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  • 1.
    Appelqvist, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Nilsson, Cathrine
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Garner, Brett
    University of Wollongong.
    Brown, Andrew J
    University of New South Wales.
    Kågedal, Katarina
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Attenuation of the Lysosomal Death Pathway by Lysosomal Cholesterol Accumulation2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 178, no 2, 629-639 p.Article in journal (Refereed)
    Abstract [en]

    In the past decade, lysosomal membrane permeabilization (LMP) has emerged as a significant component of cell death signaling. The mechanisms by which lysosomal stability is regulated are not yet fully understood, but changes in the lysosomal membrane lipid composition have been suggested to be involved. Our aim was to investigate the importance of cholesterol in the regulation of lysosomal membrane permeability and its potential impact on apoptosis. Treatment of normal human fibroblasts with U18666A, an amphiphilic drug that inhibits cholesterol transport and causes accumulation of cholesterol in lysosomes, rescued cells from lysosome-dependent cell death induced by the lysosomotropic detergent 0-methyl-serine dodecylamide hydrochloride (MSDH), staurosporine (STS), or cisplatin. LMP was decreased by pretreating cells with U18666A, and there was a linear relationship between the cholesterol content of lysosomes and their resistance to permeabilization induced by MSDH. U18666A did not induce changes in expression or localization of 70-kDa heat shock proteins (Hsp70) or antiapoptotic Bcl-2 proteins known to protect the lysosomal membrane. Induction of autophagy also was excluded as a contributor to the protective mechanism. By using Chinese hamster ovary (CHO) cells with lysosomal cholesterol overload due to a mutation in the cholesterol transporting protein Niemann-Pick type C1 (NPC1), the relationship between lysosomal cholesterol accumulation and protection from lysosome-dependent cell death was confirmed. Cholesterol accumulation in lysosomes attenuates apoptosis by increasing lysosomal membrane stability.

  • 2.
    Babbin, Brian A.
    et al.
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Koch, Stefan
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Bachar, Moshe
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Conti, Mary-Anne
    Laboratory of Molecular Cardiology, the National Heart, Lung, Blood Institute, National Institutes of Health, Bethesda, Maryland.
    Parkos, Charles A.
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Adelstein, Robert S.
    Laboratory of Molecular Cardiology, the National Heart, Lung, Blood Institute, National Institutes of Health, Bethesda, Maryland.
    Nusrat, Asma
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Ivanov, Andrei I.
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia; Gastroenterology and Hepatology Division, Department of Medicine, The University of Rochester, Rochester New York.
    Non-muscle myosin IIA differentially regulates intestinal epithelial cell restitution and matrix invasion2009In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 174, no 2, 436-448 p.Article in journal (Refereed)
    Abstract [en]

    Epithelial cell motility is critical for self-rejuvenation of normal intestinal mucosa, wound repair, and cancer metastasis. This process is regulated by the reorganization of the F-actin cytoskeleton, which is driven by a myosin II motor. However, the role of myosin II in regulating epithelial cell migration remains poorly understood. This study addressed the role of non-muscle myosin (NM) IIA in two different modes of epithelial cell migration: two-dimensional (2-D) migration that occurs during wound closure and three-dimensional (3-D) migration through a Matrigel matrix that occurs during cancer metastasis. Pharmacological inhibition or siRNA-mediated knockdown of NM IIA in SK-CO15 human colonic epithelial cells resulted in decreased 2-D migration and increased 3-D invasion. The attenuated 2-D migration was associated with increased cell adhesiveness to collagen and laminin and enhanced expression of beta1-integrin and paxillin. On the 2-D surface, NM IIA-deficient SK-CO15 cells failed to assemble focal adhesions and F-actin stress fibers. In contrast, the enhanced invasion of NM IIA-depleted cells was dependent on Raf-ERK1/2 signaling pathway activation, enhanced calpain activity, and increased calpain-2 expression. Our findings suggest that NM IIA promotes 2-D epithelial cell migration but antagonizes 3-D invasion. These observations indicate multiple functions for NM IIA, which, along with the regulation of the F-actin cytoskeleton and cell-matrix adhesions, involve previously unrecognized control of intracellular signaling and protein expression.

  • 3.
    Ceder, Rebecca
    et al.
    Karolinska Institute.
    Haig, Ylva
    Karolinska Institute.
    Merne, Marina
    Karolinska Institute.
    Hansson, Annette
    Karolinska Institute.
    Zheng, Xi
    Karolinska Institute.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of ENT - Head and Neck Surgery UHL.
    Nees, Matthias
    VTT Technical Research Centre Finland.
    Iljin, Kristiina
    VTT Technical Research Centre Finland.
    Bloor, Balvinder K
    Kings College London.
    Morgan, Peter R
    Kings College London.
    Fadeel, Bengt
    Karolinska Institute.
    Grafstrom, Roland C
    Karolinska Institute.
    Differentiation-Promoting Culture of Competent and Noncompetent Keratinocytes Identifies Biomarkers for Head and Neck Cancer2012In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 180, no 2, 457-472 p.Article in journal (Refereed)
    Abstract [en]

    Aberrant contact-inhibited proliferation and differentiation induction couple with tumor severity, albeit with an imprecise association with prognosis. Assessment of contact inhibition and differentiation-promoting culture in this study of normal and immortalized oral keratinocytes (NOK and SVpgC2a, respectively) demonstrated elevated cloning ability and saturation density in the immortalized versus normal state, including consistent absence of differentiated morphological features. Transcriptomic analysis implicated 48 gene ontology categories, 8 molecular networks, and 10 key regulator genes in confluency-induced differentiation of NOK, all of which remained nonregulated in SVpgC2a. The SVpgC2a versus NOK transcriptome enriched 52 gene ontology categories altogether, 18 molecular networks, and 39 key regulator genes, several of which were associated with epithelial-mesenchymal transition. Assessment of the previously described gene sets relative to training data sets of head and neck squamous cell carcinoma samples, one including data on tumor differentiation and patient outcome and one present in the Human Gene Expression Map, identified four genes with association to poor survival (COX7A1, MFAP5, MPDU1, and POLD1). This gene set predicted poor outcome in an independent data set of 71 head and neck squamous cell carcinomas. The present study defines, for the first time to our knowledge, the broad gene spectrum that couples to induction, and loss, of oral keratinocyte differentiation. Bioinformatics assessments of the results relative to clinical data generated novel differentiation-related tumor biomarkers relevant to patient outcome.

  • 4. Chong, Victor N H
    et al.
    Keonin, Jason
    Luthert, Phil J
    Frennesson, Christina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Ophthalmology. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL.
    Weingeist, David M
    Wolf, Rachel L
    Mullins, Robert F
    Hageman, Gregory S
    Decreased thickness and integrity of the macular elastic layer of Bruch's membrane correspond to the distribution of lesions associated with age-related macular degeneration2005In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 166, no 1, 241-251 p.Article in journal (Refereed)
    Abstract [en]

    Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. In its severest form, choroidal neovessels breach the macular Bruch's membrane, an extracellular matrix compartment comprised of elastin and collagen laminae, and grow into the retina. We sought to determine whether structural properties of the elastic lamina (EL) correspond to the region of the macula that is predilected toward degeneration in AMD. Morphometric assessment of the macular and extramacular regions of 121 human donor eyes, with and without AMD, revealed a statistically significant difference in both the integrity (P < 0.0001) and thickness (P < 0.0001) of the EL between the macular and extramacular regions in donors of all ages. The EL was three to six times thinner and two to five times less abundant in the macula than in the periphery. The integrity of the macular EL was significantly lower in donors with early-stage AMD (P = 0.028), active choroidal neovascularization (P = 0.020), and disciform scars (P = 0.003), as compared to unaffected, age-matched controls. EL thickness was significantly lower only in individuals with disciform scars (P = 0.008). The largest gaps in macular EL integrity were significantly larger in all categories of AMD (each P < 0.0001), as compared to controls. EL integrity, thickness, and gap length in donors with geographic atrophy did not differ from those of controls. These structural properties of the macular EL correspond spatially to the distribution of macular lesions associated with AMD and may help to explain why the macula is more susceptible to degenerative events that occur in this disease.

  • 5.
    Copland, DA
    et al.
    University of Bristol.
    Calder, CJ
    University of Bristol.
    Raveney, BJ
    University of Bristol.
    Nicholson, LB
    University of Bristol.
    Phillips, J
    SP Biopharma, Palo Alto, California.
    Cherwinski, H
    SP Biopharma, Palo Alto, California.
    Jenmalm, Maria
    SP Biopharma, Palo Alto, California.
    Sedgewick, JD
    SP Biopharma, Palo Alto, California.
    Dick, AD
    University of Bristol.
    Monoclonal antibody-mediated CD200 receptor signaling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis2007In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 171, no 2, 580-588 p.Article in journal (Refereed)
    Abstract [en]

    Macrophage responses are regulated by multiple secreted factors as well as by cell surface receptors, including the inhibitory signals resulting from ligation of myeloid CD200 receptors (CD200R) by the widely distributed CD200. In the absence of CD200, animals display increased susceptibility to autoimmunity and earlier onset aggressive autoimmune disease. In these current experiments, an agonist monoclonal rat anti-mouse CD200R (DX109) antibody delivered a negative signal to bone marrow-derived macrophages, which suppressed interferon (IFN)-mediated nitric oxide (NO) and interleukin-6 production. Experimental autoimmune uveoretinitis (EAU) was used as a model of organ-specific autoimmunity in the eye, a tissue with extensive neuronal and endothelial CD200 expression. In mice lacking CD200 (CD200-/-), increased numbers of retina-infiltrating macrophages displaying heightened NO responses were observed during EAU. In addition, we aimed to suppress disease by maintaining tonic suppression of macrophage activation via CD200R. Systemically administered DX109 monoclonal antibody suppressed EAU despite maintained T-cell proliferation and IFN production. Furthermore, locally administered DX109 monoclonal antibody resulted in an earlier resolution of disease. These experiments demonstrate that promoting CD200R-mediated signaling can successfully prevent full expression of IFN-mediated macrophage activation and protect against tissue damage during autoimmune responses.

  • 6.
    Dabrosin, Charlotta
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Gyorffy, S
    Margetts, P
    Ross, C
    Gauldie, J
    Therapeutic effect of angiostatin gene transfer in a murine model of endometriosis.2002In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 161, 909-918 p.Article in journal (Refereed)
  • 7.
    Kalkunte, Satyan S.
    et al.
    Brown University, RI USA .
    Neubeck, Stefan
    University of Jena, Germany .
    Norris, Wendy E.
    Brown University, RI USA .
    Cheng, Shi-Bin
    Brown University, RI USA .
    Kostadinov, Stefan
    Brown University, RI USA .
    Hoang, Dang Vu
    University of Rhode Isl, RI USA .
    Ahmed, Aftab
    University of Rhode Isl, RI USA .
    von Eggeling, Ferdinand
    University of Jena, Germany .
    Shaikh, Zahir
    University of Rhode Isl, RI USA .
    Padbury, James
    Brown University, RI 02905 USA .
    Berg, Goran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Olofsson, Anders
    Umeå University, Sweden .
    Markert, Udo R.
    University of Jena, Germany .
    Sharma, Surendra
    Brown University, RI USA .
    Transthyretin Is Dysregulated in Preeclampsia, and Its Native Form Prevents the Onset of Disease in a Preclinical Mouse Model2013In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 183, no 5, 1425-1436 p.Article in journal (Refereed)
    Abstract [en]

    Preeclampsia is a major pregnancy complication with potential short- and long-term consequences for both mother and fetus. Understanding its pathogenesis and causative biomarkers is likely to yield insights for prediction and treatment. Herein, we provide evidence that transthyretin, a transporter of thyroxine and retinal, is aggregated in preeclampsia and is present at reduced levels in sera of preeclamptic women, as detected by proteomic screen. We demonstrate that transthyretin aggregates form deposits in preeclampsia placental tissue and cause apoptosis. By using in vitro approaches and a humanized mouse model, we provide evidence for a causal link between dysregulated transthyretin and preeclampsia. Native transthyretin inhibits all preeclampsia-like features in the humanized mouse model, including new-onset proteinuria, increased blood pressure, glomerular endotheliosis, and production of anti-angiogenic factors. Our findings suggest that a focus on transthyretin structure and function is a novel strategy to understand and combat preeclampsia.

  • 8.
    Krause, Kerstin
    et al.
    Clinic for Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
    Prawitt, Susanne
    Clinic for Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
    Eszlinger, Markus
    Clinic for Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
    Ihling, Christian
    Department of Pharmaceutical Chemistry and Bioanalytics, Martin Luther University of Halle- Wittenberg, Halle-Wittenberg, Germany.
    Sinz, Andrea
    Department of Pharmaceutical Chemistry and Bioanalytics, Martin Luther University of Halle- Wittenberg, Halle-Wittenberg, Germany.
    Schierle, Katrin
    Institute of Pathology, University of Leipzig, Leipzig.
    Gimm, Oliver
    Department of General, Visceral, and Vascular Surgery, Martin Luther University of Halle- Wittenberg, Halle-Wittenberg, Germany.
    Dralle, Henning
    Department of General, Visceral, and Vascular Surgery, Martin Luther University of Halle- Wittenberg, Halle-Wittenberg, Germany.
    Steinert, Frank
    Centre for Minimally Invasive and Laparoscopic Surgery, Helios Clinic Schkeuditz, Schkeuditz, University of Duisburg-Essen, Essen, Germany.
    Sheu, Sien-Yi
    nstitute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
    Schmid, Kurt W
    nstitute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
    Fuhrer, Dagmar
    Clinic for Endocrinology, University of Duisburg-Essen, Essen, Germany.
    Dissecting molecular events in thyroid neoplasia provides evidence for distinct evolution of follicular thyroid adenoma and carcinoma.2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 179, no 6, 3066-74 p.Article in journal (Refereed)
    Abstract [en]

    Benign hypofunctional cold thyroid nodules (CTNs) are a frequent scintiscan finding and need to be distinguished from thyroid carcinomas. The origin of CTNs with follicular morphologic features is unresolved. The DNA damage response might act as a physiologic barrier, inhibiting the progression of preneoplastic lesions to neoplasia. We investigated the following in hypofunctional follicular adenoma (FA) and follicular thyroid cancer (FTC): i) the mutation rate of frequently activated oncogenes, ii) the activation of DNA damage response checkpoints, and iii) the differential proteomic pattern between FA and FTC. Both FTC and FA, which did not harbor RAS, phosphoinositide-3-kinase, or PAX/peroxisome proliferator activated receptor-γ mutations, express various proteins in common and others that are more distinctly expressed in FTC rather than in FA or normal thyroid tissue. This finding is in line with the finding of constitutive DNA damage checkpoint activation (p-Chk2, γ-H2AX) and evidence for replicative stress causing genomic instability (increased cyclin E, retinoblastoma, or E2F1 mRNA expression) in FTC but not FA. We discuss the findings of the increased expression of translationally controlled tumor protein, phosphatase 2A inhibitor, and DJ-1 in FTC compared with FA identified by proteomics and their potential implication in follicular thyroid carcinogenesis. Our present findings argue for the definition of FA as a truly benign entity and against progressive development of FA to FTC.

  • 9.
    Lord, Anna
    et al.
    Uppsala University.
    Philipson, Ola
    Uppsala University.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Westermark, Gunilla
    Uppsala University.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Nilsson, Lars N. G.
    Observations in APP Bitransgenic Mice Suggest thatDiffuse and Compact Plaques Form via IndependentProcesses in Alzheimer’s Disease2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 178, no 5, 2286-2298 p.Article in journal (Refereed)
    Abstract [en]

    Studies of familial Alzheimer's disease suggest that misfolding and aggregation of amyloid-β (Aβ) peptides initiate the pathogenesis. The Arctic mutation of Aβ precursor protein (APP) results in AD, and Arctic Aβ is more prone to form Aβ protofibrils and extracellular deposits. Herein is demonstrated that the burden of diffuse Aβ deposits but not compact plaques is increased when tg-Swe mice are crossed with tg-ArcSwe mice synthesizing low levels of Arctic Aβ. The diffuse deposits in bitransgenic mice, which contain primarily wild-type Aβ42, accumulate in regions both with and without transgene expression. However, APP processing, when compared with tg-Swe, remains unchanged in young bitransgenic mice, whereas wild-type Aβ42 aggregation is accelerated and fibril architecture is altered in vitro and in vivo when a low level of Arctic Aβ42 is introduced. Thus, the increased number of diffuse deposits is likely due to physical interactions between Arctic Aβ and wild-type Aβ42. The selective increase of a single type of parenchymal Aβ deposit suggests that different pathways lead to formation of diffuse and compact plaques. These findings could have general implications for Alzheimer's disease pathogenesis and particular relevance to patients heterozygous for the Arctic APP mutation. Moreover, it further illustrates how Aβ neuropathologic features can be manipulated in vivo by mechanisms similar to those originally conceptualized in prion research.

  • 10.
    Mucchiano, Gerd
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Cornwell III, Gibbons G.
    Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire.
    Westermark, Per
    Department of Pathology, Hospital of Jönköping, Jönköping, Sweden.
    Senile aortic amyloid: Evidence for two distinct forms of localized deposits1992In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 140, no 4, 871-877 p.Article in journal (Refereed)
    Abstract [en]

    Aortic tissues obtained at autopsy were examined from 84 patients (age, 18-96 years). Amyloid deposits were present in the media in 61 of 63 (97%) of the patients above the age of 50. In addition, intimal amyloid deposits were present in 35% of this group. Intimal amyloid differed from medial amyloid both in its morphologic characteristics and its association with atherosclerosis. An antiserum raised to a low molecular weight protein extracted from amyloid fibrils of the aortic media reacted specifically with medial amyloid but did not react with intimal deposits. Neither type of amyloid reacted with anti-ATTR (Senile systemic amyloid), anti-AANF (isolated atrial amyloid), or antisera to other known forms of amyloid. These findings are consistent with the presence of two separate forms of localized amyloid in the aging aorta.

  • 11.
    Munksgaard Persson, Matilda
    et al.
    Lund University.
    Johansson, Martin E
    Lund University.
    Monsef, Nastaran
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Planck, Maria
    Lund University.
    Beckman, Siv
    Lund University.
    Seckl, Michael J
    University of London Imperial Coll Science Technology and Medicine.
    Ronnstrand, Lars
    Lund University.
    Pahlman, Sven
    Lund University.
    Pettersson, Helen M
    Lund University.
    HIF-2 alpha Expression Is Suppressed in SCLC Cells, Which Survive in Moderate and Severe Hypoxia When HIF-1 alpha Is Repressed2012In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 180, no 2, 494-504 p.Article in journal (Refereed)
    Abstract [en]

    Small cell lung carcinoma (SCLC) is extremely aggressive and frequently metastasizes widely in its early stage. Because tumor hypoxia is related to aggressive tumor behavior and the hypoxic adaptation of SCLC is poorly documented, we stained SCLC tumors arranged in a tissue microarray for hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha proteins. We found an overall lack of HIF-2 alpha protein expression, which was confirmed in large tumor sections. HIF-1 alpha protein was strongly expressed in most tumors, frequently adjacent to necrotic regions. In concordance, cultured SCLC but not non-small cell lung carcinoma cells showed no or extremely low levels of HIF-2 alpha mRNA and no HIF-2 alpha protein at hypoxia. HIF-1 alpha was stabilized after 4 hours at hypoxia, and its accumulation increased up to 96 hours. SCLC cells survived well and showed net proliferation and low cell death in modest (1% oxygen) and severe (0.1% oxygen) hypoxia. HIF-1 alpha repression virtually did not influence cell death or viability despite reduced levels of hypoxia-inducible genes, such as BNIP3 and BNIP3L. At 1% oxygen no increased autophagy (LC3B-II activation) or NF-kappa B signaling were detected, whereas the unfolded protein response was activated at severe hypoxia. Our data indicate that HIFs are not exclusively required for SCLC cell survival at modest or severe hypoxia and that additional, yet uncharacterized, hypoxia-driven adaptation pathways may become activated.

  • 12. Nazli, Aisha
    et al.
    Yang, Ping-Chang
    Jury, Jennifer
    Howe, Kathryn
    Watson, James L
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Sherman, Philip M
    Perdue, Mary H
    McKay, Derek M
    Epithelia under metabolic stress perceive commensal bacteria as a threat2004In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 164, 947-957 p.Article in journal (Refereed)
  • 13.
    Neumann, Philipp-Alexander
    et al.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Emory University, Atlanta, Georgia; Department of General and Visceral Surgery, University of Muenster, Muenster, Germany.
    Koch, Stefan
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Emory University, Atlanta, Georgia; Division of Molecular Embryology, German Cancer Research Center, Heidelberg, Germany.
    Hilgarth, Roland S.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Emory University, Atlanta, Georgia.
    Perez-Chanona, Ernesto
    Department of Pharmacology, University of North Carolina,Chapel Hill, Chapel Hill, North Carolina.
    Denning, Patricia
    Department of Pediatrics, Emory University, Atlanta, Georgia.
    Jobin, Christian
    Department of Infectious Diseases and Pathology, University of Florida, Gainesville, Florida.
    Nusrat, Asma
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Emory University, Atlanta, Georgia.
    Gut commensal bacteria and regional Wnt gene expression in the proximal versus distal colon2014In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Am J Pathol, Vol. 184, no 3, 592-9 p.Article in journal (Refereed)
    Abstract [en]

    Regional expression of Wingless/Int (Wnt) genes plays a central role in regulating intestinal development and homeostasis. However, our knowledge of such regional Wnt proteins in the colon remains limited. To understand further the effect of Wnt signaling components in controlling intestinal epithelial homeostasis, we investigated whether the physiological heterogeneity of the proximal and distal colon can be explained by differential Wnt signaling. With the use of a Wnt signaling-specific PCR array, expression of 84 Wnt-mediated signal transduction genes was analyzed, and a differential signature of Wnt-related genes in the proximal versus distal murine colon was identified. Several Wnt agonists (Wnt5a, Wnt8b, and Wnt11), the Wnt receptor frizzled family receptor 3, and the Wnt inhibitory factor 1 were differentially expressed along the colon length. These Wnt signatures were associated with differential epithelial cell proliferation and migration in the proximal versus distal colon. Furthermore, reduced Wnt/beta-catenin activity and decreased Wnt5a and Wnt11 expression were observed in mice lacking commensal bacteria, an effect that was reversed by conventionalization of germ-free mice. Interestingly, myeloid differentiation primary response gene 88 knockout mice showed decreased Wnt5a levels, indicating a role for Toll-like receptor signaling in regulating Wnt5a expression. Our results suggest that the morphological and physiological heterogeneity within the colon is in part facilitated by the differential expression of Wnt signaling components and influenced by colonization with bacteria.

  • 14.
    Ovchinnikova, Olga
    et al.
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Robertson, Anna-Karin L.
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Wågsäter, Dick
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Folco, Eduardo J.
    Harvard Medical School, Boston, Massachusetts, USA.
    Hyry, Marjo
    University of Oulu, Finland.
    Myllyharju, Johanna
    University of Oulu, Finland .
    Eriksson, Per
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Libby, Peter
    Harvard Medical School, Boston, Massachusetts, USA.
    Hansson, Göran K.
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    T-Cell Activation Leads to Reduced Collagen Maturation in Atherosclerotic Plaques of Apoe−/− Mice2009In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 174, no 2, 693-700 p.Article in journal (Refereed)
    Abstract [en]

    Rupture of the collagenous, fibrous cap of an atherosclerotic plaque commonly causes thrombosis. Activated immune cells can secrete mediators that jeopardize the integrity of the fibrous cap. This study aimed to determine the relationship between T-cell-mediated inflammation and collagen turnover in a mouse model of experimental atherosclerosis. Both Apoe(-/-) x CD4dnT beta RII mice with defective transforming growth factor-beta receptors in T cells (and hence released from tonic suppression of T-cell activation) and lesion size-matched Apoe(-/-) mice were used. Picrosirius red staining showed a lower content of thick mature collagen fibers in lesions of Apoe(-/-) x CD4dnT beta RII mice, although both groups had similar levels of procollagen type I or M mRNA and total collagen content in lesions. Analysis of both gene expression and protein content showed a significant decrease of lysyl oxidase, the extracellular enzyme needed for collagen cross-linking, in aortas of Apoe(-/-) - CD4dnT beta RII mice. T-cell-driven inflammation provoked a selective and limited increase in the expression of proteinases that catabolize the extracellular matrix. Atheromata of Apoe(-/-) - CD4dnT beta RII mice had increased levels of matrix metalloproteinase-13 and cathepsin S mRNAs and of the active form of cathepsin S protein but no increase was detected in collagen fragmentation. our results suggest that exaggerated T-cell-driven inflammation limits collagen maturation in the atherosclerotic plaque while having little effect on collagen degradation.

  • 15.
    Roberg, Karin
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Kågedal, Katarina
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Microinjection of cathepsin D induces caspase-dependent apoptosis in fibroblasts2002In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 161, no 1, 89-96 p.Article in journal (Refereed)
    Abstract [en]

    Recent reports have indicated that enzymes such as cathepsins D and B are translocated from lysosomal compartments to the cytosol early during apoptosis. We have previously noted that a translocation of cathepsins D and B occur before cytochrome c release and caspase activation in cardiomyocytes and human fibroblasts during oxidative stress-induced apoptosis. In the present report, we use a microinjection technique to investigate if cytosolic location of the cathepsins D and B are important for induction of apoptosis. We found that microinjection of cathepsin D into the cytosol of human fibroblasts caused apoptosis, which was detected as changes in distribution of cytochrome c, cell shrinkage, activation of caspases, chromatin condensation, and formation of pycnotic nuclei. No apoptosis was, however, induced by microinjection of cathepsin B. Moreover, apoptosis was prevented in fibroblasts pretreated with a caspase-3-like inhibitor, and also when microinjected with cathepsin D mixed with the cathepsin D inhibitor, pepstatin A. These results show that cytosolic cathepsin D can act as a proapoptotic mediator upstream of cytochrome c release and caspase activation in human fibroblasts.

  • 16.
    Roberg, Karin
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Oxidative stress causes relocation of the lysosomal enzyme cathepsin D with ensuing apoptosis in neonatal rat cardiomyocytes1998In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 152, no 5, 1151-1156 p.Article in journal (Refereed)
    Abstract [en]

    Exposing neonatal rat heart myocytes to the redox cycling quinone naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) for 15 to 45 minutes led to a time-dependent release of cathepsin D from many secondary lysosomes to the cytosol, as analyzed by morphometry. Cathepsin D was detected electron microscopically using a pre-embedding immunostaining technique that utilizes antibodies conjugated to ultra-small (0.8-nm) gold particles and subsequent silver enhancement. The exposure to naphthazarin also caused a decrease in both the pH and the ATP level of the cells within the same time frame. Lipid peroxidation was, however, not detected. Pretreatment of the cultures with alpha-tocopherol succinate prevented cathepsin D relocation, as shown by immunofluorescence. After exposure to naphthazarin, cells were washed, and normal culture conditions were re-established for 18 hours. Many cells then showed apoptotic morphology (ie, cellular shrinkage and chromatin condensation) as analyzed by Giemsa staining. Also, 41% of the cells stained positive with the TUNEL technique, and DNA fragmentation was detected by separation of intact and fragmented DNA. Apoptosis was significantly decreased in cultures pretreated with alpha-tocopherol succinate.

  • 17.
    Salim, Sa'ad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Silva, Manuel A
    McMaster University.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Andersson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Perdue, Mary H
    McMaster University.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    CD83(+)CCR7(-) Dendritic Cells Accumulate in the Subepithelial Dome and Internalize Translocated Escherichia coli HB101 in the Peyers Patches of Heal Crohns Disease2009In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 174, no 1, 82-90 p.Article in journal (Refereed)
    Abstract [en]

    Recurrent Crohns disease originates with small erosions in the follicle-associated epithelium overlying the Peyers patches. Animal studies have illustrated mucosal immune regulation by dendritic cells located in the subepithelial dome. The aim of this study was to characterize the dendritic cells at this specific site in patients with Crohns disease. Heal tissues were obtained after surgery performed on Crohns patients; ileal samples from noninflammatory bowel disease and ulcerative colitis served as standard and inflammatory controls, respectively. Flow cytometry of isolated intestinal mononuclear cells showed a larger subset of dendritic cells in Crohns samples compared with controls. This finding was corroborated by confocal microscopy, showing enhanced infiltrates of cells positive for the dendritic cell markers, DC-SIGN(+) and CD83(+), in the subepithelial dome. Moreover, the CD83(+) cells in Crohns tissues showed reduced expression of the lymph node migratory receptor, CCR7, possibly contributing to the high numbers of dendritic cells. After exposure to nonpathogenic Escherichia coli in Ussing chambers, dendritic cells in the subepithelial dome of Crohns disease demonstrated increased co-localization with translocated bacteria. Immunohistochemical results revealed that DC-SIGN(+) cells in Crohns tissues were found to express toll-like receptor 4 and produce tumor necrosis factor-a. In conclusion, nonmigrating dendritic cells that accumulate in the subepithelial dome and internalize nonpathogenic bacteria may be important for the onset and perpetuation of mucosal inflammation in Crohns disease.

  • 18.
    Singh, Susmita K.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Anna-Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lindestam Arlehamn, Cecilia S.
    La Jolla Institute Allergy and Immunol, CA USA.
    Sette, Alessandro
    La Jolla Institute Allergy and Immunol, CA USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    HIV Interferes with Mycobacterium tuberculosis Antigen Presentation in Human Dendritic Cells2016In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 186, no 12, 3083-3093 p.Article in journal (Refereed)
    Abstract [en]

    HIV coinfection is the most prominent risk factor for progression of Mycobacterium tuberculosis (Mtb) infection into active tuberculosis (TB) disease. The mechanisms behind the increased transition from latent to active TB in coinfected individuals have not been well elucidated at the cellular level. We hypothesized that HIV infection contributes to Mtb pathogenesis by interfering with the dendritic cell (DC) mediated immune control. Mtb-antigen processing and presentation are key events in the immune response against TB. Human immature DCs coinfected with HIV/Mtb had decreased expression of human leukocyte antigen antigen D related and the costimulatory molecules CD40, CD80, and CD86. In addition, Mtb-infected DCs triggered a significant release of the proinflammatory cytokines IL-6, IL-1 beta, and tumor necrosis factor-alpha, whereas coinfected DCs did not. To assess the DC antigen presentation capacity, we measured interferon-gamma from co-cultures of DCs and autologous Mtb antigen-specific CD4(+) T cells. Interferon-gamma release was significantly reduced when purified protein derivative- and Ag85B-specific CD4(+) T cells had been activated with coinfected DCs compared to Mtb-infected DCs, and this effect was attributed to Mtb antigen processing rather than peptide major histocompatibility complex class II loading. Evaluating autophagy as a measure of vesicular processing and maturation further revealed that HIV efficiently blocks initiation of this pathway during coinfection. Overall, our results demonstrate that HIV impairs Mtb antigen presentation in DCs, thereby suppressing an important cell linking innate and adaptive immune response in TB.

  • 19.
    Wang, Arthur
    et al.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Keita, Åsa V.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Phan, Van
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    McKay, Catherine M.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Schoultz, Ida
    Nutrition-Gut-Brain Interactions Research Centre, the Faculty of Medicine, Örebro University, Örebro, Sweden.
    Lee, Joshua
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Murphy, Michael P.
    MRC-Mitochondrial Biology Unit, Cambridge, United Kingdom.
    Fernando, Maria
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Ronaghan, Natalie
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Balce, Dale
    Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
    Yates, Robin
    Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
    Dicay, Michael
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Beck, Paul L.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
    MacNaughton, Wallace K.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Mckay, Derek M.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Targeting Mitochondria-Derived Reactive Oxygen Species to Reduce Epithelial Barrier Dysfunction and Colitis2014In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 184, no 9, 2516-2527 p.Article in journal (Refereed)
    Abstract [en]

    Epithelial permeability is often increased in inflammatory bowel diseases. We hypothesized that perturbed mitochondrial function would cause barrier dysfunction and hence epithelial mitochondria could be targeted to treat intestinal inflammation. Mitochondrial dysfunction was induced in human colon-derived epithelial cell lines or colonic biopsy specimens using dinitrophenol, and barrier function was assessed by transepithelial flux of Escherichia coil with or without mitochondria-targeted antioxidant (MTA) cotreatment. The impact of mitochondria-targeted antioxidants on gut permeability and dextran sodium sulfate (DSS)-induced colitis in mice was tested. Mitochondrial superoxide evoked by dinitrophenol elicited significant internalization and transtocation of E. coil across epithelia and control colonic biopsy specimens, which was more striking in Crohns disease biopsy specimens; the mitochondria-targeted antioxidant, MitoTEMPO, inhibited these barrier defects. Increased gut permeability and reduced epithelial mitochondrial voltage-dependent anion channel expression were observed 3 days after DSS. These changes and the severity of DSS-colitis were reduced by MitoTEMPO treatment. In vitro DSS-stimulated IL-8 production by epithelia was reduced by MitoTEMPO. Metabolic stress evokes significant penetration of commensal bacteria across the epithelium, which is mediated by mitochondria-derived superoxide acting as a signaling, not a cytotoxic, molecule. MitoTEMPO inhibited this barrier dysfunction and suppressed colitis in DSS-colitis, likely via enhancing barrier function and inhibiting proinflammatory cytokine production. These novel findings support consideration of MTAs in the maintenance of epithelial barrier function and the management of inflammatory bowel diseases.

  • 20.
    Wangsa, Darawalee
    et al.
    Department of Oncology-Pathology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden. Genetics Branch, National Institutes of Health, Bethesda, Maryland.
    Heselmeyer-Haddad, Kerstin
    Genetics Branch, National Institutes of Health, Bethesda, Maryland.
    Ried, Patricia
    Department of Oncology-Pathology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Eriksson, Elina
    Department of Oncology-Pathology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Schäffer, Alejandro A
    Center for Cancer Research, National Cancer Institute, National Center for Biotechnology Information, National Institutes of Health, Bethesda, Maryland.
    Morrison, Larry E
    Abbott Molecular, Inc, Des Plaines, Illinois.
    Luo, Juhua
    School of Social Development and Public Policy, Beijing Normal University, Beijing, China.
    Auer, Gert
    Department of Oncology-Pathology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Munck-Wikland, Eva
    Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
    Ried, Thomas
    Genetics Branch, National Institutes of Health, Bethesda, Maryland.
    Åvall Lundqvist, Elisabeth
    Department of Gynaecologic Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
    Fluorescence in situ hybridization markers for prediction of cervical lymph node metastases.2009In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 175, no 6, 2637-2645 p.Article in journal (Refereed)
    Abstract [en]

    The presence of lymph node metastases is associated with poor prognosis in early stage cervical cancer. As of yet, no molecular markers predicting lymph node metastases have been identified. We examined single genetic markers and a composite marker, comprised of three fluorescence in situ hybridization (FISH) probes targeting the genes LAMP3, PROX1, and PRKAA1, in pretreatment cervical biopsies from 16 lymph node positive cases and 15 lymph node negative controls from women with stage IB and IIA cervical cancer. In addition, we determined clonal patterns by including CCND1 to compare the clonal constitution of primary tumors and associated lymph node metastases. The composite FISH marker allowed for classification of patients into those with and without lymph node metastases with a sensitivity and specificity of 75% and 87%, respectively (P = 0.001). The positive predictive value and negative predictive value were 86% and 76%, respectively. Clonal patterns varied among the tumors. In many cases, changes between the primary tumor and lymph node metastases in the most common clones may indicate that certain clones have a growth advantage for establishing metastases in lymph nodes. We conclude that the composite FISH marker may be useful for determining risk for subsequent development of lymph node metastases in patients with cervical cancer.

  • 21.
    Wegenast-Braun, Bettina M.
    et al.
    Hertie Institute Clin Brain Research, Germany German Centre Neurodegenerat Disease, Germany .
    Skodras, Angelos
    Hertie Institute Clin Brain Research, Germany German Centre Neurodegenerat Disease, Germany .
    Bayraktar, Gonca
    Hertie Institute Clin Brain Research, Germany University of Tubingen, Germany German Centre Neurodegenerat Disease, Germany .
    Mahler, Jasmin
    Hertie Institute Clin Brain Research, Germany University of Tubingen, Germany German Centre Neurodegenerat Disease, Germany .
    Fritschi, Sarah K.
    Hertie Institute Clin Brain Research, Germany University of Tubingen, Germany German Centre Neurodegenerat Disease, Germany .
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Mason, Jeffrey
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering.
    Liebig, Christian
    Hertie Institute Clin Brain Research, Germany German Centre Neurodegenerat Disease, Germany .
    Jucker, Mathias
    Hertie Institute Clin Brain Research, Germany German Centre Neurodegenerat Disease, Germany .
    Spectral Discrimination of Cerebral Amyloid Lesions after Peripheral Application of Luminescent Conjugated Oligothiophenes2012In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 181, no 6, 1953-1960 p.Article in journal (Refereed)
    Abstract [en]

    In vivo imaging of pathological protein aggregates provides essential knowledge of the kinetics and implications of these lesions in the progression of proteopathies, such as Alzheimer disease. Luminescent conjugated oligothiophenes are amyloid-specific ligands that bind and spectrally distinguish different types of amyloid aggregates. Herein, we report that heptamer formyl thiophene acetic acid (hFTAA) passes the blood-brain barrier after systemic administration and specifically binds to extracellular beta-amyloid deposits in the brain parenchyma (A beta plaques) and in the vasculature (cerebral beta-amyloid angiopathy) of beta-amyloid precursor protein transgenic APP23 mice. Moreover, peripheral application of hFIAA also stained intracellular lesions of hyperphosphorylated Tau protein in P301S Tau transgenic mice. Spectral profiling of all three amyloid types was acquired ex vivo using two-photon excitation. hFTAA revealed a distinct shift in its emission spectra when bound to A beta plaques versus Tau lesions. Furthermore, a spectral shift was observed for A beta plaques versus cerebral beta-amyloid angiopathy, indicating that different amyloid types and structural variances of a specific amyloid type can be distinguished. In conclusion, by adding spectral signatures to amyloid lesions, our results pave the way for a new area of in vivo amyloid imaging, allowing in vivo differentiation of amyloid (sub)types and monitoring changes of their structure/composition over time. (Am J Pathol 2012, 181: 1953-1960 http://dx.doi.org/10.1016/j.ajpath.2012.08.031)

  • 22.
    Westermark, Per
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Mucchiano, Gerd
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Marthin, Tove
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Johnson, Kenneth H.
    Department of Veterinary PathoBiology, College of Veteninary Medicine, University of Minnesota, St. Paul, Minnesota, USA.
    Sletten, Knut
    Department of Biochemistry and Biotechnology Center, Oslo University, Oslo, Norway.
    Apolipoprotein A1-derived amyloid in human aortic atherosclerotic plaques1995In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 147, no 5, 1186-1192 p.Article in journal (Refereed)
    Abstract [en]

    Amyloid deposits in the aortic intima are very common in association with atherosclerosis and aging. In the present study, a major fibril protein purified from amyloid present in human atherosclerotic plaques was shown to be a 69-amino acid N-terminal fragment of apolipoprotein AI. Although senile form of localized apolipoprotein AI-derived amyloidosis has recently been documented in pulmonary vessels of dogs, this is the first example of a localized human amyloid derived from this apolipoprotein.

  • 23. Williams, Cecilia
    et al.
    Pontén, Fredrik
    Moberg, Catherine
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Uhlén, Mathias
    Pontén, Jan
    Sitbon, Gisela
    Lundeberg, Joakim
    A high frequency of sequence alterations is due to formalin fixation of Archival specimens2000In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 155, 1467-1471 p.Article in journal (Refereed)
  • 24. Yang, Ping-Chang
    et al.
    Jury, Jennifer
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Sherman, Philip M
    McKay, Derek M
    Perdue, Mary H
    Chronic psychological stress in rats induces intestinal sensitization to luminal antigens2006In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 168, no 1, 104-114 p.Article in journal (Refereed)
    Abstract [en]

    There is increasing evidence that stress plays a role in the pathophysiology of chronic intestinal disorders, but the mechanisms remain unclear. Previous studies in rats have revealed that stress decreases gut barrier function and allows excessive uptake of luminal material. Here, we investigated whether chronic psychological stress acts to induce sensitization of intestinal tissues to oral antigens. Rats were subjected to 1 hour per day of water avoidance stress or sham stress daily for 10 days, and horseradish peroxidase (HRP) was delivered by gavage on day 5. Studies to determine sensitization were conducted on day 20. All stressed rats developed HRP-specific IgE antibodies, antigen-induced intestinal secretion, and increased numbers of inflammatory cells in gut mucosa. luminal URP was absorbed more readily by enterocytes of stressed animals. In addition, stressed rats had increased expression of interleukin-4 and decreased expression of Interferon-γ in gut mucosa, a cytokine profile that is typical of allergic conditions. Treatment of stressed rats with an antagonist to corticotropin-releasing hormone (previously shown to inhibit stress-enhanced gut permeability) eliminated the manifestations of intestinal hypersensitivity. Our results indicate that the presence of oral antigen during chronic psychological stress alters the immune response (to sensitization rather than oral tolerance) and causes subsequent antigen-induced gut pathophysiology. Copyright © American Society for Investigative Pathology.

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