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  • 351. Seppanen, Allan
    et al.
    Miettinen, Riitta
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Neuronal collagen XVII is localized to lipofuscin granules2010Inngår i: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, Vol. 21, nr 17, s. 1090-1094Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have earlier shown that collagen XVII is expressed by neurons in the human brain, although its exact intracellular location and function have remained unknown. In this study we have localized collagen XVII specifically to neuronal lipofuscin granules using electron microscopy in autopsy samples from the human brainstem. Our results show that collagen XVII expression is mainly confined to an ultrastructurally definable, specific type of lipofuscin granule. The function of neuronal collagen XVII remains unclear. However, as the functional significance of lipofuscin remains debated, the presence of collagen XVII in just some types of lipofuscin may be helpful in the process of exploring the variety of neuronal, age-related lipopigments, which are as yet defined operationally rather than functionally or structurally.

  • 352. Seppänen, Allan
    et al.
    Suuronen, Tiina
    Hofmann, Silke C
    Majamaa, Kari
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Distribution of collagen XVII in the human brain.2007Inngår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1158, s. 50-6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have recently discovered collagen XVII to be present in neurons of the human central nervous system. Collagen XVII has previously been primarily studied in the field of dermatopathology since it is abundantly expressed in the skin, which, like the nervous system, is ectodermal in origin. A link between dermatopathological and neurological entities has been implied due to clinical case studies revealing an association between bullous pemphigoid and age-related neurodegenerative disorders. The objective of this study was to assess the distribution of collagen XVII in the human brain in relation to normal ageing. Post-mortem brain tissue was obtained from 11 neurologically unimpaired subjects who had died from cardiovascular causes at the age of 17 to 78 years. Collagen XVII expression in various neuroanatomical regions, representing essentially the entire human brain, was then assessed using immunohistochemistry. We found collagen XVII to be expressed widely in the brain and to be located primarily in the soma and proximal axons of neurons. In contrast, glial cells did not express collagen XVII. The expression varied strikingly between different neuroanatomical regions, being most notable in motor nuclei and Betz cells followed by pyramidal neurons. There was no correlation between collagen XVII expression and variables such as gender, age at death, post-mortem delay and fixation time whereas a mode of death leading to notable neuronal ischemia depleted the protein expression. Many neurodegenerative disorders display a specific pattern of neuroanatomical involvement, thus the regionally variable expression of collagen XVII offers new prospects for research.

  • 353.
    Serapio, Solveig
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Perinatal, neonatal och barnkardiologisk forskning.
    Ahlsson, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Perinatal, neonatal och barnkardiologisk forskning.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Kallak, Theodora Kunovac
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktiv hälsa.
    Second Trimester Maternal Leptin Levels Are Associated with Body Mass Index and Gestational Weight Gain but not Birth Weight of the Infant2019Inngår i: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 92, nr 2, s. 106-114Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION: Obesity is increasing among the pregnant population. Leptin has an important role in the regulation of energy balance and hunger. The aim of this study was to investigate the association between maternal leptin levels with maternal obesity, gestational weight gain (GWG), single nucleotide polymorphisms (SNPs) within the leptin gene, and the age-adjusted birth weight of the child.

    MATERIAL AND METHODS: Maternal leptin levels (n = 740) and SNPs (n = 504) were analyzed in blood samples taken within the Uppsala Biobank of Pregnant women at pregnancy weeks 16-19.

    RESULTS: Maternal leptin levels differed significantly between body mass index (BMI) groups. Normal weight women had the lowest median leptin levels and levels increased with each BMI group. Leptin SNP genotype was not associated with leptin levels or BMI. There was also no association between maternal leptin levels and age-adjusted birth weight of the child except for a negative association between leptin levels and birth weight in the morbid obese group.

    DISCUSSION/CONCLUSION: Maternal BMI was identified as the best positive explanatory factor for maternal leptin levels. Leptin was a strong positive explanatory factor for GWG. Birth weight of children of uncomplicated pregnancies was, however, dependent on maternal height, BMI, GWG, and parity but not leptin levels, except for in morbid obese women where a negative association between maternal leptin levels and birth weight was found. We speculate that this indicates altered placental function, not manifested in pregnancy complication. We conclude that maternal leptin levels do not affect the birth weight of the child more than BMI, GWG, and parity.

  • 354. Seveus, Lahja
    et al.
    Amin, Kawa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för anatomi.
    Peterson, Christer
    Roomans, Godfried
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för anatomi.
    Venge, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Human neutrophil lipocalin (HNL) is a specific granule constituent of the neutrophil granulocyte: Studies in bronchial and lung parenchymal tissue and peripheral blood cells1997Inngår i: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 107, nr 5, s. 423-432, artikkel-id 9208334Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The neutrophilic granulocyte is a cytotoxic and potentially tissue-injuring cell participating in the destructive processes and symptoms seen in a variety of inflammatory diseases. Sensitive immunoassays have been introduced to measure the levels of specific secretory proteins of various inflammatory cells in blood and other body fluids. The aim has been to develop highly specific markers for each cell type. The results obtained by immunoassay have indicated that human neutrophil lipocalin (HNL) is a protein unique to the neutrophil. The present study investigated the specificity of HNL as a neutrophil marker in peripheral blood and lung tissue by using flow cytometry and immunocytochemistry. Flow cytometry and immunocytochemistry on peripheral blood showed that monoclonal antibodies to HNL only react with neutrophils and not with other types of leukocytes. Immunocytochemistry on plastic-embedded sections and on frozen sections of lung tissue showed that a cocktail of six monoclonal antibodies to HNL specifically reacts with neutrophils and not with epithelial cells or macrophages. By immunoelectron microscopical studies performed on healthy human neutrophils after low temperature embedding in Lowicryl K4M following aldehyde fixation and partial dehydration, it could be shown that HNL colocalized with lactoferrin (a known marker for secondary or specific granules) and that myeloperoxidase was localized in the primary or azurophil granules. The results confirm that HNL is a unique component of the secondary granules of the neutrophil granulocyte.

  • 355.
    Shen, Qiujin
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Björkesten, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Galli, Joakim
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ekman, Daniel
    Olink Biosci, Uppsala, Sweden..
    Broberg, John
    Olink Prote, Uppsala, Sweden..
    Nordberg, Niklas
    Olink Prote, Uppsala, Sweden..
    Tillander, Annika
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Kamali-Moghaddam, Masood
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Tybring, Gunnel
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Landegren, Ulf
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Strong impact on plasma protein profiles by precentrifugation delay but not by repeated freeze-thaw cycles, as analyzed using multiplex proximity extension assays2018Inngår i: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 56, nr 4, s. 582-594Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: A number of factors regarding blood collection, handling and storage may affect sample quality. The purpose of this study was to assess the impact on plasma protein profiles by delayed centrifugation and plasma separation and multiple freeze-thaw cycles.

    Methods: Blood samples drawn from 16 healthy individuals were collected into ethylenediaminetetraacetic acid tubes and kept either at 4 degrees C or 22 degrees C for 1-36 h prior to centrifugation. Plasma samples prepared 1 h after venipuncture were also subjected to two to eight cycles of freezing at -80 degrees C and thawing at 22 degrees C. Multiplex proximity extension assay, an antibody-based protein assay, was used to investigate the influence on plasma proteins.

    Results: Up to 36 h delay before blood centrifugation resulted in significant increases of 16 and 40 out of 139 detectable proteins in samples kept at 4 degrees C or 22 degrees C, respectively. Some increases became noticeable after 8 h delay at 4 degrees C but already after 1 h at 22 degrees C. For samples stored at 4 degrees C, epidermal growth factor (EGF), NF-kappa-B essential modulator, SRC, interleukin 16 and CD6 increased the most, whereas the five most significantly increased proteins after storage at 22 degrees C were CD40 antigen ligand (CD40-L), EGF, platelet-derived growth factor subunit B, C-X-C motif chemokine ligand 5 and matrix metallopeptidase 1 (MMP1). Only matrix metallopeptidase 7 (MMP7) decreased significantly over time and only after storage at 22 degrees C. No protein levels were found to be significantly affected by up to eight freeze-thaw cycles.

    Conclusions: Plasma should be prepared from blood after a limited precentrifugation delay at a refrigerated temperature. By contrast, the influence by several freeze-thaw cycles on detectable protein levels in plasma was negligible.

  • 356. Siddiqui, Moneeza Kalhan
    et al.
    Veluchamy, Abirami
    Maroteau, Cyrielle
    Tavendale, Roger
    Carr, Fiona
    Pearson, Ewan
    Colhoun, Helen
    Morris, Andrew D
    George, Jacob
    Doney, Alexander
    Pirmohamed, Munir
    Alfirevic, Ana
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Maitland van der Zee, Anke H
    Ridker, Paul M
    Chasman, Daniel I
    Palmer, Colin N A
    CKM Glu83Gly Is Associated With Blunted Creatine Kinase Variation, but Not With Myalgia2017Inngår i: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 10, nr 4, artikkel-id e001737Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Glu83Gly (rs11559024) with constitutive creatine phosphokinase (CK) levels, CK variation, and inducibility. Given the diagnostic importance of CK in determining muscle damage, we tested the association of the variant with myalgia.

    METHODS AND RESULTS: ) lower for carriers of the variant, respectively. The variant was not associated with myalgia (odds ratio, 0.84; 95% confidence interval, 0.52-1.38).

    CONCLUSIONS: This study highlights that a genetic factor known to be associated with constitutive CK levels is also associated with CK variability and inducibility. This is discussed in the context of evidence to suggest that the variant has an impact on inducibility of CK by trauma through a previously reported case of a homozygous carrier. However, the lack of association between the variant and myalgia suggests that it cannot reliably be used as a biomarker for muscle symptoms.

  • 357.
    Siesing, Christina
    et al.
    Lund Univ, Skane Univ Hosp, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    Sorbye, Halfdan
    Univ Bergen, Haukeland Univ Hosp, Dept Oncol, Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala Univ, Uppsala Univ Hosp, Sect Pathol, Uppsala, Sweden.
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Qvortrup, Camilla
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala Univ, Uppsala Univ Hosp, Sect Pathol, Uppsala, Sweden.
    Jirström, Karin
    Lund Univ, Skane Univ Hosp, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Eberhard, Jakob
    Lund Univ, Skane Univ Hosp, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    High RBM3 expression is associated with an improved survival and oxaliplatin response in patients with metastatic colorectal cancer2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 8, artikkel-id e0182512Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: High expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinumbased chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC) as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy.

    Methods: Immunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan- Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS) and progressionfree survival (PFS).

    Results: High RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50-0.90 and HR 0.66, 95% CI 0.48-0.91, respectively). PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively).

    Conclusion: High RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first-line oxaliplatin based chemotherapy.

    Fulltekst (pdf)
    fulltext
  • 358. Sillars-Hardebol, Anke H
    et al.
    Carvalho, Beatriz
    Tijssen, Marianne
    Beliën, Jeroen A M
    de Wit, Meike
    Delis-van Diemen, Pien M
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    van de Wiel, Mark A
    Fijneman, Remond J A
    Meijer, Gerrit A
    TPX2 and AURKA promote 20q amplicon-driven colorectal adenoma to carcinoma progression2012Inngår i: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 61, nr 11, s. 1568-1575Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and objective

    Progression of a colorectal adenoma to invasive cancer occurs in a minority of adenomas and is the most crucial step in colorectal cancer pathogenesis. In the majority of cases, this is associated with gain of a substantial part of chromosome 20q, indicating that multiple genes on the 20q amplicon may drive carcinogenesis. The aim of this study was to identify genes located on the 20q amplicon that promote progression of colorectal adenoma to carcinoma.

    Design

    Functional assays were performed for 32 candidate driver genes for which a positive correlation between 20q DNA copy number and mRNA expression had been demonstrated. Effects of gene knockdown on cell viability, anchorage-independent growth, and invasion were analysed in colorectal cancer cell lines with 20q gain. Colorectal tumour protein expression was examined by immunohistochemical staining of tissue microarrays.

    Results

    TPX2, AURKA, CSE1L, DIDO1, HM13, TCFL5, SLC17A9, RBM39 and PRPF6 affected cell viability and/or anchorage-independent growth. Chromosome 20q DNA copy number status correlated significantly with TPX2 and AURKA protein levels in a series of colorectal adenomas and carcinomas. Moreover, downmodulation of TPX2 and AURKA was shown to inhibit invasion.

    Conclusion

    These data identify TPX2 (20q11) and AURKA (20q13.2) as two genes located on distinct regions of chromosome 20q that promote 20q amplicon-driven progression of colorectal adenoma to carcinoma. Therefore the selection advantage imposed by 20q gain in tumour progression is achieved by gain-of-function of multiple cancer-related genes-knowledge that can be translated into novel tests for early diagnosis of progressive adenomas.

  • 359. Sintorn, Ida-Maria
    et al.
    Haag, L.
    Kylberg, Gustav
    Malm, P.
    Ryner, M.
    Hultenby, Kjell
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Introducing MiniTEM for ultrastructural pathology2017Inngår i: 29th European Congress of Pathology / [ed] Virchows Archives, 2017, Vol. 471, s. S9-S10, artikkel-id DOI 10.1007/s00428-017-2205-0Konferansepaper (Fagfellevurdert)
  • 360.
    Sipe, Jean D.
    et al.
    Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA..
    Benson, Merrill D.
    Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA..
    Buxbaum, Joel N.
    Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA..
    Ikeda, Shu-ichi
    Shinshu Univ, Sch Med, Dept Med Neurol & Rheumatol, Matsumoto, Nagano, Japan..
    Merlini, Giampaolo
    Univ Pavia, Amyloid Res & Treatment Ctr, Pavia, Italy.;IRCCS Policlin San Matteo, Pavia, Italy..
    Saraiva, Maria J. M.
    Univ Porto, Inst Mol & Cellular Biol, Amyloid Unit, Oporto, Portugal..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines2016Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 23, nr 4, s. 209-213Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XVth Symposium of the Society, 3 July-7 July 2016, Uppsala, Sweden, to assess and formulate recommendations for nomenclature for amyloid fibril proteins and the clinical classification of the amyloidoses. An amyloid fibril must exhibit affinity for Congo red and with green, yellow or orange birefringence when the Congo red-stained deposits are viewed with polarized light. While congophilia and birefringence remain the gold standard for demonstration of amyloid deposits, new staining and imaging techniques are proving useful. To be included in the nomenclature list, in addition to congophilia and birefringence, the chemical identity of the protein must be unambiguously characterized by protein sequence analysis when possible. In general, it is insufficient to identify a mutation in the gene of a candidate amyloid protein without confirming the variant changes in the amyloid fibril protein. Each distinct form of amyloidosis is uniquely characterized by the chemical identity of the amyloid fibril protein that deposits in the extracellular spaces of tissues and organs and gives rise to the disease syndrome. The fibril proteins are designated as protein A followed by a suffix that is an abbreviation of the parent or precursor protein name. To date, there are 36 known extracellular fibril proteins in humans, 2 of which are iatrogenic in nature and 9 of which have also been identified in animals. Two newly recognized fibril proteins, AApoCII derived from apolipoprotein CII and AApoCIII derived from apolipoprotein CIII, have been added. AApoCII amyloidosis and AApoCIII amyloidosis are hereditary systemic amyloidoses. Intracellular protein inclusions displaying some of the properties of amyloid, intracellular amyloid have been reported. Two proteins which were previously characterized as intracellular inclusions, tau and -synuclein, are now recognized to form extracellular deposits upon cell death and thus have been included in Table 1 as ATau and ASyn.

  • 361. Skram, Marius Kurås
    et al.
    Gulati, Sasha
    Larsson, Erik
    Lindal, Sigurd
    Torp, Sverre Helge
    Muscle biopsies in children: an evaluation of histopathology and clinical value during a 5-year period2009Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 114, nr 1, s. 41-45Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Muscle biopsy is an important diagnostic tool in the investigation of children with neuromuscular disorders. This report presents the experience with paediatric muscle biopsies during a 5-year period at a routine pathology laboratory. A total number of 58 cases were included, and indications, microscopical findings, and final histopathological diagnoses were recorded. A total of 21 biopsies were from females (36%) and 37 biopsies from males (64%); 53% of the cases were from children under 2 years of age. Major pathological findings were found in 30% comprising muscular dystrophy, neurogenic atrophy, and congenital and metabolic disorders, even in cases with vague clinical manifestations. These findings confirm the high diagnostic yield of muscle biopsies, especially as new techniques have been introduced such as immunohistochemistry. Muscle pathology is difficult and emphasizes the importance of this service being undertaken by specialized laboratories with an experienced staff. Microscopical examination of muscle biopsies should be based on adequate clinical information, demonstrating the necessity of close contact between pathologists and referring physicians.

  • 362. Smid, Joost H
    et al.
    Althaus, Christian L
    Low, Nicola
    Unemo, Magnus
    Herrmann, Bjőrn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rise and fall of the new variant of Chlamydia trachomatis in Sweden: mathematical modelling study.2019Inngår i: Sexually Transmitted Infections, ISSN 1368-4973, E-ISSN 1472-3263, artikkel-id sextrans-2019-054057Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: A new variant of Chlamydia trachomatis (nvCT) was discovered in Sweden in 2006. The nvCT has a plasmid deletion, which escaped detection by two nucleic acid amplification tests (Abbott-Roche, AR), which were used in 14 of 21 Swedish counties. The objectives of this study were to assess when and where nvCT emerged in Sweden, the proportion of nvCT in each county and the role of a potential fitness difference between nvCT and co-circulating wild-type strains (wtCT).

    METHODS: We used a compartmental mathematical model describing the spatial and temporal spread of nvCT and wtCT. We parameterised the model using sexual behaviour data and Swedish spatial and demographic data. We used Bayesian inference to fit the model to surveillance data about reported diagnoses of chlamydia infection in each county and data from four counties that assessed the proportion of nvCT in multiple years.

    RESULTS: Model results indicated that nvCT emerged in central Sweden (Dalarna, Gävleborg, Västernorrland), reaching a proportion of 1% of prevalent CT infections in late 2002 or early 2003. The diagnostic selective advantage enabled rapid spread of nvCT in the presence of high treatment rates. After detection, the proportion of nvCT decreased from 30%-70% in AR counties and 5%-20% in counties that Becton Dickinson tests, to around 5% in 2015 in all counties. The decrease in nvCT was consistent with an estimated fitness cost of around 5% in transmissibility or 17% reduction in infectious duration.

    CONCLUSIONS: We reconstructed the course of a natural experiment in which a mutant strain of C. trachomatis spread across Sweden. Our modelling study provides support, for the first time, of a reduced transmissibility or infectious duration of nvCT. This mathematical model improved our understanding of the first nvCT epidemic in Sweden and can be adapted to investigate the impact of future diagnostic escape mutants.

  • 363.
    Sohrabian, Azita
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Noraddin, Feria Hikmet
    Flodin, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Fredricsson, Annika
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Particle enhanced turbidimetric immunoassay for the determination of urine cystatin C on Cobas c5012012Inngår i: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 45, nr 4-5, s. 339-344Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    Urinary cystatin C has been reported to be a good marker for tubular damage and acute kidney injury. The aim of this study was to develop a high throughput assay for the quantification of urine cystatin C.

    METHODS:

    Antigen-excess, imprecision, interference, linearity, recovery, sample stability and reference values were evaluated on Cobas c501.

    RESULTS:

    The assay was linear over the dynamic range of the study (R(2)=0.9994). The total assay imprecision was below 5%. The assay recovery was estimated at 87-100%. No tendency to antigen-excess (up to 35mg/L), nor interference with haemoglobin (1.25-10g/L) was observed. Cystatin C was stable for 1day at ambient temperature (19-23°C) but for 2days at +4°C. The reference interval for cystatin C in urine was <0.414mg/L.

    CONCLUSIONS:

    The urinary cystatin C assay verified to be a reliable assay with convenient performance characteristics, enabling routine testing on clinical chemistry platforms.

  • 364. Sorbye, Halfdan
    et al.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sundström, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Pfeiffer, Per
    Thunberg, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Bergfors, Monica
    Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Aasebo, Kristine
    Eide, Geir Egil
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Qvortrup, Camilla
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    High BRAF Mutation Frequency and Marked Survival Differences in Subgroups According to KRAS/BRAF Mutation Status and Tumor Tissue Availability in a Prospective Population-Based Metastatic Colorectal Cancer Cohort2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 6, artikkel-id e0131046Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    RAS and BRAF mutations impact treatment and prognosis of metastatic colorectal cancer patients (mCRC), but the knowledge is based on trial patients usually not representative for the general cancer population. Patient characteristics, treatment and efficacy according to KRAS, BRAF and MSI status were analyzed in a prospectively collected unselected population-based cohort of 798 non-resectable mCRC patients. The cohort contained many patients with poor performance status (39% PS 2-4) and elderly (37% age>75), groups usually not included in clinical trials. Patients without available tissue micro array (TMA) (42%) had worse prognostic factors and inferior survival (all patients; 7m vs 11m, chemotherapy-treated; 12m vs 17m). The 92 patients (21%) with BRAF mutation had a poor prognosis regardless of microsatellite instability, but receipt of 1-2nd chemotherapy was similar to wildtype BRAF patients. Median survival in this cohort varied from 1 month in BRAF mutated patients not given chemotherapy to 26 months in wildtype KRAS/BRAF patients <75 years in good PS. TMA availability, BRAF mutation and KRAS mutation were all independent prognostic factors for survival. The observed 21% BRAF mutation incidence is higher than the previously and repeatedly reported incidence of 5-12% in mCRC. Screening for BRAF mutations before selection of treatment is relevant for many patients, especially outside clinical trials. A BRAF mutation only partly explained the very poor prognosis of many mCRC patients. Survival in unselected metastatic colorectal cancer patients is extremely variable and subgroups have an extremely short survival compared to trial patients. Patients without available TMA had worse prognostic factors and shorter survival, which questions the total generalizability of present TMA studies and implies that we lack information on the biologically worst mCRC cases. Lack of available tissue is an important underexposed issue which introduces sample bias, and this should be recognized more clearly when conclusions are made from translational mCRC studies.

  • 365.
    Sottile, Rosa
    et al.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Tannazi, Milad
    Univ Utrecht, Fac Sci, Dept Pharmaceut Sci, Utrecht, Netherlands.
    Johansson, Maria H.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Cristiani, Costanza Maria
    Magna Graecia Univ Catanzaro, Tumor Immunol & Immunopathol Lab, Dept Expt & Clin Med, Catanzaro, Italy.
    Calabro, Luana
    Univ Hosp Siena, Ctr Immunooncol Med Oncol & Immunotherapy, Siena, Italy.
    Ventura, Valeria
    Magna Graecia Univ Catanzaro, Tumor Immunol & Immunopathol Lab, Dept Expt & Clin Med, Catanzaro, Italy.
    Cutaia, Ornella
    Univ Hosp Siena, Ctr Immunooncol Med Oncol & Immunotherapy, Siena, Italy.
    Chiarucci, Carla
    Univ Hosp Siena, Ctr Immunooncol Med Oncol & Immunotherapy, Siena, Italy.
    Covre, Alessia
    Univ Hosp Siena, Ctr Immunooncol Med Oncol & Immunotherapy, Siena, Italy.
    Garofalo, Cinzia
    Magna Graecia Univ Catanzaro, Tumor Immunol & Immunopathol Lab, Dept Expt & Clin Med, Catanzaro, Italy.
    Ponten, Victor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Tallerico, Rossana
    Magna Graecia Univ Catanzaro, Tumor Immunol & Immunopathol Lab, Dept Expt & Clin Med, Catanzaro, Italy.
    Frumento, Paolo
    Karolinska Inst, Inst Environm Med, Unit Biostat, Stockholm, Sweden.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Maio, Michele
    Univ Hosp Siena, Ctr Immunooncol Med Oncol & Immunotherapy, Siena, Italy.
    Karre, Klas
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Carbone, Ennio
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden;Magna Graecia Univ Catanzaro, Tumor Immunol & Immunopathol Lab, Dept Expt & Clin Med, Catanzaro, Italy.
    NK- and T-cell subsets in malignant mesothelioma patients: Baseline pattern and changes in the context of anti-CTLA-4 therapy2019Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, nr 8, s. 2238-2248Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Malignant mesothelioma (MM) is a highly aggressive form of cancer with limited treatment options. Although the role of NK cells has been studied in many solid tumors, the pattern of NK-cell subsets and their recognition of mesothelioma cells remain to be explored. We used RNA expression data of MM biopsies derived from the cancer genome atlas to evaluate the immune cell infiltrates. We characterized the phenotype of circulating NK and T cells of 27 MM patients before and after treatment with an anti-CTLA-4 antibody (tremelimumab). These immune cell profiles were compared to healthy controls. The RNA expression data of the MM biopsies indicated the presence of NK cells in a subgroup of patients. We demonstrated that NK cells recognize MM cell lines and that IL-15 stimulation improved NK cell-mediated lysis in vitro. Using multivariate projection models, we found that MM patients had a perturbed ratio of CD56(bright) and CD56(dim) NK subsets and increased serum concentrations of the cytokines IL-10, IL-8 and TNF-alpha. After tremelimumab treatment, the ratio between the CD56(bright) and CD56(dim) subsets shifted back towards physiological levels. Furthermore, the improved overall survival was correlated with low TIM-3(+)CD8(+) T-cell frequency, high DNAM-1(+)CD56(dim) NK-cell frequency and high expression levels of NKp46 on the CD56(dim) NK cells before and after immune checkpoint blockade. Together, our observations suggest that NK cells infiltrate MM and that they can recognize and kill mesothelioma cells. The disease is associated with distinct lymphocytes patterns, some of which correlate with prognosis or are affected by treatment with tremelimumab.

  • 366.
    Sreedharan, Smitha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. CSIR, Inst Genom & Integrat Biol, South Campus,Mathura Rd, New Delhi 110025, India.
    Maturi, Naga Prathyusha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Xie, Yuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sundström, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jarvius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Libard, Sylwia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Weishaupt, Holger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Swartling, Fredrik J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mouse models of pediatric supratentorial high-grade glioma reveal how cell-of-origin influences tumor development and phenotype2017Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, nr 3, s. 802-812Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High-grade glioma (HGG) is a group of primary malignant brain tumors with dismal prognosis. Whereas adult HGG has been studied extensively, childhood HGG, a relatively rare disease, is less well-characterized. Here, we present two novel platelet-derived growth factor (PDGF)-driven mouse models of pediatric supratentorial HGG. Tumors developed from two different cells of origin reminiscent of neural stem cells (NSC) or oligodendrocyte precursor cells (OPC). Cross-species transcriptomics showed that both models are closely related to human pediatric HGG as compared with adult HGG. Furthermore, an NSC-like cell-of-origin enhanced tumor incidence, malignancy, and the ability of mouse glioma cells (GC) to be cultured under stem cell conditions as compared with an OPC-like cell. Functional analyses of cultured GC from these tumors showed that cells of NSC-like origin were more tumorigenic, had a higher rate of self-renewal and proliferation, and were more sensitive to a panel of cancer drugs compared with GC of a more differentiated origin. These two mouse models relevant to human pediatric supratentorial HGG propose an important role of the cell-of-origin for clinicopathologic features of this disease.

  • 367.
    Sridhar, Sriram
    et al.
    Nanyang Technol Univ, Sch Elect & Elect Engn, 50 Nanyang Ave, Singapore 639798, Singapore.
    Mishra, Sachin
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 59 Nanyang Dr, Singapore 636921, Singapore.
    Gulyas, Miklos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Padmanabhan, Parasuraman
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 59 Nanyang Dr, Singapore 636921, Singapore.
    Gulyas, Balazs
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 59 Nanyang Dr, Singapore 636921, Singapore.
    An Overview of Multimodal Neuroimaging Using Nanoprobes2017Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 18, nr 2, artikkel-id 311Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Nanomaterials have gained tremendous significance as contrast agents for both anatomical and functional preclinical bio-imaging. Contrary to conventional medical practices, molecular imaging plays an important role in exploring the affected cells, thus providing precision medical solutions. It has been observed that incorporating nanoprobes improves the overall efficacy of the diagnosis and treatment processes. These nano-agents and tracers are therefore often incorporated into preclinical therapeutic and diagnostic applications. Multimodal imaging approaches are well equipped with nanoprobes to explore neurological disorders, as they can display more than one type of characteristic in molecular imaging. Multimodal imaging systems are explored by researchers as they can provide both anatomical and functional details of tumors and affected tissues. In this review, we present the state-of-the-art research concerning multimodal imaging systems and nanoprobes for neuroimaging applications.

    Fulltekst (pdf)
    fulltext
  • 368. Staaf, Johan
    et al.
    Isaksson, Sofi
    Karlsson, Anna
    Jönsson, Mats
    Johansson, Leif
    Jönsson, Per
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Baldetorp, Bo
    Planck, Maria
    Landscape of somatic allelic imbalances and copy number alterations in human lung carcinoma2013Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 132, nr 9, s. 2020-2031Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Lung cancer is the worldwide leading cause of death from cancer and has been shown to be a heterogeneous disease at the genomic level. To delineate the genomic landscape of copy number alterations, amplifications, loss-of-heterozygosity (LOH), tumor ploidy and copy-neutral allelic imbalance in lung cancer, microarray-based genomic profiles from 2,141 tumors and cell lines including adenocarcinomas (AC, n = 1,206), squamous cell carcinomas (SqCC, n = 467), large cell carcinomas (n = 37) and small cell lung carcinomas (SCLC, n = 88) were assembled from different repositories. Copy number alteration differences between lung cancer histologies were confirmed in 285 unrelated tumors analyzed by BAC array comparative genomic hybridization. Tumor ploidy patterns were validated by DNA flow cytometry analysis of 129 unrelated cases. Eighty-nine recurrent copy number alterations (55 gains, 34 losses) were identified harboring genes with gene expression putatively driven by gene dosage through integration with gene expression data for 496 cases. Thirteen and 26 of identified regions discriminated AC/SqCC and AC/SqCC/SCLC, respectively, while 48 regions harbored recurrent (n > 15) high-level amplifications comprising established and putative oncogenes, differing in frequency and coamplification patterns between histologies. Lung cancer histologies displayed differences in patterns/frequency of copy number alterations, genomic architecture, LOH, copy-neutral allelic imbalance and tumor ploidy, with AC generally displaying less copy number alterations and allelic imbalance. Moreover, a strong association was demonstrated between different types of copy number alterations and allelic imbalances with tumor aneuploidy. In summary, these analyses provide a comprehensive overview of the landscape of genomic alterations in lung cancer, highlighting differences but also similarities between subgroups of the disease.

  • 369.
    Starlander, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin, Klinisk bakteriologi.
    Wirén, Marcus
    Melhus, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin, Klinisk bakteriologi.
    First documented case of a Staphylococcus lugdunensis strain carrying the mecA gene in Northern Europe2011Inngår i: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 1, s. 8410-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Staphylococcus lugdunensis is a clinically common wound pathogen belonging to coagulase-negative staphylococci. We herein report the first case of a S. lugdunensis isolate carrying the mecA gene in Northern Europe.

  • 370. Stening, Kent D
    et al.
    Berg, Göran
    Hammar, Mats
    Voster, Helene
    Eriksson, Olle
    Amandusson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Blomqvist, Anders
    Influence of Estrogen Levels on Thermal Perception, Pain Thresholds, and Pain Tolerance: Studies on Women Undergoing in Vitro Fertilization.2012Inngår i: Journal of Pain, ISSN 1526-5900, E-ISSN 1528-8447, Vol. 13, nr 5, s. 459-466Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We examined the relationship between estrogen and pain in women undergoing in vitro fertilization (IVF). Quantitative sensory tests (QST) were performed twice during the IVF-regimen: once during hormonal down-regulation and once during hormonal up-regulation. A group of healthy men and a group of women using monophasic contraceptives were also examined, to control for session-to-session effects. Among the women undergoing IVF, serum 17β-estradiol levels differed strongly between treatments as expected, and increased from 65.7 (SD = 26) pmol/L during the down-regulation phase, to 5,188 (SD = 2,524) pmol/L during the up-regulation phase. Significant outcomes in the QST were only seen for temperature perception thresholds (1.7°C versus 2.2°C; P = .003) and cold pain threshold (11.5°C versus 14.5°C; P = .04). A similar change in cold pain threshold was also seen in the 2 control groups, however, and statistical analysis suggested that this change was due to a session-to-session effect rather than being the result of hormonal modulation. Heat pain thresholds, heat tolerance, pressure pain thresholds, and the cold pressor test showed no significant differences between sessions. These data demonstrate that pain perception and pain thresholds in healthy women show little, if any, changes even with major variations in serum estradiol levels. PERSPECTIVE: This study shows that pain perception and tolerance in women undergoing in vitro fertilization do not vary, despite the dramatic changes in 17β-estradiol levels induced by the treatment regimen. The result thus suggests that in humans, contrary to experimental animals, changes in estrogen levels have little influence on pain sensitivity.

  • 371. Storm, Tina
    et al.
    Tranebjærg, Lisbeth
    Frykholm, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Birn, Henrik
    Verroust, Pierre J
    Nevéus, Tryggve
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Sundelin, Birgitta
    Hertz, Jens Michael
    Holmström, Gerd
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Oftalmiatrik.
    Ericson, Katharina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Christensen, Erik I
    Nielsen, Rikke
    Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration2013Inngår i: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 28, nr 3, s. 585-591Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    The reabsorption of filtered plasma proteins, hormones and vitamins by the renal proximal tubules is vital for body homeostasis. Studies of megalin-deficient mice suggest that the large multi-ligand endocytic receptor megalin plays an essential role in this process. In humans, dysfunctional megalin causes the extremely rare Donnai-Barrow/Facio-Oculo-Acustico-Renal (DB/FOAR) syndrome characterized by a characteristic and multifaceted phenotype including low-molecular-weight proteinuria. In this study, we examined the role of megalin for tubular protein reabsorption in humans through analysis of proximal tubular function in megalin-deficient patients.

    Methods

    Direct sequencing of the megalin-encoding gene (LRP2) was performed in a family in which three children presented with classical DB/FOAR manifestations. Renal consequences of megalin deficiency were investigated through immunohistochemical analyses of renal biopsy material and immunoblotting of urine samples.

    Results

    In the patients, a characteristic urinary protein profile with increased urinary excretion of vitamin D-binding protein, retinol-binding protein and albumin was associated with absence of, or reduced, proximal tubular endocytic uptake as shown by renal immunohistochemistry. In the absence of tubular uptake, urinary albumin excretion was in the micro-albuminuric range suggesting that limited amounts of albumin are filtered in human glomeruli.

    Conclusions

    This study demonstrated that megalin plays an essential role for human proximal tubular protein reabsorption and suggests that only limited amounts of albumin is normally filtered in the human glomeruli. Finally, we propose that the characteristic urinary protein profile of DB/FOAR patients may be utilized as a diagnostic marker of megalin dysfunction.

  • 372.
    Strang-Karlsson, Sonja
    et al.
    Univ Helsinki, Folkhaelsan Inst Genet, Folkhaelsan Dept Med Genet, Helsinki, Finland; Univ Helsinki, Dept Med & Clin Genet, Helsinki, Finland; Helsinki Univ Hosp, Childrens Hosp, Helsinki, Finland; Univ Helsinki, Helsinki, Finland.
    Johnson, Katherine
    Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Töpf, Ana
    Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Xu, Liwen
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA; Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Lek, Monkol
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA; Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    MacArthur, Daniel G.
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA; Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Williams, Maria
    Aland Cent Hosp, Mariehamn, Aland, Finland.
    Straub, Volker
    Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Wallgren-Pettersson, Carina
    Univ Helsinki, Folkhaelsan Inst Genet, Folkhaelsan Dept Med Genet, Helsinki, Finland; Univ Helsinki, Dept Med & Clin Genet, Helsinki, Finland.
    A novel compound heterozygous mutation in the POMK gene causing limb-girdle muscular dystrophy-dystroglycanopathy in a sib pair2018Inngår i: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 28, nr 7, s. 614-618Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We describe two Finnish siblings in whom an incidentally detected elevated creatine kinase activity eventually led to a diagnosis of limb-girdle muscular dystrophy-dystroglycanopathy (Type C12; MDDGC12). When diagnosed at age 10 and 13 years, they were mildly affected with a slow or non-progressive disease course. The main symptoms comprised infrequent hip cramps triggered by flexion, neck cramps triggered by yawning, transient growing pains, calf hypertrophy and mild proximal muscle weakness. Their cognitive and motor developments were unremarkable and they were physically active. Whole-exome sequencing revealed compound heterozygous mutations, both of which were novel, in the protein O-mannosyl kinase (POMK) gene in both siblings; a missense mutation, p.Pro322Leu (c.965C > T), and a nonsense mutation, p.Arg46Ter (c.136C > T). The results were confirmed by Sanger sequencing, showing that the parents were heterozygous carriers of one mutation each. This report adds to the literature by providing phenotype and genotype data on this ultra-rare POMK-related dystroglycanopathy.

  • 373.
    Stålberg, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Jitter analysis with concentric needle electrodes2013Inngår i: Myasthenia Gravis and Related Disorders / [ed] Wolfe, GI; Meriggioli, MN; Ciafaloni, E; Ruff, RL, 2013, Vol. 1274, nr 1, s. 77-85Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Because of certain restrictions in medical praxis, reusable materials are only allowed in some countries. This also applies to electrodes for electromyography; the special single-fiber electromyography electrode must be replaced. This article gives some details of the possibilities of using an alternative-a small concentric needle electrode. Practical hints, reference values, and the application in diagnostic work for myasthenia gravis are summarized.

  • 374.
    Stålberg, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Kouyoumdjian, João
    Sanders, Donald
    Reference values in concentric needle electrode studies2013Inngår i: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 124, nr 6, s. 1255-1256Artikkel i tidsskrift (Fagfellevurdert)
  • 375.
    Suhr, O. B.
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Lundgren, E.
    Umea Univ, Dept Mol Biol, Umea, Sweden..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    One mutation, two distinct disease variants: unravelling the impact of transthyretin amyloid fibril composition2017Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, nr 4, s. 337-347Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Although hereditary transthyretin (h-ATTR) amyloidosis is a monogenetic disease, a large variation in its phenotype has been observed. The common hypothesis of amyloid fibril formation involves dissociation of the transthyretin (TTR) tetramer into monomers that after misfolding reassemble into amyloid fibrils. This notion is partly challenged by the finding of two distinct types of amyloid fibrils. One of these, type A, consists of C-terminal ATTR fragments and full-length TTR, whereas the other, type B, consists only of full-length TTR. All organs of an individual patient contain ATTR deposits of either type A or type B fibrils, and the composition in each individual remains unchanged over time. The finding of two distinct types of ATTR fibrils suggests that there are at least two different pathways in operation for ATTR fibril formation. For the most common European mutation, TTR Val30Met, ATTR fibril composition is related to the outcome of liver transplantation, which is the first successful treatment for the disease, and the penetrance of the trait. In addition, the presence of C-terminal ATTR fragments has an impact on the affinity for various tracers used for noninvasive imaging of amyloid depositions such as 99 m-technetium-diphosphono-propanodicarboxylic acid scintigraphy and positron emission tomography utilizing Pittsburgh component B, and even for the gold standard diagnostic procedure, tissue biopsy stained by Congo red and examined under polarized light. The importance of amyloid fibril composition needs to be taken into consideration when designing clinical trials of treatment modalities, and also in the evaluation of diagnostic methods such as imaging techniques.

  • 376.
    Suhr, Ole Bernt
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Wixner, Jonas
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Anan, Intissar
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Lundgren, Hans-Erik
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Wijayatunga, Priyantha
    Umea Univ, Dept Stat, Umea, Sweden.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ihse, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Amyloid fibril composition within hereditary Val30Met (p. Val50Met) transthyretin amyloidosis families2019Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 2, artikkel-id e0211983Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The amyloid fibril in hereditary transthyretin (TTR) Val30Met (pVal50Met) amyloid (ATTR Val30Met) amyloidosis is composed of either a mixture of full-length and TTR fragments (Type A) or of only full-length TTR (Type B). The type of amyloid fibril exerts an impact on the phenotype of the disease, and on the outcome of diagnostic procedures and therapy. The aim of the present study was to investigate if the type of amyloid fibril remains the same within ATTR Val30Met amyloidosis families.

    METHODS: Fifteen families were identified in whom at least two first-degree relatives had their amyloid fibril composition determined. The type of ATTR was determined by Western blot in all but two patients. For these two patients a positive 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy indicated ATTR Type A.

    RESULTS: In 14 of the 15 families, the same amyloid fibril composition was noted irrespective of differences in age at onset. In the one family, different ATTR fibril types was found in two brothers with similar ages at onset.

    CONCLUSIONS: Family predisposition appears to have an impact on amyloid fibril composition in members of the family irrespective of their age at onset of disease, but if genetically determined, the gene/genes are likely to be situated at another location than the TTR gene in the genome.

    Fulltekst (pdf)
    fulltext
  • 377.
    Sundblom, Jimmy
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Nowinski, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Plastikkirurgi.
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ryttlefors, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Removal of giant intraosseous meningioma followed by cranioplasty using a custom-made bioceramic implant: case report2019Inngår i: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 131, nr 3, s. 735-739Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Intraosseous meningioma of the chordoid type is a rare clinical entity. Radical surgical removal and subsequent cranioplasty is the treatment of choice. Here, the authors report a severe case involving more than 70% of the calvarial surface area, which was removed and repaired using a prefabricated custom-made, titanium-reinforced, bioceramic implant and bone-cutting guides. Tumor removal and good esthetic outcome were achieved, along with a 17.1% increase of intracranial volume. Bioceramic implants have shown promising initial results and may represent an important new tool in the surgeon's armamentarium.

  • 378.
    Suveer, Amit
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Sladoje, Natasa
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Lindblad, Joakim
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sintorn, Ida-Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Cilia ultrastructural visibility enhancement by multiple instance registration and super-resolution reconstruction2017Inngår i: Swedish Symposium on Image Analysis, Swedish Society for Automated Image Analysis , 2017Konferansepaper (Annet vitenskapelig)
  • 379.
    Suveer, Amit
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Sladoje, Nataša
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Lindblad, Joakim
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Sintorn, Ida-Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Enhancement of cilia sub-structures by multiple instance registration and super-resolution reconstruction2017Inngår i: Image Analysis: Part II, Springer, 2017, s. 362-374Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Ultrastructural analysis of cilia cross-sectional images using transmission electron microscopy (TEM) assists the pathologists to diagnose Primary Ciliary Dyskinesia, a genetic disease. The current diagnostic procedure is manual and difficult because of poor signal-to-noise ratio in TEM images. In this paper, we propose an automated multi-step registration approach to register many cilia cross-sectional instances. The novelty of the work is in the utilization of customized weight masks at each registration step to achieve good alignment of the specific cilium regions. Registration is followed by super-resolution reconstruction to enhance the substructural information. Landmarks matching based evaluation of registration results in pixel alignment error of 2.35&#x00B1;1.82" role="presentation">2.35±1.82 pixels, and the subjective analysis of super-resolution reconstructed cilium shows a clear improvement in the visibility of the substructures such as dynein arms, radial spokes, and central pair.

  • 380.
    Svensson, Maria C.
    et al.
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Warfvinge, Carl Fredrik
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Fristedt, Richard
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Hedner, Charlotta
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Borg, David
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Eberhard, Jakob
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Nodin, Bjoern
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    Leandersson, Karin
    Lund Univ, Dept Translat Med, Canc Immunol, Malmo, Sweden..
    Jirstroem, Karin
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden..
    The integrative clinical impact of tumor-infiltrating T lymphocytes and NK cells in relation to B lymphocyte and plasma cell density in esophageal and gastric adenocarcinoma2017Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 42, s. 72108-72126Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Several studies have demonstrated a prognostic impact of tumor-infiltrating T lymphocytes and natural killer (NK) cells in esophageal and gastric adenocarcinoma, but whether these associations differ by the density of tumor-infiltrating immune cells of the B cell lineage remains largely unknown. Results: High infiltration of any T and NK lymphocytes investigated was in general associated with a favorable prognosis, but the strongest beneficial prognostic impact was seen in combination with high B lymphocyte infiltration. These findings were most evident in gastric cancer, where significant interactions in relation to OS were observed for CD3(+), CD8(+) and FoxP3(+) with CD20(+) cells (p(interaction) = 0.012, 0.009 and 0.007, respectively) and for FoxP3(+) with IGKC(+) cells (p(interaction) = 0.034). In esophageal tumors, there was only a significant interaction for CD3(+) and CD20 (+) cells (p(interaction) = 0.028). Methods: Immunohistochemistry and automated image analysis was applied to assess the density of T lymphocytes (CD3(+), CD8(+), FoxP3(+)) and NK cells (NKp46(+)) in chemoradiotherapy-naive tumors from a consecutive cohort of 174 patients with resected esophageal or gastric adenocarcinoma. The density of B lymphocytes (CD20(+)) and plasma cells (IGKC(+)) had been assessed previously. Kaplan-Meier analysis and Cox proportional hazard's modelling was applied to examine the impact of the investigated markers on time to recurrence (TTR) and overall survival (OS). Conclusions: These data support that the antitumoral effects of tumor-infiltrating T lymphocytes in esophageal and gastric adenocarcinoma may be largely dependent on a functional interplay between T and B lymphocytes or plasma cells.

    Fulltekst (pdf)
    fulltext
  • 381. Södergren, E
    et al.
    Nourooz-Zadeh, J
    Berglund, L
    Vessby, B
    Re-evaluation of the ferrous oxidation in xylenol orange assay for the measurement of plasma lipid hydroperoxides.1998Inngår i: Journal of Biochemical and Biophysical Methods, ISSN 0165-022X, E-ISSN 1872-857X, Vol. 37, nr 3, s. 137-46Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The ferrous oxidation in xylenol orange version 2 (FOX2) assay coupled with triphenylphosphine has recently been employed for the measurement of total plasma hydroperoxides (ROOHs). In this study, we have evaluated sample handling and the effect of storage conditions on ROOH levels in human plasma (n = 32). Mean level of ROOHs in fresh plasma was 8.35 +/- 3.09 mumol/l (range 4.03-19.5 mumol/l). Addition of butylated hydroxytoluene (BHT) immediately after sample collection had no effect on the concentration of ROOHs. Storage of samples at -70 degrees C for 6 weeks was associated with a variable degree of loss of detectable ROOHs. A mean ROOH level of 6.00 +/- 2.23 mumol/l (range 2.88-13.5 mumol/l) was recorded after 6 weeks of storage at -70 degrees C. There was no difference in the mean level of ROOHs between samples stored for 6 and 60 weeks at -70 degrees C. Inclusion of BHT had no effect on the stability of plasma ROOHs during prolonged storage. Intra-assay coefficients of variation were < 12%, with the lowest variation in fresh samples (7.6%). In conclusion, these results suggest that the FOX2 assay should be a useful tool for measurement of ROOHs in fresh plasma samples but not in stored samples.

  • 382.
    Tano, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Survival of infectious agents and detection of their resistance and virulence factors2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In the first study, three different transport systems for bacteria were evaluated. The CLSI M40-A guideline was used to monitor the maintenance of both mono- and polymicrobial samples during a simulated transportation at room temperature that lasted 0-48 h. All systems were able to maintain the viability of all organisms for 24 h, but none of them could support all tested species after 48 h.  The most difficult species to recover was Neisseria gonorrhoeae, and in polymicrobial samples overgrowth was an observed problem. The aim of the second study was to study the presence of TSST-1 and three other important toxin genes in invasive isolates of Staphylococcus aureus collected during the years 2000-2012 at two tertiary hospitals. The genes encoding the staphylococcal toxins were detected by PCR, and whole-genome sequencing was used for analyzing the genetic relatedness between isolates. The results showed that the most common toxin was TSST-1, and isolates positive for this toxin exhibited a clear clonality independent of year and hospital. The typical patient was a male aged 55-74 years and with a bone or a joint infection. The third study was a clinical study of the effect of silver-based wound dressings on the bacterial flora in chronic leg ulcers. Phenotypic and genetic silver-resistance were investigated before and after topical silver treatment, by determining the silver nitrate MICs and by detecting sil genes with PCR. The silver-based dressings had a limited effect on primary wound pathogens, and the activity of silver nitrate on S. aureus was mainly bacteriostatic. A silver-resistant Enterobacter cloacae strain was identified after only three weeks of treatment, and cephalosporin-resistant members of the Enterobacteriaceae family were relatively prone to developed silver-resistance after silver exposure in vitro. The last study was undertaken in order to develop an easy-to-use method for simulating the laundering process of hospital textiles, and apply the method when evaluating the decontaminating efficacy of two different washing temperatures. The laundering process took place at professional laundries, and Enterococcus faecium was used as a bioindicator. The results showed that a lowering of the washing temperature from 70°C to 60°C did not affect the decontamination efficacy; the washing cycle alone reduced the number of bacteria with 3-5 log10 CFU, whereas the following tumble drying reduced the bacterial numbers with another 3-4 log10 CFU, yielding the same final result independent of the washing temperature. To ensure that sufficient textile hygiene is maintained, the whole laundering process needs to be monitored. The general conclusion is that all developmental work in the bacterial field requires time and a large strain collection.

    Delarbeid
    1. Evaluation of three swab transport systems for the maintenance of clinically important bacteria in simulated mono- and polymicrobial samples
    Åpne denne publikasjonen i ny fane eller vindu >>Evaluation of three swab transport systems for the maintenance of clinically important bacteria in simulated mono- and polymicrobial samples
    2011 (engelsk)Inngår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 119, nr 3, s. 198-203Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In this study, three swab transport systems were evaluated: M40 Transystem, Amies broth with a relatively new type of swab (both Copan Diagnostics, Corona, CA, USA), and SSI transportmedium (Statens Serum Institut, Copenhagen Denmark). The CLSI M40-A standard procedures and 11 culture collection strains were used. The transport systems were tested at room temperature for holding times of 0, 24, and 48 h, and both mono- and polymicrobial samples were included. After 24 h of simulated transportation, all systems were able to maintain the viability of all organisms tested. SSI transportmedium exhibited the lowest maintaining ability, whereas the two Copan systems were the most growth-promoting system. In polymicrobial samples, this latter feature was a problem. At 48 h, no transport system could maintain the viability of all strains, and the recovery rates differed depending on organism and device. The species most difficult to recover in all the three systems was Neisseria gonorrhoeae. When selecting a swab transport system, consideration must be given to the sample type, the conditions that prevail locally, and the performance in the clinical setting.

    Emneord
    Transportation, swab, fastidious bacteria, polymicrobial samples, Neisseria gonorrhoeae
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-149062 (URN)10.1111/j.1600-0463.2010.02710.x (DOI)000286838400005 ()21284737 (PubMedID)
    Tilgjengelig fra: 2011-03-15 Laget: 2011-03-15 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    2. Overrepresentation of the toxic shock syndrome toxin-1 gene among eldery men with bacteremic bone and joint infections caused by Staphylococcus aureus
    Åpne denne publikasjonen i ny fane eller vindu >>Overrepresentation of the toxic shock syndrome toxin-1 gene among eldery men with bacteremic bone and joint infections caused by Staphylococcus aureus
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Staphylococcus aureus is a leading causative agent of Gram-positive septicemia. In recent years, there have been indications that both the severity and the number of staphylococcal infections have increased. In order to study the presence of genes encoding exfoliative toxins (eta/etb), Panton-Valentine leucocidin (lucS-PV-lucF-PV), and toxic shock syndrome toxin-1 (tst) in invasive isolates over time and space, 528 blood isolates of S. aureus collected during the years 2000-2012 from two Swedish university hospitals were investigated.  Age, gender and diagnosis of patients were registered, and the antibiotic susceptibility was tested. Toxin genes were detected with PCR, and the genetic relatedness was assessed with pulsed-field gel electrophoresis and whole genome sequencing. Blood cultures positive for S. aureus increased with 57.6% during the study period. Ninety-six of the isolates (18.2%) carried 97 toxin genes (one isolate carried both eta and etb). All isolates except one (PVL-producing and methicillin-resistant) were fully susceptible to the tested antibiotics. Most frequent was tst (79.4%), followed by eta (12.4%), lucS-PV-lucF-PV (7.2%), and etb (1.0%). The typical tst-positive patient was a male aged 55-74 years with a bone or joint infection. Tst-positive isolates exhibited a clear clonality, and that was independent of year and hospital. Most common was ST30-t012. To summarize, bacteremia caused by S. aureus increased during the study period, but the frequency of four important staphylococcal toxins and the antibiotic susceptibility remained low. To screen for these toxins is only cost-effective in Swedish patients with a typical clinical presentation.

    HSV kategori
    Forskningsprogram
    Mikrobiologi
    Identifikatorer
    urn:nbn:se:uu:diva-248754 (URN)
    Tilgjengelig fra: 2015-04-08 Laget: 2015-04-08 Sist oppdatert: 2015-07-07bibliografisk kontrollert
    3. Effects of Silver-based Wound Dressings on the Bacterial Flora in Chronic Leg Ulcers and Its Susceptibility In vitro to Silver
    Åpne denne publikasjonen i ny fane eller vindu >>Effects of Silver-based Wound Dressings on the Bacterial Flora in Chronic Leg Ulcers and Its Susceptibility In vitro to Silver
    Vise andre…
    2012 (engelsk)Inngår i: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 92, nr 1, s. 34-39Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Silver-based dressings have been used extensively in wound management in recent years, but data on their antimicrobial activity in the clinical setting are limited. In order to explore their effects on chronic leg ulcer flora, 14 ulcers were cultured after at least 3 weeks treatment with Aquacel Ag (R) or Acticoat (R). Phenotypic and genetic silver resistance were investigated in a total of 56 isolates. Silver-based dressings had a limited effect on primary wound pathogens, which were present in 79% of the cultures before, and 71% after, treatment. One silver-resistant Enterobacter cloacae strain was identified (silver nitrate minimal inhibitory concentration (MIC)>512 mg/l, positive for silE, silS and silP). Further studies in vitro showed that inducible silver-resistance was more frequent in Enterobacteriaceae with cephalosporin-resistance and that silver nitrate had mainly a bacteriostatic effect on Staphylococcus aureus. Monitoring of silver resistance should be considered in areas where silver is used extensively.

    Emneord
    silver, silver-resistance, wound dressing, ESBL, derepressed mutant
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-171444 (URN)10.2340/00015555-1170 (DOI)000300388400007 ()
    Tilgjengelig fra: 2012-03-19 Laget: 2012-03-19 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    4. Level of decontamination after washing textiles at 60°C or 70°C followed by tumble drying
    Åpne denne publikasjonen i ny fane eller vindu >>Level of decontamination after washing textiles at 60°C or 70°C followed by tumble drying
    2014 (engelsk)Inngår i: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 4, artikkel-id 24314Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: Several major outbreaks in healthcare facilities have occurred with the emergence of multi-resistant bacteria. A possible route for dissemination is the hospital textiles and inadequate laundering of them. The aim of this study was to develop an easy-to-use method for simulating the laundering process of hospital textiles, and thereafter apply the method when evaluating the decontaminating efficacy of two different washing temperatures.

    METHODS: The laundering process, including tumble drying, took place at two professional laundries. Enterococcus faecium was used as bioindicator.

    RESULTS: The results showed that a lowering of the washing temperature from 70°C to 60°C did not affect the decontamination efficacy; the washing cycle alone reduced the number of bacteria with 3-5 log10 CFU, whereas the following tumble drying reduced the bacterial numbers with another 3-4 log10 CFU, yielding the same final result independent of washing temperature. Without tumble drying, there was an obvious risk of adding non-fermenting gram-negative bacteria to the fabric. These bacteria originated from the washing cycle.

    CONCLUSION: A simple method to simulate hospital laundering was developed. To save energy, it is possible to use a washing temperature of 60°C, but the washing cycle should be followed by tumble drying, and the whole laundering process needs to be monitored to maintain sufficient textile hygiene.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-246138 (URN)10.3402/iee.v4.24314 (DOI)25413829 (PubMedID)
    Tilgjengelig fra: 2015-03-02 Laget: 2015-03-02 Sist oppdatert: 2017-12-04bibliografisk kontrollert
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    fulltext
    Download (jpg)
    presentationsbild
  • 383.
    Tegler, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kärlkirurgi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Ericson, Katharina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Björck, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kärlkirurgi.
    Wanhainen, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kärlkirurgi.
    4D-PET/CT with [11C]-PK11195 and [11C]-D-deprenyl does not identify the chronic inflammation in asymptomatic abdominal aortic aneurysms2013Inngår i: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 45, nr 4, s. 351-356Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives

    The aim of this study was to investigate the relevance of inflammation in the pathogenesis of abdominal aortic aneurysm (AAA) in vivo with two novel positron emission tomography (PET) tracers: [11C]-PK11195 which targets the translocator protein (18 kDa) expressed on macrophages and [11C]-d-deprenyl with a yet unknown target receptor expressed in chronic inflammation.

    Design

    Prospective clinical study.

    Materials/methods

    Five patients were examined with [11C]-PK11195-positron emission tomography/computed tomography (PET/CT) and 10 with [11C]-d-deprenyl-PET/CT. Nine large AAAs (54–66 mm) scheduled for repair and six small AAA (35–44 mm). All 15 patients were male and the AAAs were all asymptomatic. Regional activity was measured as standardised uptake values (SUVs) and retention index was calculated. Biopsies were taken from the aneurysm wall for histological examinations, in the nine patients operated on.

    Results

    No aortic uptake was recorded on the visual inspection, neither with [11C]-PK11195 nor with [11C]-d-deprenyl. For [11C]-PK11195 the median SUV of the AAA wall was 0.9 (range 0.8–1.0) and for [11C]-d-deprenyl, 0.7 (range 0.4–1.2). No increased uptake was seen in the aneurysmal infrarenal aorta compared with the non-aneurysmal suprarenal aorta. Histological examination of the aneurysm wall showed high inflammatory cell infiltration with lymphocytes and macrophages.

    Conclusions

    The chronic inflammation observed in the vessel wall was not detectable with [11C]-PK11195 and [11C]-d-deprenyl. In order to study the relevance of the inflammation in the pathogenesis of AAA in vivo other PET tracers need to be investigated.

  • 384.
    Thunnissen, Erik
    et al.
    Vrije Univ Amsterdam Med Ctr, Dept Pathol, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands..
    Borczuk, Alain C.
    Weill Cornell Med, Dept Pathol, New York, NY USA..
    Flieder, Douglas B.
    Fox Chase Canc Ctr, Dept Pathol, Philadelphia, PA 19111 USA..
    Witte, Birgit
    Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands..
    Beasley, Mary Beth
    Mt Sinai Med Ctr, Dept Pathol, New York, NY 10029 USA..
    Chung, Jin-Haeng
    Seoul Natl Univ, Bundang Hosp, Coll Med, Dept Pathol, Seoul 151, South Korea..
    Dacic, Sanja
    Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA..
    Lantuejoul, Sylvie
    Ctr Leon Berard UNICANCER, Dept Biopathol, Lyon, France..
    Russell, Prudence A.
    St Vincent Pathol, Melbourne, Vic, Australia.;Univ Melbourne, Melbourne, Vic, Australia..
    den Bakker, Michael
    Maasstad Ziekenhuis, Dept Pathol, Rotterdam, Netherlands..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brambilla, Elisabeth
    CHU Albert Michallon, Inst Biol, Dept Anat & Cytol Pathol, Grenoble, France..
    de Cuba, Erienne
    Vrije Univ Amsterdam Med Ctr, Dept Pathol, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands..
    Geisinger, Kim R.
    Univ Mississippi, Med Ctr, Dept Pathol, Jackson, MS 39216 USA..
    Hiroshima, Kenzo
    Tokyo Womens Med Univ, Yachiyo Med Ctr, Dept Pathol, Yachiyo, Japan..
    Marchevsky, Alberto M.
    Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA..
    Minami, Yuko
    Univ Tsukuba, Inst Basic Med Sci, Dept Pathol, Tsukuba, Ibaraki, Japan..
    Moreira, Andre
    NYU, Ctr Biospecimen Res & Dev, Pulm Pathol, New York, NY USA..
    Nicholson, Andrew G.
    Royal Brompton & Harefield Hosp Natl Hlth Serv Fd, Dept Histopathol, London, England.;Imperial Coll, Natl Heart & Lung Inst, London, England..
    Yoshida, Akihiko
    Natl Canc Ctr, Dept Pathol & Clin Labs, Tokyo, Japan..
    Tsao, Ming-Sound
    Princess Margaret Hosp, Univ Hlth Network, Dept Pathol, Toronto, ON, Canada.;Univ Toronto, Toronto, ON, Canada..
    Warth, Arne
    Heidelberg Univ, Inst Pathol, Heidelberg, Germany..
    Duhig, Edwina
    John Flynn Hosp, Sullivan Nicolaides Pathol, Tugun, Qld, Australia..
    Chen, Gang
    Fudan Univ, Zhongshan Hosp, Dept Pathol, Shanghai, Peoples R China..
    Matsuno, Yoshihiro
    Hokkaido Univ Hosp, Dept Surg Pathol, Sapporo, Hokkaido, Japan..
    Travis, William D.
    Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA..
    Butnor, Kelly
    Univ Vermont, Dept Pathol, Burlington, VT 05405 USA..
    Cooper, Wendy
    Royal Prince Alfred Hosp, Tissue Pathol & Diagnost Oncol, Sydney, NSW, Australia..
    Mino-Kenudson, Mari
    Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA USA..
    Motoi, Noriko
    Natl Canc Ctr, Dept Pathol & Clin Labs, Tokyo, Japan..
    Poleri, Claudia
    Lab Patol Torac, Buenos Aires, DF, Argentina..
    Pelosi, Giuseppe
    Univ Milan, Dept Oncol & Hematol Oncol, Milan, Italy..
    Kerr, Keith
    Aberdeen Royal Infirm, Dept Pathol, Aberdeen, Scotland..
    Aisner, Seena C.
    Rutgers State Univ, Rutgers New Jersey Med Sch, Dept Pathol & Lab Med, Newark, NJ USA..
    Ishikawa, Yuichi
    Japan Fdn Canc Res, Inst Canc, Div Pathol, Tokyo, Japan..
    Buettner, Reinhard H.
    Cologne Inst Pathol, Cologne, Germany..
    Keino, Naoto
    Univ Tsukuba, Tsukuba Clin Res & Dev Org, Tsukuba, Ibaraki, Japan..
    Yatabe, Yasushi
    Aichi Canc Ctr, Dept Pathol & Mol Diagnost, Nagoya, Aichi, Japan..
    Noguchi, Masayuki
    Univ Tsukuba, Inst Basic Med Sci, Dept Pathol, Tsukuba, Ibaraki, Japan..
    The Use of Immunohistochemistry Improves the Diagnosis of Small Cell Lung Cancer and Its Differential Diagnosis. An International Reproducibility Study in a Demanding Set of Cases2017Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 12, nr 2, s. 334-346Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: The current WHO classification of lung cancer states that a diagnosis of SCLC can be reliably made on routine histological and cytological grounds but immunohistochemistry (IHC) may be required, particularly (1) in cases in which histologic features are equivocal and (2) in cases in which the pathologist wants to increase confidence in diagnosis. However, reproducibility studies based on hematoxylin and eosin-stained slides alone for SCLC versus large cell neuroendocrine carcinoma (LCNEC) have shown pairwise K scores ranging from 0.35 to 0.81. This study examines whether judicious use of IHC improves diagnostic reproducibility for SCLC.

    Methods: Nineteen lung pathologists studied interactive digital images of 79 tumors, predominantly neuroendocrine lung tumors. Images of resection and biopsy specimens were used to make diagnoses solely on the basis of morphologic features (level 1), morphologic features along with requested IHC staining results (level 2), and all available IHC staining results (level 3).

    Results: For the 19 pathologists reading all 79 cases, the rate of agreement for level 1 was 64.7%, and it increased to 73.2% and 77.5% in levels 2 and 3, respectively. With IHC, K scores for four tumor categories (SCLC, LCNEC, carcinoid tumors, and other) increased in resection samples from 0.43 to 0.60 and in biopsy specimens from 0.43 to 0.64.

    Conclusions: Diagnosis using hematoxylin and eosin staining alone showeds moderate agreement among pathologists in tumors with neuroendocrine morphology, but agreement improved to good in most cases with the judicious use of IHC, especially in the diagnosis of SCLC. An approach for IHC in the differential diagnosis of SCLC is provided. (C) 2017 International Association for the Study of Lung Cancer.

  • 385.
    Tjernberg, L. O.
    et al.
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Huddinge, Sweden..
    Rising, A.
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Huddinge, Sweden.;Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Johansson, J.
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Huddinge, Sweden.;Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Jaudzems, K.
    Latvian Inst Organ Synth, Riga, Latvia..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Transmissible amyloid2016Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 280, nr 2, s. 153-163Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    There are around 30 human diseases associated with protein misfolding and amyloid formation, each one caused by a certain protein or peptide. Many of these diseases are lethal and together they pose an enormous burden to society. The prion protein has attracted particular interest as being shown to be the pathogenic agent in transmissible diseases such as kuru, Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Whether similar transmission could occur also in other amyloidoses such as Alzheimer's disease, Parkinson's disease and serum amyloid A amyloidosis is a matter of intense research and debate. Furthermore, it has been suggested that novel biomaterials such as artificial spider silk are potentially amyloidogenic. Here, we provide a brief introduction to amyloid, prions and other proteins involved in amyloid disease and review recent evidence for their potential transmission. We discuss the similarities and differences between amyloid and silk, as well as the potential hazards associated with protein-based biomaterials. Read more articles from the symposium: Amyloid - a multifaceted player in human health and disease.

  • 386. Tjörnstrand, Axel
    et al.
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Heurling, Kerstin
    Schöll, Michael
    Gjertsson, Peter
    Himmelman, Jakob
    Itsenko, Oleksiy
    Ragnarsson, Oskar
    Filipsson Nyström, Helena
    Lower 68 Ga-DOTATOC Uptake in Non-Functioning Pituitary Neuroendocrine Tumors Compared to Normal Pituitary Gland - a Proof-of-Concept Study.2019Inngår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: 68 Ga-DOTATOC PET targets somatostatin receptors (SSTRs) and is well established for the detection of SSTR-expressing tumors, such as gastrointestinal neuroendocrine tumors. Pituitary adenomas, recently designated as pituitary neuroendocrine tumors (PitNETs), also express SSTRs, but there has been no previous evaluations of 68 Ga-DOTATOC PET in PitNET patients. The aim of this pilot study was to evaluate the diagnostic properties of 68 Ga-DOTATOC PET in the most common PitNET, i.e. non-functioning (NF)-PitNET.

    DESIGN/METHODS: NF-PitNET patients (n = 9) and controls (n = 13) were examined preoperatively with 68 Ga-DOTATOC PET for 45 min after tracer injection in dynamic list mode. Tumor specimens were collected during surgery in patients. MRI and PET images were co-registered using PMOD software. The maximum standard uptake value (SUVmax ) was analyzed in manually outlined regions of interest (ROC) around the tumor in patients and around the pituitary gland in controls. Immunohistochemical analyses were conducted on tumor specimens for assessment of tumor cell type and SSTR expression.

    RESULTS: Median SUVmax (IQR) was lower in patients than in controls (3.9 [3.4-8.5] vs 14.1 [12.5-15.9]; P < .01]. In ROC analysis, the area under the curve was 0.87 (P < .01) for SUVmax , with 78% sensitivity and 92% specificity. Immunohistochemical analysis showed NF-PitNETs were of gonadotroph (n = 7) and corticotroph (n = 2) origin. SSTR expression was high for SSTR3, low-to-moderate for SSTR2, and low for SSTR1 and SSTR5.

    CONCLUSIONS: This proof-of-concept study shows that 68 Ga-DOTATOC PET can be used to differentiate between normal pituitary tissue and NF-PitNET.

  • 387.
    Tran, Lena
    et al.
    Reg Labs Reg Skane, Dept Pathol, SE-22185 Lund, Sweden.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Nodin, Björn
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Jönsson, Per
    Lund Univ, Dept Thorac Surg, Lund, Sweden; Skane Univ Hosp, Lund, Sweden.
    Planck, Maria
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden; Skane Univ Hosp, Dept Oncol, Lund, Sweden.
    Jirström, Karin
    Reg Labs Reg Skane, Dept Pathol, SE-22185 Lund, Sweden; Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brunnström, Hans
    Reg Labs Reg Skane, Dept Pathol, SE-22185 Lund, Sweden; Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Various Antibody Clones of Napsin A, Thyroid Transcription Factor 1, and p40 and Comparisons With Cytokeratin 5 and p63 in Histopathologic Diagnostics of Non-Small Cell Lung Carcinoma2016Inngår i: Applied immunohistochemistry & molecular morphology (Print), ISSN 1541-2016, E-ISSN 1533-4058, Vol. 24, nr 9, s. 648-659Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Histopathologic classification of cancer in the lung is important for choice of treatment. Cytokeratin 5 (CK5), p63, and p40 are commonly used immunohistochemical markers for squamous cell carcinoma, and napsin A (NAPA) and thyroid transcription factor 1 (TTF-1) are markers for adenocarcinoma of the lung. The aim of the present study was to evaluate these 5 markers and to compare different commercially available antibody clones in lung cancer. Tissue microarrays including 557 cases of surgically treated primary tumors and 73 matched metastases of non-small cell lung carcinoma were stained with CK5, p63, p40 (monoclonal and polyclonal), NAPA (5 different clones/protocols), and TTF-1 (2 different clones). The sensitivity and specificity to separate squamous cell carcinomas from non-small cell carcinomas of nonsquamous type were 95% and 97%, respectively, for CK5, 95% and 87% for p63, 94% and 96% for p40, 75% to 79% and 96% to 98% for the NAPA clones/protocols and 80% to 85% and 95% to 97% for the TTF-1 clones. A combination of NAPA and TTF-1 resulted in a higher sensitivity (85% to 88%), whereas combining CK5 and p40 did not increase the diagnostic performance. The sensitivity was generally lower in evaluation of lung cancer metastases. The κ-values for comparison of staining results between monoclonal and polyclonal p40 and between the 5 NAPA clones/protocols were 0.97 to 1.0, whereas the corresponding figure for the 2 TTF-1 clones was 0.91 to 0.93. Conclusively, CK5 and p40 are good diagnostic markers for squamous cell carcinoma and superior to p63. In addition, it may be useful to combine NAPA and TTF-1 for increased sensitivity in lung cancer diagnostics. There is no substantial difference between monoclonal and polyclonal p40 and between different NAPA clones, whereas there is a difference between the TTF-1 clones 8G7G3/1 and SPT24.

  • 388.
    Tsakonas, Georgios
    et al.
    Karolinska Inst, Dept Oncol Pathol, Karolinska Univ Hosp, Thorac Oncol Ctr,Theme Canc, Stockholm, Sweden.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Rivard, Chris
    Univ Colorado, Div Med Oncol, Anschutz Med Campus, Aurora, CO USA.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Boyle, Teresa
    Univ Colorado, Div Med Oncol, Anschutz Med Campus, Aurora, CO USA.
    Hirsch, Fred R.
    Univ Colorado, Div Med Oncol, Anschutz Med Campus, Aurora, CO USA.
    Ekman, Simon
    Karolinska Inst, Dept Oncol Pathol, Karolinska Univ Hosp, Thorac Oncol Ctr,Theme Canc, Stockholm, Sweden.
    c-MET as a biomarker in patients with surgically resected non-small cell lung cancer2019Inngår i: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 133, s. 69-74Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: c-MET protein overexpression has been proposed as a biomarker in non-small cell lung cancer (NSCLC), albeit its role in the clinical setting has not been firmly established yet. Patients and methods: We designed a retrospective cohort study, consisting of 725 patients with surgically removed NSCLC. Immunohistochemistry (IHC) was conducted in tissue microarrays (TMA) from lung tumors and healthy tissue. IHC staining was quantified using H-scores (range 0-300). Association between c-MET H-score and overall survival (OS) as well as progression-free survival (PFS) was explored. Results: c-MET H-score >= 20 had a significant positive impact on OS in the multivariate analysis in the whole study population, HR = 0.79 (95%CI: 0.64 - 0.97). The prognostic effect of c-MET H-score >= 20 was even stronger in patients who received adjuvant treatment with a HR = 0.61 (95% CI: 0.40 - 0.93). In the subgroup of adenocarcinoma and squamous cell carcinoma patients with stage IIA-IIIB disease, the prognostic impact of c-MET was significant in the univariate analysis (HR = 0.60, 95% CI: 0.43 - 0.83). Conclusion: c-MET H-score >= 20 is a positive prognostic biomarker for OS in early stage NSCLC. This benefit seems to be strongly correlated to adjuvant chemotherapy, therefore rendering c-MET H-score >= 20 a possible predictive biomarker for platinum-based adjuvant chemotherapy in early stage NSCLC.

  • 389.
    Tsao, Ming Sound
    et al.
    Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Dept Pathol, Toronto, ON, Canada.
    Kerr, Keith M.
    Aberdeen Univ Med Sch, Aberdeen Royal Infirm, Dept Pathol, Aberdeen, Scotland.
    Kockx, Mark
    HistoGeneX, Antwerp, Belgium.
    Beasley, Mary-Beth
    Mt Sinai Med Ctr, Dept Pathol, New York, NY 10029 USA.
    Borczuk, Alain C.
    Weill Cornell Med, Dept Pathol, New York, NY USA.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Bubendorf, Lukas
    Univ Hosp Basel, Pathol, Inst Pathol, Basel, Switzerland.
    Chirieac, Lucian
    Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA USA.
    Chen, Gang i
    Fudan Univ, Zhongshan Hosp, Dept Pathol, Shanghai 200433, Peoples R China.
    Chou, Teh-Ying
    Taipei Vet Gen Hosp, Dept Pathol & Lab Med, Div Mol Pathol, Taipei, Taiwan.
    Chung, Jin-Haeng
    Seoul Natl Univ, Bundang Hosp, Dept Pathol, Seongnam City, Gyeonggi Do, South Korea;Seoul Natl Univ, Bundang Hosp, Resp Ctr, Seongnam City, Gyeonggi Do, South Korea.
    Dacic, Sanja
    Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA.
    Lantuejoul, Sylvie
    Ctr Leon Berard, Dept Biopathol, Lyon, France.
    Mino-Kenudson, Mari
    Harvard Med Sch, Boston, MA USA;Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.
    Moreira, Andre L.
    NYU Langone Hlth, Dept Pathol, New York, NY USA.
    Nicholson, Andrew G.
    Royal Brompton & Harefield Natl Hlth Serv Fdn Tru, Dept Histopathol, London, England;Imperial Coll, Natl Heart & Lung Inst, London, England.
    Noguchi, Masayuki
    Univ Tsukuba, Fac Med, Dept Pathol, Tsukuba, Ibaraki, Japan.
    Pelosi, Giuseppe
    Univ Milan, Dept Oncol & Hematooncol, Milan, Italy;MultiMedica, IRCCS Grp, Milan, Italy.
    Poleri, Claudia s
    Off Pathol Consultants, Buenos Aires, DF, Argentina.
    Russell, Prudence A.
    St Vincents Pathol, Fitzroy, Vic, Australia.
    Sauter, Jennifer
    Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY USA.
    Thunnissen, Erik
    Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands.
    Wistuba, Ignacio
    MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX USA.
    Yu, Hui
    Univ Colorado, Anschutz Med Campus, Aurora, CO USA.
    Wynes, Murry W.
    Int Assoc Study Lung Canc, Aurora, CO USA.
    Pintilie, Melania
    Univ Hlth Network, Princess Margaret Canc Ctr, Dept Biostat, Toronto, ON, Canada.
    Yatabe, Yasushi
    Aichi Canc Ctr, Dept Pathol & Mol Diagnost, Nagoya, Aichi, Japan.
    Hirsch, Fred R.
    Univ Colorado, Anschutz Med Campus, Aurora, CO USA;Int Assoc Study Lung Canc, Aurora, CO USA.
    PD-L1 Immunohistochemistry Comparability Study in Real-Life Clinical Samples: Results of Blueprint Phase 2 Project2018Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, nr 9, s. 1302-1311Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: The Blueprint (BP) Programmed Death Ligand 1 (PD-L1) Immunohistochemistry Comparability Project is a pivotal academic/professional society and industrial collaboration to assess the feasibility of harmonizing the clinical use of five independently developed commercial PD-L1 immunohistochemistry assays. The goal of BP phase 2 (BP2) was to validate the results obtained in BP phase 1 by using real-world clinical lung cancer samples.

    Methods: BP2 were conducted using 81 lung cancer specimens of various histological and sample types, stained with all five trial-validated PD-L1 assays (22C3, 28-8, SP142, SP263, and 73-10); the slides were evaluated by an international panel of pathologists. BP2 also assessed the reliability of PD-L1 scoring by using digital images, and samples prepared for cytological examination. PD-L1 expression was assessed for percentage (tumor proportional score) of tumor cell (TC) and immune cell areas showing PD-L1 staining, with TCs scored continuously or categorically with the cutoffs used in checkpoint inhibitor trials.

    Results: The BP2 results showed highly comparable staining by the 22C3, 28-8 and SP263 assays; less sensitivity with the SP142 assay; and higher sensitivity with the 73-10 assay to detect PD-L1 expression on TCs. Glass slide and digital image scorings were highly concordant (Pearson correlation >0.96). There was very strong reliability among pathologists in TC PD-L1 scoring with all assays (overall intraclass correlation coefficient [ICC] = 0.86–0.93), poor reliability in IC PD-L1 scoring (overall ICC = 0.18–0.19), and good agreement in assessing PD-L1 status on cytological cell block materials (ICC = 0.78–0.85).

    Conclusion: BP2 consolidates the analytical evidence for interchangeability of the 22C3, 28-8, and SP263 assays and lower sensitivity of the SP142 assay for determining tumor proportion score on TCs and demonstrates greater sensitivity of the 73-10 assay compared with that of the other assays.

  • 390.
    Tsolakis, Apostolos V
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Grimelius, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Islam, Md Shahidul
    Expression of the coiled coil domain containing protein 116 in the pancreatic islets and endocrine pancreatic tumors2012Inngår i: Islets, ISSN 1938-2022, Vol. 4, nr 5, s. 349-353Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: Coiled coil domain containing protein 116 (CCDC116) is a product of the gene coiled coil domain containing 116 located on human chromosome 22. Its function has not yet been established. The present study focuses on the expression of this protein in human pancreatic islets and in the endocrine pancreatic tumors (EPTs). Methods and Results: Expression of the protein was evaluated by immunohistochemistry in endocrine pancreas from six patients and in various EPTs from 51 patients. In pancreatic islets, virtually all insulin, approx. 75% of the somatostatin, and approx. 60% of the pancreatic polypeptide (PP) cells were immunoreactive for the CCDC116 protein whereas glucagon, ghrelin and the exocrine cells were not. All insulinomas, gastrinomas, non-functioning sporadic tumors and the hereditary multihormonal EPTs were immunoreactive with variable relative incidence. Two of the three somatostatinomas, and one of the three ACTH-secreting tumors also expressed CCDC116. Conclusions: The CCDC116 protein is expressed in all islet cell types except the glucagon and ghrelin cells. Most of the EPTs also contained CCDC116 protein. These findings suggest that this protein may play some role for the above mentioned endocrine cells and tumors. Its function has to be investigated in future studies.

  • 391.
    Tugues, Sònia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Honjo, Satoshi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    König, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Noguer, Oriol
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Hedlund, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Deschoemaeker, Sofie
    Wenes, Mathias
    Rolny, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Jahnen-Dechent, Wilhelm
    Mazzone, Massimiliano
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Genetic deficiency in plasma protein HRG enhances tumor growth and metastasis by exacerbating immune escape and vessel abnormalization2012Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Histidine-rich glycoprotein (HRG) is a 75 kDa heparin-binding plasma protein implicated in the regulation of tumor growth and vascularization. In this study, we show that hrg-/- mice challenged with fibrosarcoma or pancreatic carcinomas grow larger tumors with increased metastatic properties. Compared with wild type mice, fibrosarcomas in hrg-/- mice were more hypoxic, necrotic and less perfused, indicating enhanced vessel abnormalization. HRG-deficiency was associated with a suppressed anti-tumor immune response, with both increased infiltration of M2-marker-expressing macrophages and decreased infiltration of dendritic cells and cytotoxic T cells. Analysis of transcript expression in tumor-associated as well as peritoneal macrophages from hrg-/- mice revealed an increased expression of genes associated with a pro-angiogenic and immunoinhibitory phenotype. In accordance, expression arrays performed on HRG-treated peritoneal macrophages showed induction of genes involved in extracellular matrix biology and immune responsiveness. In conclusion, our findings demonstrate that macrophages are a direct target of HRG. HRG loss influences macrophage gene regulation, leading to excess stimulation of tumor angiogenesis, suppression of tumor immune response, and increased tumor growth and metastatic spread.

  • 392. Uesugi, Haruo
    et al.
    Sonoo, Masahiro
    Higashihara, Mana
    Stålberg, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Saito, Hisatoshi
    [Non-invasive quantitative EMG: invention of the "Clustering Index (CI)" method].2012Inngår i: Rinshō shinkeigaku = Clinical neurology, ISSN 1882-0654, Vol. 52, nr 11, s. 1249-1251Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There have been few previous studies trying to evaluate neuromuscular disorders using surface electro myography (SEMG). The greatest obstacle to such an approach must be the difficulty in identifying individual motor unit potentials (MUPs) on the SEMG signal under voluntary contraction because of their dense overlap. We tried to solve this problem by reducing the overlap of MUPs using appropriate electrode setting, as well as by developing a new method of interference pattern analysis. The tibialis anterior muscle was examined in our first study. A new method to analyse SEMG signal, the Clustering Index (CI) method, achieved 100% and 61% sensitivities for neurogenic and myopathic patients, and 97% specificity for control subjects. In the second study, the abductor digiti minimi muscle was examined. Subjects were 29 spinal and bulbar muscular atrophy patients and 27 controls. The CI method was compared with the motor unit number estimation, and the amplitude of compound muscle action potential. As results, the CI method achieved the best sensitivity and among these three techniques. The CI method is a novel, simple, and quantitative analysis method without using any special equipments, and is promising as a non-invasive complement to needle EMG.

  • 393.
    Uhlen, Mathias
    et al.
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.;Danish Tech Univ, Ctr Biosustainabil, Copenhagen, Denmark.;Royal Inst Technol, AlbaNova Univ Ctr, KTH, Sch Biotechnol, Stockholm, Sweden..
    Zhang, Cheng
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Lee, Sunjae
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Sjöstedt, Evelina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.
    Fagerberg, Linn
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Bidkhori, Gholamreza
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Benfeitas, Rui
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Arif, Muhammad
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Liu, Zhengtao
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Edfors, Fredrik
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Sanli, Kemal
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    von Feilitzen, Kalle
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Oksvold, Per
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Lundberg, Emma
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Hober, Sophia
    Royal Inst Technol, AlbaNova Univ Ctr, KTH, Sch Biotechnol, Stockholm, Sweden..
    Nilsson, Peter
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Schwenk, Jochen M.
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Brunnström, Hans
    Lund Univ, Skane Univ Hosp, Div Pathol, Lund, Sweden..
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mardinoglu, Adil
    KTH, Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.;Royal Inst Technol, AlbaNova Univ Ctr, KTH, Sch Biotechnol, Stockholm, Sweden.;Chalmers, Dept Biol & Biol Engn, SE-41296 Gothenburg, Sweden..
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    A pathology atlas of the human cancer transcriptome2017Inngår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 357, nr 6352, artikkel-id eaan2507Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cancer is one of the leading causes of death, and there is great interest in understanding the underlying molecular mechanisms involved in the pathogenesis and progression of individual tumors. We used systems-level approaches to analyze the genome-wide transcriptome of the protein-coding genes of 17 major cancer types with respect to clinical outcome. A general pattern emerged: Shorter patient survival was associated with up-regulation of genes involved in cell growth and with down-regulation of genes involved in cellular differentiation. Using genome-scale metabolic models, we show that cancer patients have widespread metabolic heterogeneity, highlighting the need for precise and personalized medicine for cancer treatment. All data are presented in an interactive open-access database (www.proteinatlas.org/pathology) to allow genome-wide exploration of the impact of individual proteins on clinical outcomes.

  • 394. Uhlén, Mathias
    et al.
    Oksvold, Per
    Algenäs, Cajsa
    Hamsten, Carl
    Fagerberg, Linn
    Klevebring, Daniel
    Lundberg, Emma
    Odeberg, Jacob
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Kondo, Tadashi
    Sivertsson, Asa
    Antibody-based Protein Profiling of the Human Chromosome 212012Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 11, nr 3Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Human Proteome Project has been proposed to create a knowledge-based resource based on a systematical mapping of all human proteins, chromosome by chromosome, in a gene-centric manner. With this background, we here describe the systematic analysis of chromosome 21 using an antibody-based approach for protein profiling using both confocal microscopy and immunohistochemistry, complemented with transcript profiling using next generation sequencing data. We also describe a new approach for protein isoform analysis using a combination of antibody-based probing and isoelectric focusing. The analysis has identified several genes on chromosome 21 with no previous evidence on the protein level, and the isoform analysis indicates that a large fraction of human proteins have multiple isoforms. A chromosome-wide matrix is presented with status for all chromosome 21 genes regarding subcellular localization, tissue distribution, and molecular characterization of the corresponding proteins. The path to generate a chromosome-specific resource, including integrated data from complementary assay platforms, such as mass spectrometry and gene tagging analysis, is discussed.

  • 395.
    Vallin, Siri
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Stability of serum analytes depending on pre-centrifugation time and platelet count in three types of sample collecting tubes2014Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [en]

    The pre-analytical phase of a blood sample is known to be very important due to the need of correct preparation and handling of the sample. If these are not executed correctly, the test results can differ from the true value. The aim of this study was to evaluate the stability of 8 serum analytes depending on pre-centrifugation time and to compare platelet count in three types of sample collecting tubes. The study was performed in a hospital laboratory with routine instruments, which are normally used for patient samples. Blood for the serum analyses was drawn from 14 people and for the platelet count from 15 people. The included analytes were alanine aminotransferase, aspartate transaminase, phosphate, calcium, potassium, lactate dehydrogenase, magnesium and sodium. The results showed that aspartate transaminase, calcium, potassium and sodium were stable for up to 4 hours in non-centrifuged tubes. Alanine aminotransferase, phosphate, lactate dehydrogenase and magnesium were less stable but the variations were not clinically relevant. Platelet count was the same in blood anticoagulated with ethylenediaminetetraacetic acid (EDTA) and sodium citrate of two concentrations. The conclusion of the study was that none of the serum analytes showed a clinically relevant difference due to a delayed pre-centrifugation time. Platelet count is not affected by the choice of sample collecting tubes.

  • 396. van Schie, Rianne M F
    et al.
    Wessels, Judith A M
    le Cessie, Saskia
    de Boer, Anthonius
    Schalekamp, Tom
    van der Meer, Felix J M
    Verhoef, Talitha I
    van Meegen, Erik
    Rosendaal, Frits R
    Maitland-van der Zee, Anke-Hilse
    Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data2011Inngår i: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 32, nr 15, s. 1909-1917Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS:

    Polymorphisms in CYP2C9 and VKORC1 influence patients' phenprocoumon (PHE) and acenocoumarol (ACE) dose requirements. To provide physicians with tools to estimate the patient's individual dose, we aimed to develop algorithms for PHE and ACE.

    METHODS AND RESULTS:

    In two Dutch anticoagulation clinics, data on age, sex, height, weight, co-medication, coumarin derivative doses, and international normalized ratio values were obtained from 624 patients taking PHE and 471 taking ACE. Single nucleotide polymorphisms relevant to coumarin derivative dosing on the CYP2C9 and VKORC1 genes were determined. Using multiple linear regression, we developed genotype-guided and non-genotype-guided algorithms to predict the maintenance dose with patient characteristics and genetic information. In addition, loading doses were derived from the calculated maintenance doses. We performed external validation in an independent data set with 229 PHE and 168 ACE users. CYP2C9 and VKORC1 genotype, weight, height, sex, age, and amiodarone use contributed to the maintenance dose of PHE and ACE. The genotype-guided algorithms explained 55.9% (PHE) and 52.6% (ACE) of the variance of the maintenance dose, the non-genetic algorithms 17.3% (PHE) and 23.7% (ACE). Validation in an independent data set resulted in an explained variation of 59.4% (PHE) and 49.0% (ACE) for the genotype-guided algorithms and for 23.5% (PHE) and 17.8% (ACE) for the non-genotype-guided algorithms, without height and weight as parameters.

    CONCLUSION:

    To our knowledge, these are the first genotype-guided loading and maintenance dose algorithms for PHE and ACE using large cohorts. The utility of these algorithms will be tested in randomized controlled trials.

  • 397.
    Vasaitis, Lilian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Theander, E
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Smedby, K E
    Askling, J
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Comparison of patients with and without pre-existing lymphoma at diagnosis of primary Sjögren's syndrome2019Inngår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 48, nr 3, s. 207-212Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: In the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome (pSS), pre-existing lymphoma is not an exclusion criterion for pSS diagnosis, as in earlier criteria. We aimed to explore whether there are differences between pSS patients with and without pre-existing lymphoma at pSS diagnosis.

    METHOD: Patients with ICD-7-10 codes for Sjögren's syndrome (SS) and a diagnosis of malignant lymphoma before or after SS diagnosis were identified by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007 (n = 224). Clinical data were collected from medical records. Lymphoma diagnoses were evaluated by tissue review. Characteristics of pSS patients with and without pre-existing lymphoma were compared.

    RESULTS: We identified 107 patients with pSS as the reason for an SS diagnosis code and a verified lymphoma. Of these, 18 (17%) had a pre-existing lymphoma at pSS diagnosis, defined as lymphoma diagnosed before or within 6 months of pSS diagnosis. Male gender (39% vs 10%, p = 0.006), enlarged lymph nodes during the pSS disease (61% vs 27%, p = 0.01), mucosa-associated lymphoid tissue (MALT) lymphoma (50% vs 22%, p = 0.02), and salivary gland lymphoma (61% vs 26%, p = 0.006) were more common in patients with a pre-existing lymphoma at pSS diagnosis. Other pSS characteristics were similar.

    CONCLUSION: In a substantial proportion of patients, particularly in men, pSS remains undiagnosed until after lymphoma diagnosis. The study highlights the importance of pSS investigation in patients with lymphoma, especially MALT lymphoma, in the salivary glands.

    Fulltekst (pdf)
    fulltext
  • 398.
    Vasaitis, Lilian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sporadic occurrence of non-diagnosed IgG4-related disease in lymphoma patients with a previous Sjögren's syndrome diagnosis.2016Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, nr 9-10, s. 1139-1144Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disorder, which may affect many organs, and often comes to clinical attention due to tumor-like organ swelling or is identified incidentally by specific biopsy findings. Typical histopathology of IgG4-RD is lymphoplasmacytic infiltration rich in IgG4 + plasma cells (PCs), storiform fibrosis, and obliterative phlebitis. Patients with sicca symptoms can be misdiagnosed as primary Sjögren's syndrome (pSS) instead of IgG4-RD because of clinical and histopathological similarities. Moreover, an association with lymphoma development is described in both diseases. This study investigated signs of IgG4-RD in a population-based cohort of patients diagnosed with pSS complicated by lymphoma.

    METHODS: Patients with pSS and lymphoma diagnoses and available lymphoma specimens were identified by linkage with the Swedish Patient Register 1964-2007 and the Cancer Register 1990-2007 (n = 79). Clinical data and lymphomas were reviewed and the diagnoses evaluated. All lymphoma tissues and available minor salivary gland biopsies (n = 11) were immunostained for IgG4 + PCs and evaluated for other histopathological signs of IgG4-RD. In a case with specific findings of IgG4-RD, other available tissue specimens of the same patient were investigated for IgG4-RD.

    RESULTS: Only one patient of 79 (1.3%) had >10 IgG4 + PCs/high power field (HPF) in the lymphoma tissue, an unspecified low-grade B-cell lymphoma localized in the submandibular gland. This patient also had other histopathological features of IgG4-RD in the lymphoma and a surgical lung biopsy taken five years before lymphoma diagnosis and, therefore, fulfilled the criteria for IgG4-RD. Occasional IgG4 + PCs (<10/HPF) without signs of IgG4-RD were observed in another six lymphomas. No IgG4 + PCs were identified in the minor salivary gland biopsies.

    CONCLUSION: Histopathological findings of IgG4-RD may co-exist with low malignant B-cell lymphoma in patients with initially suspected pSS and may be associated with an underlying IgG4-RD.

  • 399.
    Velickaite, Vilma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ström, K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Pathology Uppsala University Hospital, Uppsala, Sweden..
    Zetterberg, H
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Molndal, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden.; UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London, England.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Kilander, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Cognitive function in very old men does not correlate to biomarkers of Alzheimer's disease2017Inngår i: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 17, nr 1, artikkel-id 208Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The Alzheimer's disease (AD) brain displays atrophy with amyloid-β (Aβ) and tau deposition, whereas decreased Aβ42 and increased tau are measured in cerebrospinal fluid (CSF). The aim of this study was to relate cognitive performance to the degree of brain atrophy, CSF biomarker levels and neuropathology in a cohort of aged men.

    METHODS: Fifty-eight 86-92-year-old men from the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort underwent cognitive testing, brain computed tomography and lumbar puncture. Atrophy was graded with established scales. Concentrations of CSF Aβ42, t-tau and p-tau were measured by ELISA. Thirteen brains were examined post mortem.

    RESULTS: Forty-six of the individuals were considered non-demented, whereas twelve were diagnosed with dementia, either at baseline (n = 4) or during follow-up (n = 8). When comparing subjects with and without dementia, there were no differences in the degree of atrophy, although the mini mental state examination (MMSE) scoring correlated weakly with the degree of medial temporal atrophy (MTA) (p = 0.04). Moreover, the CSF biomarker levels did not differ significantly between healthy (n = 27) and demented (n = 8) subjects (median values 715 vs 472 pg/ml for Aβ42, 414 vs 427 pg/ml for t-tau and 63 vs 60 pg/ml for p-tau). Similarly, there were no differences in the biomarker levels between individuals with mild (n = 24) and severe (n = 11) MTA (median values 643 vs 715 pg/ml for Aβ42, 441 vs 401 pg/ml for t-tau and 64 vs 53 pg/ml for p-tau). Finally, the neuropathological changes did not correlate with any of the other measures.

    CONCLUSION: In this cohort of aged men only a weak correlation could be seen between cognitive performance and MTA, whereas the various neuroradiological, biochemical and neuropathological measures did not correlate with each other. Thus, AD biomarkers seem to be less informative in subjects of an advanced age.

    Fulltekst (pdf)
    fulltext
  • 400. Verhoef, Talitha I
    et al.
    Redekop, William K
    Darba, Josep
    Geitona, Mary
    Hughes, Dyfrig A
    Siebert, Uwe
    de Boer, Anthonius
    Maitland-van der Zee, Anke-Hilse
    Barallon, Rita
    Briz, Montserrat
    Daly, Ann
    Haschke-Becher, Elisabeth
    Kamali, Farhad
    Kirchheiner, Julia
    Manolopoulos, Vangelis G
    Pirmohamed, Munir
    Rosendaal, Frits R
    van Schie, Rianne M F
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    A systematic review of cost-effectiveness analyses of pharmacogenetic-guided dosing in treatment with coumarin derivatives.2010Inngår i: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 11, nr 7, s. 989-1002Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Anticoagulant therapy with coumarin derivatives is often sub- or supra-therapeutic, resulting in an increased risk of thromboembolic events or hemorrhage, respectively. Pharmacogenetic-guided dosing has been proposed as an effective way of reducing bleeding rates. Clinical trials to confirm the safety, efficacy and effectiveness of this strategy are ongoing, but in addition, it is also necessary to consider the cost-effectiveness of this strategy. This article describes the findings of a systematic review of published cost-effectiveness analyses of pharmacogenetic-guided dosing of coumarin derivatives. Similarities and differences in the approaches used were examined and the quality of the analyses was assessed. The results of the analyses are not sufficient to determine whether or not pharmacogenetic-guided dosing of coumarins is cost effective. More reliable cost-effectiveness estimates need to become available before it is possible to recommend whether or not this strategy should be applied in clinical practice.

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