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  • 1.
    Franklin, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Billing, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundberg, Erik
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Plasma micro-RNA alterations appear late in pancreatic cancer2018In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140, Vol. 267, no 4, p. 775-781Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this research was to study whether plasma microRNAs (miRNA) can be used for early detection of pancreatic cancer (PC) by analyzing prediagnostic plasma samples collected before a PC diagnosis. Background: PC has a poor prognosis due to late presenting symptoms and early metastasis. Circulating miRNAs are altered in PC at diagnosis but have not been evaluated in a prediagnostic setting. Methods: We first performed an initial screen using a panel of 372 miRNAs in a retrospective case-control cohort that included early-stage PC patients and healthy controls. Significantly altered miRNAs at diagnosis were then measured in an early detection case-control cohort wherein plasma samples in the cases are collected before a PC diagnosis. Carbohydrate antigen 19–9 (Ca 19–9) levels were measured in all samples for comparison. Results: Our initial screen, including 23 stage I-II PC cases and 22 controls, revealed 15 candidate miRNAs that were differentially expressed in plasma samples at PC diagnosis. We combined all 15 miRNAs into a multivariate statistical model, which outperformed Ca 19–9 in receiver-operating characteristics analysis. However, none of the candidate miRNAs, individually or in combination, were significantly altered in prediagnostic plasma samples from 67 future PC patients compared with 132 matched controls. In comparison, Ca 19–9 levels were significantly higher in the cases at <5 years before diagnosis. Conclusion: Plasma miRNAs are altered in PC patients at diagnosis, but the candidate miRNAs found in this study appear late in the course of the disease and cannot be used for early detection of the disease.

  • 2.
    Lundberg, Erik
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Bäckström, Stefan
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Sauer, Uwe
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Sauer-Eriksson, Elisabeth
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    The transthyretin-related protein: structural investigation of a novel protein family2006In: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 155, no 3, p. 445-457Article in journal (Refereed)
    Abstract [en]

    The transthyretin-related protein (TRP) family comprises proteins predicted to be structurally related to the homotetrameric transport protein transthyretin (TTR). The function of TRPs is not yet fully established, but recent data suggest that they are involved in purine catabolism. We have determined the three-dimensional structure of the Escherichia coli TRP in two crystal forms; one at 1.65 A resolution in the presence of zinc, and the other at 2.1 A resolution in the presence of zinc and bromide. The structures revealed five zinc-ion-binding sites per monomer. Of these, the zinc ions bound at sites I and II are coordinated in tetrahedral geometries to the side chains of residues His9, His96, His98, Ser114, and three water molecules at the putative ligand-binding site. Of these four residues, His9, His98, and Ser114 are conserved. His9 and His98 bind the central zinc (site I) together with two water molecules. The side chain of His98 also binds to the zinc ion at site II. Bromide ions bind at site I only, replacing one of the water molecules coordinated to the zinc ion. The C-terminal four amino acid sequence motif Y-[RK]-G-[ST] constitutes the signature sequence of the TRP family. Two Tyr111 residues form direct hydrogen bonds to each other over the tetramer interface at the area, which in TTR constitutes the rear part of its thyroxine-binding channel. The putative substrate/ligand-binding channel of TRP is consequently shallower and broader than its counterpart in TTR.

  • 3.
    Lundberg, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hagberg, Oskar
    Jahnson, Staffan
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Association between occurrence of urinary bladder cancer and treatment with statin medication2019In: Turkish Journal of Urology, ISSN 2149-3235, Vol. 45, no 2, p. 97-102Article in journal (Refereed)
    Abstract [en]

    Objective: The incidence of urinary bladder cancer (UBC) has increased in Sweden despite decreased smoking, indicating that other factors might be associated. The increased use of statin medication for elevated blood lipids might be one such influencing factor. The aim of the present study was to assess whether statins are afflicted with an increased incidence of UBC.

    Material and methods: Data from the Swedish National Register of Urinary Bladder Cancer, National Population Register, and Swedish Prescribed Drug Register were extracted. There were 22,936 patients with new diagnosed UBC between 2005 and 2014. Statin prescription was defined as any medication prescribed with the Anatomical Therapeutic Classification code C10A. For each patient, 10 control individuals were matched by age, gender, and living area, comprising 229,326 individuals. The Cochran-Mantel-Haenszel test was used to evaluate the hazards ratios.

    Results: Statins were more frequently used in patients with UBC (33.8%) than in controls (29.8%, p<0.0001). The use of statins was afflicted with a 23% increased odds ratio (OR) for UBC (OR 1.23 (1.19-1.27), p<0.001). Subgroup analyses showed that an increased OR was found in non-muscle invasive UBC only. There was a tendency that OR was stronger for men and for younger patients. Limitations include its retrospective register-based design and potential risk of bias of confounding factors, such as smoking and body mass index.

    Conclusion: This nationwide register study suggests an association between the occurrence of UBC and patients using statins. The association was found in patients with non-muscle invasive disease only. Confounding factors, such as smoking, cannot be overruled.

  • 4.
    Lundberg, Erik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Storm, Patrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schröder, Wolfgang P
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Funk, Christiane
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Crystal structure of the TL29 protein from Arabidopsis thaliana: An APX homolog without peroxidase activity2011In: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 176, no 1, p. 24-31Article in journal (Refereed)
    Abstract [en]

    TL29 is a plant-specific protein found in the thylakoid lumen of chloroplasts. Despite the putative requirement in plants for a peroxidase close to the site of photosynthetic oxygen production, and the sequence homology of TL29 to ascorbate peroxidases, so far biochemical methods have not shown this enzyme to possess peroxidase activity. Here we report the three-dimensional X-ray crystal structure of recombinant TL29 from Arabidopsis thaliana at a resolution of 2.5 Å. The overall structure of TL29 is mainly alpha helical with six longer and six shorter helical segments. The TL29 structure resembles that of typical ascorbate peroxidases, however, crucial differences were found in regions that would be important for heme and ascorbate binding. Such differences suggest it to be highly unlikely that TL29 functions as a peroxidase.

  • 5.
    Renman, David
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundberg, Erik
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Gunnarsson, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Strigård, Karin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Statin consumption as a risk factor for developing colorectal cancer: a retrospective case study2017In: World Journal of Surgical Oncology, ISSN 1477-7819, E-ISSN 1477-7819, Vol. 15, article id 222Article in journal (Refereed)
    Abstract [en]

    Background: Statins are the backbone of lipid-lowering therapy and are among the most commonly prescribed drugs in the elderly population in Sweden today. Colorectal cancer is the second most common cancer in men and women, after prostate and breast cancer, respectively, with a median age of 72 years at diagnosis. Statins induce mitochondrial damage leading to accumulation of reactive oxygen species in the cell. Reactive oxygen species can cause mutations in mitochondrial as well as nuclear DNA leading to the development of cancer. Our hypothesis was that statins increase the risk for colorectal cancer.

    Methods: A case study was performed on consecutive cases of colorectal cancer diagnosed at Norrlands University Hospital (NUS) in Umeå between 2012 and 2015 (n = 325). Patients diagnosed with diabetes mellitus type II (DM II n = 65) were excluded in the primary endpoint analysis (occurrence of colorectal cancer). As control, three databases were used to create an age-matched population in order to calculate the proportion of inhabitants using statins in the county of Västerbotten, Sweden. A secondary endpoint was cancer-specific survival among our study group of colorectal cancer patients, including those with DM II, investigating whether there was a difference if the patient was a 'recent' statin user or not at the time of diagnosis.

    Results: Statin use at the time of colorectal cancer diagnosis in the study group was 23.8%. The corresponding figure in an age-matched population in Västerbotten was 24.6%. Using a one-proportional one-sided z test, there was no significant difference between these (23.8%, 95% CI 18.6-29.0%, p = 0.601). When comparing groups 20-64 years of age, the difference was greater with recent statin use in 17.8% in the study population and 11.9% in Västerbotten (17.8%, 95% CI 9.0-26.6%, p = 0.059). When considering cancer-specific survival, no significant difference in survival was seen when comparing 'former/never' statin users as reference category with 'recent' users diagnosed with colorectal cancer (HR 1.39, 95% CI 0.89-2.16).

    Conclusions: No significant increase in risk for developing colorectal cancer among patients (type II diabetics excluded) medicated with statins was found. We found no correlation between 'recent' statin use at the time of diagnosis and cancer-specific survival.

  • 6.
    Öhlund, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Franklin, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundberg, Erik
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Type IV collagen enhances pancreatic cancer cell proliferation and migration through an autocrine loopManuscript (preprint) (Other academic)
  • 7.
    Öhlund, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Franklin, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundberg, Erik
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lundin, Christina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Type IV collagen stimulates pancreatic cancer cell proliferation, migration, and inhibits apoptosis through an autocrine loop2013In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, article id 154Article in journal (Refereed)
    Abstract [en]

    Background: Pancreatic cancer shows a highly aggressive and infiltrative growth pattern and is characterized by an abundant tumor stroma known to interact with the cancer cells, and to influence tumor growth and drug resistance. Cancer cells actively take part in the production of extracellular matrix proteins, which then become deposited into the tumor stroma. Type IV collagen, an important component of the basement membrane, is highly expressed by pancreatic cancer cells both in vivo and in vitro. In this study, the cellular effects of type IV collagen produced by the cancer cells were characterized.

    Methods: The expression of type IV collagen and its integrin receptors were examined in vivo in human pancreatic cancer tissue. The cellular effects of type IV collagen were studied in pancreatic cancer cell lines by reducing type IV collagen expression through RNA interference and by functional receptor blocking of integrins and their binding-sites on the type IV collagen molecule.

    Results: We show that type IV collagen is expressed close to the cancer cells in vivo, forming basement membrane like structures on the cancer cell surface that colocalize with the integrin receptors. Furthermore, the interaction between type IV collagen produced by the cancer cell, and integrins on the surface of the cancer cells, are important for continuous cancer cell growth, maintenance of a migratory phenotype, and for avoiding apoptosis.

    Conclusion: We show that type IV collagen provides essential cell survival signals to the pancreatic cancer cells through an autocrine loop.

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