Change search
Refine search result
45678910 301 - 350 of 555
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 301.
    Libard, Sylwia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Laurell, Katarina
    Umeå Univ, Dept Pharmacol & Clin Neurosci, Östersund.
    Cesarini, Kristina G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Progression of Alzheimer's Disease-Related Pathology and Cell Counts in a Patient with Idiopathic Normal Pressure Hydrocephalus2018In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, no 4, p. 1451-1461Article in journal (Refereed)
    Abstract [en]

    We had an opportunity to assess the change observed in the brain regarding Alzheimer’s disease (AD)-related alterations, cell count, and inflammation that took place during a period of 21 months in a subject with a definite diagnosis of AD and idiopathic Normal Pressure Hydrocephalus (iNPH). Four neuronal markers, i.e., synaptophysin, microtubule associated protein 2, non-phosphorylated neurofilament H (SMI32), and embryonic lethal abnormal visual system proteins 3/4 HuC/HuD (HuC/HuD); three microglial markers CD68, Human Leucocytic Antigen DR, ionized calcium-binding adaptor molecule 1, glial fibrillary acidic protein (GFAP); and AD-related markers, hyperphosphorylated τ (HPτ) and amyloid-β (Aβ, Aβ40, Aβ42) were assessed. Morphometrically assessed immunoreactivity of all neuronal and all microglial markers and Aβ42 decreased parallel with an increase in the HPτ in the frontal cortex. The expression of GFAP was stable with time. The first sample was obtained during the therapeutic shunting procedure for iNPH, and the second sample was obtained postmortem. Negligible reactive changes were observed surrounding the shunt channel. In conclusion, in the late stage of AD with time, a neuronal loss, increase in the HPτ, and decrease in Aβ42 and microglia was observed, whereas the expression of GFAP was rather stable. The observations described here suggest that when a brain biopsy has been obtained from an adult subject with iNPH, the assessment of postmortem brain is of major significance.

  • 302.
    Libard, Sylwia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Popova, Svetlana N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Kärjä, Vesa
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Pietiläinen, Timo
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Hämäläinen, Kirsi M
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Department of Neurosurgery, Uppsala University Hospital, Sweden.
    Bergqvist, Michael
    Department of radiation sciences, Umeå University, Sweden.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nilsson, Pelle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Pfeifer, Susan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    de Ståhl, Teresita Diaz
    Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Human cytomegalovirus tegument protein pp65 is detected in all intra- and extra-axial brain tumours independent of the tumour type or grade2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e108861-Article in journal (Refereed)
    Abstract [en]

    Human cytomegalovirus (HCMV) has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC) methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patient's age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, low-grade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.

  • 303.
    Liberta, Falk
    et al.
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Loerch, Sarah
    Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA.
    Rennegarbege, Matthies
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Schierhorn, Angelika
    Martin Luther Univ Halle Wittenberg, Inst Biochem & Biotechnol, D-06120 Halle, Saale, Germany.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Westermark, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hazenberg, Bouke P. C.
    Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, NL-9700 RB Groningen, Netherlands.
    Grigorieff, Nikolaus
    Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA.
    Faendrich, Marcus
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Schmidt, Matthias
    Ulm Univ, Inst Prot Biochem, D-89081 Ulm, Germany.
    Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 1104Article in journal (Refereed)
    Abstract [en]

    Systemic AA amyloidosis is a worldwide occurring protein misfolding disease of humans and animals. It arises from the formation of amyloid fibrils from the acute phase protein serum amyloid A. Here, we report the purification and electron cryo-microscopy analysis of amyloid fibrils from a mouse and a human patient with systemic AA amyloidosis. The obtained resolutions are 3.0 angstrom and 2.7 angstrom for the murine and human fibril, respectively. The two fibrils differ in fundamental properties, such as presence of right-hand or left-hand twisted cross-beta sheets and overall fold of the fibril proteins. Yet, both proteins adopt highly similar beta-arch conformations within the N-terminal similar to 21 residues. Our data demonstrate the importance of the fibril protein N-terminus for the stability of the analyzed amyloid fibril morphologies and suggest strategies of combating this disease by interfering with specific fibril polymorphs.

  • 304.
    Lieberman, L.
    et al.
    University of Health Network, Canada.
    Devine, D. V.
    Canadian Blood Serv, Canada; University of British Columbia, Canada,.
    Reesink, H. W.
    University of Amsterdam, Netherlands.
    Panzer, S.
    Medical University of Vienna, Austria.
    Wong, J.
    Australian Red Cross Blood Serv, Australia.
    Raison, T.
    Australian Red Cross Blood Serv, Australia.
    Benson, S.
    Australian Red Cross Blood Serv, Australia.
    Pink, J.
    Australian Red Cross Blood Serv, Australia.
    Leitner, G. C.
    University of Vienna, Austria.
    Horvath, M.
    University of Vienna, Austria.
    Compernolle, V.
    Belgian Red Cross Flanders, Belgium.
    Prado Scuracchio, P. S.
    Blood Bank Hospital Sirio Libanes, Brazil.
    Wendel, S.
    Blood Bank Hospital Sirio Libanes, Brazil.
    Delage, G.
    Hema Quebec, Canada.
    Nahirniak, S.
    Alberta Health Serv, Canada.
    Dongfu, X.
    Shanghai Blood Centre, Peoples R China.
    Krusius, T.
    Finnish Red Cross Blood Serv, Finland.
    Juvonen, E.
    Finnish Red Cross Blood Serv, Finland.
    Sainio, S.
    Finnish Red Cross Blood Serv, Finland.
    Cazenave, J. -P.
    Etab Francais Sang EFS Alsace, France.
    Guntz, P.
    Etab Francais Sang EFS Alsace, France.
    Kientz, D.
    Etab Francais Sang EFS Alsace, France.
    Andreu, G.
    Institute National Transfus Sanguine INTS, France.
    Morel, P.
    EFS Bourgogne Franche Comte, France.
    Seifried, E.
    German Red Cross, Germany.
    Hourfar, K.
    German Red Cross, Germany.
    Lin, C. K.
    Hong Kong.
    O'Riordan, J.
    National Blood Centre, Ireland.
    Raspollini, E.
    Fdn Ca Granda Osped Maggiore Policlin, Italy.
    Villa, S.
    Fdn Ca Granda Osped Maggiore Policlin, Italy.
    Rebulla, P.
    Fdn Ca Granda Osped Maggiore Policlin, Italy; Fdn Ca Granda Osped Maggiore Policlin, Italy.
    Flanagan, P.
    New Zealand Blood Serv, New Zealand.
    Teo, D.
    Health Science Author, Singapore.
    Lam, S.
    Health Science Author, Singapore.
    Ang, A. L.
    Health Science Author, Singapore.
    Lozano, M.
    University of Clin Hospital, Spain.
    Sauleda, S.
    Blood and Tissue Bank Catalonia, Spain.
    Cid, J.
    University of Clin Hospital, Spain.
    Pereira, A.
    University of Clin Hospital, Spain.
    Ekermo, Bengt
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Niederhauser, C.
    Blood Transfus Serv SRC Berne, Switzerland.
    Waldvogel, S.
    Blood Transfus Serv SRC, Switzerland.
    Fontana, S.
    Blood Transfus Serv SRC Berne, Switzerland.
    Desborough, M. J.
    John Radcliffe Hospital, England.
    Pawson, R.
    John Radcliffe Hospital, England.
    Li, M.
    Blood Syst Inc, AZ, USA.
    Kamel, H.
    Blood Syst Inc, AZ, USA.
    Busch, M.
    Blood Syst Inc, AZ, USA.
    Qu, L.
    University of Pittsburgh, PA, USA; Institute Transfus Med, PA, USA.
    Triulzi, D.
    University of Pittsburgh, PA, USA; Institute Transfus Med, PA, USA.
    Prevention of transfusion-transmitted cytomegalovirus (CMV) infection: Standards of care2014In: Vox Sanguinis, ISSN 0042-9007, E-ISSN 1423-0410, Vol. 107, no 3, p. 276-311Article in journal (Refereed)
    Abstract [en]

    n/a

  • 305. Liem, David A
    et al.
    Nsair, Ali
    Setty, Shaun P
    Cadeiras, Martin
    Wang, Ding
    Maclellan, Robb
    Lotz, Chris
    Lin, Amanda J
    Tabaraki, Jason
    Li, Hua
    Ge, Junbo
    Odeberg, Jacob
    Pontén, Fredrik
    Larsson, Erik
    Mulder, Jan
    Lundberg, Emma
    Weiss, James N
    Uhlen, Mathias
    Ping, Peipei
    Deng, Mario C
    Molecular- and organelle-based predictive paradigm underlying recovery by left ventricular assist device support2014In: Circulation Heart Failure, ISSN 1941-3289, E-ISSN 1941-3297, Vol. 7, no 2, p. 359-366Article in journal (Refereed)
  • 306.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Evaluation of HPV Genotyping Assays for Archival Clinical Samples2015In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, no 3, p. 293-301Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV) testing and genotyping of FFPE tissue samples is important in epidemiological investigations. Here, we compare four different HPV genotyping methods for use in FFPE clinical samples. Comparative testing was performed on 99 samples with a clinical suspicion of HPV. Specimens were analyzed with Anyplex II HPV28 detecting 28 genotypes using real-time PCR and melting curve analysis, CLART HPV2 detecting 35 genotypes using PCR and microarray detection, and MGP5+/6+ consensus primer system together with pyrosequencing. Results were compared to a real-time PCR reference protocol detecting 14 genotypes. In total, 68% of the samples were positive for an HPV genotype using the reference protocol and MGP5+/6+ primer system. Anyplex II HPV28 analysis and CLART HPV2 had 82% and 72% positive samples, respectively. All four methods showed good agreement when comparing the 14 genotypes included in the reference protocol. When evaluating all genotypes, the Anyplex II HPV28 assay and the CLART assay changed the status of the sample (individually or together) from negative with respect to the reference protocol to positive for either a Group 1 (n = 4) or Group 2 (n = 6) genotype. We conclude from this study that for an extended genotyping approach with a high sensitivity for FFPE specimens, both the Anyplex II HPV28 and CLART HPV2 assays are suitable alternatives despite minor intra-assay differences.

  • 307.
    Lind, Anne-Li
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Biomarkers for Better Understanding of the Pathophysiology and Treatment of Chronic Pain: Investigations of Human Biofluids2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Chronic pain affects 20 % of the global population, causes suffering, is difficult to treat, and constitutes a large economic burden for society. So far, the characterization of molecular mechanisms of chronic pain-like behaviors in animal models has not translated into effective treatments.

    In this thesis, consisting of five studies, pain patient biofluids were analyzed with modern proteomic methods to identify biomarker candidates that can be used to improve our understanding of the pathophysiology chronic pain and lead to more effective treatments.

    Paper I is a proof of concept study, where a multiplex solid phase-proximity ligation assay (SP-PLA) was applied to cerebrospinal fluid (CSF) for the first time. CSF reference protein levels and four biomarker candidates for ALS were presented. The investigated proteins were not altered by spinal cord stimulation (SCS) treatment for neuropathic pain. In Paper II, patient CSF was explored by dimethyl and label-free mass spectrometric (MS) proteomic methods. Twelve proteins, known for their roles in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity, were identified to be associated with SCS treatment of neuropathic pain. In Paper III, proximity extension assay (PEA) was used to analyze levels of 92 proteins in serum from patients one year after painful disc herniation. Patients with residual pain had significantly higher serum levels of 41 inflammatory proteins. In Paper IV, levels of 55 proteins were analyzed by a 100-plex antibody suspension bead array (ASBA) in CSF samples from two neuropathic pain patient cohorts, one cohort of fibromyalgia patients and two control cohorts. CSF protein profiles consisting of levels of apolipoprotein C1, ectonucleotide pyrophosphatase/phosphodiesterase family member 2, angiotensinogen, prostaglandin-H2 D-isomerase, neurexin-1, superoxide dismutases 1 and 3 were found to be associated with neuropathic pain and fibromyalgia. In Paper V, higher CSF levels of five chemokines and LAPTGF-beta-1were detected in two patient cohorts with neuropathic pain compared with healthy controls.

    In conclusion, we demonstrate that combining MS proteomic and multiplex antibody-based methods for analysis of patient biofluid samples is a viable approach for discovery of biomarker candidates for the pathophysiology and treatment of chronic pain. Several biomarker candidates possibly reflecting systemic inflammation, lipid metabolism, and neuroinflammation in different pain conditions were identified for further investigation.

  • 308.
    Lind, Anne-Li
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Just, David
    SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden.
    Mikus, Maria
    SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden.
    Fredolini, Claudia
    SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden.
    Ioannou, Marina
    SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden.
    Gerdle, Björn
    Linköping University, Linköping, Sweden.
    Bäckryd, Emmanuel
    Linköping University, Linköping, Sweden.
    Tanum, Lars
    Akershus University Hospital, Lørenskog, Norway.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nilsson, Peter
    SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden.
    Månberg, Anna
    SciLifeLab, School of Biotechnology, KTH – Royal Institute of Technology, Stockholm, Sweden.
    Affinity Proteomics Applied to Patient CSF Identifies Protein Profiles Associated with Neuropathic Pain and FibromyalgiaManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: Today, there are no biological tests on which to base pain diagnoses, treatment choices or to understand the biological processes underlying and accompanying chronic pain for the individual pain patient. Relevant biological markers would greatly aid in diagnosis and treatment of patients with chronic pain. Our study aimed to find proteins in CSF associated with fibromyalgia and neuropathic pain, two common and poorly understood chronic pain conditions.

    Methods: We have performed CSF protein profiling of 55 proteins using a 100-plex antibody suspension bead array. We collected, analyzed and compared CSF samples from 25 patients with neuropathic pain (two independent sets, n=14 patients for discovery and n=11 for verification), 40 patients with fibromyalgia and 135 controls without neurological disease from two different populations.

    Results: We found significant differences in CSF protein levels between patients and controls (p<0.05). Among these proteins, Apolipoprotein C1 (APOC1) was found to be increased in CSF of neuropathic pain patients compared to controls and there was a non-significant trend for increased levels also in fibromyalgia patient CSF. Ectonucleotide pyrophosphatase (ENPP2, Autotaxin) was increased in the CSF of fibromyalgia patients compared to all other groups including neuropathic pain patients.  Multivariate analysis revealed partially overlapping and partially distinct CSF profiles in neuropathic pain patients compared with fibromyalgia and controls for several other proteins including angiotensinogen (AGT), prostaglandin-H2 D-isomerase (PTGDS), neurexin-1 (NRXN1), superoxide dismutase 1 (SOD1) and superoxide dismutase 3 (SOD3).

    Conclusions: Our results, suggest that the CSF protein profiles of neuropathic pain and fibromyalgia patients may be different from each other and from those of controls. CSF levels of APOC1, ENPP2, AGT, PTGDS, NRXN1, SOD1 and SOD3 should be further investigated for their potential to serve as biomarkers of different kinds of pain pathophysiology.

  • 309. Lind, Lars
    et al.
    Sundström, Johan
    Larsson, Anders
    Lampa, Erik
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science. Karolinska Institutet.
    Ingelsson, Erik
    Longitudinal effects of aging on plasma proteins levels in older adults: associations with kidney function and hemoglobin levels2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 2, article id e0212060Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A targeted proteomics chip has been shown to be useful to discover novel associations of proteins with cardiovascular disease. We investigated how these proteins change with aging, and whether this change is related to a decline in kidney function, or to a change in hemoglobin levels.

    MATERIAL AND METHODS: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, including 1,016 participants from the general population aged 70 at baseline, 84 proteins were measured at ages 70, 75, 80. At these occasions, glomerular filtration rate (eGFR) was estimated and the hemoglobin levels were measured.

    RESULTS: Sixty-one of the 84 evaluated proteins changed significantly during the 10-year follow-up (multiple testing-adjusted alpha = 0.00059), most showing an increase. The change in eGFR was inversely related to changes of protein levels for the vast majority of proteins (74%). The change in hemoglobin was significantly related to the change in 40% of the evaluated proteins, with no obvious preference of the direction of these relationships.

    CONCLUSION: The majority of evaluated proteins increased with aging in adults. Therefore, normal ranges for proteins might be given in age-strata. The increase in protein levels was associated with the degree of reduction in eGFR for the majority of proteins, while no clear pattern was seen for the relationships between the proteins and the change in hemoglobin levels. Studies on changes in urinary proteins are warranted to understand the association between the reduction in eGFR and increase in plasma protein levels.

  • 310. Lindahl, Bengt
    et al.
    Måsbäck, Anna
    Persson, Jan
    Ranstam, Jonas
    Willlén, Roger
    Adenocarcinoma corpus uteri stage I-II: results of a treatment programme based upon cytometry2009In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 29, no 11, p. 4731-4735Article in journal (Refereed)
    Abstract [en]

    The results of a treatment method on adenocarcinoma corpus uteri stage I-II based upon cytometrically measured DNA ploidy are presented. All patients had a simple hysterectomy. Adjuvant treatment (postoperative vaginal brachytherapy) were given only to those patients with non-diploid tumours regardless of stage and grade. A total of 1,634 women with endometroid adenocarcinoma corpus uteri stage I-II were included where 1,396 patients were followed-up for at least 5 years or until death and the remaining 238 patients were followed-up 3.5-5 years or until death. By using cytometry only, we identified a low-risk group comprising 83% of the patients (with 5.2% dead from their disease) and a high-risk group of 17% (with 15.7% dead from their disease). By using grade only (well- and moderately differentiated vs poorly differentiated), the low-risk group comprised 87% of the patients (with 4.6% dead from their disease) and the high-risk group 13% (with 13% dead from their disease). By using stage only (stage Ia and Ib vs stage Ic and II), the low-risk group comprised 78% of the patients (with 3.6% dead from their disease) and the high risk group 22% (with 14.5% dead from their disease). By combining these prognostic parameters, we were able to identify small subgroups with increased mortality rates in need of adjuvant therapy. As ploidy still had a strong prognostic strength regardless of given adjuvant radiotherapy, we do not believe that this treatment was effective. We therefore recommend future research to be directed toward cytostatics as an alternative adjuvant treatment.

  • 311.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Astrom, Eva
    Karolinska Univ Hosp, Pediat Neurol, Astrid Lindgren Childrens Hosp, Stockholm, Sweden;Karolinska Inst, Dept Woman & Child Hlth, Stockholm, Sweden.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Symoens, Sofie
    Univ Hosp Ghent, Dept Med Genet, Ghent, Belgium.
    Coucke, Paul
    Univ Hosp Ghent, Dept Med Genet, Ghent, Belgium.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Paschalis, Eleftherios
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Roschger, Paul
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Gamsjaeger, Sonja
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Klaushofer, Klaus
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Fratzl-Zelman, Nadja
    Ludwig Boltzmann Inst Osteol, Hanusch Hosp WGKK, Vienna, Austria;Hanusch Hosp, Med Dept 1, AUVA Trauma Ctr Meidling, Vienna, Austria.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy2018In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 114, p. 268-277Article in journal (Refereed)
    Abstract [en]

    Background: Mutations of the endoplasmic reticulum (ER) stress transducer OASIS (encoded by CREB3L1), cause severe recessive osteogenesis imperfecta (OI) not compatible with surviving the neonatal period, as has been shown in two unrelated families through a whole gene deletion vs. a qualitative alteration of OASIS Heterozygous carriers in the described families have exhibited a mild phenotype. OASIS is a transcription factor highly expressed in osteoblasts, and OASIS(-/-) mice exhibit severe osteopenia and spontaneous fractures. Here, we expand the clinical spectrum by a detailed phenotypic characterization of the first case of OASIS-associated OI surviving the neonatal period, with heterozygous family members being unaffected.

    Methods: All OI-associated genes were sequenced. Primary human osteoblast-like cell (hOB) and fibroblast (FB) cultures were obtained for qPCR, and steady-state collagen biochemistry. FB, hOB and skin biopsies were ultrastructurally analyzed. Bone was analyzed by |mu CT, histomorphometry, quantitative backscattered electron imaging (qBEI), and Raman microspectroscopy.

    Results: The proband, a boy with severe OI, had blue sclera and tooth agenesis A homozygous CREB3L1 stop codon mutation was detected by sequencing, while several family members were heterozygotes Markedly low levels of CREB3L1 mRNA were confirmed by qPCR in hOBs (16%) and FB (21%), however, collagen I levels were only reduced in hOBs (5-10%) Electron microscopy of hOBs showed pronounced alterations, with numerous myelin figures and diminished RER vs. normal ultrastructure of FB. Bone histomorphometry and qBEI were similar to collagen I OI, with low trabecular thickness and mineral apposition rate, and increased bone matrix mineralization. Raman microspectroscopy revealed low level of glycosaminoglycans. Clinical response to lifelong bisphosphonate treatment was as expected in severe OI with steadily increasing bone mineral density, but despite this the boy suffered repeated childhood fractures.

    Conclusions: Deficiency of OASIS can cause severe OI compatible with surviving the neonatal period A marked decrease of collagen type I transcription was noted in bone tissue, but not in skin, and ultrastructure of hOBs was pathological. Results also suggested OASIS involvement in glycosaminoglycan secretion in bone.

  • 312.
    Lindberg, Ulrika
    et al.
    Lund Univ, Sweden.
    Svensson, Lisbeth
    Lund Univ, Sweden.
    Hellmark, Thomas
    Lund Univ, Sweden.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Shannon, Oonagh
    Lund Univ, Sweden.
    Increased platelet activation occurs in cystic fibrosis patients and correlates to clinical status2018In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 162, p. 32-37Article in journal (Refereed)
    Abstract [en]

    Cystic fibrosis (CF) is an inflammatory lung disease. Platelets have an emerging role in inflammation, however previous studies of platelet activation in CF have generated conflicting results. In this study, we determined platelet function in CF patients and correlated platelet activation to establish clinical and laboratory parameters. Twenty-two patients, aged 20.7 to 54.4 (mean 34.0, SD 9.45) years and with a mean FEV1% pred (forced expiratory volume in one second, % of predicted) of 72 (SD 21.4, range 32-110) were recruited. A combination of platelet assays was used: platelet aggregation, platelet activation and platelet-leukocyte complex formation. Platelets from CF patients exhibited significantly increased aggregation when stimulated ex-vivo, a tendency towards increased platelet upregulation of CD62P, but no increase of GPIIb/IIIa activation (PAC-1). Platelet-monocyte complex (PMC) formation was significantly increased in CF patients compared to controls, while platelet-neutrophil complex formation was not. In the CF group, platelet aggregation correlates with levels of anti-neutrophil cytoplasmic antibodies (ANCA) with specificity for bactericidal/permeability-increasing protein (BPI), BPI-ANCA (r = 0.56). The formation of PMCs correlates with lung function decline (1-FEV1%), CRP and BPI-ANCA (r = 0.61, 0.55, 0.5). We therefore confirm the presence of increased platelet activation in CF patients, and determine that further evaluation of platelet activation in relation to prognostic factors in CF is warranted.

  • 313.
    Lindblom, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Wallménius, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Nordberg, M
    Forsberg, P
    Eliasson, I
    Påhlson, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Seroreactivity for spotted fever rickettsiae and co-infections with other tick-borne agents among habitants in central and southern Sweden2013In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 32, no 3, p. 317-323Article in journal (Refereed)
    Abstract [en]

    Patients seeking medical care with erythema migrans or flu-like symptoms after suspected or observed tick bite in the southeast of Sweden and previously investigated for Borrelia spp. and/or Anaplasma sp. were retrospectively examined for serological evidence of rickettsial infection (Study 1). Twenty of 206 patients had IgG and/or IgM antibodies to Rickettsia spp. equal to or higher than the cut-off titre of 1:64. Seven of these 20 patients showed seroconversion indicative of recent or current infection and 13 patients had titres compatible with past infection, of which five patients were judged as probable infection. Of 19 patients with medical records, 11 were positive for Borrelia spp. as well, and for Anaplasma sp., one was judged as positive. Five of the 19 patients had antibodies against all three pathogens. Erythema migrans or rash was observed at all combinations of seroreactivity, with symptoms including fever, muscle pain, headache and respiratory problems. The results were compared by screening an additional 159 patients (Study 2) primarily sampled for the analysis of Borrelia spp. or Mycoplasma pneumoniae. Sixteen of these patients were seroreactive for Rickettsia spp., of which five were judged as recent or current infection. Symptoms of arthritis, fever, cough and rash were predominant. In 80 blood donors without clinical symptoms, approximately 1 % were seroreactive for Rickettsia spp., interpreted as past infection. The study shows that both single and co-infections do occur, which illustrate the complexity in the clinical picture and a need for further studies to fully understand how these patients should best be treated.

  • 314.
    Lindsten, Therese
    et al.
    Centralsjukhuset Karlstad.
    Hedbrant, Alexander
    Örebro universitet.
    Ramberg, Anna
    Centralsjukhuset Karlstad, Örebro universitet.
    Wijkander, Jonny
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013).
    Solterbeck, Anja
    Centralsjukhuset, Karlstad.
    Eriksson, Margareta
    Centralsjukhuset Karlstad, Örebro universitet.
    Delbro, Dick
    Örebro universitet.
    Erlandsson, Ann
    Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences (from 2013). Örebro universitet.
    Effect of macrophages on breast cancer cell proliferation, and on expression of hormone receptors, uPAR and HER-22017In: International Journal of Oncology, ISSN 1019-6439, Vol. 51, no 1, p. 104-114Article in journal (Refereed)
    Abstract [en]

    Malignant tumors, including breast cancers, are frequently infiltrated with innate immune cells and tumor-associated macrophages (TAMs) represent the major inflammatory component in stroma of many tumors. In this study, we examined the immunoreactivity of the macrophage markers CD68 and CD163 as well as the hormone receptors estrogen receptor alpha (ER alpha), progesterone receptor (PR), estrogen receptor beta 1 (ER beta 1), human epidermal growth factor receptor 2 (HER-2), matrix metalloproteinase 9 (MMP-9), urokinase-type plasminogen activator receptor (uPAR) and the proliferations marker Ki67 in 17 breast cancer biopsies. The quantitative score for CD68(+) and CD163(+) strongly indicate M2 phenotype dominance in the currently investigated biopsies. We found that an increasing level of macrophages was negatively associated with ER alpha or PR, whereas a positive association was observed for Ki-67 or uPAR. No significant association could be seen between the level of macrophage and HER-2, ER beta 1 or MMP-9 expression. Effect of conditioned media (CM) generated from cultured human M1 and M2 macrophage phenotypes were investigated on the proliferation and expression of selected markers in the T47D breast cancer cell line. We found that in contrast to the in vivo situation, in particularly the CM from M1 macrophages decreased the growth and Ki67 expression in T47D, and significantly increased ER beta 1 mRNA levels. Moreover, in accordance to the in vivo situation the CM from the macrophages decreased the expression of ER alpha protein as well as ER alpha or PR mRNA. In conclusion our results show that macrophages alone have the capability to decrease the tumor cell expression of ER alpha and PR in vitro. In the tumor environment in vivo macrophages also contribute to an increase in tumor cell expression of uPAR and Ki67, suggesting that macrophages are involved in impairing the prognosis for breast cancer patients.

  • 315. Linnankivi, T
    et al.
    Valanne, L
    Paetau, A
    Alafuzoff, Irina
    Kuopio University, Finland.
    Hakumäki, J M
    Kivelä, T
    Lönnqvist, T
    Mäkitie, O
    Pääkkönen, L
    Vainionpää, L
    Vanninen, R
    Herva, R
    Pihko, H
    Cerebroretinal microangiopathy with calcifications and cysts.2006In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 67, no 8, p. 1437-43Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Extensive cerebral calcifications and leukoencephalopathy have been reported in two rare disorders Coats plus and leukoencephalopathy with calcifications and cysts. In the latter, a progressive formation of parenchymal brain cysts is a special feature, whereas Coats plus is characterized by intrauterine growth retardation, bilateral retinal telangiectasias and exudations (Coats disease), sparse hair, and dysplastic nails without cyst formation.

    METHODS: We identified 13 patients, including two pairs of siblings, with extensive cerebral calcifications and leukoencephalopathy. We reviewed clinical, ophthalmologic, radiologic and neuropathologic data of seven deceased patients and studied five patients prospectively.

    RESULTS: Eleven patients were small for gestational age; the other symptoms emerged from infancy to adolescence. All patients had neurologic symptoms including seizures, spasticity, dystonia, ataxia, and cognitive decline. Progressive intracerebral calcifications involved deep gray nuclei, brainstem, cerebral and cerebellar white matter, and dentate nuclei and were accompanied by diffuse white matter signal changes and, in five patients, cerebral cysts. Eleven patients had retinal telangiectasias or angiomas. Additional features were skeletal and hematologic abnormalities, intestinal bleeding, and poor growth. Neuropathologic examination showed extensive calcinosis and abnormal small vessels with thickened, hyalinized wall and reduced lumen.

    CONCLUSIONS: Our data suggest that Coats plus syndrome and leukoencephalopathy with calcifications and cysts belong to the same spectrum. The primary abnormality seems to be an obliterative cerebral angiopathy involving small vessels, leading to dystrophic calcifications via slow necrosis and finally to formation of cysts and secondary white matter abnormalities.

  • 316. Lippi, Giuseppe
    et al.
    Becan-McBride, Kathleen
    Behulova, Darina
    Bowen, Raffick A.
    Church, Stephen
    Delanghe, Joris
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Kitchen, Steve
    Nybo, Mads
    Nauck, Matthias
    Nikolac, Nora
    Palicka, Vladimir
    Plebani, Mario
    Sandberg, Sverre
    Simundic, Ana-Maria
    Preanalytical quality improvement: in quality we trust2013In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 51, no 1, p. 229-241Article in journal (Refereed)
    Abstract [en]

    Total quality in laboratory medicine should be defined as the guarantee that each activity throughout the total testing process is correctly performed, providing valuable medical decision-making and effective patient care. In the past decades, a 10-fold reduction in the analytical error rate has been achieved thanks to improvements in both reliability and standardization of analytical techniques, reagents, and instrumentation. Notable advances in information technology, quality control and quality assurance methods have also assured a valuable contribution for reducing diagnostic errors. Nevertheless, several lines of evidence still suggest that most errors in laboratory diagnostics fall outside the analytical phase, and the pre- and postanalytical steps have been found to be much more vulnerable. This collective paper, which is the logical continuum of the former already published in this journal 2 years ago, provides additional contribution to risk management in the preanalytical phase and is a synopsis of the lectures of the 2nd European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)-Becton Dickinson (BD) European Conference on Preanalytical Phase meeting entitled "Preanalytical quality improvement: in quality we trust" (Zagreb, Croatia, 1-2 March 2013). The leading topics that will be discussed include quality indicators for preanalytical phase, phlebotomy practices for collection of blood gas analysis and pediatric samples, lipemia and blood collection tube interferences, preanalytical requirements of urinalysis, molecular biology hemostasis and platelet testing, as well as indications on best practices for safe blood collection. Auditing of the preanalytical phase by ISO assessors and external quality assessment for preanalytical phase are also discussed.

  • 317.
    Ljungström, Lars
    et al.
    Department of Infectious Diseases, Skaraborg Hospital.
    Jacobsson, Gunnar
    Department of Infectious Diseases, Skaraborg Hospital / The swedish strategic program against antibiotic resistance.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Tilevik, Diana
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    The diagnostic value of PCT as biomarker in patients suspected with community-onset bacterial sepsis2017Conference paper (Refereed)
  • 318.
    Llano-Diez, Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Renaud, Guillaume
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Andersson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Gonzales Marrero, Humberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Cacciani, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Engquist, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Corpeno, Rebeca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Artemenko, Konstantin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Mechanisms underlying intensive care unit muscle wasting and effects of passive mechanical loading2012In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 16, no 5, p. R209-Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: INTRODUCTION: Critical ill intensive care unit (ICU) patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decreased quality of life of survivors. Critical illness myopathy (CIM) is a frequently observed neuromuscular disorder in ICU patients. Sepsis, systemic corticosteroid hormone treatment and post-synaptic neuromuscular blockade have been forwarded as the dominating triggering factors. Recent experimental results from our group using a unique experimental rat ICU model have shown that the "mechanical silencing" associated with the ICU condition is the primary triggering factor. This study aims at (1) unraveling the mechanisms underlying CIM, and (2) evaluating the effects of a specific intervention aiming at reducing the mechanical silencing in sedated and mechanically ventilated ICU patients. METHODS: Muscle gene/protein expression, post-translational modifications (PTMs), muscle membrane excitability, muscle mass measurements, and contractile properties at the single muscle fiber level were explored in seven deeply sedated and mechanically ventilated ICU patients (not exposed to systemic corticosteroid hormone treatment, post-synaptic neuromuscular blockade or sepsis) subjected to unilateral passive mechanical loading 10 hours per day (2.5 hours, 4 times) for 9 +/- 1 days. RESULTS: These patients developed a phenotype considered pathognomonic of CIM, i.e., severe muscle wasting and a preferential myosin loss (P<0.001). In addition, myosin PTMs specific to the ICU condition were observed in parallel with an increased sarcolemmal expression and cytoplasmic translocation of nNOS. Passive mechanical loading for 9 +/- 1 resulted in a 35% higher specific force (P<0.001) compared with the unloaded leg, although it was not sufficient to prevent the loss of muscle mass. CONCLUSIONS: Mechanical silencing is suggested to be a primary mechanism underlying CIM, i.e., triggering the myosin loss, muscle wasting and myosin PTMs. The higher nNOS expression found in the ICU patients and its cytoplasmic translocation are forwarded as a probable mechanism underlying these modifications. The positive effect of passive loading on muscle fiber function strongly supports the importance of early physical therapy and mobilization in deeply sedated and mechanically ventilated ICU patients.

  • 319.
    Loftås, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Norrköping.
    Response to neoadjuvant treatment in rectal cancer surgery2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rectal cancer is one of the three most common malignancies in Sweden with an annual incidence of about 2000 cases. Current treatment consists of surgical resection of the rectum including the loco-regional lymph nodes in the mesorectum. In advanced cases, neoadjuvant chemo-radiotherapy (CRT) prior to the operative treatment reduces local recurrences and enables surgery. The neoadjuvant treatment can also eradicate the tumour completely, i.e. complete response. This research project was designed to investigate the effects of preoperative radiotherapy/ CRT and analyze methods to predict response to CRT.

    Study I investigated the expression of the FXYD-3 protein with immunohistochemistry in rectal cancer, with or without preoperative radiotherapy. The results from the total cohort showed that, strong FXYD-3 expression was correlated to infiltrative tumour growth (p = 0.02). In the radiotherapy group, strong FXYD-3 expression was related to an unfavourable prognosis (p = 0.02). Tumours with strong FXYD-3 expression had less tumour necrosis (p = 0.02) after radiotherapy. FXYD-3 expression in the primary tumour was increased compared to normal mucosa (p=0.008). We concluded that FXYD-3 expression was a prognostic factor in patients receiving preoperative radiotherapy for rectal cancer.

    Study II investigated FXYD-3 expression in tumours that developed local recurrences following surgery and compared this with expression in tumours that did not develop local recurrences. There was no difference in the expression of FXYD-3 between the group that developed local recurrences and the group that did not develop local recurrences. There was no difference in survival between those with strong or weak FXYD-3 expression. We concluded that this study could not confirm the findings from study 1 i.e. that FXYD-3 expression has prognostic significance in rectal cancer.

    Study III was a register-based study on the incidence and effects of complete response to neoadjuvant treatment. Eight per cent of the patients with adequate CRT to achieve complete response also had a complete histological response of the luminal tumor in the resected bowel. Sixteen per cent of that group had remaining lymph node metastases in the operative specimen. Chemotherapy together with radiotherapy doubled the chance of complete response in the luminal tumour. Patients with remaining lymph node metastases had a lower survival rate compared to those without. We concluded that residual nodal involvement after neoadjuvant treatment was an important factor for reduced survival after complete response in the luminal tumour.

    Study IV followed up the results from the previous study by re-evaluating magnetic resonance imaging (MRI)- images in patients with complete tumour response. Two experienced MRI radiologists performed blinded re-staging of post CRT MR- images from patients with complete response in the luminal tumour. One group with lymph node metastases and another one without were studied and the results compared with the pathology reports. The sensitivity, specificity, and positive and negative predicted values for correct staging of positive lymph nodes was 37%, 84%, 70% and 57%. The size of the largest lymph node (4.5 mm, p=0.04) seemed to indicate presence of a tumour positive lymph node. We concluded that MRI couldn’t correctly stage patients for lymph node metastases in patients with complete response to CRT in the luminal tumour.

  • 320. Lourbakos, A.
    et al.
    Yau, N.
    de Bruijn, P.
    Hiller, M.
    Kozaczynska, K.
    Jean-Baptiste, R.
    Reza, M.
    Wolterbeek, R.
    Koeks, Z.
    Ayoglu, Burcu
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    de Klerk, D.
    Campion, G.
    Zaharieva, I.
    Nadarajah, V. D.
    Nilsson, P.
    Al-Khalili Szigyarto, Cristina
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Muntoni, F.
    Lochmuller, H.
    Verschuuren, J. J.
    Goemans, N.
    Tulinius, M.
    Niks, E. H.
    de Kimpe, S.
    Aartsma-Rus, A.
    't Hoen, Peter A. C.
    Spitali, P.
    Evaluation of serum MMP-9 as predictive biomarker for antisense therapy in Duchenne2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 17888Article in journal (Refereed)
    Abstract [en]

    Duchenne Muscular Dystrophy (DMD) is a severe muscle disorder caused by lack of dystrophin. Predictive biomarkers able to anticipate response to the therapeutic treatments aiming at dystrophin re-expression are lacking. The objective of this study is to investigate Matrix Metalloproteinase-9 (MMP-9) as predictive biomarker for Duchenne. Two natural history cohorts were studied including 168 longitudinal samples belonging to 66 patients. We further studied 1536 samples obtained from 3 independent clinical trials with drisapersen, an antisense oligonucleotide targeting exon 51: an open label study including 12 patients; a phase 3 randomized, double blind, placebo controlled study involving 186 patients; an open label extension study performed after the phase 3. Analysis of natural history cohorts showed elevated MMP-9 levels in patients and a significant increase over time in longitudinal samples. MMP-9 decreased in parallel to clinical stabilization in the 12 patients involved in the open label study. The phase 3 study and subsequent extension study clarified that the decrease in MMP-9 levels was not predictive of treatment response. These data do not support the inclusion of serum MMP-9 as predictive biomarker for DMD patients.

  • 321. Low, Nicola
    et al.
    Cassell, Jackie A
    Spencer, Brenda
    Bender, Nicole
    Martin Hilber, Adriane
    van Bergen, Jan
    Andersen, Berit
    Herrmann, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Dubois-Arber, Françoise
    Hamers, Françoise F
    van de Laar, Marita
    Stephenson, Judith M
    Chlamydia control activities in Europe: cross-sectional survey2012In: European Journal of Public Health, ISSN 1101-1262, E-ISSN 1464-360X, Vol. 22, no 4, p. 556-561Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Chlamydia is the most commonly reported bacterial sexually transmitted infection in Europe. The objective of the Screening for Chlamydia in Europe (SCREen) project was to describe current and planned chlamydia control activities in Europe.

    METHODS: The authors sent a questionnaire asking about different aspects of chlamydia epidemiology and control to public health and clinical experts in each country in 2007. The principles of sexually transmitted infection control were used to develop a typology comprising five categories of chlamydia control activities. Each country was assigned to a category, based on responses to the questionnaire.

    RESULTS: Experts in 29 of 33 (88%) invited countries responded. Thirteen of 29 countries (45%) had no current chlamydia control activities. Six countries in this group stated that there were plans to introduce chlamydia screening programmes. There were five countries (17%) with case management guidelines only. Three countries (10%) also recommended case finding amongst partners of diagnosed chlamydia cases or people with another sexually transmitted infection. Six countries (21%) further specified groups of asymptomatic people eligible for opportunistic chlamydia testing. Two countries (7%) reported a chlamydia screening programme. There was no consistent association between the per capita gross domestic product of a country and the intensity of chlamydia control activities (P = 0.816).

    CONCLUSION: A newly developed classification system allowed the breadth of ongoing national chlamydia control activities to be described and categorized. Chlamydia control strategies should ensure that clinical guidelines to optimize chlamydia diagnosis and case management have been implemented before considering the appropriateness of screening programmes.

  • 322.
    Lubenow, Norbert
    et al.
    Staatl. Medizinaluntersuchungsamt, Hannover Medical School, Germany.
    Diepenbrock, F
    Schickling, H
    Bock, D
    Heckler, R
    Sander, J
    Phenylketonuria screening with a fluorometric microplate assay.1994In: European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies, ISSN 0939-4974, Vol. 32, no 7, p. 525-8Article in journal (Refereed)
    Abstract [en]

    A fluorometric assay in microtitre plates for the screening of phenylketonuria was evaluated and adapted to a neonatal screening programme. Using this assay, it is possible to determine quantitatively the phenylalanine concentration in dried blood spots on filter paper. The test exhibited a linear calibration curve with a good slope as well as sufficient precision and accuracy in the statistical analysis. Interference by other amino acids and antibiotics was not observed. Only elevated concentrations of leucine interfered to a small degree. The phenylalanine concentration in dried blood spots of 13 phenylketonuria patients correlated to that in serum. 7381 dried blood samples of newborn infants were tested simultaneously by both the fluorometric and the Guthrie test. The results did not show significant differences. We screened 29,182 newborns using the fluorometric assay and an online data processing programme. The internal repetition rate was 0.64%, the external recall rate 0.15%. False negative results were not observed. In December 1991 the fluorometric method replaced the Guthrie test in our routine programme for phenylketonuria screening, and was introduced as a follow up test for phenylketonuria patients.

  • 323.
    Lundin, Anna-Carin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tendinosis in Trigger Finger2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Trigger finger is one of the most common hand conditions, with a prevalence of almost 3%. The aetiology remains unclear even though many causes have been suggested. The prevailing paradigm is that the pathogenesis of trigger finger is ascribed to primary changes in the first fibrous condensation of the tendon sheath (A1-pulley). Several studies have investigated pathology in the pulley, but few have investigated the tendon. The general aim of this thesis was to find out if there is pathology in the trigger finger tendon and to define it.

    We first looked at trigger finger tendon biopsies in a light microscope, and found that they were histologically different from healthy tendons. They showed signs of micro-ruptures, collagen degradation, increased amounts of ground substance, both hyper- and hypo-cellular areas, round active cell nuclei and absence of inflammatory cells, all similar to tendinosis. The histological picture was further assessed by using a scoring system for Achilles tendinosis. The trigger finger tendons scored high, suggesting a similar histopathology.

    Next, we performed a quantitative real-time polymerase chain reaction (qPCR) on trigger finger tendons. We assessed the mRNA expression of 10 genes, which have been described to be differently expressed in Achilles tendinosis (collagen 1 and 3, versican, decorin, biglycan, aggrecan, MMP-2, MMP-3, ADAMTS-5, and TIMP-3). The overall expression pattern agreed with previous studies on Achilles tendinosis, suggesting that the cellular function in trigger finger tendons is disturbed in a similar way as in Achilles tendinosis.

    Recent experimental and observational research has suggested potential side effects of statin treatment on tendons, but firm evidence was lacking. We performed an epidemiological study on two large population-based cohorts. Statin use was found to increase the risk of both trigger finger and tendinosis in the shoulder and Achilles tendons, especially among men. This suggests a similar pathology in trigger finger and tendinosis.

    We have also studied the time to treatment effect after a single injection of glucocorticoid in trigger finger. Our results suggest that 60-80% of patients can expect resolution of the triggering within 14 days, and half of them within seven days. This result allows correct information to be given to the patient and proper planning of follow-ups.

    In conclusion, the pathology in trigger finger tendons is similar to tendinosis in other tendons.

  • 324.
    Lundström, Yasmin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Lundström, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Popova, Svetlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Lindblom, Rickard P.F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Detection of Changes in Immunohistochemical Stains Caused by Postmortem Delay and Fixation Time2019In: Applied immunohistochemistry & molecular morphology (Print), ISSN 1541-2016, E-ISSN 1533-4058, Vol. 27, no 3, p. 238-245Article in journal (Refereed)
    Abstract [en]

    In this study, we have systematically assessed the influence of postmortem delay (PMD) and fixation time (FT) on the immunohistochemical (IHC) staining outcome. The IHC method is frequently applied on surgical and postmortem samples in diagnostics and research. To replicate the routine situation, brain tissues from pigs were exposed to either storage in a refrigerator (+8°C), that is, PMD (1 to 168 h), or fixed in 10% buffered formalin, that is, FT (18 to 94 d). Subsequently, the tissue was routinely processed into paraffin blocks to enable construction of tissue microarrays (TMA). Sections cut from the TMA blocks were stained applying 13 different antibodies directed against neuronal and glial antigens. Immunoreactivity applying 5 antibodies was influenced by prolonged PMD and applying 2 antibodies by prolonged FT. None of the staining outcomes related to the PMD or FT were predictable. Loss of TMA cores during processing was primarily influenced by pretreatment and by tissue characteristics (gray/white matter). The test model described here confirmed that these 2 variables, PMD and FT, indeed influence the IHC outcome. The PMD and FT are particularly of importance while assessing tissue samples obtained at autopsy. The result above is also of importance while comparing the IHC outcomes seen in the postmortem setting (various PMD/FT) with surgical samples or with IHC outcome seen in experimental animal setting (controlled PMD/FT). Thus, we suggest that the test model described here is considered when assessing the reliability of the IHC outcome when analyzing tissues with various characteristics.

  • 325.
    Löf, Liza
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Arngården, Linda
    Olsson-Strömberg, Ulla
    Jansson, Mattias
    Dahlin, Joakim
    Thörn, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Christiansson, Lisa
    Hermansson, Monica
    Larsson, Anders
    Ahlstrand, Erik
    Wålinder, Göran
    Rosenquist Brandell, Richard
    Söderberg, Ola
    Landegren, Ulf
    Kamali-Moghaddam, Masood
    Flow Cytometric Measurement of BCR-ABL Fusion Protein Positive Cells in Blood from Patients with Chronic Myeloid LeukemiaManuscript (preprint) (Other academic)
  • 326. Löfdahl, Britta
    et al.
    Ahlin, Cecilia
    Holmqvist, Marit
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Amini, Rose-Marie
    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 Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Inflammatory cells in node-negative breast cancer2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 5, p. 680-686Article in journal (Refereed)
    Abstract [en]

    Background.

    To study the impact of inflammatory cells in a clinically well-defined cohort of women with node-negative breast cancer in a nested case-control study design.

    Material and methods.

    The cohort was comprised of 190 women who died from breast cancer and 190 women still alive at the date of death for the corresponding breast cancer patients were used as controls. The inclusion criteria included; a tumour size ≤ 50 mm, no lymph node metastases and no initiation of adjuvant chemotherapy. Immunohistochemical stainings for CD3, CD4, CD8, FoxP3, CD20, tryptase and CD68 were performed on TMA blocks, evaluated and correlated to each other and to age, tumour size, histological grade, ER, PgR, Ki67 and cyclin A.

    Results.

    There was no difference regarding the amount or content of inflammatory cells in the cases compared to controls. T- and B-cells were highly correlated to each other but these cell types correlated to a lesser extent to macrophages and not at all to mast cells. A weak tendency of correlations between all the subsets of inflammatory cells and histological grade, Ki67 and cyclin A was observed, although a negative correlation was seen for mast cells.

    Conclusion.

    The amount or content of inflammatory cells in invasive breast cancer did not appear to influence death in node-negative breast cancer.

  • 327.
    Löwbeer, Christian
    et al.
    Aleris Medilab och Institutionen för laboratoriemedicin, Avdelningen för klinisk kemi, Karolinska institutet, Stockholm.
    Hammarsten, Ola
    Avdelningen för Laboratoriemedicin vid Institutionen för biomedicin, Sahlgrenska universitetssjukhuset, Göteborgs universitet.
    Rönnelid, Johan
    Institutionen för immunologi, genetik och patologi, Klinisk immunologi, Uppsala universitet.
    Ridefelt, Peter
    Institutionen för medicinska vetenskaper, Klinisk kemi, Uppsala universitet.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Energiomsättning, diabetes och lipoproteinrubbningar2018In: Laurells klinisk kemi i praktisk medicin / [ed] Elvar Theodorsson, Maria Berggren Söderlund, Lund: Studentlitteratur AB, 2018, 10, p. 345-414Chapter in book (Other academic)
  • 328.
    Magnusson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Tillförlitliga referensintervall krävs för värdering av P-ALP: Nya pediatriska referensintervall för alkaliskt fosfatas har klinisk betydelse för att hitta rätt till diagnosen2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, no 42, p. 1750-1751, article id ETTHArticle in journal (Refereed)
    Abstract [sv]

    Age- and gender-specific reference intervals are pivotal to ensure appropriate interpretation of plasma alkaline phosphatase activities in the lower range Hypophosphatasia (HPP) is an inborn error of metabolism caused by loss-of-function mutations of the ALPL gene that mainly express alkaline phosphatase (ALP) in bone and liver. The clinical expression of HPP is highly variable and is classified into six different forms mainly affecting bone and tooth mineralization. The prognosis for each of these HPP forms depends upon the severity of the skeletal disease which reflects the age at presentation. The biochemical hallmark of HPP is low plasma ALP activity (hypophosphatasemia); however, HPP is often misdiagnosed because of low awareness and sometimes absence of age- and gender-specific ALP reference intervals. Children and adolescents have higher ALP levels in comparison with adults. Reliable reference intervals are pivotal for any clinical laboratory test. Harmonized age- and gender-specific plasma ALP reference intervals ought to be used to ensure appropriate interpretation of plasma ALP activities in the lower range.

  • 329. Manojlovic-Gacic, Emilija
    et al.
    Skender-Gazibara, Milica
    Popovic, Vera
    Soldatovic, Ivan
    Boricic, Novica
    Raicevic, Savo
    Pekic, Sandra
    Doknic, Mirjana
    Miljic, Dragana
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Oncogene-Induced Senescence in Pituitary Adenomas-an Immunohistochemical Study.2016In: Endocrine pathology, ISSN 1046-3976, E-ISSN 1559-0097, Vol. 27, no 1, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Oncogene-induced senescence (OIS) serves as an initial barrier to cancer development, being proposed as a possible explanation for the usually benign behavior of the pituitary adenomas. We aimed to explore the immunohistochemical expression of the OIS markers, senescence-associated lysosomal β-galactosidase (SA-β-GAL), p16, and p21 in different types of 345 pituitary adenomas and compared it with the expression in the normal pituitary and in the specimens from the repeated surgeries. SA-β-GAL was overexpressed in the pituitary adenomas, compared to the normal pituitaries. Growth hormone (GH) producing adenomas showed the strongest SA-β-GAL, with densely granulated (DG)-GH adenomas more reactive than the sparsely granulated (SG). Nuclear p21 was decreased in the adenomas, except for the SG-GH adenomas that had higher p21 than the normal pituitaries and the other adenomas. p16 was significantly lower in the adenomas, without type-related differences. SA-β-GAL was slightly lower and p16 slightly higher in the recurrences. Our findings indicate alterations of the senescence program in the different types of pituitary adenomas. Activation of senescence in the pituitary adenomas presents one possible explanation for their usually benign behavior, at least in the GH adenomas that show a synchronous increase of two OIS markers. However, subdivision into GH adenoma subtypes reveals differences that reflect complex regulatory mechanisms influenced by the interplay between the granularity pattern and the hormonal factors, with possible impact on the different clinical behavior of the SG- and DG-GH adenoma subtypes. p16 seems to have a more prominent role in the pituitary tumorigenesis than in the senescence. Recurrent growth in a subset of the pituitary adenomas is not associated with consistent changes in the senescence pattern.

  • 330.
    Mansouri, Larry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Noerenberg, Daniel
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mylonas, Elena
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Abdulla, Maysaa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frick, Mareike
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Asmar, Fazila
    Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schneider, Markus
    Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
    Yoshida, Kenichi
    Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
    Skaftason, Aron
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pandzic, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gonzalez, Blanca
    Department of Pathology, Hospital Clinic and Institut d’Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
    Tasidou, Anna
    Hematopathology Department, Evangelismos Hospital, Athens, Greece.
    Waldhueter, Nils
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Rivas-Delgado, Alfredo
    Hematology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain.
    Angelopoulou, Maria
    Department of Haematology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
    Ziepert, Marita
    Institute for Medical Informatics, Statistics, and Epidemiology, University at Leipzig, Leipzig, Germany.
    Arends, Christopher-Maximilian
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Couronne, Lucile
    Service d’Hematologie Adulte, Assistance Publique–Hopitaux de Paris, Hopital Necker, Paris, France.
    Lenze, Dido
    Institute of Pathology, Charite University Medical Center, Berlin, Germany.
    Claudia, Baldus
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Bastard, Christian
    INSERM U918, Universite de Rouen, Centre Henri Becquerel, Rouen, France.
    Okosun, Jessica
    Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
    Fitzgibbon, Jude
    Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
    Dörken, Bernd
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Drexler, Hans G
    Leibniz-Institute DSMZ–German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
    Roos-Weil, Damien
    University Paris-Sud, Orsay, France, INSERM, U1170, Institut Gustave Roussy, Villejuif, France and Equipe Labellisee Ligue Nationale Contre le Cancer, Paris, France.
    Schmitt, Clemens A
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Munch-Petersen, Helga D
    Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Zenz, Thorsten
    Departments of Molecular Therapy in Haematology and Oncology and Translational Oncology, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany, Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany and German Consortium for Translational Cancer Research, Heidelberg, Germany .
    Hansmann, Martin-Leo
    Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.
    Strefford, Jonathan C
    Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bernard, Olivier
    University Paris-Sud, Orsay, France, INSERM, U1170, Institut Gustave Roussy, Villejuif, France and Equipe Labellisee Ligue Nationale Contre le Cancer, Paris, France.
    Ralfkiaer, Elisabeth
    Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Erlanson, Martin
    Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
    Korkolopoulou, Penelope
    Department of Pathology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
    Hultdin, Magnus
    Department of Medical Biosciences, Pathology, Umeå University, Umeå Sweden.
    Papadaki, Theodora
    Hematopathology Department, Evangelismos Hospital, Athens, Greece.
    Grønbæk, Kirsten
    Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Lopez-Guillermo, Armando
    Hematology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain.
    Ogawa, Seishi
    Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
    Küppers, Ralf
    Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
    Stavroyianni, Niki
    Hematology Department and Hematopoietic Cell Transplantation Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
    Kanellis, George
    Hematopathology Department, Evangelismos Hospital, Athens, Greece.
    Rosenwald, Andreas
    Institute of Pathology, University of Würzburg, Würzburg, Germany and Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
    Campo, Elias
    Department of Pathology, Hospital Clinic and Institut d’Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Ott, German
    Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
    Vasslakopoulos, Theodoros P
    Department of Haematology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
    Hummel, Michael
    Institute of Pathology, Charite University Medical Center, Berlin, Germany.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Damm, Frederik
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany and Berlin Institute of Health, Berlin, Germany.
    Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 23, p. 2666-2670Article in journal (Refereed)
    Abstract [en]

    We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBϵ, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases, 22.7%) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases, 27.3%). NFKBIE-deleted PMBL patients were more often therapy-refractory (P=.022) and displayed inferior outcome compared to wildtype patients (5-year survival: 59% vs. 78%; P=.034); however they appeared to benefit from radiotherapy (P=.022) and rituximab-containing regimens (P=.074). NFKBIEaberrations remained an independent factor in multivariate analysis (P=.003), also when restricting to immunochemotherapy-treated patients (P=.008). Whole-exome sequencing and gene expression-profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.

  • 331. Margretardottir, Olof Birna
    et al.
    Geirsson, Gudmundur
    Agnarsdóttir, Margrét
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Ulfarsson, Elfar
    [Case of the month: woman with hematuria and depressed mental status]2012In: Læknablađiđ, ISSN 0023-7213, Vol. 98, no 7-8, p. 413-415Article in journal (Refereed)
  • 332. Marquardt, Nicole
    et al.
    Ivarsson, MA
    Sundström, E
    Åkesson, E
    Martini, E
    Eidsmo, L
    Friberg, Danielle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Mjösberg, J
    Kublickas, M
    Ek, S
    Tegerstedt, G
    Seiger, Å
    Westgren, M
    Michaëlsson, J
    Fetal CD103+ IL-17-Producing Group 3 Innate Lymphoid Cells Represent the Dominant Lymphocyte Subset in Human Amniotic Fluid.2016In: Journal of immunology (Baltimore, Md. : 1950), Vol. 197, no 8Article in journal (Refereed)
    Abstract [en]

    Amniotic fluid (AF) surrounds the growing fetus, and cells derived from AF are commonly used for diagnosis of genetic diseases. Intra-amniotic infections are strongly linked to preterm birth, which is the leading cause of perinatal mortality worldwide. Surprisingly little is known, however, about mature hematopoietic cells in AF, which could potentially be involved in immune responses during pregnancy. In this study, we show that the dominating population of viable CD45+ cells in AF is represented by a subset of fetal CD103+ group 3 innate lymphoid cells (ILCs) producing high levels of IL-17 and TNF. Fetal CD103+ ILC3s could also be detected at high frequency in second-trimester mucosal tissues (e.g., the intestine and lung). Taken together, our data indicate that CD103+ ILC3s accumulate with gestation in the fetal intestine and subsequently egress to the AF. The dominance of ILC3s producing IL-17 and TNF in AF suggests that they could be involved in controlling intra-amniotic infections and inflammation and as such could be important players in regulating subsequent premature birth.

  • 333.
    Marusik, C
    et al.
    Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden.
    Frykholm, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ericson, Katharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Diagnosis of Placental Mesenchymal Dysplasia with a focus on magnetic resonance imaging (MRI)2017In: Ultrasound in Obstetrics and Gynecology, ISSN 0960-7692, E-ISSN 1469-0705, Vol. 49, no 3, p. 410-412Article in journal (Refereed)
  • 334. Maselli, Bianca S.
    et al.
    Giron, Macelle C. G.
    Lim, Hwanmi
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Bergvall, Christoffer
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Westerholm, Roger
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Dreij, Kristian
    Watanabe, Tetsushi
    Cardoso, Arnaldo A.
    Umbuzeiro, Gisela A.
    Kummrow, Fabio
    Comparative mutagenic activity of atmospheric particulate matter from limeira, stockholm, and kyoto2019In: Environmental and Molecular Mutagenesis, ISSN 0893-6692, E-ISSN 1098-2280, Vol. 60, no 7, p. 607-616Article in journal (Refereed)
    Abstract [en]

    Atmospheric particulate matter (PM) organic fractions from urban centers are frequently mutagenic for the Salmonella/microsome assay. This mutagenicity is related to both primary and secondary pollutants, and meteorological conditions have great influence on the secondary pollutant's formation. Our objective was to compare the mutagenicity of atmospheric total suspended particulates (TSP) from three cities with marked different meteorological conditions and TSP concentrations: Limeira (Brazil) with 99.0 mu g/m(3), Stockholm (Sweden) with 6.2 mu g/m(3), and Kyoto (Japan) with 28.0 mu g/m(3). For comparison, we used the same batch of filters, sample extraction method, and Salmonella/microsome testing protocol with 11 strains of Salmonella with and without metabolic activation. Samples were collected during winter and pooled into one single extract representing each city. All samples were mutagenic for all tested strains, except for TA102. Based on the strain's selectivity, nitroarenes, polycyclic aromatic hydrocarbons, and aromatic amines play a predominant role in the mutagenicity of these samples. The mutagenic potencies expressed by mass of extracted organic material (EOM; revertants/mu g EOM) were similar (similar to twofold difference) among the cities, despite differences in meteorological conditions and pollution sources. In contrast, the mutagenic potencies expressed by air volume (rev/m(3)) varied similar to 20-fold, with Limeira > Kyoto approximate to Stockholm. These results are the first systematic assessment of air mutagenicity from cities on three continents using the same protocols. The results confirm that the mutagenic potency expressed by EOM mass is similar regardless of continent of origin, whereas the mutagenic potency expressed by air volume can vary by orders of magnitude. Environ. Mol. Mutagen. 2019.

  • 335.
    Mathot, Lucy
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kundu, Snehangshu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Svedlund, Jessica
    Moens, Lotte
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Adlerteg, Tom
    Falk-Sörqvist, Elin
    Rendo, Verónica
    Bellomo, Claudia
    Mayrhofer, Markus
    Cortina, Carme
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Isaksson, Anders
    Moustakas, Aristidis
    Batlle, Eduard
    Birgisson, Helgi
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Nilsson, Mats
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 7, no 77, p. 1730-1740Article in journal (Refereed)
    Abstract [en]

    The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses in situ confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1-induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer.

  • 336.
    Matsunaga, N
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Anan, Intissar
    Rosenberg, P
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nagai, R
    Lundström, O
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Horiuchi, S
    Ando, Y
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Advanced glycation end product is implicated in amyloid-related kidney complications2005In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 65, no 4, p. 263-272Article in journal (Refereed)
    Abstract [en]

    Background. Kidney failure is a common complication in familial amyloidotic polyneuropathy (FAP). It has been suggested that advanced glycation end products (AGEs) play an important role in the development and pathogenesis of FAP.

    Material and methods. To evaluate the impact of AGEs on FAP patients' kidney dysfunction, we measured AGE in serum and urine of 28 FAP patients and 18 healthy controls by AGE-specific enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry utilizing antibodies to AGE and the receptor for AGE (RAGE) were used on kidney tissue from 3 FAP patients and 3 diabetic patients to disclose a correlation between amyloid deposits and AGE -RAGE.

    Results. The glomeruli of FAP patients were heavily deposited with amyloid and the glomerular size was enlarged. The space between Bowman's capsule and glomerulus was totally covered by the enlarged glomerulus. AGE and RAGE were deposited in glomeruli and tubuli and correlated with amyloid deposits. Decreased AGE levels in the liver-transplanted FAP patients' serum compared with that of non-transplanted patients were noted, and AGE concentration in serum tended to be higher in non-transplanted FAP patients compared with normal control subjects. There were no differences in the AGE urine levels in FAP patients compared with controls. No correlation could be found between AGE in urine and serum compared with serum albumin, serum creatinine and creatinine clearance.

    Conclusions. The accumulation of AGE, RAGE and amyloid in the kidney of FAP patients suggests that these molecules play an important role in the origin and pathogenesis of renal failure in FAP patients.

  • 337.
    Mattsson, Johanna Sofia Margareta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Bergman, Bengt
    Grinberg, Marianna
    Edlund, Karolina
    Marincevic, Millaray
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Jirstrom, Karin
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hengstler, Jan G
    Rahnenfuhrer, Jorg
    Karlsson, Mats G
    Karlsson, Christina
    Helenius, Gisela
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Gulyas, Miklos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Prognostic impact of COX-2 in non-small cell lung cancer: A comprehensive compartment-specific evaluation of tumor and stromal cell expression2015In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 356, no 2, p. 837-845Article in journal (Refereed)
    Abstract [en]

    Cyclooxygenase-2 (COX-2) is an enzyme that has been extensively investigated as a prognostic marker in cancer. In non-small cell lung cancer (NSCLC) previous results regarding the prognostic impact of COX-2 expression are inconsistent. Therefore we evaluated the association between transcript levels and overall survival in nine publicly available gene expression data sets (total n=1337) and determined in situ compartment-specific tumor and stromal cell protein expression in two independent cohorts (n=616). Gene expression did not show any correlation with clinical parameters or with overall survival. Protein expression in tumor and stromal cells did not correlate with any clinical parameter or with overall survival in one of the analyzed cohorts, while a significant association of high stromal expression with longer survival was observed in both univariate and multivariate analysis in the other cohort. Stromal expression of COX-2 has not been separately evaluated in NSCLC previously and may be a subject of further investigation, whereas the presented findings from this comprehensive compartment specific evaluation clearly reject the hypothesis of COX-2 tumor cell expression having a prognostic value in NSCLC.

  • 338.
    Mattsson, Johanna Sofia Margareta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Brunnström, Hans
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden; Reg Labs Reg Skane, Dept Pathol, SE-22185 Lund, Sweden.
    Jabs, Verena
    TU Dortmund Univ, Dept Stat, Dortmund, Germany.
    Edlund, Karolina
    Dortmund TU, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany.
    Jirström, Karin
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden.
    Mindus, Stephanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    La Fleur, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Karlsson, Mats
    Univ Orebro, Fac Med & Hlth, Dept Res & Educ, Orebro, Sweden.
    Karlsson, Christina
    Univ Orebro, Sch Hlth Sci, Orebro, Sweden.
    Koyi, Hirsh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Brandén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Helenius, Gisela
    Univ Orebro, Fac Med & Hlth, Dept Lab Med, Orebro, Sweden.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Svensson, Maria
    Univ Orebro, Fac Med & Hlth, Clin Res Ctr, Orebro, Sweden.
    Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer2016In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, article id 603Article in journal (Refereed)
    Abstract [en]

    Background: Identification of targetable EML4-ALK fusion proteins has revolutionized the treatment of a minor subgroup of non-small cell lung cancer (NSCLC) patients. Although fluorescence in situ hybridization (FISH) is regarded as the gold standard for detection of ALK rearrangements, ALK immunohistochemistry (IHC) is often used as screening tool in clinical practice. In order to unbiasedly analyze the diagnostic impact of such a screening strategy, we compared ALK IHC with ALK FISH in three large representative Swedish NSCLC cohorts incorporating clinical parameters and gene expression data.

    Methods: ALK rearrangements were detected using FISH on tissue microarrays (TMAs), including tissue from 851 NSCLC patients. In parallel, ALK protein expression was detected using IHC, applying the antibody clone D5F3 with two different protocols (the FDA approved Ventana CDx assay and our in house Dako IHC protocol). Gene expression microarray data (Affymetrix) was available for 194 patients.

    Results: ALK rearrangements were detected in 1.7% in the complete cohort and 2.0% in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.9% and 1.5% when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (>99%), while the sensitivity was between 69% (Ventana) and 62% (in house Dako protocol). Furthermore, only 67% of the ALK IHC positive cases were positive in both IHC assays. Gene expression analysis revealed that 6/194 (3%) tumors showed high ALK gene expression (≥6AU) and of them only three were positive by either FISH or IHC.

    Conclusion: The overall frequency of ALK rearrangements based on FISH was lower than previously reported. The sensitivity of both IHC assays was low, and the concordance between the FISH and the IHC assays poor, questioning current strategies to screen with IHC prior to FISH or completely replace FISH by IHC.

  • 339.
    Medin, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Post-exercise elevation of cardiac risk markers in young athletes and evaluation of possible screening methods to prevent sudden heart failure2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 340.
    Mezheyeuski, Artur
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bergsland, Christian Holst
    Backman, Max
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Djureinovic, Dijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bruun, Jarle
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Multispectral imaging for quantitative and compartment-specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients.2018In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 244, no 4, p. 421-431Article in journal (Refereed)
    Abstract [en]

    Semiquantitative assessment of immune markers by immunohistochemistry (IHC) has significant limitations for describing the diversity of the immune response in cancer. Therefore, we evaluated a fluorescence-based multiplexed immunohistochemical method in combination with a multispectral imaging system to quantify immune infiltrates in situ in the environment of non-small-cell lung cancer (NSCLC). A tissue microarray including 57 NSCLC cases was stained with antibodies against CD8, CD20, CD4, FOXP3, CD45RO, and pan-cytokeratin, and immune cells were quantified in epithelial and stromal compartments. The results were compared with those of conventional IHC, and related to corresponding RNA-sequencing (RNAseq) expression values. We found a strong correlation between the visual and digital quantification of lymphocytes for CD45RO (correlation coefficient: r = 0.52), FOXP3 (r = 0.87), CD4 (r = 0.79), CD20 (r = 0.81) and CD8 (r = 0.90) cells. The correlation with RNAseq data for digital quantification (0.35-0.65) was comparable to or better than that for visual quantification (0.38-0.58). Combination of the signals of the five immune markers enabled further subpopulations of lymphocytes to be identified and localized. The specific pattern of immune cell infiltration based either on the spatial distribution (distance between regulatory CD8(+) T and cancer cells) or the relationships of lymphocyte subclasses with each other (e.g. cytotoxic/regulatory cell ratio) were associated with patient prognosis. In conclusion, the fluorescence multiplexed immunohistochemical method, based on only one tissue section, provided reliable quantification and localization of immune cells in cancer tissue. The application of this technique to clinical biopsies can provide a basic characterization of immune infiltrates to guide clinical decisions in the era of immunotherapy.

  • 341.
    Mezheyeuski, Artur
    et al.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Belarusian State Med Univ, Dept Pathol, Minsk, Byelarus..
    Lindh, Maja Bradic
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Guren, Tormod Kyrre
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway..
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Pfeiffer, Per
    Univ Southern Denmark, Dept Oncol, Odense, Denmark..
    Kure, Elin H.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway..
    Ikdahl, Tone
    Akershus Univ Hosp, Lorenskog, Norway..
    Skovlund, Eva
    Univ Oslo, Sch Pharm, Oslo, Norway.;Norwegian Inst Publ Hlth, Oslo, Norway..
    Corvigno, Sara
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Strell, Carina
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Pietras, Kristian
    Lund Univ, Div Translat Canc Res, Lund, Sweden..
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Mulder, Jan
    Karolinska Inst, Sci Life Lab, Dept Neurosci, Stockholm, Sweden..
    Qvortrup, Camilla
    Univ Southern Denmark, Dept Oncol, Odense, Denmark..
    Portyanko, Anna
    Belarusian State Med Univ, Dept Pathol, Minsk, Byelarus..
    Tveit, Kjell Magne
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway..
    Östman, Arne
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Survival-associated heterogeneity of marker-defined perivascular cells in colorectal cancer2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 27, p. 41948-41958Article in journal (Refereed)
    Abstract [en]

    Perivascular cells (PC) were recently implied as regulators of metastasis and immune cell activity. Perivascular heterogeneity in clinical samples, and associations with other tumor features and outcome, remain largely unknown. Here we report a novel method for digital quantitative analyses of vessel characteristics and PC, which was applied to two collections of human metastatic colorectal cancer (mCRC). Initial analyses identified marker-defined subsets of PC, including cells expressing PDGFR-beta or alpha-SMA or both markers. PC subsets were largely independently expressed in a manner unrelated to vessel density and size. Association studies implied specific oncogenic mutations in malignant cells as determinants of PC status. Semi-quantitative and digital-image-analyses-based scoring of the NORDIC-VII cohort identified significant associations between low expression of perivascular PDGFR-alpha and -beta and shorter overall survival. Analyses of the SPCRC cohort confirmed these findings. Perivascular PDGFR-alpha and -beta remained independent factors for survival in multivariate analyses. Overall, our study identified host vasculature and oncogenic status as determinants of tumor perivascular features. Perivascular PDGFR-alpha and -beta were identified as novel independent markers predicting survival in mCRC. The novel methodology should be suitable for similar analyses in other tumor collections.

  • 342.
    Mezheyeuski, Artur
    et al.
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, R8 03, Stockholm, Sweden;Belarusian State Med Univ, Dept Pathol, Minsk, Byelarus.
    Strell, Carina
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, R8 03, Stockholm, Sweden.
    Hrynchyk, Ina
    City Clin Pathologoanat Bur, Minsk, Byelarus.
    Guren, Tormod Kyrre
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, Oslo, Norway.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Doroshenko, Tatyana
    Republ Res & Prod Ctr Transfusiol & Med Biotechno, Lab Antibodies & Cytokines Biotechnol, Minsk, Byelarus.
    Pashkova, Oksana
    Republ Res & Prod Ctr Transfusiol & Med Biotechno, Lab Antibodies & Cytokines Biotechnol, Minsk, Byelarus.
    Gorgun, Julia
    Belarusian Med Acad Postgrad Educ, Dept Gastroenterol & Nutr, Minsk, Byelarus.
    Ruksha, Kseniya
    NN Alexandrov Natl Canc Ctr Belarus, Minsk, Byelarus.
    Pfeiffer, Per
    Univ Southern Denmark, Dept Oncol, Odense, Denmark.
    Kure, Elin H.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway.
    Edler, David
    Karolinska Univ Hosp Solna, Dept Mol Med & Surg, S-17176 Stockholm, Sweden.
    Martling, Anna
    Karolinska Univ Hosp Solna, Dept Mol Med & Surg, S-17176 Stockholm, Sweden.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ostman, Arne
    Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, R8 03, Stockholm, Sweden.
    Portyanko, Anna
    Belarusian State Med Univ, Dept Pathol, Minsk, Byelarus.
    Treatment-related survival associations of claudin-2 expression in fibroblasts of colorectal cancer2018In: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 472, no 3, p. 395-405Article in journal (Refereed)
    Abstract [en]

    Claudin-2 is a trans-membrane protein-component of tight junctions in epithelial cells. Elevated claudin-2 expression has been reported in colorectal cancer (CRC). The aim of this study was to investigate the expression patterns of claudin-2 in human CRC samples and analyze its association with clinical characteristics and treatment outcome. TMAs of primary tumors from two cohorts of metastatic CRC (mCRC) were used. Claudin-2 IHC staining was evaluated in a semi-quantitative manner in different regions and cell types. Claudin-2 expression was also analyzed by immunofluorescence in primary cultures of human CRC cancer-associated fibroblasts (CAFs). Initial analyses identified previously unrecognized expression patterns of claudin-2 in CAFs of human CRC. Claudin-2 expression in CAFs of the invasive margin was associated with shorter progression-free survival. Subgroup analyses demonstrated that the survival associations occurred among cases that received 5-FU+oxaliplatin combination treatment, but not in patients receiving 5-FU +/- irinotecan. The finding was validated by analyses of the independent cohort. In summary, previously unreported stromal expression of claudin-2 in CAFs of human CRC was detected together with significant association between high claudin-2 expression in CAFs and shorter survival in 5-FU+oxaliplatin-treated mCRC patients.

  • 343.
    Micke, Patrick
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Mattsson, Johanna Sofia Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Planck, Maria
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden;Skane Univ Hosp, Dept Resp Med & Allergol, SE-22185 Lund, Sweden.
    Tran, Lena
    Region Skane, Div Lab Med, Dept Genet & Pathol, SE-22185 Lund, Sweden.
    Vidarsdottir, Halla
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden;Helsingborg Hosp, Dept Surg, SE-25187 Helsingborg, Sweden.
    Nodin, Bjorn
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden.
    Jirstrom, Karin
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden;Region Skane, Div Lab Med, Dept Genet & Pathol, SE-22185 Lund, Sweden.
    Brunnstrom, Hans
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden;Region Skane, Div Lab Med, Dept Genet & Pathol, SE-22185 Lund, Sweden.
    Mucin staining is of limited value in addition to basic immunohistochemical analyses in the diagnostics of non-small cell lung cancer2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 1319Article in journal (Refereed)
    Abstract [en]

    Accurate diagnosis of histological type is important for therapy selection in lung cancer. Immunohistochemical (IHC) and histochemical stains are often used to complement morphology for definite diagnosis and are incorporated in the WHO classification. Our main aim was to compare different mucin stains and assess their value in relation to common IHC analyses in lung cancer diagnostics. Using tissue microarrays from 657 surgically treated primary lung cancers, we evaluated the mucin stains periodic acid-Schiff with diastase (PASD), alcian blue-periodic acid-Schiff (ABPAS) and mucicarmine, and compared with the IHC markers p40, p63, cytokeratin 5, thyroid transcription factor 1 (TTF-1), napsin A and cytokeratin 7. Ten or more cytoplasmic mucin inclusions in a tissue microarray core were seen in 51%, 48% and 31% of the 416 adenocarcinomas and 3%, 4% and 0.5% of the 194 squamous cell carcinomas with PASD, ABPAS and mucicarmine, respectively. Diagnostic pitfalls, such as entrapped benign epithelium, apoptotic/necrotic cells and glycogen, partly differed for the mucin stains. TTF-1 and napsin A IHC stainings had similar specificity but better sensitivity for adenocarcinoma than the mucin stains, but addition of PASD or ABPAS identified more tumors as adenocarcinomas (n = 8 and n = 10, respectively) than napsin A (n = 1) in cases with solid growth that were negative for TTF-1 and p40. We conclude that PASD and ABPAS have similar diagnostic performance and that these markers are of value in poorly differentiated cases. However, morphology and TTF-1 and p40 IHC staining is sufficient for correct diagnosis in most non-small cell lung cancers.

  • 344.
    Micke, Patrick
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Kühn, S
    Buchauer, L
    Harries, J R
    Bücking, T M
    Blaum, K
    Cieluch, A
    Egl, A
    Hollain, D
    Kraemer, S
    Pfeifer, T
    Schmidt, P O
    Schüssler, R X
    Schweiger, Ch
    Stöhlker, T
    Sturm, S
    Wolf, R N
    Bernitt, S
    Crespo López-Urrutia, J R
    The Heidelberg compact electron beam ion traps.2018In: Review of Scientific Instruments, ISSN 0034-6748, E-ISSN 1089-7623, Vol. 89, no 6, article id 063109Article in journal (Refereed)
    Abstract [en]

    Electron beam ion traps (EBITs) are ideal tools for both production and study of highly charged ions (HCIs). In order to reduce their construction, maintenance, and operation costs, we have developed a novel, compact, room-temperature design, the Heidelberg Compact EBIT (HC-EBIT). Four already commissioned devices operate at the strongest fields (up to 0.86 T) reported for such EBITs using permanent magnets, run electron beam currents up to 80 mA, and energies up to 10 keV. They demonstrate HCI production, trapping, and extraction of pulsed Ar16+ bunches and continuous 100 pA ion beams of highly charged Xe up to charge state 29+, already with a 4 mA, 2 keV electron beam. Moreover, HC-EBITs offer large solid-angle ports and thus high photon count rates, e.g., in x-ray spectroscopy of dielectronic recombination in HCIs up to Fe24+, achieving an electron-energy resolving power of E/ΔE > 1500 at 5 keV. Besides traditional on-axis electron guns, we have also implemented a novel off-axis gun for laser, synchrotron, and free-electron laser applications, offering clear optical access along the trap axis. We report on its first operation at a synchrotron radiation facility demonstrating the resonant photoexcitation of highly charged oxygen.

  • 345.
    Micke, Patrick
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Mattsson, Johanna Sofia Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Djureinovic, Dijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Nodin, Björn
    Jirström, Karin
    Tran, Lena
    Jönsson, Per
    Planck, Maria
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Brunnström, Hans
    The Impact of the Fourth Edition of the WHO Classification of Lung Tumours on Histological Classification of Resected Pulmonary NSCCs2016In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 11, no 6, p. 862-872Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Histopathological classification of lung cancer is of central importance in the diagnostic routine and guides therapy in the majority of patients. The 4(th) edition of the WHO classification was recently published and includes changes to the diagnostic procedure of non-small cell carcinomas (NSCC) with more emphasis on immunohistochemical (IHC) staining.

    METHODS: 656 unselective cases of resected pulmonary NSCC were diagnosed according to the 2004 WHO classification. After IHC staining with cytokeratin 5, p40, p63, thyroid transcription factor 1 (clones 8G7G3/1 and SPT24) and napsin A the diagnoses were revised in accordance with the new 4(th) edition of the WHO classification.

    RESULTS: Reclassification led to a new histological annotation in 36 (5%) of the 656 cases. Most notable was the decrease of cases previously classified as large cell carcinomas (56 vs. 12 cases). This was partially due to the exclusion of 21 neuroendocrine tumors from this group, while 20 cases were ascribed to the group of adenocarcinoma based on IHC markers. Only 7 cases of adenocarcinoma or squamous cell carcinoma were reclassified after the addition of IHC staining. There was a substantial overlap in staining properties between different markers of squamous and adenocarcinomatous differentiation, respectively, but in 17-31 cases (3-5%) the diagnosis depended on the choice of markers.

    CONCLUSIONS: The 4(th) edition of the WHO classification of lung tumours leads to changes of histological type in 5% of resected NSCC cases. The incorporation of IHC staining in NSCC diagnostics demands awareness that the choice of ancillary stains has an effect on diagnosis.

  • 346. Mignardi, Marco
    et al.
    Mezger, Anja
    Qian, Xiaoyan
    La Fleur, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Larsson, Chatarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Mats
    Oligonucleotide gap-fill ligation for mutation detection and sequencing in situ.2015In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 43, no 22, article id e151Article in journal (Refereed)
    Abstract [en]

    In clinical diagnostics a great need exists for targeted in situ multiplex nucleic acid analysis as the mutational status can offer guidance for effective treatment. One well-established method uses padlock probes for mutation detection and multiplex expression analysis directly in cells and tissues. Here, we use oligonucleotide gap-fill ligation to further increase specificity and to capture molecular substrates for in situ sequencing. Short oligonucleotides are joined at both ends of a padlock gap probe by two ligation events and are then locally amplified by target-primed rolling circle amplification (RCA) preserving spatial information. We demonstrate the specific detection of the A3243G mutation of mitochondrial DNA and we successfully characterize a single nucleotide variant in the ACTB mRNA in cells by in situ sequencing of RCA products generated by padlock gap-fill ligation. To demonstrate the clinical applicability of our assay, we show specific detection of a point mutation in the EGFR gene in fresh frozen and formalin-fixed, paraffin-embedded (FFPE) lung cancer samples and confirm the detected mutation by in situ sequencing. This approach presents several advantages over conventional padlock probes allowing simpler assay design for multiplexed mutation detection to screen for the presence of mutations in clinically relevant mutational hotspots directly in situ.

  • 347.
    Milovanovic, Micha
    et al.
    Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Nillsson, Ethel
    Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Järemo, Petter
    Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Relationships between platelets and inflammatory markers in rheumatoid arthritis2004In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 343, no 1-2, p. 237-240Article in journal (Refereed)
    Abstract [en]

    AIM OF THE STUDY: To investigate platelets and different inflammatory markers in conjunction with a substantial inflammatory reaction. We used individuals with active rheumatoid arthritis (RA) as an experimental cohort.

    METHODS: We selected 16 patients with active RA having at least one affected joint. On day 1, platelet and neutrophil counts together with C-reactive protein (CRP) were determined. We further analysed platelet volume (MPV) and plasma levels of thrombopoietin (TPO), P-selectin, myeloperoxidase and interleukin 6 (IL-6). After 2 years when all patients failed to show any swollen joints all analyses were repeated.

    RESULTS AND CONCLUSIONS: As expected platelet count, CRP and IL-6 were elevated in active RA. The measures correlated with each other thus reflecting the same characteristic of the inflammatory response. The neutrophil count, MPV and myeloperoxidase also mirror disease activity. They failed to correlate with other activity markers thus providing unique information. MPV and myeloperoxidase on day 1 correlated with recovery values. Therefore, they could be suitable to use when following the inflammatory reaction over a long period of time.

  • 348. Minkevich, Natalya I.
    et al.
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Iomdina, Elena N.
    Rakitina, Tatiana V.
    Bogachuk, Anna P.
    Kakuev, Dmitry L.
    Smirnova, Evgeniya V.
    Babichenko, Igor I.
    Lipkin, Valery M.
    Abnormal pigment epithelium-derived factor processing in progressive myopia2016In: Experimental Eye Research, ISSN 0014-4835, E-ISSN 1096-0007, Vol. 152, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Pigment Epithelium-Derived Factor (PEDF) is a secreted glycoprotein belonging to the family of non inhibitory serpins. It is known, that in cases of complicated myopia, the content of PEDF in aqueous humor of the anterior chamber is significantly reduced. Here we examined a bulk of Tenon's capsule samples obtained from various groups of myopes, to examine PEDF processing in progressive myopia. We have analyzed the distribution of full length PEDF50 and its truncated form PEDF45 in the soluble and insoluble fractions extracted from Tenon's capsule of myopic and control (non-myopic) patients using SDS-polyacrylamide gel electrophoresis, as well as monitored the proteolytic degradation of PEDF ex vivo by enzyme-linked immunosorbent assay. These results were complemented by PEDF mRNA analysis in correspondent tissues by using qPCR and immunohistochemistry analysis of PEDF distribution in normal and myopic specimens. We found that in the Tenon's capsule of patients suffering from a high myopia the level of "soluble" 45 kDa PEDF reduced by 2-fold, while the content of "insoluble" 50 kDa form of PEDF was increased by 4-fold compared to controls. Excessive amount of PEDF50 in myopic specimens have been shown to correlate with the abrogated PEDF processing rather than with an increase of its expression. Moreover, immunohistochemical staining of the myopic Tenon's capsule tissue sections revealed the halo of deposited PEDF50 in the fibroblast extracellular space. These findings suggest that in myopia limited proteolysis of PEDF is altered or abrogated. Accumulation of full-length PEDF insoluble aggregates in the fibroblast intercellular space may affect cell survival and consequently causes the destructive changes in the extracellular matrix of the eye connective tissues. As a result, the abrogation of full-length PEDF normal processing can be an important mechanism leading to biomechanical destabilization of the scleral capsule and myopia progression.

  • 349.
    Miyashita, Naoya
    et al.
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan.
    Horie, Masafumi
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan;Univ Southern Calif, Hastings Ctr Pulm Res, Div Pulm Crit Care & Sleep Med, Dept Med,Keck Sch Med, Los Angeles, CA USA;RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan.
    Suzuki, Hiroshi I.
    MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
    Yoshihara, Masahito
    RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan.
    Djureinovic, Dijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Persson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Brunnstrom, Hans
    Lund Univ, Lab Med Reg Skane, Dept Clin Sci Lund, Pathol, Lund, Sweden.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Elfving, Hedvig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Saito, Akira
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan;Univ Tokyo, Div Hlth Serv Promot, Tokyo, Japan.
    Nagase, Takahide
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan.
    An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1-Positive Lung Adenocarcinomas2018In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, no 11, p. 1676-1691Article in journal (Refereed)
    Abstract [en]

    Introduction: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute family bHLH transcription factor 1 (ASCL1), common to high-grade neuroendocrine tumors, small-cell lung cancer and large cell neuroendocrine carcinoma. Methods: The aim of this study was to characterize clinical and molecular features of ASCL1-positive lung adenocarcinoma by using recent transcriptome profiling in multiple patient cohorts and genome-wide epigenetic profiling including data from The Cancer Genome Atlas. Results: The ASCL1-positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor EGFR mutations. In transcriptome profiling, this subtype overlapped with the recently proposed proximal-proliferative molecular subtype. Gene expression profiling of ASCL1-positive cases suggested generally poor immune cell infiltration and none of the tumors were positive for programmed cell death ligand 1 protein expression. Genome-wide methylation analysis showed global DNA hypomethylation in ASCL1-positive cases. ASCL1 was associated with super-enhancers in ASCL1-positive lung adenocarcinoma cells, and ASCL1 silencing suppressed other super-enhancer-associated genes, suggesting thatASCL1 acts as a master transcriptional regulator. This was further reinforced by the essential roles of ASCL1 in cell proliferation, survival, and cell cycle control. Conclusions: These results suggest that ASCL1 defines a subgroup of lung adenocarcinoma with distinct molecular features by driving super-enhancer-mediated transcriptional programs.

  • 350. Modvig, S
    et al.
    Madsen, H O
    Siitonen, S M
    Rosthøj, S
    Tierens, A
    Juvonen, V
    Osnes, L T N
    Vålerhaugen, H
    Hultdin, M
    Thörn, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Matuzeviciene, R
    Stoskus, M
    Marincevic, Millaray
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Fogelstrand, L
    Lilleorg, A
    Toft, N
    Jónsson, O G
    Pruunsild, K
    Vaitkeviciene, G
    Vettenranta, K
    Lund, B
    Abrahamsson, J
    Schmiegelow, K
    Marquart, H V
    Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia2019In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, no 6, p. 1324-1336Article in journal (Refereed)
    Abstract [en]

    Minimal residual disease (MRD) measured by PCR of clonal IgH/TCR rearrangements predicts relapse in T-cell acute lymphoblastic leukemia (T-ALL) and serves as risk stratification tool. Since 10% of patients have no suitable PCR-marker, we evaluated flowcytometry (FCM)-based MRD for risk stratification. We included 274 T-ALL patients treated in the NOPHO-ALL2008 protocol. MRD was measured by six-color FCM and real-time quantitative PCR. Day 29 PCR-MRD (cut-off 10-3) was used for risk stratification. At diagnosis, 93% had an FCM-marker for MRD monitoring, 84% a PCR-marker, and 99.3% (272/274) had a marker when combining the two. Adjusted for age and WBC, the hazard ratio for relapse was 3.55 (95% CI 1.4-9.0, p = 0.008) for day 29 FCM-MRD ≥ 10-3 and 5.6 (95% CI 2.0-16, p = 0.001) for PCR-MRD ≥ 10-3 compared with MRD < 10-3. Patients stratified to intermediate-risk therapy on day 29 with MRD 10-4-<10-3 had a 5-year event-free survival similar to intermediate-risk patients with MRD < 10-4 or undetectable, regardless of method for monitoring. Patients with day 15 FCM-MRD < 10-4 had a cumulative incidence of relapse of 2.3% (95% CI 0-6.8, n = 59). Thus, FCM-MRD allows early identification of patients eligible for reduced intensity therapy, but this needs further studies. In conclusion, FCM-MRD provides reliable risk prediction for T-ALL and can be used for stratification when no PCR-marker is available.

45678910 301 - 350 of 555
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf