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  • 1.
    Ali, Zaheer
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Mukwaya, Anthonny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Biesemeier, Antje
    Univ Tubingen, Germany.
    Ntzouni, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ramskold, Daniel
    Karolinska Inst, Sweden.
    Giatrellis, Sarantis
    Karolinska Inst, Sweden.
    Mammadzada, Parviz
    Karolinska Inst, Sweden.
    Cao, Renhai
    Karolinska Inst, Sweden.
    Lennikov, Anton
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Univ Missouri, MO 65211 USA.
    Marass, Michele
    Max Planck Inst Lung and Heart Res, Germany.
    Gerri, Claudia
    Max Planck Inst Lung and Heart Res, Germany.
    Hildesjö, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Taylor, Michael
    Univ Wisconsin, WI 53706 USA.
    Deng, Qiaolin
    Karolinska Inst, Sweden.
    Peebo, Beatrice
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Bayer AB, Sweden.
    del Peso, Luis
    Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain.
    Kvanta, Anders
    Karolinska Inst, Sweden.
    Sandberg, Rickard
    Karolinska Inst, Sweden.
    Schraermeyer, Ulrich
    Univ Tubingen, Germany.
    Andre, Helder
    Karolinska Inst, Sweden.
    Steffensen, John F.
    Univ Copenhagen, Denmark.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Cao, Yihai
    Karolinska Inst, Sweden.
    Kele, Julianna
    Karolinska Inst, Sweden.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Univ Autonoma Madrid, Spain; UAM, Spain.
    Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization2019In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 39, no 7, p. 1402-1418Article in journal (Refereed)
    Abstract [en]

    Objective—

    Pathological neovascularization is crucial for progression and morbidity of serious diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. While mechanisms of ongoing pathological neovascularization have been extensively studied, the initiating pathological vascular remodeling (PVR) events, which precede neovascularization remains poorly understood. Here, we identify novel molecular and cellular mechanisms of preneovascular PVR, by using the adult choriocapillaris as a model.

    Approach and Results—

    Using hypoxia or forced overexpression of VEGF (vascular endothelial growth factor) in the subretinal space to induce PVR in zebrafish and rats respectively, and by analyzing choriocapillaris membranes adjacent to choroidal neovascular lesions from age-related macular degeneration patients, we show that the choriocapillaris undergo robust induction of vascular intussusception and permeability at preneovascular stages of PVR. This PVR response included endothelial cell proliferation, formation of endothelial luminal processes, extensive vesiculation and thickening of the endothelium, degradation of collagen fibers, and splitting of existing extravascular columns. RNA-sequencing established a role for endothelial tight junction disruption, cytoskeletal remodeling, vesicle- and cilium biogenesis in this process. Mechanistically, using genetic gain- and loss-of-function zebrafish models and analysis of primary human choriocapillaris endothelial cells, we determined that HIF (hypoxia-induced factor)-1α-VEGF-A-VEGFR2 signaling was important for hypoxia-induced PVR.

    Conclusions—

    Our findings reveal that PVR involving intussusception and splitting of extravascular columns, endothelial proliferation, vesiculation, fenestration, and thickening is induced before neovascularization, suggesting that identifying and targeting these processes may prevent development of advanced neovascular disease in the future.

    Visual Overview—

    An online visual overview is available for this article.

  • 2.
    Aljabery, Firas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Jahnson, Staffan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Shabo, Ivan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    M2-macrophage infiltration and macrophage traits of tumor cells in urinary bladder cancer2018In: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 36, no 4, article id 159.e19Article in journal (Refereed)
    Abstract [en]

    Background

    Tumor-associated macrophages (TAMs) constitute a subset of nonneoplastic cells in tumor stroma and influence cancer progression in solid tumors. The clinical significance of TAMs in urinary bladder cancer(UBC) is controversial.

    Methods

    We prospectively studied 103 patients with stage pT1–T4 UBC treated with cystectomy and pelvic lymph node dissection. Tumor sections were immunostained with M2-specific macrophage marker CD163 and proliferation marker Ki-67. The expression of these markers in cancer cells as well as macrophage infiltration (MI) in tumor stroma was analyzed in relation to clinical data and outcome.

    Results

    The mean rate of CD163 and Ki-67 expressed by cancer cells were 35% and 78%, respectively. With borderline significance, MI was associated with lower rate of lymph node metastasis (P = 0.06). CD163 expression in cancer cells was proportional to MI (P<0.014). Patients with CD163-positive tumors and strong MI had significantly longer cancer-specific survival (CSS) (76 months), compared to patient with CD163-positive tumors and weak MI (28 months) (P = 0.02).

    Conclusions

    M2-specific MI tends to be inversely correlated with LN metastasis and improved CSS in UBC. MI might have protective impact in CD163-positive tumors. Expression of CD163 in cancer cells is significantly correlated with MI and might have a tumor promoting impact.

  • 3.
    Aljabery, Firas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Shabo, Ivan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Jahnson, Staffan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    The expression profile of p14, p53 and p21 in tumour cells is associated with disease-specific survival and the outcome of postoperative chemotherapy treatment in muscle-invasive bladder cancer2018In: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 36, no 12, p. 530.e7-530.e18, article id 530.e7Article in journal (Refereed)
    Abstract [en]

    Purpose: We investigated the effects of alterations in the biological markers p14, p53, p21, and p16 in relation to tumour cell proliferation, T-category, N- category, lymphovascular invasion, and the ability to predict prognosis in patients with muscle-invasive bladder cancer (MIBC) treated with cystectomy and, if applicable, chemotherapy.

    Materials and methods: We prospectively studied patients with urinary bladder cancer pathological stage pT1 to pT4 treated with cystectomy, pelvic lymph node dissection and postoperative chemotherapy. Tissue microarrays from paraffin-embedded cystectomy tumour samples were examined for expression of immunostaining of p14, p53, p21, p16 and Ki-67 in relation to other clinical and pathological factors as well as cancer-specific survival.

    Results: The median age of the 110 patients was 70 years (range 51-87 years), and 85 (77%) were male. Pathological staging was pT1 to pT2 (organ-confined) in 28 (25%) patients and pT3 to pT4 (non-organ-confined) in 82 (75%) patients. Lymph node metastases were found in 47 patients (43%). P14 expression was more common in tumours with higher T-stages (P = 0.05). The expression of p14 in p53 negative tumours was associated with a significantly shorter survival time (P=0.003). Independently of p53 expression, p14 expression was associated with an impaired response to chemotherapy (P=0.001). The expression of p21 in p53 negative tumours was associated with significantly decrease levels of tumour cell proliferation detected as Ki-67 expression (P=0.03).

    Conclusions: The simultaneous expression of the senescence markers involved in the p53-pathway shows a more relevant correlation to the pathological outcome of MIBC than each protein separately. P14 expression in tumours with non-altered (p53-) tumours is associated with poor prognosis. P14 expression is associated with impaired response to chemotherapy. P21 expression is related to decreased tumour cell proliferation.

  • 4.
    Aljabery, Firas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Shabo, Ivan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Department of Breast and Endocrine Surgery, Karolinska University Hospital, Solna Stockholm, Sweden .
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Jahnson, Staffan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology.
    Radio-guided sentinel lymph node detection and lymph node mapping in invasive urinary bladder cancer: a prospective clinical study.2017In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 120, no 3, p. 329-336Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To investigate the possibility of detecting sentinel lymph nodes (SNs) in patients with urinary bladder cancer (BCa) intra-operatively and whether the histopathological status of the identified SNs reflected that of the lymphatic field.

    PATIENTS AND METHODS: We studied 103 patients with BCa pathological stage T1-T4 who were treated with cystectomy and pelvic lymph node (LN) dissection during 2005-2011 at the Department of Urology, Linköping University Hospital. Radioactive tracer Nanocoll 70 MBq and blue dye were injected into the bladder wall around the primary tumour before surgery. SNs were detected ex vivo during the operation with a handheld Geiger probe (Gamma Detection System; Neoprobe Corp., Dublin, OH, USA). All LNs were formalin-fixed, sectioned three times, mounted on slides and stained with haematoxylin and eosin. An experienced uropathologist evaluated the slides.

    RESULTS: The mean age of the patients was 69 years, and 80 (77%) were male. Pathological staging was T1-12 (12%), T2-20 (19%), T3-48 (47%) and T4-23 (22%). A mean (range) number of 31 (7-68) nodes per patient were examined, totalling 3 253 nodes. LN metastases were found in 41 patients (40%). SNs were detected in 83 of the 103 patients (80%). Sensitivity and specificity for detecting metastatic disease by SN biopsy (SNB) varied between LN stations, with average values of 67% and 90%, respectively. LN metastatic density (LNMD) had a significant prognostic impact; a value of ≥8% was significantly related to shorter survival. Lymphovascular invasion (LVI) occurred in 65% of patients (n = 67) and was significantly associated with shorter cancer-specific survival (P < 0.001).

    CONCLUSION: We conclude that SNB is not a reliable technique for peri-operative localization of LN metastases during cystectomy for BCa; however, LNMD has a significant prognostic value in BCa and may be useful in the clinical context and in BCa oncological and surgical research. LVI was also found to be a prognostic factor.

  • 5.
    Alkaissi, Hammoudi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Havarinasab, Said
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Nielsen, Jesper Bo
    Univ Southern Denmark, Denmark.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 7, article id e0199979Article in journal (Refereed)
    Abstract [en]

    Systemic autoimmune rheumatic disorders (SARD) represent important causes of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Mercury-induced autoimmunity (HgIA) in mice is an established model to study the mechanisms of the development of antinuclear antibodies (ANA), which is a hallmark in the diagnosis of SARD. A.SW mice with HgIA show a significantly higher titer of antinucleolar antibodies (ANoA) than the B10.S mice, although both share the same MHC class II (H-2). We applied a genome-wide association study (GWAS) to their Hg-exposed F2 offspring to investigate the non-MHC genes involved in the development of ANoA. Quantitative trait locus (QTL) analysis showed a peak logarithm of odds ratio (LOD) score of 3.05 on chromosome 3. Microsatellites were used for haplotyping, and fine mapping was conducted with next generation sequencing. The candidate genes Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkbl (nuclear factor kappa B subunit 1) were identified by additional QTL analysis. Expression of the Bank1 and Nfkb1 genes and their downstream target genes involved in the intracellular pathway (Tlr9,II6, Tnf) was investigated in mercury-exposed A.SW and B10.S mice by real-time PCR. Bank1 showed significantly lower gene expression in the A.SW strain after Hg-exposure, whereas the B10.S strain showed no significant difference. Nfkb1, Tlr9, II6 and Tnf had significantly higher gene expression in the A.SW strain after Hg-exposure, while the B10.S strain showed no difference. This study supports the roles of Bank1 (produced mainly in B-cells) and Nfkbl (produced in most immune cells) as key regulators of ANoA development in HgIA.

  • 6.
    Ansell - Schultz, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Reyes, Juan
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Samuelsson, My
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Reduced retromer function results in the accumulation of amyloid-beta oligomers2018In: Molecular and Cellular Probes, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 93, p. 18-26Article in journal (Refereed)
    Abstract [en]

    Alzheimers disease (AD) is a neurodegenerative disorder characterized by a progressive loss of multiple cognitive functions. Accumulation of amyloid beta oligomers (oA beta) play a major role in the neurotoxicity associated with the disease process. One of the early affected brain regions is the hippocampus, wherein a reduction of the vacuolar protein sorting-associated protein 35 (VPS35), the core protein comprising the retromer complex involved in cellular cargo sorting, has been identified. To investigate the role of the retromer function on the accumulation and clearance of oA beta, we reduced retromer function by selectively inhibiting VPS35 gene expression using siRNA in differentiated neuronal SH-SY5Y cells. As cell-to-cell transfer of oA beta to new brain regions is believed to be important for disease progression we investigated the effect of VPS35 reduction both in cells with direct uptake of oA beta and in cells receiving oA beta from donor cells. We demonstrate that reduced retromer function increases oA beta accumulation in both cell systems, both the number of cells containing intracellular oA beta and the amount within them. This effect was shown at different time points and regardless if the AD originated from the extracellular milieu or via a direct neuronal cell-to-cell transfer. Interestingly, not only did reduced VPS35 cause oA beta accumulation, but oA beta treatment alone also lead to a reduction of VPS35 protein content. The accumulated oA beta seems to co-localize with VPS35 and early endosome markers. Together, these findings provide evidence that reduced retromer function decreases the ability for neurons to transport and clear neurotoxic oA beta received through different routes resulting in the accumulation of oA beta. Thus, enhancing retromer function may be a potential therapeutic strategy to slow down the pathophysiology associated with the progression of AD.

  • 7.
    Appelgren, Daniel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Knopf, Jasmin
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany.
    Bilyy, Rostyslav
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany; Danylo Halytsky Lviv Natl Med Univ, Ukraine.
    Vovk, Volodymyr
    Danylo Halytsky Lviv Natl Med Univ, Ukraine.
    Sundgren, Pia C.
    Lund Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Munoz, Luis E.
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany.
    Herrmann, Martin
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Germany.
    Höög, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Karolinska Inst, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Active NET formation in Libman-Sacks endocarditis without antiphospholipid antibodies: A dramatic onset of systemic lupus erythematosus2018In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 51, no 6, p. 310-318Article in journal (Refereed)
    Abstract [en]

    Although neutrophil extracellular traps (NETs) have been highlighted in several systemic inflammatory diseases, their clinical correlates and potential pathological role remain obscure. Herein, we describe a dramatic onset of systemic lupus erythematosus (SLE) with clear-cut pathogenic implications for neutrophils and NET formation in a young woman with cardiac (Libman-Sacks endocarditis) and central nervous system (psychosis and seizures) involvement. Despite extensive search, circulating antiphospholipid autoantibodies, a hallmark of Libman-Sacks endocarditis, could not be detected. Instead, we observed active NET formation in the tissue of the mitral valve, as well as in the circulation. Levels of NET remnants were significantly higher in serially obtained sera from the patient compared with sex-matched blood donors (p=.0011), and showed a non-significant but substantial correlation with blood neutrophil counts (r=0.65, p=.16). The specific neutrophil elastase activity measured in serum seemed to be modulated by the provided immunosuppressive treatment. In addition, we found anti-Ro60/SSA antibodies in the cerebrospinal fluid of the patient but not NET remnants or increased elastase activity. This case illustrates that different disease mechanisms mediated via autoantibodies can occur simultaneously in SLE. NET formation with release of cytotoxic NET remnants is a candidate player in the pathogenesis of this non-canonical form of Libman-Sacks endocarditis occurring in the absence of traditional antiphospholipid autoantibodies. The case description includes longitudinal results with clinical follow-up data and a discussion of the potential roles of NETs in SLE.

    The full text will be freely available from 2019-10-28 14:40
  • 8.
    Asa, Sylvia
    et al.
    Department of Pathology, University Health Network, Toronto, Ontario, Canada.
    Bodén, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Treanor, Darren
    University of Leeds, and Leeds Teaching Hospitals NHS Trust Leeds, UK.
    Lundström, Claes
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Pantatnowitz, Liron
    Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, USA.
    2020 vision of digital pathology in action2019In: Journal of Pathology Informatics, ISSN 2229-5089, E-ISSN 2153-3539, Vol. 10, no 27Article in journal (Refereed)
  • 9.
    Blockhuys, S.
    et al.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Celauro, E.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Hildesjö, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Feizi, A.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fierro-González, J.C.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Wittung-Stafshede, P.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Defining the human copper proteome and analysis of its expression variation in cancers.2017In: Metallomics : integrated biometal science, ISSN 1756-591X, Vol. 9, no 2, p. 112-123Article in journal (Refereed)
    Abstract [en]

    Copper (Cu) is essential for living organisms, and acts as a cofactor in many metabolic enzymes. To avoid the toxicity of free Cu, organisms have specific transport systems that 'chaperone' the metal to targets. Cancer progression is associated with increased cellular Cu concentrations, whereby proliferative immortality, angiogenesis and metastasis are cancer hallmarks with defined requirements for Cu. The aim of this study is to gather all known Cu-binding proteins and reveal their putative involvement in cancers using the available database resources of RNA transcript levels. Using the database along with manual curation, we identified a total of 54 Cu-binding proteins (named the human Cu proteome). Next, we retrieved RNA expression levels in cancer versus normal tissues from the TCGA database for the human Cu proteome in 18 cancer types, and noted an intricate pattern of up- and downregulation of the genes in different cancers. Hierarchical clustering in combination with bioinformatics and functional genomics analyses allowed for the prediction of cancer-related Cu-binding proteins; these were specifically inspected for the breast cancer data. Finally, for the Cu chaperone ATOX1, which is the only Cu-binding protein proposed to have transcription factor activities, we validated its predicted over-expression in patient breast cancer tissue at the protein level. This collection of Cu-binding proteins, with RNA expression patterns in different cancers, will serve as an excellent resource for mechanistic-molecular studies of Cu-dependent processes in cancer.

  • 10.
    Blockhuys, Stephanie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Chalmers University of Technology, Sweden.
    Rani Agarwal, Nisha
    Chalmers University of Technology, Sweden; McMaster University, Canada; McMaster University, Canada.
    Hildesjö, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Jarlsfelt, Ingvar
    Ryhov Hospital, Sweden.
    Wittung-Stafshede, Pernilla
    Chalmers University of Technology, Sweden.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Second harmonic generation for collagen I characterization in rectal cancer patients with and without preoperative radiotherapy2017In: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 22, no 10, article id 106006Article in journal (Refereed)
    Abstract [en]

    Rectal cancer is treated with preoperative radiotherapy (RT) to downstage the tumor, reduce local recurrence, and improve patient survival. Still, the treatment outcome varies significantly and new biomarkers are desired. Collagen I (Col-I) is a potential biomarker, which can be visualized label-free by second harmonic generation (SHG). Here, we used SHG to identify Col-I changes induced by RT in surgical tissue, with the aim to evaluate the clinical significance of RT-induced Col-I changes. First, we established a procedure for quantitative evaluation of Col-I by SHG in CDX2-stained tissue sections. Next, we evaluated Col-I properties in material from 31 non-RT and 29 RT rectal cancer patients. We discovered that the Col-I intensity and anisotropy were higher in the tumor invasive margin than in the inner tumor and normal mucosa, and RT increased and decreased the intensity in inner tumor and normal mucosa, respectively. Furthermore, higher Col-I intensity in the inner tumor was related to increased distant recurrence in the non-RT group but to longer survival in the RT group. In conclusion, we present a new application of SHG for quantitative analysis of Col-I in surgical material, and the first data suggest Col-I intensity as a putative prognostic biomarker in rectal cancer. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License.

  • 11.
    Bruhn, H.
    et al.
    Cty Hosp Ryhov, Sweden.
    Strandeus, M.
    Cty Hosp Ryhov, Sweden.
    Milos, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Lind, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Improved survival of Swedish glioblastoma patients treated according to Stupp2018In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 138, no 4, p. 332-337Article in journal (Refereed)
    Abstract [en]

    ObjectivesThe median survival in glioblastoma (GBM) patients used to be less than 1year. Surgical removal of the tumor with subsequent concomitant radiation/temozolomide (the Stupp regimen) has been shown to prolong survival. The Stupp protocol was implemented in the county of Jonkoping in 2006. The purpose of this study was to examine if the Stupp treatment has prolonged overall survival, in an unselected patient cohort with histologically verified GBM. Material and MethodThis study includes all patients from the county of Jonkoping, with a diagnosis of GBM from January 2001 to December 2012. Patients were divided into 2 cohorts, 2001-2005 and 2006-2012, that is before and after implementation of the Stupp regimen. By reviewing the medical case notes, the dates of the histological diagnosis and of death were identified. The median and mean overall survival and Kaplan-Meier survival analysis were calculated and compared between the 2 cohorts. ResultsThe mean survival was 110days longer in the cohort treated according to the Stupp regimen. Four patients in the 2006-2012 cohort and 1 patient in the 2001-2005 cohort are still alive. When comparing survival in patients with radical surgery vs biopsy, those that underwent radical surgery survived longer. The significance was slightly greater in the 2001-2005 cohort (mean 163 vs 344days, Pamp;lt;.001) than in the 2006-2012 cohort (mean 220 vs 397days, P=.02). ConclusionSurvival significantly improved after the implementation of the Stupp regimen in the study region of Sweden.

  • 12.
    Capitanio, Arrigo
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Dina, R. E.
    Imperial Coll NHS Trust, England.
    Treanor, Darren
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Leeds Teaching Hosp NHS Trust, England.
    Digital cytology: A short review of technical and methodological approaches and applications2018In: Cytopathology, ISSN 0956-5507, E-ISSN 1365-2303, Vol. 29, no 4, p. 317-325Article, review/survey (Refereed)
    Abstract [en]

    The recent years have been characterised by a rapid development of whole slide imaging (WSI) especially in its applications to histology. The application of WSI technology to cytology is less common because of technological problems related to the three-dimensional nature of cytology preparations (which requires capturing of z-stack information, with an increase in file size and usability issues in viewing cytological preparations). The aim of this study is to provide a review of the literature on the use of digital cytology and provide an overview of cytological applications of WSI in current practice as well as identifying areas for future development.

  • 13.
    Capitanio, Arrigo
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Dina, Roberto E.
    Imperial Coll NHS Trust, England.
    Treanor, Darren
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Leeds Teaching Hosp NHS Trust, England.
    Reply to Van Es et al. Digital pathology: A constant evolution2019In: Cytopathology, ISSN 0956-5507, E-ISSN 1365-2303, Vol. 30, no 2, p. 264-264Article in journal (Other academic)
    Abstract [en]

    n/a

  • 14.
    Chow, Joyce A
    et al.
    RISE Interactive Institute, Norrköping, Sweden.
    Törnros, Martin E
    Interaktiva Rum Sverige, Gothenburg, Sweden.
    Waltersson, Marie
    Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Richard, Helen
    Region Östergötland, Center for Diagnostics, Clinical pathology.
    Kusoffsky, Madeleine
    RISE Interactive Institute, Norrköping, Sweden.
    Lundström, Claes
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering. Sectra AB, Linköping, Sweden.
    Kurti, Arianit
    RISE Interactive Institute, Norrköping, Sweden.
    A Design Study Investigating Augmented Reality and Photograph Annotation in a Digitalized Grossing Workstation2017In: Journal of Pathology Informatics, ISSN 2229-5089, E-ISSN 2153-3539, Vol. 8, no 31Article in journal (Refereed)
    Abstract [en]

    Context: Within digital pathology, digitalization of the grossing procedure has been relatively underexplored in comparison to digitalization of pathology slides. 

    Aims: Our investigation focuses on the interaction design of an augmented reality gross pathology workstation and refining the interface so that information and visualizations are easily recorded and displayed in a thoughtful view. 

    Settings and Design: The work in this project occurred in two phases: the first phase focused on implementation of an augmented reality grossing workstation prototype while the second phase focused on the implementation of an incremental prototype in parallel with a deeper design study. 

    Subjects and Methods: Our research institute focused on an experimental and “designerly” approach to create a digital gross pathology prototype as opposed to focusing on developing a system for immediate clinical deployment. 

    Statistical Analysis Used: Evaluation has not been limited to user tests and interviews, but rather key insights were uncovered through design methods such as “rapid ethnography” and “conversation with materials”. 

    Results: We developed an augmented reality enhanced digital grossing station prototype to assist pathology technicians in capturing data during examination. The prototype uses a magnetically tracked scalpel to annotate planned cuts and dimensions onto photographs taken of the work surface. This article focuses on the use of qualitative design methods to evaluate and refine the prototype. Our aims were to build on the strengths of the prototype's technology, improve the ergonomics of the digital/physical workstation by considering numerous alternative design directions, and to consider the effects of digitalization on personnel and the pathology diagnostics information flow from a wider perspective. A proposed interface design allows the pathology technician to place images in relation to its orientation, annotate directly on the image, and create linked information. 

    Conclusions: The augmented reality magnetically tracked scalpel reduces tool switching though limitations in today's augmented reality technology fall short of creating an ideal immersive workflow by requiring the use of a monitor. While this technology catches up, we recommend focusing efforts on enabling the easy creation of layered, complex reports, linking, and viewing information across systems. Reflecting upon our results, we argue for digitalization to focus not only on how to record increasing amounts of data but also how these data can be accessed in a more thoughtful way that draws upon the expertise and creativity of pathology professionals using the systems.

  • 15.
    Clarke, Emily L.
    et al.
    Univ Leeds, England; Leeds Teaching Hosp NHS Trust, England.
    Revie, Craig
    FFEI Ltd, England.
    Brettle, David
    Leeds Teaching Hosp NHS Trust, England.
    Shires, Michael
    Univ Leeds, England.
    Jackson, Peter
    Leeds Teaching Hosp NHS Trust, England.
    Cochrane, Ravinder
    FFEI Ltd, England.
    Wilson, Robert
    FFEI Ltd, England.
    Mello-Thoms, Claudia
    Univ Sydney, Australia.
    Treanor, Darren
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Clinical pathology. Univ Leeds, England; Leeds Teaching Hosp NHS Trust, England.
    Development of a novel tissue-mimicking color calibration slide for digital microscopy2018In: Color Research and Application, ISSN 0361-2317, E-ISSN 1520-6378, Vol. 43, no 2, p. 184-197Article in journal (Refereed)
    Abstract [en]

    Digital microscopy produces high resolution digital images of pathology slides. Because no acceptable and effective control of color reproduction exists in this domain, there is significant variability in color reproduction of whole slide images. Guidance from international bodies and regulators highlights the need for color standardization. To address this issue, we systematically measured and analyzed the spectra of histopathological stains. This information was used to design a unique color calibration slide utilizing real stains and a tissue-like substrate, which can be stained to produce the same spectral response as tissue. By closely mimicking the colors in stained tissue, our target can provide more accurate color representation than film-based targets, whilst avoiding the known limitations of using actual tissue. The application of the color calibration slide in the clinical setting was assessed by conducting a pilot user-evaluation experiment with promising results. With the imminent integration of digital pathology into the routine work of the diagnostic pathologist, it is hoped that this color calibration slide will help provide a universal color standard for digital microscopy thereby ensuring better and safer healthcare delivery.

  • 16.
    Dessauvagie, Benjamin F.
    et al.
    Leeds Teaching Hosp NHS Trust, England; Univ Leeds, England; Fiona Stanley Hosp, Australia; Univ Western Australia, Australia; Univ Western Australia, Australia.
    Lee, Andrew H. S.
    Nottingham Univ Hosp NHS Trust, England.
    Meehan, Katie
    Univ Western Australia, Australia; Univ Western Australia, Australia.
    Nijhawan, Anju
    Leeds Teaching Hosp NHS Trust, England.
    Tan, Puay Hoon
    Singapore Gen Hosp, Singapore.
    Thomas, Jeremy
    Western Gen Hosp, Scotland.
    Tie, Bibiana
    Fiona Stanley Hosp, Australia.
    Treanor, Darren
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Leeds Teaching Hosp NHS Trust, England; Univ Leeds, England.
    Umar, Seemeen
    Leeds Teaching Hosp NHS Trust, England.
    Hanby, Andrew M.
    Leeds Teaching Hosp NHS Trust, England; Univ Leeds, England.
    Millican-Slater, Rebecca
    Leeds Teaching Hosp NHS Trust, England.
    Interobserver variation in the diagnosis of fibroepithelial lesions of the breast: a multicentre audit by digital pathology2018In: Journal of Clinical Pathology, ISSN 0021-9746, E-ISSN 1472-4146, Vol. 71, no 8, p. 672-679Article in journal (Refereed)
    Abstract [en]

    Aim Fibroepithelial lesions (FELs) of the breast span a morphological continuum including lesions where distinction between cellular fibroadenoma (FA) and benign phyllodes tumour (PT) is difficult. The distinction is clinically important with FAs managed conservatively while equivocal lesions and PTs are managed with surgery. We sought to audit core biopsy diagnoses of equivocal FELs by digital pathology and to investigate whether digital point counting is useful in clarifying FEL diagnoses. Method Scanned slide images from cores and subsequent excisions of 69 equivocal FELs were examined in a multicentre audit by eight pathologists to determine the agreement and accuracy of core needle biopsy (CNB) diagnoses and by digital point counting of stromal cellularity and expansion to determine if classification could be improved. Results Interobserver variation was high on CNB with a unanimous diagnosis from all pathologists in only eight cases of FA, diagnoses of both FA and PT on the same CNB in 15 and a weak mean kappa agreement between pathologists (k=0.36). Moderate agreement was observed on CNBs among breast specialists (k=0.44) and on excision samples (k=0.49). Up to 23% of lesions confidently diagnosed as FA on CNB were PT on excision and up to 30% of lesions confidently diagnosed as PT on CNB were FA on excision. Digital point counting did not aid in the classification of FELs. Conclusion Accurate and reproducible diagnosis of equivocal FELs is difficult, particularly on CNB, resulting in poor interobserver agreement and suboptimal accuracy. Given the diagnostic difficulty, and surgical implications, equivocal FELs should be reported in consultation with experienced breast pathologists as a small number of benign FAs can be selected out from equivocal lesions.

  • 17.
    Forsgren, Mikael
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Karlsson, Markus
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dahlström, Nils
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Norén, Bengt
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Romu, Thobias
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Ekstedt, Mattias
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Lundberg, Peter
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Cedersund, Gunnar
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Model-inferred mechanisms of liver function from magnetic resonance imaging data: Validation and variation across a clinically relevant cohort2019In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, PLOS COMPUTATIONAL BIOLOGY, Vol. 15, no 6, article id e1007157Article in journal (Refereed)
    Abstract [en]

    Estimation of liver function is important to monitor progression of chronic liver disease (CLD). A promising method is magnetic resonance imaging (MRI) combined with gadoxetate, a liver-specific contrast agent. For this method, we have previously developed a model for an average healthy human. Herein, we extended this model, by combining it with a patient-specific non-linear mixed-effects modeling framework. We validated the model by recruiting 100 patients with CLD of varying severity and etiologies. The model explained all MRI data and adequately predicted both timepoints saved for validation and gadoxetate concentrations in both plasma and biopsies. The validated model provides a new and deeper look into how the mechanisms of liver function vary across a wide variety of liver diseases. The basic mechanisms remain the same, but increasing fibrosis reduces uptake and increases excretion of gadoxetate. These mechanisms are shared across many liver functions and can now be estimated from standard clinical images.

    Author summary

    Being able to accurately and reliably estimate liver function is important when monitoring the progression of patients with liver disease, as well as when identifying drug-induced liver injury during drug development. A promising method for quantifying liver function is to use magnetic resonance imaging combined with gadoxetate. Gadoxetate is a liver-specific contrast agent, which is taken up by the hepatocytes and excreted into the bile. We have previously developed a mechanistic model for gadoxetate dynamics using averaged data from healthy volunteers. In this work, we extended our model with a non-linear mixed-effects modeling framework to give patient-specific estimates of the gadoxetate transport-rates. We validated the model by recruiting 100 patients with liver disease, covering a range of severity and etiologies. All patients underwent an MRI-examination and provided both blood and liver biopsies. Our validated model provides a new and deeper look into how the mechanisms of liver function varies across a wide variety of liver diseases. The basic mechanisms remain the same, but increasing fibrosis reduces uptake and increases excretion of gadoxetate.

  • 18.
    Fotouhi, Omid
    et al.
    German Cancer Consortium (DKTK) partner site Freiburg, German Cancer Research Center (DKFZ) and Department of Urology, Medical Center-University of Freiburg, Germany.
    Zedenius, Jan
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Breast and Endocrine Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Höög, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Juhlin, Carl Christofer
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Regional differences in somatostatin receptor 2 (SSTR2) immunoreactivity is coupled to level of bowel invasion in small intestinal neuroendocrine tumors2018In: Neuro - endocrinology letters, ISSN 0172-780X, Vol. 39, no 4, p. 305-309Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Somatostatin receptor (SSTR) expression constitutes a pivotal cornerstone for accurate radiological detection and medical treatment of small intestinal neuroendocrine tumors (SI-NETs), and the development of somatostatin analogues for these purposes have revolutionized the clinical work-up. Previous assessments of SSTR isoform expression in SI-NETs have found correlations to overall prognosis and treatment response, however these analyses usually report overall tumoral immunoreactivity, and little is reported regarding histo-regional differences in expressional patterns.

    METHODS: Thirty-seven primary SI-NETs (WHO grade I, n=32 and WHO grade II, n=5) were collected and assessed for SSTR2 immunohistochemistry. Samples were stratified with regards to histological level of bowel infiltration and spread (mucosal region, muscularis propria region, subserosal region) and each of these tumoral regions was separately scored by SSTR2 staining localization (membrane, cytoplasmic), overall staining intensity and local staining differences within each region.

    RESULTS: SSTR2 immunoreactivity was progressively weaker as the tumor cells advanced through the small intestinal layers. This was exemplified by a reduction in the amount of tumor samples with strong SSTR2 expression in the deeper histological levels of the section; 56% of tumors displayed strong SSTR2 expression in the mucosal region, as compared to 29% and 30% of tumors within muscularis propria and subserosal layers, respectively.

    CONCLUSIONS: This observation indicates a down-regulation of SSTR2 expression as the tumors progress through the intestinal wall, which might signify underlying biological processes of importance for SI-NET invasion behavior.

  • 19.
    Garvin, Stina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Oda, Husam
    Cty Hosp Ryhov, Sweden; Umea Univ, Sweden.
    Arnesson, Lars-Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Lindström, Annelie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Shabo, Ivan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Tumor cell expression of CD163 is associated to postoperative radiotherapy and poor prognosis in patients with breast cancer treated with breast-conserving surgery2018In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 144, no 7, p. 1253-1263Article in journal (Refereed)
    Abstract [en]

    Cancer cell fusion with macrophages results in highly tumorigenic hybrids that acquire genetic and phenotypic characteristics from both maternal cells. Macrophage traits, exemplified by CD163 expression, in tumor cells are associated with advanced stages and poor prognosis in breast cancer (BC). In vitro data suggest that cancer cells expressing CD163 acquire radioresistance. Tissue microarray was constructed from primary BC obtained from 83 patients treated with breast-conserving surgery, 50% having received postoperative radiotherapy (RT) and none of the patients had lymph node or distant metastasis. Immunostaining of CD163 in cancer cells and macrophage infiltration (MI) in tumor stroma were evaluated. Macrophage:MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation (0, 2.5 and 5 Gy gamma-radiation), both hybrids and their maternal MCF-7 cells were examined by clonogenic survival. CD163-expression by cancer cells was significantly associated with MI and clinicopathological data. Patients with CD163-positive tumors had significantly shorter disease-free survival (DFS) after RT. In vitro generated macrophage:MCF-7 hybrids developed radioresistance and exhibited better survival and colony forming ability after radiation compared to maternal MCF-7 cancer cells. Our results suggest that macrophage phenotype in tumor cells results in radioresistance in breast cancer and shorter DFS after radiotherapy.

  • 20.
    Geessink, Oscar G. F.
    et al.
    Radboud Univ Nijmegen, Netherlands; Radboud Univ Nijmegen, Netherlands; Lab Pathol East Netherlands LabPON, Netherlands.
    Baidoshvili, Alexi
    Lab Pathol East Netherlands LabPON, Netherlands.
    Klaase, Joost M.
    Medisch Spectrum Twente, Netherlands.
    Bejnordi, Babak Ehteshami
    Radboud Univ Nijmegen, Netherlands.
    Litjens, Geert J. S.
    Radboud Univ Nijmegen, Netherlands.
    van Pelt, Gabi W.
    Leiden Univ, Netherlands.
    Mesker, Wilma E.
    Leiden Univ, Netherlands.
    Nagtegaal, Iris D.
    Radboud Univ Nijmegen, Netherlands.
    Ciompi, Francesco
    Radboud Univ Nijmegen, Netherlands.
    van der Laak, Jeroen
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Radboud Univ Nijmegen, Netherlands.
    Computer aided quantification of intratumoral stroma yields an independent prognosticator in rectal cancer2019In: Cellular Oncology, ISSN 2211-3428, E-ISSN 2211-3436, Vol. 42, no 3, p. 331-341Article in journal (Refereed)
    Abstract [en]

    PurposeTumor-stroma ratio (TSR) serves as an independent prognostic factor in colorectal cancer and other solid malignancies. The recent introduction of digital pathology in routine tissue diagnostics holds opportunities for automated TSR analysis. We investigated the potential of computer-aided quantification of intratumoral stroma in rectal cancer whole-slide images.MethodsHistological slides from 129 rectal adenocarcinoma patients were analyzed by two experts who selected a suitable stroma hot-spot and visually assessed TSR. A semi-automatic method based on deep learning was trained to segment all relevant tissue types in rectal cancer histology and subsequently applied to the hot-spots provided by the experts. Patients were assigned to a stroma-high or stroma-low group by both TSR methods (visual and automated). This allowed for prognostic comparison between the two methods in terms of disease-specific and disease-free survival times.ResultsWith stroma-low as baseline, automated TSR was found to be prognostic independent of age, gender, pT-stage, lymph node status, tumor grade, and whether adjuvant therapy was given, both for disease-specific survival (hazard ratio=2.48 (95% confidence interval 1.29-4.78)) and for disease-free survival (hazard ratio=2.05 (95% confidence interval 1.11-3.78)). Visually assessed TSR did not serve as an independent prognostic factor in multivariate analysis.ConclusionsThis work shows that TSR is an independent prognosticator in rectal cancer when assessed automatically in user-provided stroma hot-spots. The deep learning-based technology presented here may be a significant aid to pathologists in routine diagnostics.

  • 21.
    Gustafsson, Gabriel
    et al.
    Uppsala Univ, Sweden.
    Loov, Camilla
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Persson, Emma
    Uppsala Univ, Sweden.
    Lazaro, Diana F.
    Univ Med Ctr Gottingen, Germany.
    Takeda, Shuko
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Bergstrom, Joakim
    Uppsala Univ, Sweden.
    Erlandsson, Anna
    Uppsala Univ, Sweden.
    Sehlin, Dag
    Uppsala Univ, Sweden.
    Balaj, Leonora
    Massachusetts Gen Hosp, MA 02129 USA; Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Gyorgy, Bence
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Outeiro, Tiago F.
    Univ Med Ctr Gottingen, Germany; Max Planck Inst Expt Med, Germany; Newcastle Univ, England.
    Breakefield, Xandra O.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Hyman, Bradley T.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Ingelsson, Martin
    Uppsala Univ, Sweden; Massachusetts Gen Hosp, MA 02129 USA; Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Secretion and Uptake of -Synuclein Via Extracellular Vesicles in Cultured Cells2018In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 38, no 8, p. 1539-1550Article in journal (Refereed)
    Abstract [en]

    In Parkinsons disease and other Lewy body disorders, the propagation of pathology has been accredited to the spreading of extracellular -synuclein (-syn). Although the pathogenic mechanisms are not fully understood, cell-to-cell transfer of -syn via exosomes and other extracellular vesicles (EVs) has been reported. Here, we investigated whether altered molecular properties of -syn can influence the distribution and secretion of -syn in human neuroblastoma cells. Different -syn variants, including -syn:hemi-Venus and disease-causing mutants, were overexpressed and EVs were isolated from the conditioned medium. Of the secreted -syn, 0.1-2% was associated with vesicles. The major part of EV -syn was attached to the outer membrane of vesicles, whereas a smaller fraction was found in their lumen. For -syn expressed with N-terminal hemi-Venus, the relative levels associated with EVs were higher than for WT -syn. Moreover, such EV-associated -syn:hemi-Venus species were internalized in recipient cells to a higher degree than the corresponding free-floating forms. Among the disease-causing mutants, A53T -syn displayed an increased association with EVs. Taken together, our data suggest that -syn species with presumably lost physiological functions or altered aggregation properties may shift the cellular processing towards vesicular secretion. Our findings thus lend further support to the tenet that EVs can mediate spreading of harmful -syn species and thereby contribute to the pathology in -synucleinopathies.

  • 22.
    Haj-Hosseini, Neda
    et al.
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Richter, Johan
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Milos, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Stereotactic Brain Tumor Optical Biopsy2018Conference paper (Other academic)
    Abstract [en]

    To provide guidance for targeting diagnostic tumor tissue and to avoid vessel rupture during the biopsy procedure an application specific fiber optic probe was devel-oped. The setup incorporated an in-house developed fluorescence spectroscopy system for 5-aminolevulinic acid (5-ALA) induced protopophyrin IX (PpIX) for detection in the tumor, and laser Doppler flowmeter (LDF) system for measurement of blood perfusion. Fluorescence and blood flow were recorded millimeter-wise towards the pre-calculated target. In conclusion, the optical probe made real-time detection of tumor possible and has a potential for vessel detection during the biopsy procedures. Moreover, the PpIX fluorescence, autofluorescence and blood flow in the tumor could be studied at precise positions in the brain and the tumor. In the next step, further anal-ysis will be added.

  • 23.
    Haj-Hosseini, Neda
    et al.
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Richter, Johan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Kobayashi Frisk, Lisa
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Milos, Peter
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Fluorescence Guidance for Brain Tumor Biopsies2018Conference paper (Refereed)
    Abstract [en]

    To provide guidance during stereotactic biopsy in brain tumors, fluorescence spectroscopy was used in ten patients. It was shown that the fiber optical probe could provide real-time guidance with clear fluorescence in all patients.

  • 24.
    Haj-Hosseini, Neda
    et al.
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Richter, Johan
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Milos, Peter
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    5-ALA fluorescence and laser Doppler flowmetry for guidance in a stereotactic brain tumor biopsy2018In: Biomedical Optics Express, E-ISSN 2156-7085, Vol. 9, no 5, p. 2284-2296Article in journal (Refereed)
    Abstract [en]

    A fiber optic probe was developed for guidance during stereotactic brain biopsy procedures to target tumor tissue and reduce the risk of hemorrhage. The probe was connected to a setup for the measurement of 5-aminolevulinic acid (5-ALA) induced fluorescence and microvascular blood flow. Along three stereotactic trajectories, fluorescence (n = 109) and laser Doppler flowmetry (LDF) (n = 144) measurements were done in millimeter increments. The recorded signals were compared to histopathology and radiology images. The median ratio of protoporphyrin IX (PpIX) fluorescence and autofluorescence (AF) in the tumor was considerably higher than the marginal zone (17.3 vs 0.9). The blood flow showed two high spots (3%) in total. The proposed setup allows simultaneous and real-time detection of tumor tissue and microvascular blood flow for tracking the vessels.

  • 25.
    Höög, Anders
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Kjellman, Magnus
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Mattsson, Per
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Juhlin, C. Christofer
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Shabo, Ivan
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Somatostatin Receptor Expression in Renal Cell Carcinoma-A New Front in the Diagnostics and Treatment of Renal Cell Carcinoma2018In: Clinical Genitourinary Cancer, ISSN 1558-7673, E-ISSN 1938-0682, Vol. 16, no 3, p. E517-E520Article in journal (Refereed)
    Abstract [en]

    Clinical Practice Points

    Renal cell carcinoma (RCC) has a poor prognosis and is difficult to treat because of its ability to spread asymptomatically and its resistance to chemotherapy.

    In this patient series, we report that RCC metastases can be identified using gallium-68 (68Ga)-edotreotide (DOTATOC) positron emission tomography/computed tomography (PET/CT).

    Immunostaining of tumor tissue from primary RCC tumors and their matched adrenal, pancreatic, and thyroid metastases showed that RCC cells express membranous somatostatin receptor 2.

    These findings indicate that 68Ga-DOTATOC PET/CT can be used as a new imaging modality in management of metastatic RCC and might contribute to the development of new somatostatin analogue-based methods for the treatment of metastatic RCC.

  • 26.
    Isaksson, Sofi
    et al.
    Lund University, Sweden.
    Jonsson, Per
    Lund University, Sweden.
    Monsef, Nastaran
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Brunnstrom, Hans
    Lund University, Sweden.
    Bendahl, Par-Ola
    Lund University, Sweden.
    Jonsson, Mats
    Lund University, Sweden.
    Staaf, Johan
    Lund University, Sweden.
    Planck, Maria
    Lund University, Sweden.
    CA 19-9 and CA 125 as potential predictors of disease recurrence in resectable lung adenocarcinoma2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 10, article id e186284Article in journal (Refereed)
    Abstract [en]

    Objectives Among patients who underwent primary surgery for non-small cell lung cancer (NSCLC), recurrent disease is frequent and cannot be accurately predicted solely from TNM stage and histopathological features. The aim of this study was to examine the association of tumor markers in pre-operative serum with recurrent disease. Material and methods Blood samples were collected prior to lung cancer surgery from 107 patients with stage I-III lung adenocarcinoma surgically treated at Lund University hospital, Lund, Sweden, between 2005 and 2011. The serum tumor markers Carcinoembryonic antigen (CEA), Neuron-specific enolase (NSE), Cancer antigen 125 (CA 125), Human epididymis protein 4 (HE4) and Carbohydrate antigen (CA 19-9) were analyzed retrospectively and clinical follow-up data were collected from patient charts. Forty (37%) patients were diagnosed with recurrent disease. Results Sixty-eight (64%) patients had at least one elevated tumor marker prior to surgery. In analysis of disease-free survival (DFS), CA 125 and/or CA 19-9 were significantly associated with recurrent disease adjusted to stage and adjuvant treatment (hazard ratio 2.8, 95% confidence interval 1.4-5.7, p = 0.006). Conclusion High pre-operative serum CA 19-9 and/or CA 125 might indicate an increased incidence of recurrent disease in resectable lung adenocarcinomas.

  • 27.
    Jedlinski, Adam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Garvin, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Johansson, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Edqvist, Per-Henrik
    Uppsala University, Uppsala, Sweden.
    Pontén, Fredrik
    Uppsala University, Uppsala, Sweden.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Cetuximab sensitivity of head and neck squamous cell carcinoma xenografts is associated with treatment-induced reduction of EGFR, pEGFR, and pSrc2017In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, no 9, p. 717-724Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of this study was to validate in vitro drug sensitivity testing of head and neck squamous cell carcinoma (HNSCC)cell lines in an in vivo xenograft model, and to identify treatment-induced changes in the EGFR signaling pathway that could be used as markersfor cetuximab treatment response.

    METHODS: The in vitro cetuximab sensitivity of two HNSCC cell lines, UT-SCC-14 and UTSCC-45, was assessed using a crystal violet assay. In order to determine the corresponding in vivo sensitivity, UT-SCC-14 and UT-SCC-45 xenografts were generated in female BALB/c (nu/nu) nude mice. Mice were given three injections of intraperitoneal cetuximab or PBS and the tumor volume was recorded continuously. The expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR (pEGFR), phosphorylated Src (pSrc), and Ki67 was investigated by immunohistochemistry.

    RESULTS: The treatment sensitive UT-SCC-14 cells were found to have an intrinsic cetuximab sensitivity (ICmabS) of 0.15 whereas the ICmabS of the insensitive cell line UT-SCC-45 was 0.78. The corresponding size ratio between untreated and cetuximab treated xenografts was 0.22 and 0.83 for UT-SCC-14 and UT-SCC-45, respectively. UT-SCC-14 cells had a higher baseline expression of pEGFR as compared to UT-SCC-45. Furthermore, in UT-SCC-14 xenografts there was a decrease in EGFR, pEGFR and pSrc upon cetuximab treatment. In contrast, a slight cetuximab-induced increase in EGFR, pEGFR and pSrc was observed in treatment-resistant UT-SCC-45 xenografts.

    CONCLUSIONS: The in vitro treatment sensitivity was reproduced in the in vivo model and cetuximab sensitivity was found to associate with a treatment-induced reduction in pEGFR and pSrc.

  • 28.
    Karlsson, Anna
    et al.
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    Cirenajwis, Helena
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    Ericson-Lindquist, Kajsa
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Department of Pathology, Regional Laboratories Region Skåne, Lund, Sweden.
    Brunnstrom, Hans
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Department of Pathology, Regional Laboratories Region Skåne, Lund, Sweden.
    Reutersward, Christel
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    Jönsson, Mats
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    Ortiz-Villalon, Cristian
    Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Hussein, Aziz
    Department of Pathology and cytology, Sahlgrenska university hospital, Gothenburg, Sweden.
    Bergman, Bengt
    Department of Respiratory Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Vikström, Anders
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Monsef, Nastaran
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Branden, Eva
    Respiratory Medicine Unit, Department of Medicine Solna and CMM, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Koyi, Hirsh
    Respiratory Medicine Unit, Department of Medicine Solna and CMM, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    de Petris, Luigi
    Thoracic Oncology Unit, Karolinska University Hospital and Department Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Patthey, Annika
    Department of Pathology, Umeå University Hospital, Umeå, Sweden.
    Behndig, Annelie F.
    Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, Umeå, Sweden.
    Johansson, Mikael
    Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
    Planck, Maria
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden; Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund, Sweden.
    Staaf, Johan
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    A combined gene expression tool for parallel histological prediction and gene fusion detection in non-small cell lung cancer2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 5207Article in journal (Refereed)
    Abstract [en]

    Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11-199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.

  • 29.
    Karlsson, Markus
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Ekstedt, Mattias
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Dahlström, Nils
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Forsgren, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Norén, Bengt
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Lundberg, Peter
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Liver R2*is affected by both iron and fat: A dual biopsy-validated study of chronic liver disease2019In: Journal of Magnetic Resonance Imaging, ISSN 1053-1807, E-ISSN 1522-2586, Vol. 50, no 1, p. 325-333Article in journal (Refereed)
    Abstract [en]

    Background Liver iron content (LIC) in chronic liver disease (CLD) is currently determined by performing an invasive liver biopsy. MRI using R2* relaxometry is a noninvasive alternative for estimating LIC. Fat accumulation in the liver, or proton density fat fraction (PDFF), may be a possible confounder of R2* measurements. Previous studies of the effect of PDFF on R2* have not used quantitative LIC measurement. Purpose To assess the associations between R2*, LIC, PDFF, and liver histology in patients with suspected CLD. Study Type Prospective. Population Eighty-one patients with suspected CLD. Field Strength/Sequence 1.5 T. Multiecho turbo field echo to quantify R2*. PRESS MRS to quantify PDFF. Assessment Each patient underwent an MR examination, followed by two needle biopsies immediately following the MR examination. The first biopsy was used for conventional histological assessment of LIC, whereas the second biopsy was used to quantitatively measure LIC using mass spectrometry. R2* was correlated with both LIC and PDFF. A correction for the influence of fat on R2* was calculated. Statistical Tests Pearson correlation, linear regression, and area under the receiver operating curve. Results There was a positive linear correlation between R2* and PDFF (R = 0.69), after removing data from patients with elevated iron levels, as defined by LIC. R2*, corrected for PDFF, was the best method for identifying patients with elevated iron levels, with a correlation of R = 0.87 and a sensitivity and specificity of 87.5% and 98.6%, respectively. Data Conclusion PDFF increases R2*. Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:325-333.

    The full text will be freely available from 2020-09-13 14:26
  • 30.
    Lindström, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Midtbö, Kristine Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Arnesson, Lars-Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Garvin, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Shabo, Ivan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Fusion between M2-macrophages and cancer cells results in a subpopulation of radioresistant cells with enhanced DNA-repair capacity2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 31, p. 51370-51386Article in journal (Refereed)
    Abstract [en]

    Cell fusion is a natural biological process in normal development and tissue regeneration. Fusion between cancer cells and macrophages results in hybrids that acquire genetic and phenotypic characteristics from both maternal cells. There is a growing body of in vitro and in vivo data indicating that this process also occurs in solid tumors and may play a significant role in tumor progression. However, investigations of the response of macrophage: cancer cell hybrids to radiotherapy have been lacking. In this study, macrophage: MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation, both hybrids and their maternal MCF-7 cells were treated with 0 Gy, 2.5 Gy and 5 Gy.-radiation and examined by clonogenic survival and comet assays at three time points (0 h, 24 h, and 48 h). Compared to maternal MCF-7 cells, the hybrids showed increased survival fraction and plating efficiency (colony formation ability) after radiation. The hybrids developed less DNA-damage, expressed significantly lower residual DNA-damage, and after higher radiation dose showed less heterogeneity in DNA-damage compared to their maternal MCF-7 cells. To our knowledge this is the first study that demonstrates that macrophage: cancer cell fusion generates a subpopulation of radioresistant cells with enhanced DNA-repair capacity. These findings provide new insight into how the cell fusion process may contribute to clonal expansion and tumor heterogeneity. Furthermore, our results provide support for cell fusion as a mechanism behind the development of radioresistance and tumor recurrence.

  • 31.
    Lundgren, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland.
    Martinsson, Klara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland.
    Cederbrant, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Södertälje, Sweden.
    Jirholt, Johan
    AstraZeneca RandD, Sweden.
    Mucs, Daniel
    Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Södertälje, Sweden.
    Madeyski-Bengtson, Katja
    AstraZeneca RandD, Sweden.
    Havarinasab, Said
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    HLA-DR7 and HLA-DQ2: Transgenic mouse strains tested as a model system for ximelagatran hepatotoxicity2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0184744Article in journal (Refereed)
    Abstract [en]

    The oral thrombin inhibitor ximelagatran was withdrawn in the late clinical trial phase because it adversely affected the liver. In approximately 8% of treated patients, drug-induced liver injury (DILI) was expressed as transient alanine transaminase (ALT) elevations. No evidence of DILI had been revealed in the pre-clinical in vivo studies. A whole genome scan study performed on the clinical study material identified a strong genetic association between the major histocompatibility complex alleles for human leucocyte antigens (HLA) (HLA-DR7 and HLA-DQ2) and elevated ALT levels in treated patients. An immunemediated pathogenesis was suggested. Here, we evaluated whether HLA transgenic mice models could be used to investigate whether the expression of relevant HLA molecules was enough to reproduce the DILI effects in humans. In silico modelling performed in this study revealed association of both ximelagatran (pro-drug) and melagatran (active drug) to the antigen-presenting groove of the homology modelled HLA-DR7 molecule suggesting "altered repertoire" as a key initiating event driving development of DILI in humans. Transgenic mouse strains (tgms) expressing HLA of serotype HLA-DR7 (HLA-DRB1*0701, -DRA*0102), and HLA-DQ2 (HLA-DQB1*0202, -DQA1*0201) were created. These two lines were crossed with a human (h) CD4 transgenic line, generating the two tgms DR7xhCD4 and DQ2xhCD4. To investigate whether the DILI effects observed in humans could be reproduced in tgms, the mice were treated for 28 days with ximelagatran. Results revealed no signs of DILI when biomarkers for liver toxicity were measured and histopathology was evaluated. In the ximelagatran case, presence of relevant HLA-expression in a preclinical model did not fulfil the prerequisite for reproducing DILI observed in patients. Nonetheless, for the first time an HLA-transgenic mouse model has been investigated for use in HLA-associated DILI induced by a low molecular weight compound. This study shows that mimicking of genetic susceptibility, expressed as DILI-associated HLA-types in mice, is not sufficient for reproducing the complex pathogenesis leading to DILI in man.

  • 32.
    Nasr, Patrik
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Forsgren, Mikael F.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV). Wolfram MathCore AB, Linköping, Sweden.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Dahlström, Nils
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Cedersund, Gunnar
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Norén, Bengt
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Ekstedt, Mattias
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Lundberg, Peter
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Using a 3% Proton Density Fat Fraction as a Cut-off Value Increases Sensitivity of Detection of Hepatic Steatosis, Based on Results from Histopathology Analysis2017In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 153, no 1, p. 53-+Article in journal (Refereed)
    Abstract [en]

    It is possible to estimate hepatic triglyceride content by calculating the proton density fat fraction (PDFF), using proton magnetic resonance spectroscopy (less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS), instead of collecting and analyzing liver biopsies to detect steatosis. However, the current PDFF cut-off value (5%) used to define steatosis by magnetic resonance was derived from studies that did not use histopathology as the reference standard. We performed a prospective study to determine the accuracy of less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS PDFF in measurement of steatosis using histopathology analysis as the standard. We collected clinical, serologic, less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS PDFF, and liver biopsy data from 94 adult patients with increased levels of liver enzymes (6 months or more) referred to the Department of Gastroenterology and Hepatology at Linköping University Hospital in Sweden from 2007 through 2014. Steatosis was graded using the conventional histopathology method and fat content was quantified in biopsy samples using stereological point counts (SPCs). We correlated less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS PDFF findings with SPCs (r = 0.92; P less than.001). less thansuperscriptgreater than1less than/superscriptgreater thanH-MRS PDFF results correlated with histopathology results (ρ = 0.87; P less than.001), and SPCs correlated with histopathology results (ρ = 0.88; P less than.001). All 25 subjects with PDFF values of 5.0% or more had steatosis based on histopathology findings (100% specificity for PDFF). However, of 69 subjects with PDFF values below 5.0% (negative result), 22 were determined to have steatosis based on histopathology findings (53% sensitivity for PDFF). Reducing the PDFF cut-off value to 3.0% identified patients with steatosis with 100% specificity and 79% sensitivity; a PDFF cut-off value of 2.0% identified patients with steatosis with 94% specificity and 87% sensitivity. These findings might be used to improve non-invasive detection of steatosis.

  • 33.
    Nasr, Patrik
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Ekstedt, Mattias
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Natural history of nonalcoholic fatty liver disease: A prospective follow-up study with serial biopsies.2018In: Hepatology communications, ISSN 2471-254X, Vol. 2, no 2, p. 199-210Article in journal (Refereed)
    Abstract [en]

    Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world. The complete natural history of NAFLD is unknown because few high-quality follow-up studies have been conducted. Our aim was to find variables predicting disease severity through an extended follow-up with serial biopsies. In a prospective cohort study, 129 patients who enrolled between 1988 and 1993 were asked to participate in a follow-up study on two occasions; biochemical, clinical, and histologic data were documented. The mean time between biopsies was 13.7 (±1.7) and 9.3 (±1.0) years, respectively. At the end of the study period, 12 patients (9.3%) had developed end-stage liver disease and 34% had advanced fibrosis. Out of the 113 patients with baseline low fibrosis (<3), 16% developed advanced fibrosis. Fibrosis progression did not differ among the different stages of baseline fibrosis (P = 0.374). Fifty-six patients (43%) had isolated steatosis, of whom 9% developed advanced fibrosis (3 patients with biopsy-proven fibrosis stage F3-F4 and 2 patients with end-stage liver disease). Fibrosis stage, ballooning, and diabetes were more common in patients who developed end-stage liver disease; however, there were no baseline clinical, histologic, or biochemical variables that predicted clinical significant disease progression. Conclusion: NAFLD is a highly heterogeneous disease, and it is surprisingly hard to predict fibrosis progression. Given enough time, NAFLD seems to have a more dismal prognosis then previously reported, with 16% of patients with fibrosis stage <3 developing advanced fibrosis and 9.3% showing signs of end-stage liver disease. (Hepatology Communications 2018;2:199-210).

  • 34.
    Nilsson, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Elander, Louise
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Örtegren (Kugelberg), Unn
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    The involvement of prostaglandin E2 in interleukin-1β evoked anorexia is strain dependent2017In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 60, p. 27-31Article in journal (Refereed)
    Abstract [en]

    From experiments in mice in which the prostaglandin E2 (PGE2) synthesizing enzyme mPGES-1 was genetically deleted, as well as from experiments in which PGE2 was injected directly into the brain, PGE2 has been implicated as a mediator of inflammatory induced anorexia. Here we aimed at examining which PGE2 receptor (EP1–4) that was critical for the anorexic response to peripherally injected interleukin-1β (IL-1β). However, deletion of neither EP receptor in mice, either globally (for EP1, EP2, and EP3) or selectively in the nervous system (EP4), had any effect on the IL-1β induced anorexia. Because these mice were all on a C57BL/6 background, whereas previous observations demonstrating a role for induced PGE2 in IL-1β evoked anorexia had been carried out on mice on a DBA/1 background, we examined the anorexic response to IL-1β in mice with deletion of mPGES-1 on a C57BL/6 background and a DBA/1 background, respectively. We confirmed previous findings that mPGES-1 knock-out mice on a DBA/1 background displayed attenuated anorexia to IL-1β; however, mice on a C57BL/6 background showed the same profound anorexia as wild type mice when carrying deletion of mPGES-1, while displaying almost normal food intake after pretreatment with a cyclooxygenase-2 inhibitor. We conclude that the involvement of induced PGE2 in IL-1β evoked anorexia is strain dependent and we suggest that different routes that probably involve distinct prostanoids exist by which inflammatory stimuli may evoke an anorexic response and that these routes may be of different importance in different strains of mice.

  • 35.
    Nyström, Sofie
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Vahdat Shariat Panahi, Aida
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Westermark, Per
    d Department of Immunology , Genetics and Pathology, Uppsala University , Uppsala , Sweden.
    Westermark, Gunilla T.
    e Department of Medical Cell Biology , Uppsala University , Uppsala , Sweden.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lundmark, Katarzyna
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Seed-dependent templating of murine AA amyloidosis2017In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, no sup1, p. 140-141Article in journal (Other academic)
    Abstract [en]

    n/a

  • 36.
    Orfanidis, Kyriakos
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology.
    Wäster, Petra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lundmark, Katarzyna
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Rosdahl, Inger
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Evaluation of tubulin β-3 as a novel senescence-associated gene in melanocytic malignant transformation.2017In: Pigment Cell & Melanoma Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 30, no 2, p. 243-254Article in journal (Refereed)
    Abstract [en]

    Malignant melanoma might develop from melanocytic nevi in which the growth-arrested state has been broken. We analyzed the gene expression of young and senescent human melanocytes in culture and compared the gene expression data with a dataset from nevi and melanomas. A concordant altered gene expression was identified in 84 genes when comparing the growth-arrested samples with proliferating samples. TUBB3, which encodes the microtubule protein tubulin β-3, showed a decreased expression in senescent melanocytes and nevi and was selected for further studies. Depletion of tubulin β-3 caused accumulation of cells in the G2/M phase and decreased proliferation and migration. Immunohistochemical assessment of tubulin β-3 in benign lesions revealed strong staining in the superficial part of the intradermal components, which faded with depth. In contrast, primary melanomas exhibited staining without gradient in a disordered pattern and strong staining of the invasive front. Our results describe an approach to find clinically useful diagnostic biomarkers to more precisely identify cutaneous malignant melanoma and present tubulin β-3 as a candidate marker. This article is protected by copyright. All rights reserved.

  • 37.
    Pollard, K. Michael
    et al.
    Scripps Research Institute, CA 92037 USA.
    Escalante, Gabriela M.
    Scripps Research Institute, CA 92037 USA.
    Huang, Hua
    Scripps Research Institute, CA 92037 USA.
    Haraldsson, Katarina M.
    Scripps Research Institute, CA 92037 USA.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Christy, Joseph M.
    Scripps Research Institute, CA 92037 USA.
    Pawar, Rahul D.
    Scripps Research Institute, CA 92037 USA.
    Mayeux, Jessica M.
    Scripps Research Institute, CA 92037 USA.
    Gonzalez-Quintial, Rosana
    Scripps Research Institute, CA 92037 USA.
    Baccala, Roberto
    Scripps Research Institute, CA 92037 USA.
    Beutler, Bruce
    University of Texas Southwestern Medical Centre Dallas, USA.
    Theofilopoulos, Argyrios N.
    Scripps Research Institute, CA 92037 USA.
    Kono, Dwight H.
    Scripps Research Institute, CA 92037 USA.
    Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN2017In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 199, no 11, p. 3739-3747Article in journal (Refereed)
    Abstract [en]

    Type I IFN and nucleic acid-sensing TLRs are both strongly implicated in the pathogenesis of lupus, with most patients expressing IFN-induced genes in peripheral blood cells and with TLRs promoting type I IFNs and autoreactive B cells. About a third of systemic lupus erythematosus patients, however, lack the IFN signature, suggesting the possibility of type I IFN-independent mechanisms. In this study, we examined the role of type I IFN and TLR trafficking and signaling in xenobiotic systemic mercury-induced autoimmunity (HgIA). Strikingly, autoantibody production in HgIA was not dependent on the type I IFN receptor even in NZB mice that require type I IFN signaling for spontaneous disease, but was dependent on the endosomal TLR transporter UNC93B1 and the endosomal proton transporter, solute carrier family 15, member 4. HgIA also required the adaptor protein-3 complex, which transports TLRs from the early endosome to the late endolysosomal compartments. Examination of TLR signaling pathways implicated the canonical NF-kappa B pathway and the proinflammatory cytokine IL-6 in autoantibody production, but not IFN regulatory factor 7. These findings identify HgIA as a novel type I IFN-independent model of systemic autoimmunity and implicate TLR-mediated NF-kappa B proinflammatory signaling from the late endocytic pathway compartments in autoantibody generation.

  • 38.
    Reyes, Juan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Sackmann, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Hoffmann, Alana
    Univ Hosp Erlangen, Germany.
    Svenningsson, Per
    Karolinska Inst, Sweden.
    Winkler, Juergen
    Univ Hosp Erlangen, Germany.
    Ingelsson, Martin
    Uppsala Univ, Sweden.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Binding of -synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes2019In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 138, no 1, p. 23-47Article in journal (Refereed)
    Abstract [en]

    The intercellular transfer of alpha-synuclein (-syn) has been implicated in the progression of Parkinsons disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of -syn oligomeric assemblies (o-syn) in neurons and oligodendrocytes. In vitro, we demonstrate a clear correlation between Cx32 expression and o-syn uptake. Pharmacological and genetic strategies targeting Cx32 successfully blocked o-syn uptake. In cellular and transgenic mice modeling PD and MSA, we observed significant upregulation of Cx32 which correlates with -syn accumulation. Notably, we could alsodemonstrate a direct interaction between -syn and Cx32 in two out of four human PD cases that was absent in all four age-matched controls. These data are suggestive of a link between Cx32 and PD pathophysiology. Collectively, our results provide compelling evidence for Cx32 as a novel target for therapeutic intervention in PD and related -synucleinopathies.

  • 39.
    Richter, Johan
    et al.
    Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Haj Hosseini, Neda
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Combination of Hand-Held Probe and Microscopy for Fluorescence Guided Surgery in the Brain Tumor Marginal Zone2017In: Photodiagnosis and Photodynamic Therapy, ISSN 1572-1000, Vol. 18, p. 185-192Article in journal (Refereed)
    Abstract [en]

    Background

    Visualization of the tumor is crucial for differentiating malignant tissue from healthy brain during surgery, especially in the tumor marginal zone. The aim of the study was to introduce a fluorescence spectroscopy-based hand-held probe (HHF-probe) for tumor identification in combination with the fluorescence guided resection surgical microscope (FGR-microscope), and evaluate them in terms of diagnostic performance and practical aspects of fluorescence detection.

    Material and Methods

    Eighteen operations were performed on 16 patients with suspected high-grade glioma. The HHF-probe and the FGR-microscope were used for detection of protoporphyrin (PpIX) fluorescence induced by 5-aminolevulinic acid (5-ALA) and evaluated against histopathological analysis and visual grading done through the FGR-microscope by the surgeon. A ratio of PpIX fluorescence intensity to the autofluorescence intensity (fluorescence ratio) was used to quantify the spectra detected by the probe.

    Results

    Fluorescence ratio medians (range 0 – 40) measured by the probe were related to the intensity of the fluorescence in the FGR-microscope, categorized as “none” (0.3, n = 131), “weak” (1.6, n = 34) and “strong” (5.4, n = 28). Of 131 “none” points in the FGR-microscope, 88 (67%) exhibited fluorescence with the HHF-probe. For the tumor marginal zone, the area under the receiver operator characteristics (ROC) curve was 0.49 for the FGR-microscope and 0.65 for the HHF-probe.

    Conclusions

    The probe was integrated in the established routine of tumor resection using the FGR-microscope. The HHF-probe was superior to the FGR-microscope in sensitivity; it detected tumor remnants after debulking under the FGR-microscope. The combination of the HHF-probe and the FGR-microscope was beneficial especially in the tumor marginal zone.

  • 40.
    Sackmann, Valerie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Ansell - Schultz, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Sackmann, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Lund, Harald
    Karolinska Hospital Solna, Sweden.
    Harris, Robert A.
    Karolinska Hospital Solna, Sweden.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Nilsberth, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.
    Anti-inflammatory (M2) macrophage media reduce transmission of oligomeric amyloid beta in differentiated SH-SY5Y cells2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 60, p. 173-182Article in journal (Refereed)
    Abstract [en]

    Neuroinflammation plays an influential role in Alzheimers disease (AD), although the mechanisms underlying this phenomenon remain largely unknown. Microglia are thought to be responsible for the majority of these effects and can be characterized into resting (M0), proinflammatory (M1), or anti-inflammatory (M2) functional phenotypes. We investigated the effects of conditioned macrophage media, as an analogue to microglia, on the transfer of oligomeric amyloid beta (oA beta) between differentiated SH-SY5Y cells. We also investigated how the different inflammatory environments related to intercellular and intracellular changes. We demonstrate that M2 products decrease interneuronal transfer of oA beta, while recombinant interleukin (IL)-4, IL-10, and IL-13 increase transfer. There were no alterations to the mRNA of a number of AD-related genes in response to the combination of oA beta and M0, M1, or M2, but several intracellular proteins, some relating to protein trafficking and the endosomal/lysosomal system, were altered. Stimulating microglia to an M2 phenotype may thus slow down the progression of AD and could be a target for future therapies. (C) 2017 Elsevier Inc. All rights reserved.

  • 41.
    Sardar Sinha, Maitrayee
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Ansell - Schultz, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Civitelli, Livia
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Hildesjö, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Larsson, Max
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Lannfelt, Lars
    Uppsala Univ, Sweden; BioArctic AB, Sweden.
    Ingelsson, Martin
    Uppsala Univ, Sweden.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Alzheimers disease pathology propagation by exosomes containing toxic amyloid-beta oligomers2018In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 136, no 1, p. 41-56Article in journal (Refereed)
    Abstract [en]

    The gradual deterioration of cognitive functions in Alzheimers disease is paralleled by a hierarchical progression of amyloid-beta and tau brain pathology. Recent findings indicate that toxic oligomers of amyloid-beta may cause propagation of pathology in a prion-like manner, although the underlying mechanisms are incompletely understood. Here we show that small extracellular vesicles, exosomes, from Alzheimer patients brains contain increased levels of amyloid-beta oligomers and can act as vehicles for the neuron-to-neuron transfer of such toxic species in recipient neurons in culture. Moreover, blocking the formation, secretion or uptake of exosomes was found to reduce both the spread of oligomers and the related toxicity. Taken together, our results imply that exosomes are centrally involved in Alzheimers disease and that they could serve as targets for development of new diagnostic and therapeutic principles.

  • 42.
    Sardar Sinha, Maitrayee
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Villamil Giraldo, Ana Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Civitelli, Livia
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Lipid vesicles affect the aggregation of 4-hydroxy-2-nonenal-modified alpha-synuclein oligomers2018In: Biochimica et Biophysica Acta - Molecular Basis of Disease, ISSN 0925-4439, E-ISSN 1879-260X, Vol. 1864, no 9, p. 3060-3068Article in journal (Refereed)
    Abstract [en]

    Parkinsons disease (PD) and other synucleinopathies are characterized by accumulation of misfolded aggregates of alpha-synuclein (alpha-syn). The normal function of alpha-syn is still under investigation, but it has been generally linked to synaptic plasticity, neurotransmitter release and the maintenance of the synaptic pool. alpha-Syn localizes at synaptic terminals where it can bind to synaptic vesicles as well as to other cellular membranes. It has become clear that these interactions have an impact on both alpha-syn functional role and its propensity to aggregate. In this study, we investigated the aggregation process of alpha-syn covalently modified with 4-hydroxy-2-nonenal (HNE). HNE is a product of lipid peroxidation and has been implicated in the pathogenesis of different neurodegenerative diseases by modifying the kinetics of soluble toxic oligomers. Although HNE-modified alpha-syn has been reported to assemble into stable oligomers, we found that slightly acidic conditions promoted further protein aggregation. Lipid vesicles delayed the aggregation process in a concentration-dependent manner, an effect that was observed only when they were added at the beginning of the aggregation process. Co-aggregation of lipid vesicles with HNE-modified alpha-syn also induced cytotoxic effects on differentiated SHSY-SY cells. Under conditions in which the aggregation process was delayed cell viability was reduced. By exploring the behavior and potential cytotoxic effects of HNE-alpha-syn under acidic conditions in relation to protein-lipid interactions our study gives a framework to examine a possible pathway leading from a physiological setting to the pathological outcome of PD.

  • 43.
    Shariatpanahi, Aida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Westermark, Gunilla T.
    Uppsala Univ, Sweden.
    Lundmark, Katarzyna
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Lipid membranes accelerate amyloid formation in the mouse model of AA amyloidosis2019In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, no 1, p. 34-44Article in journal (Refereed)
    Abstract [en]

    Introduction: AA amyloidosis develops as a result of prolonged inflammation and is characterized by deposits of N-terminal proteolytic fragments of the acute phase reactant serum amyloid A (SAA). Macrophages are usually found adjacent to amyloid, suggesting their involvement in the formation and/or degradation of the amyloid fibrils. Furthermore, accumulating evidence suggests that lipid membranes accelerate the fibrillation of different amyloid proteins.

    Methods: Using an experimental mouse model of AA amyloidosis, we compared the amyloidogenic effect of liposomes and/or amyloid-enhancing factor (AEF). Inflammation was induced by subcutaneous injection of silver nitrate followed by intravenous injection of liposomes and/or AEF to accelerate amyloid formation.

    Results: We showed that liposomes accelerate amyloid formation in inflamed mice, but the amyloidogenic effect of liposomes was weaker compared with AEF. Regardless of the induction method, amyloid deposits were mainly found in the marginal zones of the spleen and coincided with the depletion of marginal zone macrophages, while red pulp macrophages and metallophilic marginal zone macrophages proved insensitive to amyloid deposition.

    Conclusions: We conclude that increased intracellular lipid content facilitates AA amyloid fibril formation and show that the mouse model of AA amyloidosis is a suitable system for further mechanistic studies.

  • 44.
    Skoglund, Karin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Rose, Jeronimo
    Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Lindvall, Martin
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV). Sectra AB, Linköping, Sweden.
    Lundström, Claes
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV). Sectra AB, Linköping, Sweden.
    Treanor, Darren
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Clinical pathology. St. James University Hospital, Leeds, UK.
    Annotations, ontologies, and whole slide images: Development of an annotated ontology-driven whole slide image library of normal and abnormal human tissue2019In: Journal of Pathology Informatics, ISSN 2229-5089, E-ISSN 2153-3539, Vol. 10, no 22Article in journal (Refereed)
    Abstract [en]

    Objective: Digital pathology is today a widely used technology, and the digitalization of microscopic slides into whole slide images (WSIs) allows the use of machine learning algorithms as a tool in the diagnostic process. In recent years, “deep learning” algorithms for image analysis have been applied to digital pathology with great success. The training of these algorithms requires a large volume of high-quality images and image annotations. These large image collections are a potent source of information, and to use and share the information, standardization of the content through a consistent terminology is essential. The aim of this project was to develop a pilot dataset of exhaustive annotated WSI of normal and abnormal human tissue and link the annotations to appropriate ontological information. 

    Materials and Methods: Several biomedical ontologies and controlled vocabularies were investigated with the aim of selecting the most suitable ontology for this project. The selection criteria required an ontology that covered anatomical locations, histological subcompartments, histopathologic diagnoses, histopathologic terms, and generic terms such as normal, abnormal, and artifact. WSIs of normal and abnormal tissue from 50 colon resections and 69 skin excisions, diagnosed 2015-2016 at the Department of Clinical Pathology in Linköping, were randomly collected. These images were manually and exhaustively annotated at the level of major subcompartments, including normal or abnormal findings and artifacts. 

    Results: Systemized nomenclature of medicine clinical terms (SNOMED CT) was chosen, and the annotations were linked to its codes and terms. Two hundred WSI were collected and annotated, resulting in 17,497 annotations, covering a total area of 302.19 cm2, equivalent to 107,7 gigapixels. Ninety-five unique SNOMED CT codes were used. The time taken to annotate a WSI varied from 45 s to over 360 min, a total time of approximately 360 h. 

    Conclusion: This work resulted in a dataset of 200 exhaustive annotated WSIs of normal and abnormal tissue from the colon and skin, and it has informed plans to build a comprehensive library of annotated WSIs. SNOMED CT was found to be the best ontology for annotation labeling. This project also demonstrates the need for future development of annotation tools in order to make the annotation process more efficient.

  • 45.
    Tiefenböck Hansson, Katharina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Haapaniemi, Aaro
    Helsinki University Hospital, Finland; University of Helsinki, Finland.
    Farnebo, Lovisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Speech language pathology, Audiology and Otorhinolaryngology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Palmgren, Bjorn
    Karolinska University Hospital, Sweden.
    Tarkkanen, Jussi
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Farnebo, Marianne
    Karolinska Institute, Sweden.
    Munck-Wikland, Eva
    Karolinska University Hospital, Sweden.
    Makitie, Antti
    Helsinki University Hospital, Finland; University of Helsinki, Finland; Karolinska University Hospital, Sweden.
    Garvin, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    WRAP53 beta, survivin and p16(INK4a) expression as potential predictors of radiotherapy/chemoradiotherapy response in T2N0-T3N0 glottic laryngeal cancer2017In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 38, no 4, p. 2062-2068Article in journal (Refereed)
    Abstract [en]

    The current treatment recommendation for T2-3N0M0 glottic squamous cell carcinoma (SCC) in the Nordic countries comprises of radiotherapy (RT) and chemoradiotherapy (CRT). Tumor radiosensitivity varies and another option is primary surgical treatment, which underlines the need for predictive markers in this patient population. The aim of the present study was to investigate the relation of the proteins WRAP53 beta, survivin and p16INK4a to RT/CRT response and ultimate outcome of patients with T2-T3N0 glottic SCC. Protein expression was determined using immunohistochemistry on tumors from 149 patients consecutively treated with RT or CRT at Helsinki University Hospital, Karolinska University Hospital, and Linkping University Hospital during 1999-2010. Our results demonstrate a significantly better 5-year relapse-free survival, disease-free survival (DFS), disease-specific survival and overall survival of patients with T3N0 tumors treated with CRT compared with RT alone. Patients with tumors showing a cytoplasmic staining of WRAP53 beta revealed significantly worse DFS compared with those with nuclear staining. For survivin, we observed a trend towards better 5-year DFS in patients with strong nuclear survivin expression compared with those with weak nuclear survivin expression (p=0.091). Eleven (7%) tumors showed p16 positivity, with predilection to younger patients, and this age group of patients with p16-positive SCC had a significantly better DFS compared with patients with p16-negative SCC. Taken together, our results highlight WRAP53 beta as a potential biomarker for predicting RT/CRT response in T2-T3N0 glottic SCC. p16 may identify a small but distinct group of glottic SCC with favorable outcome. Furthermore, for T3N0 patients better outcome was observed following CRT compared to RT alone.

  • 46.
    Tribonias, George
    et al.
    Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Daferera, Niki
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Manola, Margarita-Eleni
    Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Svernlöv, Rikard
    Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Hjortswang, Henrik
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science.
    How familiar are we with decision-making concerning the treatment of perforation after endoscopic mucosal resection (EMR) in the colon? A case report2018In: Endoscopy International Open, ISSN 2196-9736, E-ISSN 2196-9736, Vol. 6, no 3, p. E308-E312Article in journal (Refereed)
    Abstract [en]

    Background and study aims We describe a case of perforation after colonic endoscopic mucosal resection (EMR) that was treated conservatively. We would like to highlight the importance of decision-making mainly based on the endoscopists point of view in combination with the surgical consultation. Although the radiological imaging is always needed, it cannot solely lead to a decision for operation. Intraperitoneal gas in computed tomography is not always associated with a hole in the endoscopic field and could be possibly explained from a "balloon" phenomenon. The amount of extraluminal air after an EMR does not correlate reciprocally with patients pain after the procedure. Even though perforation is a radiological diagnosis and endoscopists should be aware of the common post-EMR radiological findings, the surgical examination is mandatory and should be coupled with the endoscopic opinion in order to guide appropriately the treatment in patients with acute pain.

  • 47.
    Veenstra, Cynthia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Mirwani, Sanam Mirwani
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fornander, Tommy
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Perez Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    The effects of PTPN2 loss on cell signalling and clinical outcome in relation to breast cancer subtype2019In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 145, no 7, p. 1845-1856Article in journal (Refereed)
    Abstract [en]

    PurposeThe protein tyrosine phosphatase PTPN2 dephosphorylates several tyrosine kinases in cancer-related signalling pathways and is thought to be a tumour suppressor. As PTPN2 is not frequently studied in breast cancer, we aimed to explore the role of PTPN2 and the effects of its loss in breast cancer.MethodsProtein expression and gene copy number of PTPN2 were analysed in a cohort of pre-menopausal breast cancer patients with immunohistochemistry and droplet digital PCR, respectively. PTPN2 was knocked down in three cell lines, representing different breast cancer subtypes, with siRNA transfection. Several proteins related to PTPN2 were analysed with Western blot.ResultsLow PTPN2 protein expression was found in 50.2% of the tumours (110/219), gene copy loss in 15.4% (33/214). Low protein expression was associated with a higher relapse rate in patients with Luminal A and HER2-positive tumours, but not triple-negative tumours. In vitro studies further suggested a subtype-specific role of PTPN2. Knockdown of PTPN2 had no effect on the triple-negative cell line, whilst knockdown in MCF7 inhibited phosphorylation of Met and promoted that of Akt. Knockdown in SKBR3 led to increased Met phosphorylation and decreased Erk phosphorylation as well as EGF-mediated STAT3 activation.ConclusionWe confirm previous studies showing that the PTPN2 protein is lost in half of the breast cancer cases and gene deletion occurs in 15-18% of the cases. Furthermore, the results suggest that the role of PTPN2 is subtype-related and should be further investigated to assess how this could affect breast cancer prognosis and treatment response.

  • 48.
    Westermark, Gunilla T.
    et al.
    Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Fändrich, Marcus
    Institute of Protein Biochemistry, Ulm University, Ulm, Germany.
    Lundmark, Katarzyna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Westermark, Per
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Noncerebral Amyloidoses: Aspects on Seeding, Cross-Seeding, and Transmission2018In: Cold Spring Harbor Perspectives in Medicine, ISSN 0103-3247, E-ISSN 2157-1422, Vol. 8, no 1, article id a024323Article, review/survey (Refereed)
    Abstract [en]

    More than 30 proteins form amyloid in humans, most of them outside of the brain. Deposition of amyloid in extracerebral tissues is very common and seems inevitable for an aging person. Most deposits are localized, small, and probably without consequence, but in some instances, they are associated with diseases such as type 2 diabetes. Other extracerebral amyloidoses are systemic, with life-threatening effects on the heart, kidneys, and other organs. Here, we review how amyloid may spread through seeding and whether transmission of amyloid diseases may occur between humans. We also discuss whether cross-seeding is important in the development of amyloidosis, focusing specifically on the amyloid proteins AA, transthyretin, and islet amyloid polypeptide (IAPP).

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