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  • 1. Berggren, D. Moreno
    et al.
    Folkvaljon, Y.
    Engvall, M.
    Sundberg, J.
    Lehman, S.
    Lambe, M.
    Antunovic, P.
    Garelius, H.
    Hellstrom-Lindberg, E.
    Jadersten, M.
    Lorenz, Fryderyk
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nilsson, L.
    Ejerblad, E.
    VALIDATION OF PROGNOSTIC SCORING SYSTEMS FOR MYELODYSPLASTIC SYNDROMES IN THE SWEDISH MDS-REGISTER2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 243-243Article in journal (Other academic)
  • 2.
    Bergh, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Graffmo, Karin Sixtensdotter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Jonsson, P. Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Lang, Lisa
    Stockholm, Sweden.
    Danielsson, Jens
    Stockholm, Sweden.
    Oliveberg, Mikael
    Stockholm, Sweden.
    Marklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 14, p. 4489-4494Article in journal (Refereed)
    Abstract [en]

    Despite considerable progress in uncovering the molecular details of protein aggregation in vitro, the cause and mechanism of protein-aggregation disease remain poorly understood. One reason is that the amount of pathological aggregates in neural tissue is exceedingly low, precluding examination by conventional approaches. We present here a method for determination of the structure and quantity of aggregates in small tissue samples, circumventing the above problem. The method is based on binary epitope mapping using anti-peptide antibodies. We assessed the usefulness and versatility of the method in mice modeling the neurodegenerative disease amyotrophic lateral sclerosis, which accumulate intracellular aggregates of superoxide dismutase-1. Two strains of aggregates were identified with different structural architectures, molecular properties, and growth kinetics. Both were different from superoxide dismutase-1 aggregates generated in vitro under a variety of conditions. The strains, which seem kinetically under fragmentation control, are associated with different disease progressions, complying with and adding detail to the growing evidence that seeding, infectivity, and strain dependence are unifying principles of neurodegenerative disease.

  • 3.
    Borssén, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nordlund, J
    Haider, Z
    Landfors, M
    Larsson, P
    Forestier, E
    Heyman, M
    Hultdin, M
    Lönnerholm, G
    Syvänen, AC
    Degerman, S
    DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemiaManuscript (preprint) (Other academic)
  • 4.
    Cederquist, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Palmqvist, Richard
    Emanuelsson, Monica
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Grönberg, Henrik
    Retained immunohistochemical staining in a large Swedish HNPCC family with a pathogenic MLH1 missense mutationManuscript (preprint) (Other academic)
  • 5. Cif, Laura
    et al.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Unit of Functional Neurosurgery, University College London-Institute of Neurology, Queen Square, London, UK.
    Seventy Years of Pallidotomy for Movement Disorders2017In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 32, no 7, p. 972-982Article in journal (Other academic)
    Abstract [en]

    The year 2017 marks the 70th anniversary of the birth of human stereotactic neurosurgery. The first procedure was a pallidotomy for Huntington's disease. However, it was for Parkinson's disease that pallidotomy was soon adopted worldwide. Pallidotomy was abandoned in the late 1950s in favor of thalamotomy because of the latter's more striking effect on tremor. The advent of levodopa put a halt to all surgery for PD. In the mid-1980s, Laitinen reintroduced the posteroventral pallidotomy of Leksell, and this procedure spread worldwide thanks to its efficacy on most parkinsonian symptoms including levodopa-induced dyskinesias and thanks to basic scientific work confirming the role of the globus pallidus internus in the pathophysiology of PD. With the advent of deep brain stimulation of the subthalamic nucleus, pallidotomy was again abandoned, and even DBS of the GPi has been overshadowed by STN DBS. The GPi reemerged in the late 1990s as a major stereotactic target for DBS in dystonia and, recently, in Tourette syndrome. Lately, lesioning of the GPI is being proposed to treat refractory status dystonicus or to treat DBS withdrawal syndrome in PD patients. Hence, the pallidum as a stereotactic target for either lesioning or DBS has been the phoenix of functional stereotactic neurosurgery, constantly abandoned and then rising again from its ashes. This review is a tribute to the pallidum on its 70th anniversary as a surgical target for movement disorders, analyzing its ebbs and flows and highlighting its merits, its versatility, and its resilience.

  • 6. Davies, Brandon S J
    et al.
    Beigneux, Anne P
    Barnes, Richard H
    Tu, Yiping
    Gin, Peter
    Weinstein, Michael M
    Nobumori, Chika
    Nyrén, Rakel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Goldberg, Ira
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Bensadoun, André
    Young, Stephen G
    Fong, Loren G
    GPIHBP1 is responsible for the entry of lipoprotein lipase into capillaries.2010In: Cell metabolism, ISSN 1932-7420, Vol. 12, no 1, p. 42-52Article in journal (Refereed)
    Abstract [en]

    The lipolytic processing of triglyceride-rich lipoproteins by lipoprotein lipase (LPL) is the central event in plasma lipid metabolism, providing lipids for storage in adipose tissue and fuel for vital organs such as the heart. LPL is synthesized and secreted by myocytes and adipocytes, but then finds its way into the lumen of capillaries, where it hydrolyzes lipoprotein triglycerides. The mechanism by which LPL reaches the lumen of capillaries has remained an unresolved problem of plasma lipid metabolism. Here, we show that GPIHBP1 is responsible for the transport of LPL into capillaries. In Gpihbp1-deficient mice, LPL is mislocalized to the interstitial spaces surrounding myocytes and adipocytes. Also, we show that GPIHBP1 is located at the basolateral surface of capillary endothelial cells and actively transports LPL across endothelial cells. Our experiments define the function of GPIHBP1 in triglyceride metabolism and provide a mechanism for the transport of LPL into capillaries.

  • 7. de Veer, Simon J.
    et al.
    Swedberg, Joakim E.
    Akcan, Muharrem
    Rosengren, K. Johan
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Craik, David J.
    Harris, Jonathan M.
    Engineered protease inhibitors based on sunflower trypsin inhibitor-1 (SFTI-1) provide insights into the role of sequence and conformation in Laskowski mechanism inhibition2015In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 469, no 2, p. 243-253Article in journal (Refereed)
    Abstract [en]

    Laskowski inhibitors regulate serine proteases by an intriguing mode of action that involves deceiving the protease into synthesizing a peptide bond. Studies exploring naturally occurring Laskowski inhibitors have uncovered several structural features that convey the inhibitor's resistance to hydrolysis and exceptional binding affinity. However, in the context of Laskowski inhibitor engineering, the way that various modifications intended to fine-tune an inhibitor's potency and selectivity impact on its association and dissociation rates remains unclear. This information is important as Laskowski inhibitors are becoming increasingly used as design templates to develop new protease inhibitors for pharmaceutical applications. In this study, we used the cyclic peptide, sunflower trypsin inhibitor-1 (SFTI-1), as a model system to explore how the inhibitor's sequence and structure relate to its binding kinetics and function. Using enzyme assays, MD simulations and NMR spectroscopy to study SFTI variants with diverse sequence and backbone modifications, we show that the geometry of the binding loop mainly influences the inhibitor's potency by modulating the association rate, such that variants lacking a favourable conformation show dramatic losses in activity. Additionally, we show that the inhibitor's sequence (including both the binding loop and its scaffolding) influences its potency and selectivity by modulating both the association and the dissociation rates. These findings provide new insights into protease inhibitor function and design that we apply by engineering novel inhibitors for classical serine proteases, trypsin and chymotrypsin and two kallikrein-related peptidases (KLK5 and KLK14) that are implicated in various cancers and skin diseases.

  • 8.
    Degerman, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Siwicki, Jan Konrad
    Revie, John
    Borssen, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Evelönn, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Chrzanowska, Krystyna H.
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Keith, W. Nicol
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias2014In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, no 7, p. 606-615Article in journal (Refereed)
    Abstract [en]

    We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.

  • 9. Drager, Luciano F.
    et al.
    Li, Jianguo
    Shin, Mi-Kyung
    Reinke, Christian
    Aggarwal, Neil R.
    Jun, Jonathan C.
    Bevans-Fonti, Shannon
    Sztalryd, Carole
    OByrne, Sheila M.
    Kroupa, Olessia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Blaner, William S.
    Polotsky, Vsevolod Y.
    Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea2012In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 33, no 6, p. 783-U33Article in journal (Refereed)
    Abstract [en]

    Delayed lipoprotein clearance is associated with atherosclerosis. This study examined whether chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnoea (OSA), can lead to hyperlipidaemia by inhibiting clearance of triglyceride rich lipoproteins (TRLP). Male C57BL/6J mice on high-cholesterol diet were exposed to 4 weeks of CIH or chronic intermittent air (control). FIO2 was decreased to 6.5 once per minute during the 12 h light phase in the CIH group. After the exposure, we measured fasting lipid profile. TRLP clearance was assessed by oral gavage of retinyl palmitate followed by serum retinyl esters (REs) measurements at 0, 1, 2, 4, 10, and 24 h. Activity of lipoprotein lipase (LpL), a key enzyme of lipoprotein clearance, and levels of angiopoietin-like protein 4 (Angptl4), a potent inhibitor of the LpL activity, were determined in the epididymal fat pads, skeletal muscles, and heart. Chronic intermittent hypoxia induced significant increases in levels of total cholesterol and triglycerides, which occurred in TRLP and LDL fractions (P 0.05 for each comparison). Compared with control mice, animals exposed to CIH showed increases in REs throughout first 10 h after oral gavage of retinyl palmitate (P 0.05), indicating that CIH inhibited TRLP clearance. CIH induced a 5-fold decrease in LpL activity (P 0.01) and an 80 increase in Angptl4 mRNA and protein levels in the epididymal fat, but not in the skeletal muscle or heart. CIH decreases TRLP clearance and inhibits LpL activity in adipose tissue, which may contribute to atherogenesis observed in OSA.

  • 10.
    Ekhtiari Bidhendi, Elaheh
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Bergh, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease2016In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 126, no 6, p. 2249-2253Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is an adult-onset degeneration of motor neurons that is commonly caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Both patients and Tg mice expressing mutant human SOD1 (hSOD1) develop aggregates of unknown importance. In Tg mice, 2 different strains of hSOD1 aggregates (denoted A and B) can arise; however, the role of these aggregates in disease pathogenesis has not been fully characterized. Here, minute amounts of strain A and B hSOD1 aggregate seeds that were prepared by centrifugation through a density cushion were inoculated into lumbar spinal cords of 100-day-old mice carrying a human SOD1 Tg. Mice seeded with A or B aggregates developed premature signs of ALS and became terminally ill after approximately 100 days, which is 200 days earlier than for mice that had not been inoculated or were given a control preparation. Concomitantly, exponentially growing strain A and B hSOD1 aggregations propagated rostrally throughout the spinal cord and brainstem. The phenotypes provoked by the A and B strains differed regarding progression rates, distribution, end-stage aggregate levels, and histopathology. Together, our data indicate that the aggregate strains are prions that transmit a templated, spreading aggregation of hSOD1, resulting in a fatal ALS-like disease.

  • 11.
    Halin Bergström, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rudolfsson, Stina H.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rat Prostate Tumor Cells Progress in the Bone Microenvironment to a Highly Aggressive Phenotype2016In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 18, no 3, p. 152-161Article in journal (Refereed)
    Abstract [en]

    Prostate cancer generally metastasizes to bone, and most patients have tumor cells in their bone marrow already at diagnosis. Tumor cells at the metastatic site may therefore progress in parallel with those in the primary tumor. Androgen deprivation therapy is often the first-line treatment for clinically detectable prostate cancer bone metastases. Although the treatment is effective, most metastases progress to a castration-resistant and lethal state. To examine metastatic progression in the bone microenvironment, we implanted androgen-sensitive, androgen receptor-positive, and relatively slow-growing Dunning G (G) rat prostate tumor cells into the tibial bone marrow of fully immune-competent Copenhagen rats. We show that tumor establishment in the bone marrow was reduced compared with the prostate, and whereas androgen deprivation did not affect tumor establishment or growth in the bone, this was markedly reduced in the prostate. Moreover, we found that, with time, G tumor cells in the bone microenvironment progress to a more aggressive phenotype with increased growth rate, reduced androgen sensitivity, and increased metastatic capacity. Tumor cells in the bone marrow encounter lower androgen levels and a higher degree of hypoxia than at the primary site, which may cause high selective pressures and eventually contribute to the development of a new and highly aggressive tumor cell phenotype. It is therefore important to specifically study progression in bone metastases. This tumor model could be used to increase our understanding of how tumor cells adapt in the bone microenvironment and may subsequently improve therapy strategies for prostate metastases in bone.

  • 12.
    Isoz, Isabelle
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Role of yeast DNA polymerase epsilon during DNA replication2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Each cell division, the nuclear DNA must be replicated efficiently and with high accuracy to avoid mutations which can have an effect on cell function. There are three replicative DNA polymerases essential for the synthesis of DNA during replication in eukaryotic cells. DNA polymerase α (Pol α) synthesize short primers required for DNA polymerase δ (Pol δ) and DNA polymerase ε (Pol ε) to carry out the bulk synthesis. The role of Pol δ and Pol ε at the replication fork has been unclear. The aim of this thesis was to examine what role Pol ε has at the replication fork, compare the biochemical properties of Pol δ and Pol ε, and to study the function of the second largest and essential subunit of Pol ε, Dpb2.

    To identify where Pol ε replicates DNA in vivo, a strategy was taken where the active site of Pol ε was altered to create a mutator polymerase leaving a unique error-signature. A series of mutant pol ε proteins were purified and analyzed for enzyme activity and fidelity of DNA synthesis. Two mutants, M644F and M644G, exhibited an increased mutation rate and close to normal polymerase activity. One of these, the M644G gave rise to a specific increase of mismatch mutations resulting from T-dTMP mis-pairing during DNA synthesis in vitro. The M644G mutant was introduced in yeast strains carrying a reporter gene, URA3, on either side of an origin in different orientations. Mutations which inactivated the URA3 gene in the M644G mutant strains were analyzed. A strand specific signature was found demonstrating that Pol ε participates in the synthesis of the leading strand.

    Pol δ and Pol ε are both stimulated by the processivity clamp, PCNA, in in vitro replication assays. To clarify any differences they were challenged side by side in biochemical assays. Pol ε was found to require that single-stranded template (ssDNA) was entirely coated with RPA, whereas Pol δ was much less sensitive to uncoated ssDNA. The processivity of Pol δ was stimulated to a much higher degree by PCNA than of Pol ε. In presence of PCNA the processivity of Pol δ and Pol ε was comparable. In contrast, Pol ε was approximately four times slower than Pol δ when replicating a single-primed circular template in the presence of all accessory proteins and an excess of polymerase. The biochemical characterization of the system suggests that Pol ε and Pol δ are loaded onto the PCNA-primer-ternary complex by separate mechanisms. A model is proposed where the loading of Pol ε onto the leading strand is independent of the PCNA interaction motif which is required by enzymes acting on the lagging strand.

    The essential gene DPB2 encodes for the second largest subunit of Pol ε. We carried out a genetic screen in S.cerevisiae and isolated a lethal mutant allele of dpb2 (dpb2-200). When over-expressed together with the remaining three subunits of Polε, Pol2, Dpb3 and Dpb4, the dpb2-201 did not copurify. The biochemical property of Pol2/Dpb3/Dpb4 complex was compared with wild-type four-subunit Pol ε (Pol2/Dpb2/Dpb3/Dpb4) and a Pol2/Dpb2 complex in replication assays. The absence of Dpb2 in the complex did not significantly affect the specific activity or the processivity, but gave a slightly reduced efficiency in holoenzyme assays when compared to wild-type four-subunit Pol ε. We propose that Dpb2 is not essential for the enzyme activity of Pol ε.

  • 13.
    Jonsson, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Byström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Davidson, Alice E.
    UCL Institute of Ophthalmology, London, UK.
    Backman, Ludvig J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kellgren, Therese
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Tuft, Stephen J.
    UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK.
    Koskela, Timo
    Koskelas Eye Clinic, Umeå, Sweden.
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Hardcastle, Alison J.
    UCL Institute of Ophthalmology, London, UK.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mutations in Collagen, Type XVII, Alpha 1 (COL17A1) Cause Epithelial Recurrent Erosion Dystrophy (ERED)2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 4, p. 463-473Article in journal (Refereed)
    Abstract [en]

    Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.

  • 14. Kyro, Cecilie
    et al.
    Olsen, Anja
    Bueno-de-Mesquita, H. B(as).
    Skeie, Guri
    Loft, Steffen
    Aman, Per
    Leenders, Max
    Dik, Vincent K.
    Siersema, Peter D.
    Pischon, Tobias
    Christensen, Jane
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Cottet, Vanessa
    Kuehn, Tilman
    Chang-Claude, Jenny
    Boeing, Heiner
    Trichopoulou, Antonia
    Naska, Androniki
    Oikonomidou, Despoina
    Masala, Giovanna
    Pala, Valeria
    Tumino, Rosario
    Vineis, Paolo
    Mattiello, Amalia
    Peeters, Petra H.
    Bakken, Toril
    Weiderpass, Elisabete
    Asli, Lene Angell
    Sanchez, Soledad
    Jakszyn, Paula
    Sanchez, Maria-Jose
    Amiano, Pilar
    Maria Huerta, Jose
    Barricarte, Aurelio
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J.
    Travis, Ruth C.
    Slimani, Nadia
    Freisling, Heinz
    Ferrari, Pietro
    Gunter, Marc J.
    Murphy, Neil
    Riboli, Elio
    Tjonneland, Anne
    Landberg, Rikard
    Plasma alkylresorcinol concentrations, biomarkers of whole-grain wheat and rye intake, in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort2014In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 111, no 10, p. 1881-1890Article in journal (Refereed)
    Abstract [en]

    Whole-grain intake has been reported to be associated with a lower risk of several lifestyle-related diseases such as type 2 diabetes, CVD and some types of cancers. As measurement errors in self-reported whole-grain intake assessments can be substantial, dietary biomarkers are relevant to be used as complementary tools for dietary intake assessment. Alkylresorcinols (AR) are phenolic lipids found almost exclusively in whole-grain wheat and rye products among the commonly consumed foods and are considered as valid biomarkers of the intake of these products. In the present study, we analysed the plasma concentrations of five AR homologues in 2845 participants from ten European countries from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition. High concentrations of plasma total AR were found in participants from Scandinavia and Central Europe and lower concentrations in those from the Mediterranean countries. The geometric mean plasma total AR concentrations were between 35 and 41nmol/l in samples drawn from fasting participants in the Central European and Scandinavian countries and below 23nmol/l in those of participants from the Mediterranean countries. The whole-grain source (wheat or rye) could be determined using the ratio of two of the homologues. The main source was wheat in Greece, Italy, the Netherlands and the UK, whereas rye was also consumed in considerable amounts in Germany, Denmark and Sweden. The present study demonstrates a considerable variation in the plasma concentrations of total AR and concentrations of AR homologues across ten European countries, reflecting both quantitative and qualitative differences in the intake of whole-grain wheat and rye.

  • 15. Lindqvist, Breezy M.
    et al.
    Wingren, Sten
    Motlagh, Parviz Behnam
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Whole genome DNA methylation signature of HER2-positive breast cancer2014In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 9, no 8, p. 1149-1162Article in journal (Refereed)
    Abstract [en]

    In order to obtain a comprehensive DNA methylation signature of HER2-positive breast cancer (HER2+ breast cancer), we performed a genome-wide methylation analysis on 17 HER2+ breast cancer and compared with ten normal breast tissue samples using the Illumina Infinium HumanMethylation450 BeadChip (450K). In HER2+ breast cancer, we found altered DNA methylation in genes involved in multicellular development, differentiation and transcription. Within these genes, we observed an overrepresentation of homeobox family genes, including several genes that have not been previously reported in relation to cancer (DBX1, NKX2-6, SIX6). Other affected genes included several belonging to the PI3K and Wnt signaling pathways. Notably, HER2, AKT3, HK1, and PFKP, genes for which altered methylation has not been previously reported, were also identified in this analysis. In total, we report 69 candidate biomarker genes with maximum differential methylation in HER2+ breast cancer. External validation of gene expression in a selected group of these genes (n = 13) revealed lowered mean gene expression in HER2+ breast cancer. We analyzed DNA methylation in six top candidate genes (AKR1B1, INA, FOXC2, NEUROD1, CDKL2, IRF4) using EpiTect Methyl II Custom PCR Array and confirmed the 450K array findings. Future clinical studies focusing on these genes, as well as on homeobox-containing genes and HER2, AKT3, HK1, and PFKP, are warranted which could provide further insights into the biology of HER2+ breast cancer.

  • 16.
    Ling, Agnes
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Immune cell infiltration and prognosis in colorectal cancer2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Colorectal cancer (CRC) is globally the second most common form of cancer among women, and third in men. It is also one of the most common causes of cancer-related death in high-income countries. Surgical resection is the basis for curative therapy but still almost half of the patients die from metastatic disease. It is therefore imperative to strive on in the search for more efficient strategies to improve patient survival. The success scores for accurate prediction of patient prognosis remain discouraging and novel markers to identify high-risk patients are called for.

    The tumour immune response has proven critical to prognosis in CRC. A high amount of tumour infiltrating lymphocytes have in studies been found to significantly improve patient outcome. The opposite has been seen in patients with sparsely infiltrated tumours. Findings in this area have driven forth the design of the Immunoscore® system, which may be implemented in clinic as a complement to the TNM staging system. Ongoing research is also focusing on which immune evading mechanisms CRC might deploy in order to progress and metastasize.

    Aim: To study immune cell infiltration in relation to prognosis in CRC. More specifically the aim has been to investigate the prognostic importance of different subsets of immune cells infiltrating the tumour, not only according to quantity but also to intratumoural subsite (tumour invasive front, tumour centre and within the tumour epithelium). The tumour immune response was also evaluated in different molecular subgroups of CRC. Another part of this thesis concerns possible molecular mechanisms involved in tumour immune escape in CRC.

    Methods: CRC cases in the Colorectal Cancer in Umeå Study (CRUMS) were evaluated using immunohistochemistry, gene expression analyses as well as methylation analyses. Cytokine and chemokine expression was evaluated in CRC tumour tissues and one CRC cell line (Caco2) and derivatives using semi-quantitative real-time PCR. Methylation was analysed using methylation-specific pyrosequencing.

    Results: We found high quantities of both cytotoxic T cells (CTLs) as well as of regulatory T cells (Tregs) to associate with a better patient outcome. The infiltration of CTLs within the tumour epithelium provided the strongest prognostic information, whilst Tregs withheld the strongest association to prognosis at the tumour invasive front and tumour centre. We could further show that a high Th1 lymphocyte infiltration was strongly associated with a better prognosis in patients with CRC, independently of intratumoural subsite. Another finding was that the extent of Th1 infiltration and patient outcome differed in different molecular subgroups of CRC. We also found down-regulation of TAP1, a protein involved in antigen presentation by MHC class I, to be significantly associated with low infiltration of various subtypes of immune cells. Down-regulation of TAP1 was also correlated to poor prognosis in patients with early stages of CRC. Furthermore, we found TAP1 expression to be inversely correlated with methylation at sites close to the TAP1 promoter region.

    Conclusion: Tumour infiltrating T lymphocytes have a significant positive impact on prognosis in CRC patients. Different subsets of T lymphocytes vary in their dependency on intratumoural subsite, in to what extent they exert their prognostic influence. We moreover found varying Th1 lymphocyte infiltration rates as well as prognostic impact thereof, in different molecular subgroups of CRC. Our results also show down-regulation of TAP1 to be a mechanism of tumour immune escape in CRC. Further findings suggest methylation of the TAP1 gene to be a putative mechanism for TAP1 down-regulation.

  • 17.
    Lundholm, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. anders.bergh@umu.se.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15651Article in journal (Refereed)
    Abstract [en]

    Macrophage infiltration has been associated with an improved prognosis in patients with colorectal cancer (CRC), but a poor prognosis in prostate cancer (PC) patients. In this study, the distribution and prognostic value of proinflammatory M1 macrophages (NOS2(+)) and immunosuppressive M2 macrophages (CD163(+)) was evaluated in a cohort of 234 PC patients. We found that macrophages infiltrating PC were mainly of an M2 type and correlated with a more aggressive tumor and poor patient prognosis. Furthermore, the M1/M2 ratio was significantly decreased in PC compared to CRC. Using in vitro cell culture experiments, we could show that factors secreted from CRC and PC cells induced macrophages of a proinflammatory or immunosuppressive phenotype, respectively. These macrophages differentially affected autologous T lymphocyte proliferation and activation. Consistent with this, CRC specimens were found to have higher degrees of infiltrating T-helper 1 cells and active cytotoxic T lymphocytes, while PC specimens displayed functionally inactive T cells. In conclusion, our results imply that tumour-secreted factors from cancers of different origin can drive macrophage differentiation in opposite directions and thereby regulate the organization of the anti-tumour immune response. Our findings suggest that reprogramming of macrophages could be an important tool in the development of new immunotherapeutic strategies.

  • 18. Marincevic-Zuniga, Yanara
    et al.
    Zachariadis, Vasilios
    Cavelier, Lucia
    Castor, Anders
    Barbany, Gisela
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Fogelstrand, Linda
    Heyman, Mats
    Abrahamsson, Jonas
    Lonnerholm, Gudmar
    Nordgren, Ann
    Syvanen, Ann-Christine
    Nordlund, Jessica
    PAX5-ESRRB is a recurrent fusion gene in B-cell precursor pediatric acute lymphoblastic leukemia2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 1, p. E20-E23Article in journal (Refereed)
  • 19.
    Nilsson, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Adamo, Hanibal
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Halin Bergström, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Inhibition of Lysyl Oxidase and Lysyl Oxidase-Like Enzymes Has Tumour-Promoting and Tumour-Suppressing Roles in Experimental Prostate Cancer2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 19608Article in journal (Refereed)
    Abstract [en]

    Lysyl oxidase (LOX) and LOX-like (LOXL) enzymes are key players in extracellular matrix deposition and maturation. LOX promote tumour progression and metastasis, but it may also have tumour-inhibitory effects. Here we show that orthotopic implantation of rat prostate AT-1 tumour cells increased LOX and LOXLs mRNA expressions in the tumour and in the surrounding non-malignant prostate tissue. Inhibition of LOX enzymes, using Beta-aminopropionitrile (BAPN), initiated before implantation of AT-1 cells, reduced tumour growth. Conversely, treatment that was started after the tumours were established resulted in unaffected or increased tumour growth. Moreover, treatment with BAPN did not suppress the formation of spontaneous lymph node metastases, or lung tumour burden, when tumour cells were injected intravenously. A temporal decrease in collagen fibre content, which is a target for LOX, was observed in tumours and in the tumour-adjacent prostate tissue. This may explain why early BAPN treatment is more effective in inhibiting tumour growth compared to treatment initiated later. Our data suggest that the enzymatic function of the LOX family is context-dependent, with both tumour-suppressing and tumour-promoting properties in prostate cancer. Further investigations are needed to understand the circumstances under which LOX inhibition may be used as a therapeutic target for cancer patients.

  • 20.
    Nilsson, Torbjörn K.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Böttiger, Anna K.
    Henriquez, Patricia
    Serra Majem, Lluis
    MTHFR polymorphisms and serum cobalamin affect plasma homocysteine concentrations differentially in females and males2014In: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 10, no 5, p. 2706-2712Article in journal (Refereed)
    Abstract [en]

    A total of 523 subjects (297 females and 226 males) from the Canary Islands Nutrition Study (ENCA) were studied in order to examine the effect of the MTHFR 677C>T, 1298A>C and 1793G>A polymorphisms, adjusted for age, serum (5)-folate and S-cobalamin levels, on total plasma homocysteine concentrations (tHcy). Genotyping was performed with Pyrosequencing(R) technology. The MTHFR 677T-allele was associated with increased tHcy concentrations only in males (P=0.005). The MTHFR 1298C-allele was found to be associated with higher tHcy levels but similarly, only in males (P=0.025). The MTHFR 1793A-allele was associated with decreased tHcy concentrations in the younger males (P=0.042). A haplotype-based approach was marginally superior in explaining the genetic interaction of the MTHFR polymorphisms on tHcy plasma levels (R-2 0.352 vs. 0.342 for a simple genotype-based approach). A nutrigenetic interaction between the MTHFR 677C>T genotype and S-cobalamin on tHcy levels was demonstrated in both genders. The increase in tHcy was more pronounced with decreasing S-cobalamin quintiles in 677TT homozygotes (P=0.005 for males and P=0.015 for females) than with decreasing S-folate quintiles (P for trend not significant). It was concluded that gene-nutrient interactions may differ depending on the sex and age of the subjects. The transferability of gene-nutrient interactions from one community to others may therefore be limited not only by different food patterns but also by different ages, genders and genotype distributions.

  • 21.
    Schock, Helena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hormone concentrations during pregnancy and maternal risk of epithelial ovarian cancer2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: The aim of this thesis was to study the relationship of pre-diagnostic circulating concentrations of sex steroid hormones (androgens, estradiol, 17-hydroxyprogesterone, and progesterone), growth factors (insulin-like growth factor-I (IGF-I), placental growth hormone (GH)), sex hormone binding globulin (SHBG), and anti-Müllerian hormone (AMH) with risk of epithelial ovarian cancer (EOC) overall, and by tumor invasiveness and histology. A longitudinal study was used to assess patterns of hormonal changes during a single pregnancy, and in two consecutive pregnancies.

    Materials & Methods: A case-control study was nested within the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort. A total of 1 052 EOC cases were identified through linkages with the cancer registries in both countries. For each case, 2-3 controls were selected. Cases and controls were matched on cohort, age and date at blood draw, as well as for parity at blood draw and at diagnosis (n=2 695). Odds ratios (OR) and corresponding 95% confidence intervals [CI] were estimated using conditional logistic regression. The longitudinal study was based on 71 pregnant Finnish women, who donated blood samples in each trimester of pregnancy.

    Results: Higher androgen concentrations were associated with an increased risk of overall EOC (e.g., testosterone ORT3 vs. T1: 1.56 [1.30-1.87], ptrend<0.0001), while the risk of endometrioid tumors increased with higher estradiol concentrations (ORT3 vs. T1: 2.76 [1.04-7.33], ptrend=0.03). Higher IGF-I was associated with a non-significant decrease in risk for invasive (ORT3 vs. T1: 0.79 [0.62-1.02], ptrend=0.07) and endometrioid tumors (ORT3 vs. T1: 0.55 [0.28-1.07], ptrend=0.07). The inverse association between IGF-I levels and risk of invasive EOC was stronger in analyses limited to women aged <55 years at diagnosis (ORT3 vs. T1: 0.74 [0.57-0.96], ptrend=0.03). No associations were observed between pre-diagnostic progesterone, SHBG, placental GH, and AMH with EOC risk overall, or by tumor invasiveness and histology.

    The longitudinal study showed that hormone concentrations were more strongly correlated between consecutive trimesters of a pregnancy than between the 1st and 3rd trimesters. Further, 3rd trimester hormone concentrations can be estimated from 1st or 2nd trimester measurements.

    Conclusion: Higher pre-diagnostic androgens, estradiol, and IGF-I are associated with EOC risk, and associations differ by tumor invasiveness and histology.

  • 22.
    Schock, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. German Cancer Research Center, Heidelberg.
    Fortner, Renée T
    German Cancer Research Center, Heidelberg.
    Surcel, Heljä-Marja
    National Institute for Health and Welfare, Oulu, Finland.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Pukkala, Eero
    School of Public Health, University of Tampere, Finland.
    Lehtinen, Matti
    School of Public Health, University of Tampere, Finland.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Early pregnancy IGF-I and placental GH and risk of epithelial ovarian cancer: A nested case-control study2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 2, p. 439-447Article in journal (Refereed)
    Abstract [en]

    Insulin-like growth factor-I (IGF-I) signaling may promote ovarian tumor development by exerting mitotic, antiapoptotic and proangiogenic effects. During pregnancy, maternal production of IGF-I is regulated by placental growth hormone (GH). Parity is an established protective factor for ovarian cancer, however, no prior study has evaluated placental GH and IGF-I in pregnancy and epithelial ovarian cancer (EOC). Prior prospective studies on the association between IGF-I and EOC in nonpregnant populations were inconclusive and did not address associations in subtypes of EOC. Among members of the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort, we identified 1,045 EOC cases, diagnosed after recruitment (1975-2008) and before March 2011 and 2,658 individually matched controls. Placental GH and IGF-I were measured in serum from the last pregnancy before EOC diagnosis or selection as control. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for tertiles and a doubling of hormone concentrations. Higher IGF-I was associated with a nonsignificant decrease in risk for invasive [ORT3 vs. T1 : 0.79 (0.62-1.02); ptrend  = 0.07] and endometrioid tumors [ORT3 vs. T1 : 0.55 (0.28-1.07); ptrend  = 0.07]. The protective association between higher IGF-I levels and risk of invasive EOC was stronger in analyses limited to women aged <55 years at diagnosis [ORT3 vs. T1 : 0.74 (0.57-0.96); ptrend  = 0.03]. Our study provides the first data on placental GH and IGF-I in pregnancy and EOC risk overall and by subtype. Our data suggest higher IGF-I levels in pregnancy may be associated with lower risk of invasive and endometrioid EOC.

  • 23.
    Schock, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Division of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
    Surcel, Helja-Marja
    Oulu, Finland.
    Zeleniuch-Jacquotte, Anne
    Umeå University, Faculty of Medicine, Department of Biobank Research. New York, USA.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lakso, Hans-Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Fortner, Renee Turzanski
    Heidelberg, Germany.
    Kaaks, Rudolf
    Heidelberg, Germany.
    Pukkala, Eero
    Helsinki, Finland; Tampere, Finland.
    Lehtinen, Matti
    Tampere, Finland.
    Toniolo, Paolo
    New York, USA; Lausanne, Switzerland.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Early pregnancy sex steroids and maternal risk of epithelial ovarian cancer2014In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, no 6, p. 831-844Article in journal (Refereed)
    Abstract [en]

    Well-established associations between reproductive characteristics and epithelial ovarian cancer (EOC) support an involvement of sex steroid hormones in the etiology of EOC. Limited previous studies have evaluated circulating androgens and the risk of EOC, and estrogens and progesterone have been investigated in only one of the previous studies. Furthermore, there is little data on potential heterogeneity in the association between circulating hormones and EOC by histological subgroup. Therefore, we conducted a nested case-control study within the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort to investigate the associations between circulating pre-diagnostic sex steroid concentrations and the histological subtypes of EOC. We identified 1052 EOC cases among cohort members diagnosed after recruitment (1975-2008) and before March 2011. Up to three controls were individually matched to each case (n=2694). Testosterone, androstenedione, 17-hydroxyprogesterone (17-OHP), progesterone, estradiol (E-2), and sex hormone-binding globulin levels were measured in serum samples collected during the last pregnancy before EOC diagnosis. We used conditional logistic regression to estimate odds ratios (ORs) and 95% CIs. Associations between hormones and EOC differed with respect to tumor histology and invasiveness. Sex steroid concentrations were not associated with invasive serous tumors; however, doubling of testosterone and 17-OHP concentration was associated with approximately 40% increased risk of borderline serous tumors. A doubling of androgen concentrations was associated with a 50% increased risk of mucinous tumors. The risk of endometrioid tumors increased with higher E-2 concentrations (OR: 1.89 (1.20-2.98)). This large prospective study in pregnant women supports a role of sex steroid hormones in the etiology of EOC arising in the ovaries.

  • 24.
    Schock, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. German Cancer Research Center, Heidelberg, Germany.
    Zeleniuch-Jacquotte, A
    New York University school of medicine, New York, USA.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Lakso, Hans-Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Surcel, HM
    National Institute for Health and Welfare, Oulu, Finland.
    Fortner, RT
    German Cancer Research Center, Heidelberg, Germany.
    Longitudinal Assessment of Pregnancy HormonesManuscript (preprint) (Other academic)
    Abstract [en]

    Evidence suggests that the hormonal milieu of pregnancy is an important determinant of subsequent cancer and other chronic diseases in both the mother and the offspring. How well a single blood specimen collected during a pregnancy characterizes exposure to these hormones throughout gestation, and also in subsequent pregnancies, is not well understood. We used serial serum samples from 71 pregnant women (25 primiparous, 25 biparous, and 21 with 2 consecutive pregnancies) with natural, complication-free pregnancies and a healthy offspring at term who participated in a population-based screening trial for congenital infections in Finland between January 1st, 1988 and June 30, 1989 and provided a blood sample in each trimester. Hormone levels were more strongly correlated between consecutive trimesters of a pregnancy than between the 1st and 3rd trimester (e.g. estradiol, 1st vs. 2nd and 2nd vs. 3rd trimester r=0.51 and r=0.60, p<0.01; 1st vs. 3rd trimester r=0.32, p<0.05). Concentrations of sRANKL remained stable throughout gestation, whereas estradiol, estrone, progesterone, testosterone, prolactin, and osteoprotegerin increased throughout pregnancy. First trimester hormone concentrations explained less of the variation in the third trimester on their own than second trimester hormone levels (e.g. estradiol R²T1=16% and R²T2=42%). Addition of maternal (e.g., smoking) and/or child characteristics (e.g., sex) improved the accuracy of the 3rd trimester estimates for some of the hormones. In conclusion, one hormone measurement in early pregnancy, in conjunction with maternal and fetal characteristics, permits estimation of 3rd trimester hormone concentrations.

  • 25. Seele, Jana
    et al.
    Beineke, Andreas
    Hillermann, Lena-Maria
    Jaschok-Kentner, Beate
    von Pawel-Rammingen, Ulrich
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Valentin-Weigand, Peter
    Baums, Christoph Georg
    The immunoglobulin M-degrading enzyme of Streptococcus suis, Ide(Ssuis), is involved in complement evasion2015In: Veterinary research (Print), ISSN 0928-4249, E-ISSN 1297-9716, Vol. 46, article id 45Article in journal (Refereed)
    Abstract [en]

    Streptococcus (S.) suis is one of the most important pathogens in pigs causing meningitis, arthritis, endocarditis and serositis. Furthermore, it is also an emerging zoonotic agent. In our previous work we identified a highly specific IgM protease in S. suis, designated IdeSsuis. The objective of this study was to characterize the function of IdeSsuis in the host-pathogen interaction. Edman-sequencing revealed that Ide(Ssuis) cleaves the heavy chain of the IgM molecule between constant domain 2 and 3. As the C1q binding motif is located in the C3 domain, we hypothesized that IdeSsuis is involved in complement evasion. Complement-mediated hemolysis induced by porcine hyperimmune sera containing erythrocyte-specific IgM was abrogated by treatment of these sera with recombinant IdeSsuis. Furthermore, expression of IdeSsuis reduced IgM-triggered complement deposition on the bacterial surface. An infection experiment of prime-vaccinated growing piglets suggested attenuation in the virulence of the mutant 10 Delta IdeSsuis. Bactericidal assays confirmed a positive effect of IdeSsuis expression on bacterial survival in porcine blood in the presence of high titers of specific IgM. In conclusion, this study demonstrates that IdeSsuis is a novel complement evasion factor, which is important for bacterial survival in porcine blood during the early adaptive (IgM-dominated) immune response.

  • 26. Seele, Jana
    et al.
    Hillermann, Lena-Maria
    Beineke, Andreas
    Seitz, Maren
    von Pawel-Rammingen, Ulrich
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Valentin-Weigand, Peter
    Baums, Christoph G.
    The immunoglobulin M-degrading enzyme of Streptococcus suis, Ide(Ssuis), is a highly protective antigen against serotype 22015In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 33, no 19, p. 2207-2212Article in journal (Refereed)
    Abstract [en]

    Streptococcus suis (S. suis) is a major porcine pathogen causing meningitis, arthritis and several other pathologies. Recently, we identified a highly specific immunoglobulin M degrading enzyme of S. suis, designated IdeSsuis, which is expressed by various serotypes. The objective of this work was to access the immunogenicity and protective efficacy of a recombinant vaccine including IdeSsuis. Vaccination with rIdeSsuis elicited antibodies efficiently neutralizing the IgM protease activity. Importantly, 18 piglets vaccinated with rIdeSsuis alone or in combination with bacterin priming were completely protected against mortality and severe morbidity after S. suis serotype 2 challenge. In contrast, 12 of the 17 piglets either treated with the placebo or primed with the bacterin only, succumbed to S. suis disease. Immunity against Idessuis was associated with increased killing of S. suis wt in porcine blood ex vivo leading to a tenfold difference in the bacterial survival factor in blood of placebo-treated and rIdeSsuis-vaccinated piglets. In conclusion, the results of this study indicate that rIdeSsuis is a highly protective antigen in pigs.

  • 27.
    Talvitie, Heidi
    et al.
    Department of Oncology–Pathology, Karolinska Institutet.
    Åstrom, Kristina
    Department of Oncology–Pathology, Karolinska Institutet.
    Larsson, Olle
    Department of Oncology–Pathology, Karolinska Institutet.
    Åhlen, Jan
    Department of Surgery, Karolinska University Hospital, Stockholm .
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Egevad, Lars
    Department of Oncology–Pathology, Karolinska Institute .
    Solitary fibrous tumor of the prostate: A report of two cases2011In: Pathology international (Print), ISSN 1320-5463, E-ISSN 1440-1827, Vol. 61, no 9, p. 536-538Article in journal (Refereed)
    Abstract [en]

    We here report two cases of solitary fibrous tumor (SFT) arising in the prostate. Two men, 66 and 69 years old, with urinary tract symptoms were diagnosed with SFT on transrectal needle biopsy and transurethral resection of the prostate, respectively. The tumors were removed by a low anterior resection including tumor, prostate and rectum en bloc and cystoprostatectomy, respectively. Both tumors were well-circumscribed but also showed some infiltration of the prostate glands. They were composed of storiform bundles of bland spindle cells that stained strongly for CD34 and vimentin but negative for muscle markers. Although rare, SFT should be considered as differential diagnosis of spindle cell lesions on prostate biopsies.

  • 28. Vymetalkova, Veronika
    et al.
    Vodicka, Pavel
    Pardini, Barbara
    Rosa, Fabio
    Levy, Miroslav
    Schneiderova, Michaela
    Liska, Vaclav
    Vodickova, Ludmila
    Nilsson, Torbjorn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Farkas, Sanja A.
    Epigenome-wide analysis of DNA methylation reveals a rectal cancer-specific epigenomic signature2016In: Epigenomics, ISSN 1750-1911, Vol. 8, no 9, p. 1193-1207Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of the present study is to address a genome-wide search for novel methylation biomarkers in the rectal cancer (RC), as only scarce information on methylation profile is available. Materials & methods: We analyzed methylation status in 25 pairs of RC and adjacent healthy mucosa using the Illumina Human Methylation 450 BeadChip. Results: We found significantly aberrant methylation in 33 genes. After validation of our results by pyrosequencing, we found a good agreement with our findings. The BPIL3 and HBBP1 genes resulted hypomethylated in RC, whereas TIFPI2, ADHFE1, FLI1 and TLX1 were hypermethylated. An external validation by TCGA datasets confirmed the results. Conclusion: Our study, with external validation, has demonstrated the feasibility of using specific methylated DNA signatures for developing biomarkers in RC.

  • 29. Yakymovych, Ihor
    et al.
    Yakymovych, Mariya
    Zang, Guangxiang
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mu, Yabing
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Heldin, Carl-Henrik
    CIN85 modulates TGF beta signaling by promoting the presentation of TGF beta receptors on the cell surface2015In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 210, no 2, p. 319-332Article in journal (Refereed)
    Abstract [en]

    Members of the transforming growth factor beta (TGF beta) family initiate cellular responses by binding to TGF beta receptor type II (Tf3R11) and type I (TpRI) serine/threonine kinases, whereby Srnad2 and Smad3 are phosphorylated and activated, promoting their association with Smadzi. We report here that T beta RI interacts with the SH3 domains of the adaptor protein CIN85 in response to TGF beta stimulation in a TRAF6-dependent manner. Small interfering RNA mediated knockdown of CIN85 resulted in accumulation of T beta RI in intracellular compartments and diminished TGF beta-stimulated Sniad2 phosphorylation. Overexpression of CIN85 instead increased the amount of T beta RI at the cell surface. This effect was inhibited by a dominant-negative mutant of Rab11, suggesting that CIN85 promoted recycling of TGF beta receptors. CIN85 enhanced TGF beta-stimulated Smad2 phosphorylation, transcriptional responses, and cell migration. CIN85 expression correlated with the degree of malignancy of prostate cancers. Collectively, our results reveal that CIN85 promotes recycling of TGF beta receptors and thereby positively regulates TGF beta signaling.

1 - 29 of 29
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