Granell, Antoni
    Guarner, Francisco
    Hubbard, Tim
    Jackson, Scott A.
    Jennings, Jennifer L.
    Joly, Yann
    Jones, Steven M.
    Kaye, Jane
    Kennedy, Karen L.
    Knoppers, Bartha Maria
    Kyrpides, Nikos C.
    Lowrance, William W.
    Luo, Jingchu
    MacKay, John J.
    Martín-Rivera, Luis
    McCombie, W. Richard
    McPherson, John D.
    Miller, Linda
    Miller, Webb
    Moerman, Don
    Mooser, Vincent
    Morton, Cynthia C.
    Ostell, James M.
    Ouellette, B. F. Francis
    Parkhill, Julian
    Raina, Parminder S.
    Rawlings, Christopher
    Scherer, Steven E.
    Scherer, Stephen W.
    Schofield, Paul N.
    Sensen, Christoph W.
    Stodden, Victoria C.
    Sussman, Michael R.
    Tanaka, Toshihiro
    Thornton, Janet
    Tsunoda, Tatsuhiko
    Valle, David
    Vuorio, Eero I.
    Walker, Neil M.
    Wallace, Susan
    Weinstock, George
    Whitman, William B.
    Worley, Kim C.
    Wu, Cathy
    Wu, Jiayan
    Yu, Jun
    Prepublication data sharing2009In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 461, no 7261, p. 168-170Article in journal (Refereed)
    Abstract [en]

    Rapid release of prepublication data has served the field of genomics well. Attendees at a workshop in Toronto recommend extending the practice to other biological data sets.

  • 350. Birney, Ewan
    et al.
    Stamatoyannopoulos, John A.
    Dutta, Anindya
    Guigó, Roderic
    Gingeras, Thomas R.
    Margulies, Elliott H.
    Weng, Zhiping
    Snyder, Michael
    Dermitzakis, Emmanouil T.
    Thurman, Robert E.
    Kuehn, Michael S.
    Taylor, Christopher M.
    Neph, Shane
    Koch, Christoph M.
    Asthana, Saurabh
    Malhotra, Ankit
    Adzhubei, Ivan
    Greenbaum, Jason A.
    Andrews, Robert M.
    Flicek, Paul
    Boyle, Patrick J.
    Cao, Hua
    Carter, Nigel P.
    Clelland, Gayle K.
    Davis, Sean
    Day, Nathan
    Dhami, Pawandeep
    Dillon, Shane C.
    Dorschner, Michael O.
    Fiegler, Heike
    Giresi, Paul G.
    Goldy, Jeff
    Hawrylycz, Michael
    Haydock, Andrew
    Humbert, Richard
    James, Keith D.
    Johnson, Brett E.
    Johnson, Ericka M.
    Frum, Tristan T.
    Rosenzweig, Elizabeth R.
    Karnani, Neerja
    Lee, Kirsten
    Lefebvre, Gregory C.
    Navas, Patrick A.
    Neri, Fidencio
    Parker, Stephen C.
    Sabo, Peter J.
    Sandstrom, Richard
    Shafer, Anthony
    Vetrie, David
    Weaver, Molly
    Wilcox, Sarah
    Yu, Man
    Collins, Francis S.
    Dekker, Job
    Lieb, Jason D.
    Tullius, Thomas D.
    Crawford, Gregory E.
    Sunyaev, Shamil
    Noble, William S.
    Dunham, Ian
    Denoeud, France
    Reymond, Alexandre
    Kapranov, Philipp
    Rozowsky, Joel
    Zheng, Deyou
    Castelo, Robert
    Frankish, Adam
    Harrow, Jennifer
    Ghosh, Srinka
    Sandelin, Albin
    Hofacker, Ivo L.
    Baertsch, Robert
    Keefe, Damian
    Dike, Sujit
    Cheng, Jill
    Hirsch, Heather A.
    Sekinger, Edward A.
    Lagarde, Julien
    Abril, Josep F.
    Shahab, Atif
    Flamm, Christoph
    Fried, Claudia
    Hackermüller, Jörg
    Hertel, Jana
    Lindemeyer, Manja
    Missal, Kristin
    Tanzer, Andrea
    Washietl, Stefan
    Korbel, Jan
    Emanuelsson, Olof
    Pedersen, Jakob S.
    Holroyd, Nancy
    Taylor, Ruth
    Swarbreck, David
    Matthews, Nicholas
    Dickson, Mark C.
    Thomas, Daryl J.
    Weirauch, Matthew T.
    Gilbert, James
    Drenkow, Jorg
    Bell, Ian
    Zhao, XiaoDong
    Srinivasan, K. G.
    Sung, Wing-Kin
    Ooi, Hong Sain
    Chiu, Kuo Ping
    Foissac, Sylvain
    Alioto, Tyler
    Brent, Michael
    Pachter, Lior
    Tress, Michael L.
    Valencia, Alfonso
    Choo, Siew Woh
    Choo, Chiou Yu
    Ucla, Catherine
    Manzano, Caroline
    Wyss, Carine
    Cheung, Evelyn
    Clark, Taane G.
    Brown, James B.
    Ganesh, Madhavan
    Patel, Sandeep
    Tammana, Hari
    Chrast, Jacqueline
    Henrichsen, Charlotte N.
    Kai, Chikatoshi
    Kawai, Jun
    Nagalakshmi, Ugrappa
    Wu, Jiaqian
    Lian, Zheng
    Lian, Jin
    Newburger, Peter
    Zhang, Xueqing
    Bickel, Peter
    Mattick, John S.
    Carninci, Piero
    Hayashizaki, Yoshihide
    Weissman, Sherman
    Hubbard, Tim
    Myers, Richard M.
    Rogers, Jane
    Stadler, Peter F.
    Lowe, Todd M.
    Wei, Chia-Lin
    Ruan, Yijun
    Struhl, Kevin
    Gerstein, Mark
    Antonarakis, Stylianos E.
    Fu, Yutao
    Green, Eric D.
    Karaöz, U.
    Siepel, Adam
    Taylor, James
    Liefer, Laura A
    Wetterstrand, Kris A.
    Good, Peter J.
    Feingold, Elise A.
    Guyer, Mark S.
    Cooper, Gregory M.
    Asimenos, George
    Dewey, Colin N.
    Hou, Minmei
    Nikolaev, Sergey
    Montoya-Burgos, Juan I.
    Löytynoja, Ari
    Whelan, Simon
    Pardi, Fabio
    Massingham, Tim
    Huang, Haiyan
    Zhang, Nancy R.
    Holmes, Ian
    Mullikin, James C.
    Ureta-Vidal, Abel
    Paten, Benedict
    Seringhaus, Michael
    Church, Deanna
    Rosenbloom, Kate
    Kent, W. James
    Stone, Eric A.
    Batzoglou, Serafim
    Goldman, Nick
    Hardison, Ross C.
    Haussler, David
    Miller, Webb
    Sidow, Arend
    Trinklein, Nathan D.
    Zhang, Zhengdong D.
    Barrera, Leah
    Stuart, Rhona
    King, David C.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Bieda, Mark C.
    Kim, Jonghwan
    Bhinge, Akshay A.
    Jiang, Nan
    Liu, Jun
    Yao, Fei
    Vega, Vinsensius B.
    Lee, Charlie W.
    Ng, Patrick
    Shahab, Atif
    Yang, Annie
    Moqtaderi, Zarmik
    Zhu, Zhou
    Xu, Xiaoqin
    Squazzo, Sharon
    Oberley, Matthew J.
    Inman, David
    Singer, Michael A.
    Richmond, Todd A.
    Munn, Kyle J.
    Rada-Iglesias, Alvaro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Fowler, Joanna C.
    Couttet, Phillippe
    Bruce, Alexander W.
    Dovey, Oliver M.
    Ellis, Peter D.
    Langford, Cordelia F.
    Nix, David A.
    Euskirchen, Ghia
    Hartman, Stephen
    Urban, Alexander E.
    Kraus, Peter
    Van Calcar, Sara
    Heintzman, Nate
    Kim, Tae Hoon
    Wang, Kun
    Qu, Chunxu
    Hon, Gary
    Luna, Rosa
    Glass, Christopher K.
    Rosenfeld, M. Geoff
    Aldred, Shelley Force
    Cooper, Sara J.
    Halees, Anason
    Lin, Jane M.
    Shulha, Hennady P.
    Zhang, Xiaoling
    Xu, Mousheng
    Haidar, Jaafar N.
    Yu, Yong
    Ruan, Yijun
    Iyer, Vishwanath R.
    Green, Roland D.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Farnham, Peggy J.
    Ren, Bing
    Harte, Rachel A.
    Hinrichs, Angie S.
    Trumbower, Heather
    Clawson, Hiram
    Hillman-Jackson, Jennifer
    Zweig, Ann S.
    Smith, Kayla
    Thakkapallayil, Archana
    Barber, Galt
    Kuhn, Robert M.
    Karolchik, Donna
    Armengol, Lluis
    Bird, Christine P.
    de Bakker, Paul I.
    Kern, Andrew D.
    Lopez-Bigas, Nuria
    Martin, Joel D.
    Stranger, Barbara E.
    Woodroffe, Abigail
    Davydov, Eugene
    Dimas, Antigone
    Eyras, Eduardo
    Hallgrí­msdóttir, Ingileif B.
    Huppert, Julian
    Zody, Michael C.
    Abecasis, G. R.
    Estivill, Xavier
    Bouffard, Gerard G.
    Guan, Xiaobin
    Hansen, Nancy F.
    Idol, Jacquelyn R.
    Maduro, Valerie V.
    Maskeri, Baishali
    McDowell, Jennifer C.
    Park, Morgan
    Thomas, Pamela J.
    Young, Alice C.
    Blakesley, Robert W.
    Muzny, Donna M.
    Sodergren, Erica
    Wheeler, David A.
    Worley, Kim C.
    Jiang, Huaiyang
    Weinstock, George M.
    Gibbs, Richard A.
    Graves, Tina
    Fulton, Robert
    Mardis, Elaine R.
    Wilson, Richard K.
    Clamp, Michele
    Cuff, James
    Gnerre, Sante
    Jaffe, David B.
    Chang, Jean L.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lander, Eric S.
    Koriabine, Maxim
    Nefedov, Mikhail
    Osoegawa, Kazutoyo
    Yoshinaga, Yuko
    Zhu, Baoli
    de Jong, Pieter J.
    Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 447, no 7146, p. 799-816Article in journal (Refereed)
    Abstract [en]

    We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

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