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  • 1.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Patients suffering from both Hodgkin's disease and non-Hodgkin's lymphoma: a clinico-pathological and immuno-histochemical population-based study of 32 patients1997In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 71, no 4, 510-516 p.Article in journal (Refereed)
    Abstract [en]

    The occurrence of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) appearing in the same individual indicates a closer relationship between the 2 diseases than previously believed. The purpose of our study was to analyze cases of HD and NHL in a defined population clinically, histopathologically and immunohistochemically to look for similarities indicating a common cellular origin. Between 1974 and 1994, 77 individuals were identified from the Swedish Cancer Registry and the National Health Care Programme for HD as potentially having both diagnoses. Thirty-two patients who had both HD and NHL were available for histo-pathological re-examination and immunohistochemical staining with CD30, CD15, LMP, p53, CD45 (LCA), CD3, CD45R0 (UCHL-1), L26, MB2 and CD45R (4KB5). The most common relation was HD preceding a high-grade malignant NHL (16 of 32 patients), unexpectedly often of T-cell phenotype (7 of 16 patients). The next common association was NHL of B-CLL type followed by HD (7 of 32 patients). At clinical presentation, the first lymphoma did not differ from lymphomas not associated with a second lymphoma, whereas the second one often appeared with a disseminated and aggressive clinical form. There was a significant correlation between the expression of p53 and LMP in first and second lymphomas. CD3 antibody was frequently expressed both in HD and NHL, whereas positivity for B-cell-related antibodies, CD30, CD15 and CD45R0, was less frequent and generally lower than previously described. The occurrence of HD and NHL in an individual is unusual. Tumour biological features common to both HD and NHL may indicate a similar cellular origin, regardless of the time interval between the diagnoses, and may contribute to the understanding of the pathogenesis of lymphoma.

  • 2.
    Andersson, Ann-Catrin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Merza, Malik
    Venables, Patrick JW
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Cohen, Maurice
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Elevated levels of the human endogenous retrovirus ERV3 in human sebaceous glands1996In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 106, no 1, 125-128 p.Article in journal (Refereed)
    Abstract [en]

    ERV3 (HERV-R) is a complete human endogenous retrovirus located on the long arm of chromosome 7. Long terminal repeat-envelope (env) gene spliced mRNAs of 9 and 3.5 kb are widely expressed in human tissues and cells, but gag-pol mRNAs have not been found. Furthermore, the env gp70 gene contains an open reading frame throughout its length. The highest expression of ERV3 mRNA detected so far is in placenta and the lowest in choriocarcinoma cell lines. We have previously shown that the human monoblastic cell line U-937 and some normal and neoplastic tissues also express high levels of ERV3 env message by Northern blot analysis; however, this method does not distinguish between mRNA expression in different cell types in tissues. In this report, we have studied the ERV3 mRNA expression in specific cell types of human skin by in situ hybridization. We found high levels expression of ERV3 env mRNA in human sebaceous glands in normal skin and dermoid cysts of the ovary. In all glands, the expression is maximal in the periphery of the lobule and ceases towards the center in the region of characteristic holocrine secretion. Since it is known that the regulation of sebaceous glands is primarily via steroid hormones, particularly androgens, it is possible that expression of ERV3 is hormone dependent.

  • 3.
    Andersson, Ann-Catrin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Venables, Patrick JW
    Tönjes, Ralf R
    Scherer, Jürgen
    Eriksson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Developmnental expression of HERV-R (ERV3) and HERV-K in human tissue2002In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 297, no 2, 220-225 p.Article in journal (Refereed)
    Abstract [en]

    The human endogenous retroviruses (HERVs), ERV3 (HERV-R) and HERV-K, are both known to be transcriptionally active in human placenta. In the case of ERV3 there is also indirect evidence for its participation in cellular differentiation. In this study we examined the expression of ERV3 (HERV-R) and HERV-K in human normal fetal tissues by in situ hybridization. The highest level of ERV3 env expression was detected in primitive adrenal cortex. Elevated levels of expression were also found in the following developing tissues: kidneys (tubules), tongue, heart, liver, and central nervous system. Tissue-specific expression was found for HERV-K rec (former cORF) but not for pol/int transcripts. The highest rec expression was found in placenta and levels slightly higher than sense control were found in the rest of the tissues examined. Pol/Int was not possible to quantitate. It appears that ERV3 is expressed in an organ-specific way during embryogenesis and might suggest a possible role in the development and differentiation of human tissues.

  • 4. Bergqvist, Jenny
    et al.
    Ohd, J. F.
    Smeds, J.
    Klaar, Sigrid
    Isola, J.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Elmberger, G. P.
    Hellborg, H.
    Bjohle, J.
    Borg, A-L.
    Skoog, L.
    Bergh, J.
    Quantitative real-time PCR analysis and microarray-based RNA expression of HER2 in relation to outcome2007In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 18, no 5, 845-850 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Our aim was to use quantitative real-time PCR (Q-PCR) and RNA expression profiles (RNA-EPs) to investigate HER2 status in relation to outcome. PATIENTS AND METHODS: Cut-off levels for Q-PCR and RNA-EP were established in relation to immunohistochemistry (IHC) validated by FISH in a test set of frozen tissue samples from 40 primary breast cancers. The HER2 status was subsequently studied in another validation set of 306 tumors, where Q-PCR and RNA-EP results were compared with previously carried out IHC that we had validated by chromogenic in situ hybridization (CISH). RESULTS: Q-PCR and RNA-EP offered similar sensitivity (90% versus 77%), specificity (93% versus 95%), and negative (99% versus 98%) and positive (63% versus 61%) predictive values for HER2 determinations. Analyses of relapse-free survival (RFS) and overall survival on the basis of 5 and 10 years of follow-up indicated equivalent hazard ratios for all three techniques. In contrast to IHC/CISH, both Q-PCR and RNA-EP analyses of HER2 also gave statistically significant results regarding RFS and breast cancer-corrected survival after 10 years of follow-up. CONCLUSION: The use of RNA-EP and Q-PCR to analyze HER2 in frozen and formalin-fixed breast cancer samples may be an alternate approach to IHC in combination with FISH/CISH.

  • 5.
    Blom, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology.
    Huang, Ryanyang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology.
    Aveskogh, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology.
    Phenotypic characterization of KU812, a cell line identified as an immature human basophilic leukocyte1992In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 22, no 8, 2025-2032 p.Article in journal (Refereed)
    Abstract [en]

    The knowledge about the differentiation of basophilic leukocytes is fragmentary. This report discusses a detailed phenotypic characterization of molecular markers for hematopoietic differentiation in a basophilic leukemia cell line, KU812. The expression of markers for lymphoid, erythroid, neutrophil, eosinophil, monocytic, megakaryocytic, mast cell and basophil differentiation was analyzed at the mRNA level by Northern blots in the KU812 cells, and for reference, in a panel of human cell lines representative of the different hematopoietic differentiation lineages. KU812 was found to express a number of mast cell and basophil-related proteins, i.e. mast cell tryptase, mast cell carboxypeptidase A, high-affinity immunoglobulin (IgE) receptor α and γ chains and the core protein for heparin and chondroitin sulphate synthesis. We found no expression of a number of monocyte/-macrophage or neutrophil leukocyte markers except for lysozyme. From earlier studies, it has been shown that lysozyme is not expressed in murine mucosal mast cell lines. This finding, together with the expression of the mast cell carboxypeptidase in KU812 might distinguish the phenotype of this cell line from that typical of mucosal mast cell lines in rodents. We found a low level of expression of the eosinophil and basophil marker, major basic protein, which might indicate a relationship between basophils and eosinophils. No expression is, however, detected with the eosinophil-specific markers, eosinophil cationic protein, eosinophil-derived neurotoxin or eosinophil peroxidase. We also report an extensive screening for inducers of basophilic differentiation of the KU812 cells. The most efficient protocol of induction included serum starvation which led to a dramatic increase in a number of markers specific for mast cells and basophils such as tryptase, carboxypeptidase A and the heparin core protein. Finally, diisopropylfluorophosphate analysis of total protein extracts from KU812 show four labeled protein bands with sodium dodecyl sulfate-polyacrylamide gel electrophoresis, indicating that this cell line expresses at least three previously undescribed serine proteases of which one or more could be a potential basophil-specific marker(s).

  • 6.
    Blume-Jensen, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Zsebo, Krisztina M.
    AMGEN Inc., AMGEN Center, Thousand Oaks, CA 91320, USA.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis1991In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 10, no 13, 4121-4128 p.Article in journal (Refereed)
    Abstract [en]

    The proto-oncogene c-kit is allelic with the murine white spotting (W) locus and encodes a transmembrane protein tyrosine kinase that is structurally related to the receptors for platelet-derived growth factor (PDGF) and colony-stimulating factor-1 (CSF-1). Recently the ligand for the c-kit product, stem cell factor (SCF), was identified in both transmembrane and soluble forms. In order to examine the mechanism for receptor activation by SCF and biological properties of the activated c-kit product, we transfected the wild-type human c-kit cDNA into porcine aortic endothelial cells. We found that the receptor was down-regulated and transmitted a mitogenic signal in response to stimulation with soluble SCF. We also demonstrate that SCF induces dimerization of the c-kit product in intact cells, and that dimerization of the receptor is correlated with activation of its kinase. Activation of the c-kit product by SCF was found to induce circular actin reorganization indistinguishable from that mediated by the PDGF beta-receptor in response to PDGF-BB. Furthermore, soluble SCF was a potent chemotactic agent for cells expressing the c-kit product, a property which might be of importance during embryonic development.

  • 7. Busch, Christer
    et al.
    Sakena, Puspha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Funa, Keiko
    Nordlinder, Hans
    Eriksson, Ulf
    Tissue Distribution of Cellular Retinol-Binding Proteinand Cellular Retinoic Acid-Binding Protein: Use of Monospecific Antibodies for Immunohistochemistryand cRNA for in Situ Localization of mRNA1990In: Methods in Enzymology, ISSN 0076-6879, E-ISSN 1557-7988, Vol. 189, 315-324 p.Article, review/survey (Refereed)
  • 8.
    Busch, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Siegenthaler, Georges
    Vahlquist, Anders
    Nordlinder, Hans
    Sundelin, Johan
    Saksena, Pushpa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Eriksson, Ulf
    Expression of Cellular Retinoid-Binding Proteins During Normal and Abnormal Epidermal Differentiation1992In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 99, no 6, 795-802 p.Article in journal (Refereed)
    Abstract [en]

    Retinoids have important roles in growth and differentiation of epidermal cells. We have analyzed the expression of two intracellular retinoid-binding proteins, the cellular retinol-binding protein type I and the cellular retinoic acid - binding protein type I, during normal and abnormal epidermal differentiation. Both proteins were found to be expressed in normal epidermis with increasing expression from basal layer towards superficial layers. In psoriatic lesions, a hyperproliferative condition of the skin, the epidermal expression of cellular retinol-binding protein I was induced, whereas expression of cellular retinoic acid-binding protein I was sharply down-regulated. This and other features of psoriatic lesions indicate that down-regulation of cellular retinoic acid - binding protein I expression might cause aberrant retinoid-regulated gene expression in skin. In basal and squamous cell carcinomas, cellular retinoic acid - binding protein I expression was down-regulated, whereas cellular retinol-binding protein I was expressed. Apart from epidermal cells, a mesenchymal, dendritic cell-type, strongly expressing cellular retinoic acid-binding protein I, was identified in the dermis. In several hyperproliferative conditions of the skin, including psoriasis, and squamous and basal cell carcinomas, this cell type was abundant. These results have implications for the role of retinoids in normal and abnormal epidermal differentiation and suggest that part of the phenotype of psoriasis is due to inappropriate metabolism of retinoic acid in skin.

  • 9. Emdin, Stefan O.
    et al.
    Granstrand, Bengt
    Ringberg, Anita
    Sandelin, Kerstin
    Arnesson, Lars-Gunnar
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Anderson, Harald
    Garmo, Hans
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Wallgren, Arne
    SweDCIS: Radiotherapy after sector resection for ductal carcinoma in situ of the breast. Results of a randomised trial in a population offered mammography screening2006In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 45, no 5, 536-543 p.Article in journal (Refereed)
    Abstract [en]

    We studied the effect of postoperative radiotherapy (RT) after breast sector resection for ductal carcinoma in situ (DCIS). The study protocol stipulated radical surgery but microscopically clear margins were not mandatory. We randomised 1,046 operated women to postoperative RT or control between 1987 and 1999. The primary endpoint was ipsilateral local recurrence. Secondary endpoints were contralateral breast cancer, distant metastasis and death. After a median follow-up of 5.2 years (range 0.1-13.8) there were 44 recurrences in the RT group corresponding to a cumulative incidence of 0.07 (95% confidence interval (CI) 0.05-0.10). In the control group there were 117 recurrences giving a cumulative incidence of 0.22 (95% CI 0.18-0.26) giving an overall hazard ratio of 0.33 (95% CI 0.24-0.47, p < 0.0001). Twenty two percent of the patients had microscopically unknown or involved margins. We found no evidence for different effects of RT on the relative risk of invasive or in situ recurrence. Secondary endpoints did not differ. Women undergoing sector resection for DCIS under conditions of population based screening mammography benefit from postoperative RT to the breast. Seven patients needed RT-treatment to prevent one recurrence.

  • 10.
    Forsberg, Ole
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Hamberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Tötterman, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Identification of prostate infiltrating lymphocytes and activation of prostate antigen-specific T cells isolated from prostate cancer patientsManuscript (Other academic)
    Abstract [en]

    Although prostate antigen-specific CD8+ T lymphocytes have been found both in peripheral blood and in tumor area of prostate cancer patients there has not yet been any adequate adoptive T lymphocyte transfer trial for prostate cancer patients. Methods for efficient generation of large number of prostate antigen-specific T cells are still lacking. In the present study we isolate and expand prostate infiltrating lymphocytes (PILs) from resected prostates by fine needle aspiration of patients with localized prostate cancer. By using HLA-A*0201-restricted tetramers, specific for the prostate tumor-associated antigen epitopes TARP(P5L)4-13, STEAP262-270 and PSA53-61, we were able to identify prostate antigen-specific CD8+ PILs in 5 out of 5 patients. Most frequent were STEAP262-270-specific T cells (5/5). Furthermore, by using fast-matured dendritic cells (DCs) transduced with an adenoviral vector encoding the STEAP antigen we were able to generate CD8+ T cells from peripheral blood of prostate cancer patients, for three HLA-A*0201-restricted STEAP epitopes simultaneously by one stimulation only. If combined, an effective protocol for generation of prostate antigen-specific T cells may be developed.

  • 11.
    Giacobini, MaiBritt M J
    et al.
    Department of Histology and Neurobiology, Karolinska Institute, Stockholm Sweden.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Funa, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Westermark, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Olson, L
    Department of Histology and Neurobiology, Karolinska Institute, Stockholm Sweden.
    Differential effects of platelet-derived growth factors on fetal hippocampal and cortical grafts: evidence from intraocular transplantation in rats1992In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 136, no 2, 227-231 p.Article in journal (Refereed)
    Abstract [en]

    Effects of platelet-derived growth factor-AA (PDGF-AA) and platelet-derived growth factor-BB (PDGF-BB) on developing parietal cortex (E16) and hippocampal (E18-E19) grafts were studied using the in vivo method of intraocular transplantation. Survival and growth of grafts in the anterior eye chamber of adult host rats under the influence of regular treatments with 0.5 ng (in a 100 ng/ml concentration) PDGF-AA or PDGF-BB was followed and compared to those receiving vehicle solution alone (0.5 mg HSA/ml Hanks). Both PDGF-AA and PDGF-BB increased the volume of transplanted cortical grafts. PDGF-BB also exerted trophic effects on grafted hippocampal tissue whereas PDGF-AA seemed to inhibit hippocampal growth. Histological and immunohistochemical studies revealed an increase in the density of astroglial elements in PDGF-AA- and PDGF-BB-treated cortical grafts whereas the PDGF-AA- and PDGF-BB-treated hippocampal grafts maintained a cytoarchitecture closely resembling that of control grafts. These findings support in vitro experiments showing that developing glial cells are stimulated by PDGFs and we further propose regional differences of action of PDGFs in the developing central nervous system.

  • 12.
    Hagberg, Hans E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Åström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Value of transsternal core biopsy in patients with a newly diagnosed mediastinal mass2000In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 39, no 2, 195-198 p.Article in journal (Refereed)
    Abstract [en]

    Histopathologic analysis of an anterior mediastinal mass of unknown origin is essential for treatment decision. Mediastinoscopy is the most common procedure performed to obtain biopsies, but general anaesthesia and hospitalization are necessary. The aim of this study was to evaluate whether transsternal core biopsies, an easy outpatient biopsy technique, could be an alternative to mediastinoscopy. A biopsy instrument that makes it possible to reach tumours hidden behind bone was used for transsternal CT-guided core biopsies in 21 patients with a newly diagnosed anterior mediastinal mass. No severe side effects were observed. In 19/21 (90%) patients the biopsies were diagnostic. In 2/21 patients additional biopsy techniques had to be used. In these two patients Hodgkin's disease was suspected in the first biopsy procedures. The diagnosis was confirmed by new core biopsies, from other parts of the tumour, not using a transsternal approach (transclavicular and parasternal, respectively). In addition, one mediastinoscopy was performed in a patient who was diagnosed with a non-Hodgkin's lymphoma but where more material was needed for lymphoma subclassification. It is concluded that CT-guided transsternal core biopsy is a clinically valuable method in patients with a newly diagnosed anterior mediastinal mass.

  • 13. Hallén, Karin
    et al.
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nilsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Wanders, Alkwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Vanishing bile duct-like syndrome in a patient with Hodgkin lymphoma: pathological development and restitution2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 9, 1271-1275 p.Article in journal (Refereed)
  • 14.
    Heldin, Carl-Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Mechanism of action and in vivo role of platelet-derived growth factor1999In: Physiological Reviews, ISSN 0031-9333, E-ISSN 1522-1210, Vol. 79, no 4, 1283-1316 p.Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) is a major mitogen for connective tissue cells and certain other cell types. It is a dimeric molecule consisting of disulfide-bonded, structurally similar A- and B-polypeptide chains, which combine to homo- and heterodimers. The PDGF isoforms exert their cellular effects by binding to and activating two structurally related protein tyrosine kinase receptors, denoted the alpha-receptor and the beta-receptor. Activation of PDGF receptors leads to stimulation of cell growth, but also to changes in cell shape and motility; PDGF induces reorganization of the actin filament system and stimulates chemotaxis, i.e., a directed cell movement toward a gradient of PDGF. In vivo, PDGF has important roles during the embryonic development as well as during wound healing. Moreover, overactivity of PDGF has been implicated in several pathological conditions. The sis oncogene of simian sarcoma virus (SSV) is related to the B-chain of PDGF, and SSV transformation involves autocrine stimulation by a PDGF-like molecule. Similarly, overproduction of PDGF may be involved in autocrine and paracrine growth stimulation of human tumors. Overactivity of PDGF has, in addition, been implicated in nonmalignant conditions characterized by an increased cell proliferation, such as atherosclerosis and fibrotic conditions. This review discusses structural and functional properties of PDGF and PDGF receptors, the mechanism whereby PDGF exerts its cellular effects, and the role of PDGF in normal and diseased tissues.

  • 15. Henriksson, A E
    et al.
    Vancea, E
    Pitkänen, P
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Bergqvist, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Neuroendocrine tumour cells in the wall of a splenic artery aneurysm2007In: Journal of Clinical Pathology, ISSN 0021-9746, E-ISSN 1472-4146, Vol. 60, no 7, 837-838 p.Article in journal (Refereed)
    Abstract [en]

    Neuroendocrine tumours are reported from the alimentary and respiratory tracts. A case of a 57-year-old man with an unsuspected histopathological finding of neuroendocrine tumour cells in the wall of a splenic artery aneurysm is reported.

    Visceral artery aneurysms are uncommon but clinically important owing to the risk of rupture and of intra-abdominal bleeding.1 There are several possible aetiologies, atherosclerosis being one, and often the cause is unknown or at least not stated.1 The case of a patient with two visceral artery aneurysms and unsuspected histopathological finding is reported.

  • 16.
    Huang, Ranyang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology.
    Åbrink, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology.
    Gobl, Anders Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Aveskogh, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology.
    Larsson, Lars-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology.
    Expression of a Mast Cell Tryptase in the Human Monocytic Cell Lines U-937 and Mono Mac 61993In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 38, no 4, 359-367 p.Article in journal (Refereed)
    Abstract [en]

    Expression of a mast cell tryptase mRNA was detected in two human monocytic cell lines, the U-937 and the Mono Mac 6, and in normal human peripheral blood(PB) monocytes. In the U-937 cell line but not in normal PB monocytes, the tryptase expression was upregulated 3-50 fold following phorbol ester (PMA)-induced differentiation, but no such induction was seen after retinoic acid, interferon-gamma or vitamin D3 exposure. The tryptases expressed in PMA-induced and non-induced U-937 and in Mono Mac 6 were characterized by PCR amplification and nucleotide sequence analysis. The U-937 cell line was found to express a tryptase identical to one of the previously cloned mast-cell beta tryptases (Tryptase I), and the tryptase expressed in Mono Mac 6 was found to be nearly identical to the previously cloned alpha tryptase. By northern blot analysis with oligonucleotide probes specific for the alpha and beta tryptases both cell lines were found to express only one type of tryptase. Densitometric quantifications of tryptase mRNA levels, in the two cell lines, showed approximately 80 times higher mRNA levels in Mono Mac 6 compared to non-induced U-937. Immunohistochemical staining for tryptase showed a marked heterogeneity in the Mono Mac 6 cell line. Only one out of 10 cells were positive for the protein but the levels in these cells were very high, equivalent, or even higher than the levels seen in the human mast cell line HMC-1. This shows that the expression of a single tryptase, in this case the alpha tryptase, is sufficient for the production of a stable protein and probably also a stable proteolytically active tetramer. The family of human mast-cell tryptases has been considered to represent a class of proteases specifically expressed in mast cells and basophilic leucocytes. The expression of tryptases in two monocytic cell lines and in normal PB monocytes indicate that in humans, the lineage specificity of these serine proteases is less restricted than earlier expected. The cloning of a full length cDNA for the murine counterpart to the human mast cell tryptases, the MMCP-6, is presented. No expression of the MMCP-6 was detected in a panel of mouse monocyte or macrophage cell lines indicating a species difference in the lineage specificity of the 'mast cell tryptases'.

  • 17.
    Karlsson, Britt-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Andersson Forsman, Catarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lindgren, Per-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Jacobson, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Efficiency of percutaneous core biopsy in pancreatic tumor diagnosis1996In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 120, no 1, 75-79 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Radiologic diagnosis of pancreatic tumors exhibits limited precision. The aim of this study was to investigate the outcome and complications of pancreatic core biopsy in patients with suspected pancreatic neoplasms.

    METHODS:

    One hundred patients underwent ultrasonography-guided core biopsy of 1.2 mm external diameter. Medical charts were examined for biochemical and clinical signs of complications. Final diagnosis was settled by operation, autopsy, and clinical signs of the disease including survival with at least 2.3 years of follow-up.

    RESULTS:

    Histopathologic biopsy evaluation showed correct discrimination between exocrine and endocrine tumors and nonneoplastic conditions in 89 patients. No false-positive cancer diagnosis was found, and guidance on nature of primary tumors was obtained for eight of eight metastases. The sensitivity was 91% for exocrine and 87% for endocrine pancreatic tumors, and negative predictive values of these diagnoses were 83% and 97%, respectively. No clinically significant complications were noted.

    CONCLUSIONS:

    Core biopsy is an attractive alternative to diagnostic laparotomy in unresectable pancreatic cancer and efficiently provides diagnosis of endocrine tumors and pancreatic metastases in conjunction with rare complications. Benign biopsy findings cannot be used to exclude presence of primary or metastatic pancreatic neoplasms.

  • 18.
    Khan, Tanweera Shaheena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vincristine, Cisplatin, Teniposide and Cyclophosphamide Combination in the Treatment of Recurrent or Metastatic Adrenocortical Cancer2004In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 21, no 2, 167-177 p.Article in journal (Refereed)
    Abstract [en]

    The efficacy and tolerability of a combination of vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) in 11 patients (median age, 45 yr) with recurrent and/or metastatic adrenocortical cancer (ACC) (seven functional and four nonfunctional) were evaluated. All patients received this regimen after the failure of streptozocin and o,p'-DDD (SO) combination therapy. The regimen comprised cyclophosphamide, 600 mg/m2, and vincristine, 1.5 mg/m2, maximum dose 2.0 mg (d 1); cisplatin, 100 mg/m2 (d 2) and teniposide, 150 mg/m2 (d 4). Cycles were repeated every 4 wk. One to eight cycles (median, six cycles) of OPEC were administered to each patient. The median duration of treatment was 6 mo. The overall 2-yr survival rate was 82% and the median survival since diagnosis was 44 mo while it was 21 mo since start of OPEC therapy. Responses were obtained in nine patients: partial response in two patients, and stable disease in seven patients. The median duration of response was 6.75 mo. A total of 60 cycles of chemotherapy were given to all patients; grade 1-2 toxicity occurred in 57 cycles, while grade 3 toxicity was observed only in two cycles, according to NCI's Common Toxicity Criteria. We conclude that the OPEC regimen may be considered in recurrent or metastatic ACC as a second-line medical treatment. However, the combination is accompanied by considerable side effects and dose modifications are necessary in order to be able to recommend the treatment. This regimen needs further evaluation compared with SO therapy preferably in a randomized multicenter trial.

  • 19.
    Lindahl, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Eriksson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Caterson, Bruce
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Selective loss of cerebral keratan sulfate in Alzheimer's disease1996In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 271, no 29, 16991-16994 p.Article in journal (Refereed)
    Abstract [en]

    Proteoglycans, especially heparan sulfate-substituted species, are known to be associated with the deposition of amyloid in Alzheimer's disease, We previously found that heparan sulfate from afflicted brains, and from control subjects, differed minimally in quantity and structure (Lindahl, B., Eriksson, L., and Lindahl, U. (1995) Biochem, J, 306, 177-184), In the present study, a glyco saminoglycan fraction, shown to contain heparan sulfate and keratan sulfate, was radiolabeled by partial N-deacetylation (hydrazinolysis) followed by re-N-acetylation using [H-3]acetic anhydride, Quantitation of the H-3-labeled polysaccharides, based on digestion with heparitinase I from Flavobacterium heparinum and keratanase from Pseudomonas sp., revealed that the amounts of keratan sulfate in Alzheimer cerebral cortex are reduced to less than half of control values. Moreover, a monoclonal antibody against a highly sulfated keratan sulfate epitope bound to the majority of the neurons in normal cortex but not in the diseased tissue. The lack of highly sulfated keratan sulfate structures may reflect a specific functional defect of the cells.

  • 20. Mykkanen, Kati
    et al.
    Junna, Maija
    Amberla, Kaarina
    Bronge, Lena
    Kaariainen, Helena
    Poyhonen, Minna
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Viitanen, Matti
    Different Clinical Phenotypes in Monozygotic CADASIL Twins With a Novel NOTCH3 Mutation2009In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 40, no 6, 2215-2218 p.Article in journal (Refereed)
    Abstract [en]

    Background and Purpose-CADASIL is a hereditary arteriopathy causing recurrent strokes and cognitive decline. Because monozygotic twins have identical genetic background, differences in their environment and lifestyle could reveal factors that may influence CADASIL patients' clinical course, which is highly variable even within the same family. Methods-We describe differences in clinical and imaging findings in a pair of monozygotic CADASIL twins. Results-Twin B experienced his first-ever stroke 14 years earlier than twin A, and his symptoms, signs, and imaging findings were more severe. Distinguishing factors were twin B's smoking as well as twin A's physical activity and earlier statin treatment. Causative NOTCH3 mutation was a novel c.752G>A -substitution (p.Cys251Tyr). Conclusions-The phenotypic differences in these monozygotic twins suggest influence of environmental and lifestyle factors on the clinical course of CADASIL. (Stroke. 2009; 40: 2215-2218.)

  • 21. Möller, E.
    et al.
    Stenman, G.
    Mandahl, N.
    Hamberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Mölne, L.
    van den Oord, J. J.
    Brosjö, O.
    Mertens, F.
    Panagopoulos, I.
    POU5F1, encoding a key regulator of stem cell pluripotency, is fused to EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands2008In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 215, no 1, 78-86 p.Article in journal (Refereed)
    Abstract [en]

    The EWSR1 gene is known to play a crucial role in the development of a number of different bone and soft tissue tumours, notably Ewing's sarcoma. POU5F1 is expressed during early development to maintain the totipotent status of embryonic stem and germ cells. In the present study, we report the fusion of EWSR1 and MUM in two types of epithelial tumours: hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands. This finding not only broadens considerably the spectrum of neoplasms associated with EWSR1 fusion genes but also strengthens the evidence for shared pathogenetic mechanisms in the development of adnexal and salivary gland tumours. Reminiscent of the previously reported fusion genes involving EWSR1, the identified transcript is predicted to encode a chimeric protein consisting of the EWSR1 amino-terminal domain and the POU5F1 carboxy-terminal domain. We assessed the transcriptional activation potential of the chimera compared to the wild-type proteins, as well as activation of transcription through the oct/sox composite element known to bind POU5F1. Among other POU5F1 target genes, this element is present in the promoter of NANOG and in the distal enhancer of POU5F1 itself. Our results show that although the chimera is capable of significant transcriptional activation, it may in fact convey a negative regulatory effect on target genes.

  • 22.
    Nilsson, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Forsberg-Nilsson, Karin
    Xiang, Z
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Nilsson, K
    Metcalfe, Dean D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Human mast cells express functional TrkA and are a source of nerve growth factor1997In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 27, no 9, 2295-2301 p.Article in journal (Refereed)
    Abstract [en]

    Mast cells are the principal effector cells in IgE-dependent hypersensitivity reactions. Despite reports that rodent mast cells proliferate in the presence of nerve growth factor (NGF), human mast cells reportedly do not respond to this factor. To determine if human mast cells express the NGF receptors, TrkA tyrosine receptor and the low affinity NGF receptor (LNGFR), we first analyzed the mRNA expression by RT-PCR of TrkA and LNGFR in a human mast cell line (HMC-1) and in human mast cells cultured in the presence of stem cell factor. Both HMC-1 and cultured human mast cells were found to express TrkA but not LNGFR. TrkA protein was demonstrated by Western blot analysis of HMC-1 lysates. Using flow cytometric analysis and mast cell tryptase as a mast cell marker, both HMC-1 cells and cultured human mast cells were shown to coexpress tryptase and TrkA. Treatment of mast cells with NGF resulted in phosphorylation of TrkA on tyrosine residues as detected by immunoblotting with an antiphosphotyrosine antibody. Furthermore, NGF induced the immediate early gene c-fos in HMC-1 cells. HMC-1 cells and cultured human mast cells were also found to express NGF mRNA, and conditioned medium from HMC-1 cells stimulated neurite outgrowth from chicken embryonic sensory ganglia in culture. This effect was blocked by anti-NGF. Thus, mast cells express functional TrkA and synthesize NGF, suggesting a mechanism by which NGF may act as an autocrine factor for human mast cells, and by which mast cells and nerves may interact.

  • 23. Nilsson, Ingrid
    et al.
    Sturegård, Erik
    Barup, Björn
    Willén, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Abu Al-Soud, Waleed
    Hultberg, Anita
    Hammarström, Lennart
    Nilsson, Hans-Olof
    Wadström, Torkel
    Helicobacter ganmani infection associated with a spontaneous outbreak of inflammatory bowel-like disease in an IL-10-deficient mouse colony2008In: Scandinavian Journal of Laboratory Animal Science, ISSN 0901-3393, Vol. 35, no 1, 13-24 p.Article in journal (Refereed)
    Abstract [en]

    Background: A breeding colony of IL-10 deficient B6.129P2-Il10(tmICgn/J) mice, kept under conventional conditions, developed an inflammatory bowel-like disease (IBD) with rectal prolapse and blood tinged diarrhoea. No clinical signs of disease were observed at the time of arrival to our animal house. These animals were originally planned to serve as a negative control group in an experimental infection study with Helicobacter species to investigate colonization of the murine gut. Results: A spiral-shaped, Gram-negative bacterium was isolated from the breeding mice colony. In a first group of six animals, tissue specimens from the liver, small and large intestines, faeces and blood, were analysed by culture, PCR-denaturing gradient gel electrophoresis (PCR-DGGE), species-specific PCR assays and DNA-sequencing, histology and serology. Helicobacter ganmani, but no other Helicobacter species, was isolated from the liver, small bowel, caecum, colon and faeces. We found inflammation in caeca, colon and livers, most pronounced in the caecal areas of culture positive mice with a severe typhlitis with cystic dilatation of glandular structures and irregular crypt architecture. Some animals showed a pronounced colitis with mucosal and sub-mucosal inflammatory infiltrates. Other animals displayed large lymphoid infiltrates in the livers and hepatitis. Tissue samples and sera from 18 additional animals from the same breeding colony were analysed by the same methods, except for culture. H. ganmani was identified by PCR in most tissue samples of the 18 additional animals as well. Sero-conversion to H. ganmani correlated well with histopathological changes. Conclusions: Our findings emphasize the importance of using Helicobacter-free animals to develop murine models of chronic hepatitis and colitis.

  • 24. Nilsson, J
    et al.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Rosén, A
    Thioredoxin prolongs survival of B-type chronic lymphocytic leukemia cells2000In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 95, no 4, 1420-1426 p.Article in journal (Refereed)
    Abstract [en]

    Thioredoxin (Trx) is a ubiquitous protein disulfide oxidoreductase with antioxidant, cytokine, and chemotactic properties. Previously, we showed that Trx, in synergy with interleukin 1 (IL-1), IL-2, IL-4, tumor necrosis factor alpha (TNF-alpha), and CD40-ligation induced S-phase entry and mitosis in normal B cells and B-type chronic lymphocytic leukemia (B-CLL) cells. The viability of B-CLL cells stimulated by these protocols is high, and it has been hypothesized that the overexpression of Bcl-2 found in B-CLL protects the cells from apoptosis in vitro and in vivo. In this study, we have analyzed the response of cells derived from 12 samples of patients with B-CLL to recombinant human Trx in spontaneous apoptosis, with special reference to the Bcl-2 expression. Long-term cultures of B-CLL clones showed significantly higher viability when supplemented with human Trx (P =.031), also exemplified with clones surviving more than 2 months. Short-term cultures of B-CLL cells exposed to 1 microg/mL of Trx for 1, 5, or 12 days maintained expression or delayed down-regulation of Bcl-2 compared with control cultures containing RPMI 1640 medium and 10% fetal calf serum only (P =.032,. 002,.026, respectively). All B-CLL cells expressed constitutive Trx at varying but low levels, in contrast to adult T-cell leukemias, which overexpress Trx, as previously reported. We found that Trx added to B-CLL cells increased in a dose-dependent fashion the release of TNF-alpha, which has been suggested to be an autocrine growth factor for these cells. In conclusion, we have found that human recombinant Trx induced TNF-alpha secretion, maintained Bcl-2, and reduced apoptosis in B-CLL cells.

  • 25. Nilsson, Magnus H. L.
    et al.
    Spurr, Nigel K.
    Saksena, Pushpa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Nordlinder, Hans
    Peterson, Per A.
    Rask, Lars
    Sundelin, Johan
    Isolation and characterization of a cDNA clone corresponding to bovine cellular retinoic-acid-binding protein and chromosomal localization of the corresponding human gene1988In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 173, no 1, 45-51 p.Article in journal (Refereed)
    Abstract [en]

    A bovine adrenal cDNA library was constructed and a clone corresponding to cellular retinoic-acid-binding protein (CRABP) mRNA was isolated and sequenced. The insert of the clone corresponds to 75 bp of the 5′ untranslated portion, the whole translated and the complete 3′ untranslated portion of the bovine CRABP mRNA. A genomic Southern blot, probed with CRABP cDNA, indicated that only one copy of the gene is present in the human genome. Hybridizing bands in restricted chicken and fish DNA were also observed. Using the CRABP cDNA as probe we have located the human CRABP gene to chromosome 3 in hybridizations to mouse-human, hamster-human and rat-human cell hybrids. In situ hybridizations on rat testis cells probed with CRABP and cellular retinol-binding protein antisense mRNA indicate that both proteins are expressed in tubuli cells.

  • 26. Nordfors, K.
    et al.
    Haapasalo, J.
    Helén, P.
    Paetau, A.
    Paljärvi, L.
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Kinnula, V. L.
    Soini, Y.
    Haapasalo, H.
    Peroxiredoxins and antioxidant enzymes in pilocytic astrocytomas2007In: Clinical Neuropathology, ISSN 0722-5091, Vol. 26, no 5, 210-218 p.Article in journal (Refereed)
    Abstract [en]

    Objective: Peroxiredoxins are antioxidant enzymes (AOEs), which are redox-regulated thiol proteins with potential effects on the growth, invasion and drug resistance of neoplastic cells. In this study, their biology and clinical significance were examined in pilocytic astrocytomas (PAs). Material and methods: The expression of peroxiredoxins (Prx I-VI) was investigated in 105 PAs by the means of immunohistochemistry and compared with the expression of selected other antioxidant enzymes, cell proliferation, angiogenesis, apoptosis, p53, histopathology and patient survival. Results: Peroxiredoxins were strongly expressed in general suggesting that oxidative damage and consequent defense takes place during the progression of pilocytic astrocytomas. In agreement with this hypothesis, several other AOEs correlated with the degenerative features and angiogenesis possibly associated with reactive oxygen species-derived cellular damage. Moreover, the expression of the AOEs was associated with each other indicating a concurrent activation of the enzymes. With the exception of manganese superoxide dismutase (MnSOD), a strong expression of AOEs was generally associated with higher cell proliferation. Prx VI seemed to have a positive association with a longer recurrence-free interval while other AOEs had no association with patient survival. Many AOEs, such as MnSOD, induce chemo- and radioresistance and are highly elevated in aggressive malignancies. PAs lack this confounding factor, and these tumors are treated only by surgery Conclusions: Taken together, the results of this study on pilocytic astrocytomas suggest that the levels of Prxs and other AOEs and their related thiol proteins are generally strongly expressed in these tumors. At least Prx VI can contribute to tumor behavior which can make it a potential prognostic factor.

  • 27.
    Påhlman, S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Hoehner, J C
    Nånberg, E
    Hedborg, F
    Fagerström, S
    Gestblom, C
    Johansson, I
    Larsson, U
    Lavenius, E
    Ortoft, E
    Kaihola, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Differentiation and survival influences of growth factors in human neuroblastoma.1995In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 31A, no 4, 453-8 p.Article in journal (Refereed)
    Abstract [en]

    Human neuroblastoma cell lines are established from high-stage, highly malignant tumours. Despite this and the fact that these tumours are arrested at an early, immature stage, many cell lines have the capacity to undergo neuronal differentiation under proper growth conditions. One such cell line is the noradrenergic SH-SY5Y cell line. These cells can be induced to mature by a variety of modalities, resulting in different mature phenotypes. The use of this cell system as a model to study the stem cell character of neuroblastoma is reviewed and discussed. In particular, we focus on growth factor dependencies in the SH-SY5Y system, and compare that to the normal situation, i.e. growth factor control of sympathetic neuronal and neuroendocrine differentiation during human and rat embryogenesis.

  • 28. Ringberg, A.
    et al.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Thorstensson, S.
    Idvall, I.
    Garmo, Hans
    Uppsala University.
    Granstrand, B.
    Arnesson, L. G.
    Sandelin, K.
    Wallgren, A.
    Anderson, H.
    Emdin, S.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Histopathological risk factors for ipsilateral breast events after breast conserving treatment for ductal carcinoma in situ of the breast - Results from the Swedish randomised trial2007In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 43, no 2, 291-298 p.Article in journal (Refereed)
    Abstract [en]

    AIM: The primary aims were to study risk factors for an ipsilateral breast event (IBE) after sector resection for ductal carcinoma in situ of the breast (DCIS) in a trial comparing adjuvant radiotherapy to no therapy and to assess predictive factors for response to radiotherapy. Secondary aims were to analyse reproducibility of the histopathological evaluation and to estimate correctness of diagnosis in the trial. SETTING: A randomised trial in Sweden (the SweDCIS trial), including 1046 women with a median of 5.2 years of follow-up in a population, offered routine mammographic screening. METHODS: A case-cohort design with a total of 161 cases of IBE (42 of those being members of the subcohort) and 284 sampled for the sub-cohort. Ninety five percent of the participants' slides could be retrieved and were re-evaluated by three experienced pathologists. RESULTS: Low nuclear grade (NG 1-2) and absence of necrosis halves the risk of IBE in both irradiated and non-irradiated patients. Lesion size, margins of excision and age at diagnosis did not modify these associations. The presence of necrosis modified the effect of radiotherapy: relative risk was 0.40 with necrosis present and 0.07 with necrosis absent (p-value for interaction 0.068). In all subsets of prognostic factors, radiotherapy conferred a substantial benefit. The risk factors for in situ and invasive IBE were similar. The agreement between pathologists was moderate (kappa=0.486). Correctness of diagnosis in the subcohort of SweDCIS was 84.8%. CONCLUSION: Although nuclear grade and necrosis carry prognostic information, we could not define a group with very low risk after sector resection alone. Radiotherapy has a protective effect in all substrata of risk factors studied. The interaction between the presence of necrosis and radiotherapy is a clinically and biologically relevant research area.

  • 29. Ringborg, Ulrik
    et al.
    de Valeriola, Dominique
    van Harten, Wim
    Llombart Bosch, Antonio
    Lombardo, Claudio
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Philip, Thierry
    Pierotti, Marco A.
    Riegman, Peter
    Saghatchian, Mahasti
    Storme, Guy
    Tursz, Thomas
    Verellen, Dirk
    Improvement of European translational cancer research: Collaboration between comprehensive cancer centers2008In: Tumori (Milano), ISSN 0300-8916, E-ISSN 2038-2529, Vol. 94, no 2, 143-146 p.Article in journal (Refereed)
    Abstract [en]

    Even though the increasing incidence of cancer is mainly a consequence of a population with a longer life span, part of this augmentation is related to the increasing prevalence of patients living with a chronic cancer disease. To fight the problem, improved preventive strategies are mandatory in combination with an innovative health care provision that is driven by research. To overcome the weakness of translational research the OECI is proposing a practical approach as part of a strategy foreseen by the EUROCAN+PLUS feasibility study, which was launched by the EC in order to identify mechanisms for the coordination of cancer research in Europe.

  • 30.
    Ripoll, Montserrat Alemany
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Siösteen, B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Hartman, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    MR detectability and appearance of small experimental intracranial hematomas at 1.5 T and 0.5 T: A 6-7-month follow-up study2003In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 44, no 2, 199-205 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate the detectability and appearance of small experimental intracranial hemorrhages on MR at 0.5 T and 1.5 T in a long-term follow-up. MATERIAL AND METHODS: Autologous blood (1 ml) was injected into the brain of 7 rabbits to create intraparenchymal hematomas. The injected blood leaked partially into the cerebrospinal fluid (CSF) spaces. MR imaging at 0.5 T and 1.5 T were performed immediately before and after hematoma creation, at 2 weeks and monthly up to 6 or 7 months using T1-, proton density- and T2-weighted (w) spin-echo (SE), FLAIR and T2*-w gradient echo (GE) pulse sequences. RESULTS: Blood was detected both in the brain and in the CSF spaces of all animals during the first hours after hematoma creation at 1.5 T. In the last examination after 6-7 months, the T2*-w GE sequences still showed residues of the intraparenchymal hematomas in all the rabbits at 1.5 T, but the signal pattern was not specific for the age of the hematomas. SE and FLAIR sequences were insensitive. The histopathology revealed iron deposits in all brains. CONCLUSION: Residues of small intraparenchymal hematomas can be seen for months with T2*-w GE sequences on brain MR imaging at 1.5 T. The age of the microhematomas cannot be estimated with MR imaging.

  • 31.
    Rodriguez, M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Rehn, S M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nyman, Rickard S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Sundström, J C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Glimelius, Bengt L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    CT in malignancy grading and prognostic prediction of non-Hodgkin's lymphoma1999In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 40, no 2, 191-197 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    The presence of tumor inhomogeneities in MR images of non-Hodgkin's lymphoma (NHL) provides information about malignancy grade and prognosis. The aim of this study was to determine whether CT images are also informative in these respects.

    MATERIAL AND METHODS:

    Sixty-three CT examinations in patients with NHL (32 high-grade and 31 low-grade tumors) were reviewed retrospectively by two senior radiologists. The tumor patterns were classified subjectively as homogeneous, slightly inhomogeneous or severely inhomogeneous and their relations to malignancy grade, clinical characteristics and prognosis were determined.

    RESULTS:

    Sixteen out of 17 patients with a severely inhomogeneous tumor pattern had high-grade NHL tumors while 21 out of 29 patients with a homogeneous tumor appearance had low-grade NHL tumors. Among chemotherapy-treated patients, those with the highest degree of inhomogeneity had a significantly worse prognosis (9 out of 11 patients died). This relationship was not found in patients treated with radiotherapy.

    CONCLUSION:

    A severely inhomogeneous tumor pattern on CT images was found to be associated with a high malignancy grade in NHL. This CT pattern was also compatible with a poor prognosis in patients treated with chemotherapy.

  • 32.
    Rodriguez, Miriam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Sundín, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Rehn, Suzanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    [18F] FDG PET in gastric non-Hodgkin's lymphoma1997In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 36, no 6, 577-584 p.Article in journal (Refereed)
    Abstract [en]

    The possibility of using [18F] FDG PET for assessment of tumor extension in primary gastric non-Hodgkin's lymphoma (NHL) was studied in 8 patients (6 high-grade and 2 low-grade, one of the MALT type) and in a control group of 7 patients (5 patients with NHL without clinical signs of gastric involvement, 1 patient with NHL and benign gastric ulcer and 1 patient with adenocarcinoma of the stomach). All patients with gastric NHL and the two with benign gastric ulcer and adenocarcinoma, respectively, underwent endoscopy including multiple biopsies for histopathological diagnosis. All patients with high-grade and one of the two with low-grade NHL and the patient with adenocarcinoma displayed high gastric uptake of [18F] FDG corresponding to the pathological findings at endoscopy and/or CT. No pathological tracer uptake was seen in the patient with low-grade gastric NHL of the MALT type. In 6/8 patients with gastric NHL, [18F] FDG PET demonstrated larger tumor extension in the stomach than was found at endoscopy, and there was high tracer uptake in the stomach in two patients who were evaluated as normal on CT. [18F] FDG PET correctly excluded gastric NHL in the patient with a benign gastric ulcer and in the patients with NHL without clinical signs of gastric involvement. Although the experience is as yet limited, [18F] FDG PET affords a novel possibility for evaluation of gastric NHL and would seem valuable as a complement to endoscopy and CT in selected patients, where the technique can yield additional information decisive for the choice of therapy.

  • 33.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ahlqvist, Kati
    Bartoccioni, Emanuela
    Scuderi, Flavia
    Marino, Mariapaola
    Suomalainen, Anu
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Neurophysiological and mitochondrial abnormalities in MuSK antibody seropositive myasthenia gravis compared to other immunological subtypes2006In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 117, no 7, 1434-1443 p.Article in journal (Refereed)
    Abstract [en]

    Objective: To compare the electrophysiological and histopathological features of immunological myasthenia gravis (MG) subtypes.Methods: Fifty MG patients underwent clinical examination, MuSK-Ab and AChR-Ab analysis. The majority underwent quantitative andsingle-fiber electromyography (QEMG, SFEMG), repetitive nerve stimulation and deltoid muscle biopsy. From muscle specimens withhistological mitochondrial dysfunction, we amplified mitochondrial DNA (mtDNA). In specimens with mtDNA deletions, the nuclear genePOLG1 was sequenced.Results: Five AChR-Ab seropositive [AChR(C)] and 5 seronegative [AChR(K)] patients were MuSK-Ab seropositive [MuSK(C)]. Five of7 neurophysiologically examined MuSK(C) patients (71%) had proximal myopathic pattern, compared to 7 of 31 MuSK(K)/AChR(C)patients (23%) (PZ0.012). SFEMG was abnormal in all examined MuSK(C) patients. All 7 biopsied MuSK(C) and 32 MuSK(K) patients(89%) had cytochrome c oxidase (COX) negative fibers. Three of five MuSK(C) and 13 of 20 MuSK(K) patients analyzed had multiplemtDNA deletions but no POLG1 mutations.Conclusions: Similar degree of SFEMG abnormalities was present in proximal muscles among MuSK(C) and AChR(C) patients. Proximalmyopathy was over-represented in MuSK(C) patients; however, both MuSK(C) and MuSK(K) patients had mild myopathy with frequentmitochondrial abnormalities.Significance: The weakness in MuSK(C) patients is most likely due to disturbed neuromuscular transmission. The frequently encounteredmitochondrial dysfunction in MG warrants further study.

  • 34.
    Stenborg, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Viitanen, Matti
    Terént, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Impaired Endothelial Function of Forearm Resistance Arteries in CADASIL Patients2007In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 38, no 10, 2692-2697 p.Article in journal (Refereed)
    Abstract [en]

    Background and Purpose-Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy, which mainly involves the brain causing stroke and dementia. Mice expressing the mutated protein display early dysfunction in vasoreactivity in resistance arteries, but studies of patients have been inconclusive so far. Methods-We examined peripheral endothelium-dependent vasodilatation in 10 CADASIL-patients and 20 controls using 3 methods: venous occlusion plethysmography of forearm blood flow with intraarterial acetylcholine and sodium nitroprusside infusions for evaluation of resistance arteries, ultrasound with flow mediated vasodilatation (FMD) of the brachial artery for evaluation of a conduit artery, and the pulse wave method with measurements before and after terbutaline for evaluation of systemic endothelium-dependent vasodilation. Results-The CADASIL patients displayed reductions in both basal (P=0.034) and stimulated blood flow (P=0.023 for the highest dose of acetylcholine) and an impaired endothelium-dependent vasodilation when investigated in forearm resistance arteries (P=0.019). The FMD and the pulse wave method did not show any reduction in endothelium-dependent vasodilation in the patients. Conclusions-Endothelium-dependent vasodilation was impaired in resistance arteries, but not in a conduit artery, in the forearm of CADASIL patients.

  • 35.
    Sundblom, Jimmy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Österdahl, Maria
    Rücker, Franz
    Montelius, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Nennesmo, Inger
    Islander, Gunilla
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bedside diagnosis of rippling muscle disease in CAV3 p.A46T mutation carriers2010In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 41, no 6, 751-757 p.Article in journal (Refereed)
    Abstract [en]

    Thirty-nine members, ages 1 to 67 years, of a Swedish family with rippling muscle disease (RMD) were investigated to assess genotype-phenotype correlations. Clinical, neurophysiological, and muscle morphological examinations were performed. Genetic analysis was performed in 38 individuals. Twenty-three patients had percussion-induced muscle mounding (PIMM) and percussion-induced rapid contractions (PIRC). Rippling and hyperCKemia were not found in all patients. Weakness was minor or absent. The electromyogram showed absence of electrical activity in ripples and PIMM, and muscle biopsy specimens confirmed caveolin-3 deficiency and absence of caveolae. Genetic analysis revealed a CAV3 c.G136A transition resulting in a p.A46T missense mutation in affected family members. The phenotype in these 23 cases of RMD with this mutation appears to be homogenous, benign, and nonprogressive. The presence of PIMM and PIRC seems to be diagnostic at all ages, whereas the absence of hyperCKemia and rippling does not exclude the diagnosis.

  • 36.
    Söderberg, Ola
    Uppsala University, Department of Pathology.
    Regulation of growth, differentiation and survival of B-chronic lymphocytic leukemia cells1997Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Chronic lymphocytic leukemia of B cell type (B-CLL) is the most commonform of leukemia in the Western countries. The signals regulating theexpansion of the B-CLL clone in vivo is yet far from being fully understood. Inthis thesis the regulation of proliferation, differentiation and survival bycell-cell interactions, cytokines and thioredoxin (Trx) has been investigatedin B-CLL cells in vitro. IL-4-induced homotypic adhesion did not influence theTPA-induced proliferation and differentiation of B-CLL cells. B-CLL cellswere found to differ from normal B cells in their requirement for Trx and in theresponse to CD40-stimulation. IL-2 and IL-15, in combination with Trx,induced proliferation of B-CLL cells from some patients with an advanceddisease in the absence of Ig-cross-linking by Staphylococcus aureus Cowanstrain 1 (SAC) particles. Further, the IL-2/IL-15+Trx or SAC+IL-2/IL-15+Trx-induced proliferation of B-CLL cells was inhibited by CD40-stimulation. Bythe sequential use of two protocols for induction of proliferation (i.e. SAC+IL-2+Trx and CD40-stimulation+IL-4+IL-10+Trx) B-CLL cells could be expandedand maintained in culture for more than one month in the absence of Epstein-Barr virus infection. Trx was found to inhibit apoptosis of in vitro cultured B-CLL cells, and the kinetics of survival correlated with an inhibition of Bcl-2down-regulation.

  • 37.
    Wang, Shu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Zhou, Yinghua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Lukinius, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Gobl, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Molecular cloning and characterization of a cDNA encoding mouse phospholipase C-β31998In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1393, no 1, 173-178 p.Article in journal (Other academic)
    Abstract [en]

    A cDNA encoding mouse PLC-beta3 (mPLC-beta3) was identified by screening a mouse kidney cDNA library and using the rapid amplification of cDNA ends (RACE) method. The predicted open reading frame was 3705 bp in length. The deduced 1235 amino acid (aa) sequence shares 95.3% and 92% homology with the sequences of rat and human PLC-beta3, respectively. The corresponding mRNA is highly expressed in kidney, skeletal muscle, liver, lung, heart and brain. In spleen, mPLC-beta3 mRNA was not detectable, which is in contrast to humans where there is a distinct expression. Using ultrastructural immunocytochemistry, mPLC-beta3 expression was detected in the heterochromatin of the nucleus in mouse brain neurons. The observation of PLC-beta3 nuclear localization suggests that PLC-beta3 may have intranuclear functions.

  • 38.
    Zainuddin, Norafiza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Wanders, Alkwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Ren, Zhi-Ping
    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, Molecular and Morphological Pathology.
    Lindell, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Roos, Göran
    Department of Medical Biosciences, Pathology, Umeå University, Umeå.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    TP53 mutations predict for poor survival in de novo diffuse large B-cell lymphoma of germinal center subtype2009In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 33, no 1, 60-66 p.Article in journal (Refereed)
    Abstract [en]

    Presence of TP53 mutations has been associated with poor prognosis in diffuse large B-cell lymphoma (DLBCL), although this has remained controversial. The TP53 codon 72 polymorphism has shown negative impact on cancer survival, but this has not been analyzed in DLBCL. Furthermore, the MDM2 SNP309 has been associated with earlier age of onset in DLBCL. Here, we investigated the clinical impact of TP53 mutations, MDM2 SNP309 and TP53 codon 72 polymorphisms on survival in DLBCL of germinal center (GC) and non-GC subtypes. Thirteen of the 102 (12.7%) patients displayed TP53 mutations. Overall, TP53 mutations had a significant effect on lymphoma-specific survival (LSS, P=0.009) and progression-free survival (PFS, P=0.028). In particular, inferior survival was observed in TP53-mutated DLBCLs of GC subtype (LSS, P=0.002 and PFS, P=0.006). Neither MDM2 SNP309 nor the TP53 codon 72 polymorphism had an impact on age of onset or survival. Altogether, our data suggests that TP53 mutations are associated with poor outcome in GC-DLBCL patients.

  • 39.
    Zainuddin, Norafiza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lindell, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Roos, Göran
    Department of Medical Biosciences, Pathology, Umeå University, Umeå.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Quantitative evaluation of p16INK4a promoter methylation using pyrosequencing in de novo diffuse large B-cell lymphoma2011In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 35, no 4, 438-443 p.Article in journal (Refereed)
    Abstract [en]

    The p16INK4a tumor suppressor gene can be inactivated by a variety of events including promoter hypermethylation. In diffuse large B-cell lymphoma (DLBCL), p16INK4a methylation has been associated with advanced disease stage and higher IPI. The prognostic impact of p16INK4a methylation in DLBCL remains unclear; however, it has been suggested to correlate with inferior outcome. To further investigate the clinical impact of p16INK4a methylation in DLBCL, promoter methylation of this gene was assessed quantitatively by pyrosequencing. Forty-two of 113 (37%) DLBCL patients with methylation level above 5% were categorized as methylated and subsequently divided into low, intermediate and high methylation categories. Overall, no association was shown between the extent of p16INK4a methylation and patients’ clinical characteristics, except disease stage (P=0.049). Moreover, we could not reveal any impact of p16INK4a methylation on lymphoma-specific survival. Although >25% of p16INK4a methylation correlated with a better progression-free survival (P=0.048), the significance of this finding, if any, needs to be further investigated. In conclusion, our finding questions the role of p16INK4a promoter methylation as a negative prognostic factor in DLBCL.

  • 40.
    Zhang, Xiao-Qun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Afink, Gijs
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Svensson, Kristian
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
    Jacobs, Jacqueline J.L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Gunther, T
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    vanZoelen, EJJ
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Nister, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Specific expression in mouse mesoderm- and neural crest-derived tissues of a human PDGFRA promoter/lacZ transgene1998In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 70, no 1-2, 167-180 p.Article in journal (Refereed)
    Abstract [en]

    The platelet-derived growth factor alpha-receptor (PDGFR-alpha) displays a lineage-specific expression pattern in the mouse embryo and is required for normal development of mesoderm and cephalic neural crest derivatives. The purpose of the present study was to demonstrate the in vivo promoter function of genomic DNA fragments representing the 5'-flanking part of the human PDGFRA gene. 2.2, 0.9 and 0.4 kb PDGFRA promoter fragments, ligated to a lacZ reporter gene, were microinjected into fertilized mouse eggs and transgenic mouse lines were established. The expression patterns were basically similar in the 2.2 and 0.9 kb lines and overlapped grossly the endogenous Pdgfra gene expression pattern. The transgenic line with the highest expression level was chosen for detailed analysis. Expression was, as expected, mainly confined to tissues of mesodermal and neural crest origin. No expression was found in epithelial tissues of endo- or ectodermal origin. The promoter fragments were also active in neuroepithelium and in certain neuronal cell types that did not faithfully express PDGFR-alpha mRNA, while they failed to specify reporter expression in PDGFR-alpha expressing O-2A progenitor cells and other glial elements of the central nervous system. Thus, the isolated human PDGFRA promoter contains most but not all of the regulatory elements that are necessary to establish tissue specific gene expression during development.

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