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Showing 1 - 200 of 3044 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 22, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 21, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 84, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 23, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 28, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 4)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 5, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 341, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 1)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 215, SJR: 3.683, h-index: 202)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.615, h-index: 21)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.442, h-index: 21)
Acta Oecologica     Hybrid Journal   (Followers: 10, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 23, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 4, SJR: 0.383, h-index: 19)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 2)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 5, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 4, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 3)
Acute Pain     Full-text available via subscription   (Followers: 13)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 5)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 21)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 135, SJR: 5.2, h-index: 222)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.265, h-index: 53)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.299, h-index: 15)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 25, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 6, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 10, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 22, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 25, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 25, SJR: 0.183, h-index: 23)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.665, h-index: 29)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 10, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 28, SJR: 0.938, h-index: 33)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 16, SJR: 0.223, h-index: 22)
Advances in Dermatology     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 5)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 41, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 25, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 40, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 3)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 48, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 15)
Advances in Genetics     Full-text available via subscription   (Followers: 15, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 21, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.497, h-index: 31)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 35, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 3, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 2)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 15, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 24, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 13)
Advances in Pharmacology     Full-text available via subscription   (Followers: 15, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 7, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 61)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 2, SJR: 0.1, h-index: 2)
Advances in Space Research     Full-text available via subscription   (Followers: 349, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Surgery     Full-text available via subscription   (Followers: 7, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 30, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 16)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 43, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 318, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 5, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 8, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 407, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 15, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 30, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 39, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 54, SJR: 1.879, h-index: 120)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.434, h-index: 14)
Air Medical J.     Hybrid Journal   (Followers: 5, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 9, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 8)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access  
Algal Research     Partially Free   (Followers: 8, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 4, SJR: 0.776, h-index: 35)
Alpha Omegan     Full-text available via subscription   (SJR: 0.121, h-index: 9)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 8, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 47, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 5)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 3)
American Heart J.     Hybrid Journal   (Followers: 48, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 45, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 39, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 6, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 16, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 31, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 24, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 33, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 46, SJR: 2.023, h-index: 189)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 192, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 56, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 4)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.249, h-index: 88)
American J. of Otolaryngology     Hybrid Journal   (Followers: 24, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 26, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 21, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 34, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 55, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 9)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 2, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 37, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 167, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 8, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 11)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 1)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 22, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 157, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
Annales d'Endocrinologie     Full-text available via subscription   (Followers: 1, SJR: 0.394, h-index: 30)
Annales d'Urologie     Full-text available via subscription  
Annales de Cardiologie et d'Angéiologie     Full-text available via subscription   (SJR: 0.177, h-index: 13)
Annales de Chirurgie de la Main et du Membre Supérieur     Full-text available via subscription  
Annales de Chirurgie Plastique Esthétique     Full-text available via subscription   (Followers: 2, SJR: 0.354, h-index: 22)
Annales de Chirurgie Vasculaire     Full-text available via subscription   (Followers: 1)

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Journal Cover American Journal of Pathology
  [SJR: 2.653]   [H-I: 228]   [26 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0002-9440
   Published by Elsevier Homepage  [3044 journals]
  • Elucidating Mechanisms of Bladder Repair after Hyaluronan Instillation in
           Ketamine-Induced Ulcerative Cystitis in Animal Model
    • Authors: Yi-Lun Lee; Kun-Ling Lin; Shu-Mien Chuang; Yung-Chin Lee; Mei-Chin Lu; Bin-Nan Wu; Wen-Jeng Wu; Shyng-Shiou F. Yuan; Wan-Ting Ho; Yung-Shun Juan
      Pages: 1945 - 1959
      Abstract: Publication date: September 2017
      Source:The American Journal of Pathology, Volume 187, Issue 9
      Author(s): Yi-Lun Lee, Kun-Ling Lin, Shu-Mien Chuang, Yung-Chin Lee, Mei-Chin Lu, Bin-Nan Wu, Wen-Jeng Wu, Shyng-Shiou F. Yuan, Wan-Ting Ho, Yung-Shun Juan
      Ketamine-induced ulcerative cystitis (KIC) initially damaged the bladder mucosa and induced contracted bladder thereafter. Hyaluronan (hyaluronic acid; HA) instillation to the bladder has been used to treat KIC. The present study investigated bladder injury by urothelial defect and HA degeneration and bladder repair by urothelium proliferation and differentiation. This work was based on the hypothesis that HA treatment altered the bladder urothelial layer and the expression of hyaluronan-metabolizing enzymes and/or HA receptors in KIC. Cystometrogram study and tracing analysis of voiding behavior revealed that the ketamine-treated rats exhibited significant bladder hyperactivity with an increase in micturition frequency and a decrease in bladder capacity. The expression of inflammatory and fibrosis markers was also increased in the ketamine-treated group. Moreover, ketamine administration decreased the expression of urothelial barrier–associated protein, altered HA production, and induced abnormal urothelial differentiation, which might attribute to urothelial lining defects. However, HA instillation ameliorated bladder hyperactivity, lessened bladder mucosa damage, and decreased interstitial fibrosis. HA instillation also improved the level of HA receptors (CD44, Toll-like receptor-4, and receptor for HA-mediated motility) and HA synthases 1 to 3 and decreased the expression of hyaluronidases in the urothelial layer of bladder, resulting in enhanced mucosal regeneration. These findings suggested that HA could modulate inflammatory responses, enhance mucosal regeneration, and improve urothelial lining defects in KIC.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.06.004
  • Associations of Autoimmunity, Immunodeficiency, Lymphomagenesis, and Gut
           Microbiota in Mice with Knockins for a Pathogenic Autoantibody
    • Authors: Shweta Jain; Jerrold M. Ward; Dong-Mi Shin; Hongsheng Wang; Zohreh Naghashfar; Alexander L. Kovalchuk; Herbert C. Morse
      Pages: 2020 - 2033
      Abstract: Publication date: September 2017
      Source:The American Journal of Pathology, Volume 187, Issue 9
      Author(s): Shweta Jain, Jerrold M. Ward, Dong-Mi Shin, Hongsheng Wang, Zohreh Naghashfar, Alexander L. Kovalchuk, Herbert C. Morse
      A number of mouse strains transgenic for B-cell receptors specific for nucleic acids or other autoantigens have been generated to understand how autoreactive B cells are regulated in normal and autoimmune mice. Previous studies of nonautoimmune C57BL/6 mice heterozygous for both the IgH and IgL knockins of the polyreactive autoantibody, 564, produced high levels of autoantibodies in a largely Toll-like receptor 7–dependent manner. Herein, we describe studies of mice homozygous for the knockins that also expressed high levels of autoantibodies but, unlike the heterozygotes, exhibited a high incidence of mature B-cell lymphomas and enhanced susceptibility to bacterial infections. Microarray analyses and serological studies suggested that lymphomagenesis might be related to chronic B-cell activation promoted by IL-21. Strikingly, mice treated continuously with antibiotic-supplemented water did not develop lymphomas or abscesses and exhibited less autoimmunity. This mouse model may help us understand the reasons for enhanced susceptibility to lymphoma development exhibited by humans with a variety of autoimmune diseases, such as Sjögren syndrome, systemic lupus erythematosus, and highly active rheumatoid arthritis.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.05.017
  • Magnetic Resonance Monitoring of Disease Progression in mdx Mice on
           Different Genetic Backgrounds
    • Authors: Ravneet Vohra; Abhinandan Batra; Sean C. Forbes; Krista Vandenborne; Glenn A. Walter
      Pages: 2060 - 2070
      Abstract: Publication date: September 2017
      Source:The American Journal of Pathology, Volume 187, Issue 9
      Author(s): Ravneet Vohra, Abhinandan Batra, Sean C. Forbes, Krista Vandenborne, Glenn A. Walter
      Genetic modifiers alter disease progression in both preclinical models and subjects with Duchenne muscular dystrophy (DMD). Using multiparametric magnetic resonance (MR) techniques, we compared the skeletal and cardiac muscles of two different dystrophic mouse models of DMD, which are on different genetic backgrounds, the C57BL/10ScSn-Dmdmdx (B10-mdx) and D2.B10-Dmdmdx (D2-mdx). The proton transverse relaxation constant (T2) using both MR imaging and spectroscopy revealed significant age-related differences in dystrophic skeletal and cardiac muscles as compared with their age-matched controls. D2-mdx muscles demonstrated an earlier and accelerated decrease in muscle T2 compared with age-matched B10-mdx muscles. Diffusion-weighted MR imaging indicated differences in the underlying muscle structure between the mouse strains. The fractional anisotropy, mean diffusion, and radial diffusion of water varied significantly between the two dystrophic strains. Muscle structural differences were confirmed by histological analyses of the gastrocnemius, revealing a decreased muscle fiber size and increased fibrosis in skeletal muscle fibers of D2-mdx mice compared with B10-mdx and control. Cardiac involvement was also detected in D2-mdx myocardium based on both decreased function and myocardial T2. These data indicate that MR parameters may be used as sensitive biomarkers to detect fibrotic tissue deposition and fiber atrophy in dystrophic strains.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.05.010
  • Multifaceted C-X-C Chemokine Receptor 4 (CXCR4) Inhibition Interferes with
           Anti–Vascular Endothelial Growth Factor Therapy–Induced Glioma
    • Authors: Jean-Pierre Gagner; Yasmeen Sarfraz; Valerio Ortenzi; Fawaz M. Alotaibi; Luis A. Chiriboga; Awab T. Tayyib; Garry J. Douglas; Eric Chevalier; Barbara Romagnoli; Gérald Tuffin; Michel Schmitt; Guillaume Lemercier; Klaus Dembowsky; David Zagzag
      Pages: 2080 - 2094
      Abstract: Publication date: September 2017
      Source:The American Journal of Pathology, Volume 187, Issue 9
      Author(s): Jean-Pierre Gagner, Yasmeen Sarfraz, Valerio Ortenzi, Fawaz M. Alotaibi, Luis A. Chiriboga, Awab T. Tayyib, Garry J. Douglas, Eric Chevalier, Barbara Romagnoli, Gérald Tuffin, Michel Schmitt, Guillaume Lemercier, Klaus Dembowsky, David Zagzag
      Resistance to antiangiogenic therapy in glioblastoma (GBM) patients may involve hypoxia-induced expression of C-X-C motif chemokine receptor 4 (CXCR4) on invading tumor cells, macrophage/microglial cells (MGCs), and glioma stem cells (GSCs). We determined whether antagonizing CXCR4 with POL5551 disrupts anti–vascular endothelial growth factor (VEGF) therapy–induced glioma growth and dissemination. Mice bearing orthotopic CT-2A or GL261 gliomas received POL5551 and/or anti–VEGF antibody B20-4.1.1. Brain tissue was analyzed for tumor volume, invasiveness, hypoxia, vascular density, proliferation, apoptosis, GSCs, and MGCs. Glioma cells were evaluated for CXCR4 expression and polymorphism and POL5551's effects on CXCR4 ligand binding, cell viability, and migration. No CXCR4 mutations were identified. POL5551 inhibited CXCR4 binding to its ligand, stromal cell–derived factor-1α, and reduced hypoxia- and stromal cell–derived factor-1α–mediated migration dose–dependently but minimally affected cell viability. In vivo, B20-4.1.1 increased hypoxic foci and invasiveness, as seen in GBM patients receiving anti-VEGF therapy. Combination of POL5551 and B20-4.1.1 reduced both glioma invasiveness by 16% to 39% and vascular density compared to B20-4.1.1 alone in both glioma models. Reduced populations of GSCs and MGCs were also seen in CT-2A tumors. POL5551 concentrations, evaluated by mass spectrometry, were higher in tumors than in neighboring brain tissues, likely accounting for the results. Inhibition of CXCR4-regulated tumoral, stem cell, and immune mechanisms by adjunctive CXCR4 antagonists may help overcome antiangiogenic therapy resistance, benefiting GBM patients.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.04.020
  • Smooth Muscle Nitric Oxide Responsiveness and Clinical Maturation of
           Hemodialysis Arteriovenous Fistulae
    • Authors: Xiaoyong Tong; Xiuyun Hou; Christopher Wason; Tal Kopel; Richard A. Cohen; Laura M. Dember
      Pages: 2095 - 2101
      Abstract: Publication date: September 2017
      Source:The American Journal of Pathology, Volume 187, Issue 9
      Author(s): Xiaoyong Tong, Xiuyun Hou, Christopher Wason, Tal Kopel, Richard A. Cohen, Laura M. Dember
      The arteriovenous fistula is the preferred type of hemodialysis vascular access for patients with end-stage renal disease, but a high proportion of newly created fistulas fail to mature for use. Stenosis caused by neointimal hyperplasia often is present in fistulas with maturation failure, suggesting that local mechanisms controlling vascular smooth muscle cell (SMC) migration and proliferation are important contributors to maturation failure. SMCs cultured from explants of vein tissue obtained at the time of fistula creation from 19 patients with end-stage renal disease were studied to determine whether smooth muscle responsiveness to nitric oxide is associated with fistula maturation outcomes. Nitric oxide–induced inhibition of smooth muscle cell migration, but not proliferation, was greater in cells from patients with subsequent fistula maturation success than from patients with subsequent fistula maturation failure (mean inhibition percentage, 17 versus 5.7, respectively; P = 0.035). Impaired nitric oxide responsiveness was associated with oxidation of the calcium regulatory protein, sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), and was reversed by overexpressing SERCA (1.8-fold increase in inhibition, P = 0.0128) or down-regulating Nox4-based NADPH oxidase (2.3-fold increase in inhibition; P = 0.005). Our data suggest that the nitric oxide responsiveness of SMC migration is associated with fistula maturation success and raises the possibility that therapeutic restoration of nitric oxide responsiveness through manipulation of local mediators may prevent fistula maturation failure.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.05.006
  • Linking Sex Differences in Non-Alcoholic Fatty Liver Disease to Bile Acid
           Signaling, Gut Microbiota, and High Fat Diet
    • Authors: John Y.L. Chiang
      Pages: 1658 - 1659
      Abstract: Publication date: August 2017
      Source:The American Journal of Pathology, Volume 187, Issue 8
      Author(s): John Y.L. Chiang
      Teaser This commentary highlights the article by Jena et al that studied the complex interplay between diet, bile acids, sex, and dysbiosis in hepatic steatosis and inflammation.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.06.001
  • Antifibrotic Actions of Peroxisome Proliferator-Activated Receptor γ
           Ligands in Corneal Fibroblasts Are Mediated by β-Catenin–Regulated
    • Authors: Kye-Im Jeon; Richard P. Phipps; Patricia J. Sime; Krystel R. Huxlin
      Pages: 1660 - 1669
      Abstract: Publication date: August 2017
      Source:The American Journal of Pathology, Volume 187, Issue 8
      Author(s): Kye-Im Jeon, Richard P. Phipps, Patricia J. Sime, Krystel R. Huxlin
      Wound healing after corneal injury typically involves fibrosis, with transforming growth factor β1 (TGF-β1) as one of its strongest mediators. A class of small molecules—peroxisome proliferator–activated receptor γ (PPARγ) ligands—exert potent antifibrotic effects in the cornea by blocking phosphorylation of p38 mitogen-activated protein kinase (MAPK). However, why this blocks fibrosis remains unknown. Herein, we show that PPARγ ligands (rosiglitazone, troglitazone, and 15-deoxy-Δ12,14-prostaglandin J2) decrease levels of β-catenin. We also show that β-catenin siRNA and the Wingless/integrated (Wnt) inhibitor pyrvinium block the ability of corneal fibroblasts to up-regulate synthesis of α-smooth muscle actin (α-SMA), collagen 1 (COL1), and fibronectin (FN) in response to TGF-β1. Activation of TGF-β receptors and p38 MAPK increased glycogen synthase kinase 3β (GSK3β) phosphorylation, whereas a chemical inhibitor of p38 MAPK (SB203580) reduced the phosphorylation of GSK3β, decreasing active β-catenin levels in both cytoplasmic and nuclear fractions. Finally, lithium chloride, a GSK3 inhibitor, also attenuated the TGF-β1–induced increase in α-SMA, COL1, and FN expression. All in all, our results suggest that TGF-β1 stimulation increases active β-catenin concentration in cultured corneal fibroblasts through p38 MAPK regulation of canonical Wnt/β-catenin signaling, increasing α-SMA, COL1, and FN synthesis. Thus, PPARγ ligands, by blocking TGF-β1–induced p38 MAPK phosphorylation, prevent increases in both total and active β-catenin through p38 MAPK-GSK3β signaling.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.04.002
  • Exome Sequencing Landscape Analysis in Ovarian Clear Cell Carcinoma Shed
           Light on Key Chromosomal Regions and Mutation Gene Networks
    • Authors: Ryusuke Murakami; Noriomi Matsumura; J.B. Brown; Koichiro Higasa; Takanobu Tsutsumi; Mayumi Kamada; Hisham Abou-Taleb; Yuko Hosoe; Sachiko Kitamura; Ken Yamaguchi; Kaoru Abiko; Junzo Hamanishi; Tsukasa Baba; Masafumi Koshiyama; Yasushi Okuno; Ryo Yamada; Fumihiko Matsuda; Ikuo Konishi; Masaki Mandai
      Abstract: Publication date: Available online 6 September 2017
      Source:The American Journal of Pathology
      Author(s): Ryusuke Murakami, Noriomi Matsumura, J.B. Brown, Koichiro Higasa, Takanobu Tsutsumi, Mayumi Kamada, Hisham Abou-Taleb, Yuko Hosoe, Sachiko Kitamura, Ken Yamaguchi, Kaoru Abiko, Junzo Hamanishi, Tsukasa Baba, Masafumi Koshiyama, Yasushi Okuno, Ryo Yamada, Fumihiko Matsuda, Ikuo Konishi, Masaki Mandai
      Previous studies have reported genome-wide mutation profile analyses in ovarian clear cell carcinomas (OCCCs). This study aims to identify specific novel molecular alterations by combined analyses of somatic mutation and copy number variation. We performed whole exome sequencing of 39 OCCC samples with 16 matching blood tissue samples. Four hundred twenty-six genes had recurrent somatic mutations. Among the 39 samples, ARID1A (62%) and PIK3CA (51%) were frequently mutated, as were genes such as KRAS (10%), PPP2R1A (10%), and PTEN (5%), that have been reported in previous OCCC studies. We also detected mutations in MLL3 (15%), ARID1B (10%), and PIK3R1 (8%), which are associations not previously reported. Gene interaction analysis and functional assessment revealed that mutated genes were clustered into groups pertaining to chromatin remodeling, cell proliferation, DNA repair and cell cycle checkpointing, and cytoskeletal organization. Copy number variation analysis identified frequent amplification in chr8q (64%), chr20q (54%), and chr17q (46%) loci as well as deletion in chr19p (41%), chr13q (28%), chr9q (21%), and chr18q (21%) loci. Integration of the analyses uncovered that frequently mutated or amplified/deleted genes were involved in the KRAS/phosphatidylinositol 3-kinase (82%) and MYC/retinoblastoma (75%) pathways as well as the critical chromatin remodeling complex switch/sucrose nonfermentable (85%). The individual and integrated analyses contribute details about the OCCC genomic landscape, which could lead to enhanced diagnostics and therapeutic options.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.06.012
  • This Month in AJP
    • Abstract: Publication date: September 2017
      Source:The American Journal of Pathology, Volume 187, Issue 9

      Teaser The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.

      PubDate: 2017-09-06T16:00:52Z
  • Correction
    • Abstract: Publication date: September 2017
      Source:The American Journal of Pathology, Volume 187, Issue 9

      PubDate: 2017-09-06T16:00:52Z
  • Lymphotoxins Promote the Progression of Human Lymphatic Malformation by
           Enhancing Lymphatic Endothelial Cell Proliferation
    • Authors: Jie-Gang Yang; Yan-Fang Sun; Ke-Fei He; Jian-Gang Ren; Zhuo-Jue Liu; Bing Liu; Wei Zhang; Yi-Fang Zhao
      Abstract: Publication date: Available online 31 August 2017
      Source:The American Journal of Pathology
      Author(s): Jie-Gang Yang, Yan-Fang Sun, Ke-Fei He, Jian-Gang Ren, Zhuo-Jue Liu, Bing Liu, Wei Zhang, Yi-Fang Zhao
      Formation of inflammation-related tertiary lymphoid organs promotes human lymphatic malformation (LM) development. However, the role of lymphotoxins (LTs) and LT-related inducible ligand, the crucial mediators for tertiary lymphoid organ formation, is undetermined in LMs. Herein, we show that LTs and LT-related inducible ligand promote LM development by enhancing lymphatic endothelial cell (LEC) proliferation via activating NF-κB pathways. The expression of LTs and their receptors was increased in LMs, especially the infected ones, when compared with normal skins. Nuclear translocation of p65, p52, and RelB in the LECs of LMs indicated the activation of classical and alternative NF-κB pathways. Pearson's correlation and cluster analysis suggested the close relationship between LEC proliferation and NF-κB activation. Moreover, in vitro data demonstrated LTs accelerated the proliferation of human dermal lymphatic endothelial cells (HdLECs) through activation of NF-κB. Additionally, LPS up-regulated LT receptor expression in HdLECs, leading to increased sensitivity to LTs. Suppression of LT receptors hampered lipopolysaccharide-enhanced HdLEC proliferation, indicating the crucial role of LT pathways in inflammatory lymphangiogenesis. Besides, evidences from the LM rat models demonstrated LTα and lipopolysaccharide enhanced LEC proliferation, therefore promoting LM development. Blocking LT pathways by neutralizing antibodies against LTα and LTβR may decelerate the growth of the disease. In summary, our present study demonstrated activation of LT signaling pathways in LECs contributed to the progression of LMs.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.019
  • Essential Role of Interleukin-12 in Angiogenesis in Type 2 Diabetes
    • Authors: Maha Ali; Vishal Mali; Samuel Haddox; Soad M. AbdelGhany; Sahar E.M. El-deek; Atif Abulfadl; Khalid Matrougui; Souad Belmadani
      Abstract: Publication date: Available online 22 August 2017
      Source:The American Journal of Pathology
      Author(s): Maha Ali, Vishal Mali, Samuel Haddox, Soad M. AbdelGhany, Sahar E.M. El-deek, Atif Abulfadl, Khalid Matrougui, Souad Belmadani
      Recently interleukin-12 (IL-12) emerged as a critical player in type 2 diabetes complications. We previously reported that ischemia-induced angiogenesis is compromised in type 2 diabetic mice. In this study, we determined that IL-12 disruption rescued angiogenesis and arteriogenesis in type 2 diabetic mice. To induce type 2 diabetes, Wild type (WT); p40IL-12−/− (p40−/−) and p35IL-12−/− (p35−/−) mice were fed high-fat diet (HFD) for 12 weeks. Body weight, glucose test tolerance, and insulin test tolerance were assessed. After 12 weeks of HFD, femoral artery was ligated and blood flow recovery was measured every week for four weeks. WT, p40−/− and p35−/− mice fed HFD become obese after 12 weeks and exhibit glucose intolerance and insulin resistance. Blood flow recovery was fully restored in 2 to 3 weeks after femoral artery ligation in all group of mice fed normal diet. However, after 12 weeks of HFD, blood flow recovery was compromised in WT mice while it was fully recovered in p40−/− and p35−/−. The mechanism of blood flow recovery involves an increase in capillaries/ arterioles density, eNOS/Akt/VEGFR2 signaling, and a reduction in oxidative stress and inflammation. The disruption of IL-12 promotes angiogenesis and increases blood flow recovery in obese type 2 diabetic mice by eNOS/Akt/VEGFR2/Oxidative stress-inflammation dependent mechanism.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.021
  • Systemic monocyte chemotactic protein-1 inhibition modifies renal
           macrophages and restores glomerular endothelial glycocalyx and barrier
           function in diabetic nephropathy
    • Authors: Margien G.S. Boels; Angela Koudijs; M. Cristina Avramut; Wendy M.P.J. Sol; Gangqi Wang; Annemarie M. van Oeveren-Rietdijk; Anton Jan van Zonneveld; Hetty C. de Boer; Johan van der Vlag; Cees van Kooten; Dirk Eulberg; Bernard M. van den Berg; Daphne H.T. IJpelaar; Ton J. Rabelink
      Abstract: Publication date: Available online 22 August 2017
      Source:The American Journal of Pathology
      Author(s): Margien G.S. Boels, Angela Koudijs, M. Cristina Avramut, Wendy M.P.J. Sol, Gangqi Wang, Annemarie M. van Oeveren-Rietdijk, Anton Jan van Zonneveld, Hetty C. de Boer, Johan van der Vlag, Cees van Kooten, Dirk Eulberg, Bernard M. van den Berg, Daphne H.T. IJpelaar, Ton J. Rabelink
      Inhibition of monocyte chemotactic protein-1 (MCP)-1 with the Spiegelmer emapticap pegol (NOX-E36) shows long-lasting albuminuria-reducing effects in diabetic nephropathy. MCP-1 regulates inflammatory cell recruitment and differentiation of macrophages. Since the endothelial glycocalyx is also reduced in diabetic nephropathy, we hypothesized that MCP-1 inhibition restores glomerular barrier function through influencing macrophage cathepsin L secretion, thus reducing activation of the glycocalyx degrading enzyme heparanase. Four weeks treatment of diabetic Apoe KO mice with the mouse specific mNOX-E36 attenuated albuminuria without any change in systemic hemodynamics, despite persistent loss of podocyte function. MCP-1 inhibition, however, increased glomerular endothelial glycocalyx coverage with preservation of heparan sulfate. Mechanistically, both glomerular cathepsin L and heparanase expression were reduced. MCP-1 inhibition resulted in reduced CCR2-expressing Ly6Chi monocytes in the peripheral blood without affecting overall number of kidney macrophages at the tissue level. However, CD206+/Mac3+ cell ratio as an index of presence of anti-inflammatory macrophages increased in diabetic mice after treatment. Functional analysis of isolated renal macrophages showed increased release of interleukin-10, whereas tumor necrosis factor and cathepsin L release was reduced, further confirming polarization of tissue macrophages toward an anti-inflammatory phenotype during mNOX-E36 treatment. We show that MCP-1 inhibition restores glomerular endothelial glycocalyx and barrier function and reduces tissue inflammation in the presence of ongoing diabetic injury, suggesting a therapeutic potential for NOX-E36 in diabetic nephropathy.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.020
  • Reduced glutathione level promotes epithelial-mesenchymal transition in
           lens epithelial cells via a Wnt/β-catenin-mediated pathway: relevance for
           cataract therapy
    • Authors: Zongbo Wei; Jane Caty; Jeremy Whitson; Amy D. Zhang; Ramkumar Srinivasagan; Terrance J. Kavanagh; Hong Yan; Xingjun Fan
      Abstract: Publication date: Available online 19 August 2017
      Source:The American Journal of Pathology
      Author(s): Zongbo Wei, Jane Caty, Jeremy Whitson, Amy D. Zhang, Ramkumar Srinivasagan, Terrance J. Kavanagh, Hong Yan, Xingjun Fan
      The epithelial-mesenchymal transition (EMT) process plays a pivotal role in the pathogenesis of posterior capsular opacification (PCO) owing to remnant lens epithelial cell proliferation, migration and transformation after cataract surgery. The latter, we hypothesize, may result in posterior capsule wrinkling and opacification due to a profound change in the lens growth environment via a 1000-fold reduction of extracellular glutathione (GSH) levels. To test this hypothesis, we investigated the EMT process in cell culture and GSH biosynthesis deficiency mouse models. Our data indicate a dramatic increase of pro-EMT markers, such as type I collagen, alpha smooth muscle actin (αSMA), vimentin, and fibronectin under conditions of lens GSH depletion. Further study suggests that decreased GSH triggers the Wnt/β-catenin signal transduction pathway independent of TGFβ. Equally important, the antioxidants N-acetyl cysteine (NAC) and glutathione ethyl ester (GSH-EE) could significantly attenuate the EMT signaling stimulated by decreased GSH levels. These findings were further confirmed by mock cataract surgery in both Gclc and Gclm knockout mouse models. Remarkably increased EMT marker expression, β-catenin activation and translocation into the nucleus were found in both knockout mice compared to the wild type and such increased expression could be significantly attenuated by NAC or GSH-EE treatment. This study, for the first time we believe, links oxidative stress to lens fibrosis and PCO formation via EMT-mediated mechanisms.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.018
  • Estetrol, a fetal selective estrogen receptor modulator, acts on the
           vagina of mice through nuclear ERα activation
    • Authors: Thibaut Benoit; Marie-Cecile Valera; Coralie Fontaine; Melissa Buscato; Francoise Lenfant; Isabelle Raymond-Letron; Florence Tremollieres; Michel Soulie; Jean-Michel Foidart; Xavier Game; Jean-Francois Arnal
      Abstract: Publication date: Available online 19 August 2017
      Source:The American Journal of Pathology
      Author(s): Thibaut Benoit, Marie-Cecile Valera, Coralie Fontaine, Melissa Buscato, Francoise Lenfant, Isabelle Raymond-Letron, Florence Tremollieres, Michel Soulie, Jean-Michel Foidart, Xavier Game, Jean-Francois Arnal
      The genito-urinary syndrome of menopause has a negative impact on quality of life of postmenopausal women. The treatment of vulvo-vaginal atrophy (VVA) includes administration of estrogens. However, oral estrogen treatment is controversial due to its potential risks on venous thrombosis and breast cancer. Estetrol (E4) is a natural estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered as a weak estrogen. However, E4 was recently evaluated in a phase I-II clinical studies and found to act as an oral contraceptive in combination with a progestin, without increasing the level of coagulation factors. We recently showed that E4 stimulates uterine epithelial proliferation through nuclear estrogen receptor (ER) α, but failed to elicit endothelial responses. Here, we first evaluated the morphological and functional impacts of E4 on the vagina of ovariectomized mice and we determined the molecular mechanism mediating these effects. Vaginal epithelial proliferation and lubrication after stimulation were found to increase following E4 chronic treatment. Using the combination of pharmacological and genetic approaches, we demonstrated that these E4 effects on vagina are mediated by nuclear ERα activation. Altogether, we demonstrate that the selective activation of nuclear ERα is both necessary and sufficient to elicit functional and structural effects on the vagina, and therefore E4 appears promising as a therapeutic option to improve VVA.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.013
  • In vivo expression of miR-32 induces proliferation in prostate epithelium
    • Authors: Leena Latonen; Mauro Scaravilli; Andrew Gillen; Samuli Hartikainen; Fu-Ping Zhang; Pekka Ruusuvuori; Paula Kujala; Matti Poutanen; Tapio Visakorpi
      Abstract: Publication date: Available online 19 August 2017
      Source:The American Journal of Pathology
      Author(s): Leena Latonen, Mauro Scaravilli, Andrew Gillen, Samuli Hartikainen, Fu-Ping Zhang, Pekka Ruusuvuori, Paula Kujala, Matti Poutanen, Tapio Visakorpi
      Micro RNAs (miRNAs) are important regulators of gene expression and often deregulated in cancer. We have previously shown that miR-32 is an androgen receptor-regulated miRNA overexpressed in castration resistant prostate cancer, and that miR-32 can improve prostate cancer cell growth in vitro. To assess effects of miR-32 in vivo, we developed transgenic mice overexpressing miR-32 in the prostate. The study indicated that transgenic miR-32 expression increases replicative activity in the prostate epithelium. We further observed an aging-associated increase in the incidence of goblet cell metaplasia in the prostate epithelium. Furthermore, aged miR-32 transgenic mice exhibited metaplasia-associated PIN at a low frequency. When cross-bred with mice lacking the other allele of tumor suppressor Pten (miR-32xPten+/- mice), miR-32 expression increased both the incidence and the replicative activity of PIN lesions in the dorsal prostate. The miR-32xPten+/- mice also demonstrated increased goblet cell metaplasia as compared with Pten+/- mice. By performing a microarray analysis of mouse prostate tissue to screen downstream targets and effectors of miR-32, we identified RAC2 as a potential, and clinically relevant, target of miR-32. We also demonstrate downregulation of several interesting, potentially prostate cancer relevant genes (Spink1, Spink5, and Casp1) by miR-32 in the prostate tissue. The results demonstrate that miR-32 increases proliferation and promotes metaplastic transformation in mouse prostate epithelium, which may promote neoplastic alterations in the prostate.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.012
  • Deletion of Endothelial TGF-β Signaling Leads to Choroidal
    • Authors: Anja Schlecht; Sarah V. Leimbeck; Herbert Jägle; Annette Feuchtinger; Ernst R. Tamm; Barbara M. Braunger
      Abstract: Publication date: Available online 18 August 2017
      Source:The American Journal of Pathology
      Author(s): Anja Schlecht, Sarah V. Leimbeck, Herbert Jägle, Annette Feuchtinger, Ernst R. Tamm, Barbara M. Braunger
      The molecular pathogenesis of choroidal neovascularization (CNV), an angiogenic process that critically contributes to vision loss in age-related macular degeneration (AMD) is unclear. Here we analyzed the role of transforming growth factor (TGF)-β signaling for CNV formation by generating a series of mutant mouse models with induced conditional deletion of TGF-β signaling in the entire eye, the retinal pigment epithelium (RPE) or the vascular endothelium. Deletion of TGF-β signaling in the eye caused CNV, irrespectively if it was ablated in newborn or three-week-old mice. Areas of CNV showed photoreceptor degeneration, multilayered RPE, basal lamina deposits and accumulations of monocytes/macrophages. The changes progressed leading to marked structural and functional alterations of the retina. While the specific deletion of TGF-β signaling in the RPE caused no obvious changes, specific deletion in vascular endothelial cells caused CNV and a phenotype quite similar to that observed after the deletion in the entire eye. We conclude that impairment of TGF-β signaling in the vascular endothelium of the eye is sufficient to trigger CNV formation. Our findings highlight the importance of TGF-β signaling as key player in the development of ocular neovascularization and indicate a fundamental role of TGF-β signaling in the pathogenesis of AMD.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.06.018
  • Ggnbp2 Null Mutation in Mice Leads to Male Infertility Due to a Defect at
           the Spermiogenesis Stage
    • Authors: Lingyun Liu; Yan He; Kaimin Guo; Linying Zhou; Xian Li; Michael Tseng; Lu Cai; Zi-Jian Lan; Junmei Zhou; Hongliang Wang; Zhenmin Lei
      Abstract: Publication date: Available online 18 August 2017
      Source:The American Journal of Pathology
      Author(s): Lingyun Liu, Yan He, Kaimin Guo, Linying Zhou, Xian Li, Michael Tseng, Lu Cai, Zi-Jian Lan, Junmei Zhou, Hongliang Wang, Zhenmin Lei
      Gametogenetin binding protein 2 (GGNBP2) is an evolutionarily conserved zinc finger protein. Although Ggnbp2 null embryos in the B6 background died due to a defective placenta, 6.8% of Ggnbp2 null mice in the B6/129 mixed background were viable and continued to adulthood. Adult Ggnbp2 null males were sterile with smaller testes and an azoospermic phenotype, while mutant females were fertile. Histopathological analysis of 2-month-old Ggnbp2 null testes revealed absence of mature spermatozoa in the seminiferous tubules and epididymides and reduction of the number of spermatids. Ultrastructural analysis indicated dramatic morphological defects of developing spermatids in the Ggnbp2 null testes, including irregularly shaped acrosomes, acrosome detachment, cytoplasmic remnant, ectopic manchette and ill-formed head shape in both elongating and elongated spermatids. However, the numbers of spermatogonia, spermatocytes, Leydig cells and Sertoli cells in Ggnbp2 null testes did not significantly differ from the wild-type (WT) siblings. Gonadotropins, testosterone and the blood-testis barrier were essentially unaffected. Western blot analyses showed increases in α-E-catenin, β-catenin and N-cadherin, decreases in E-cadherin, afadin and nectin-3, and were unchanged in vinculin, nectin-2, FAK and integrin-β1 protein levels in Ggnbp2 null testes compared to WT siblings. Together, this study demonstrates that GGNBP2 is critically required for maintenance of the adhesion integrity of the adlumenal germ epithelium and is indispensable for normal spermatid transformation into mature spermatozoa in mice.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.016
  • Cysteine protease–dependent mucus disruptions and differential mucin
           gene expression in Giardia duodenalis infection
    • Authors: Christina B. Amat; Jean-Paul Motta; Elena Fekete; France Moreau; Kris Chadee; Andre G. Buret
      Abstract: Publication date: Available online 18 August 2017
      Source:The American Journal of Pathology
      Author(s): Christina B. Amat, Jean-Paul Motta, Elena Fekete, France Moreau, Kris Chadee, Andre G. Buret
      The intestinal mucus layer provides a critical host defense against pathogen exposure and epithelial injury, and yet little is known of how enteropathogens may circumvent this physiological barrier. Giardia duodenalis is a small intestinal parasite responsible for diarrheal disease and chronic post-infectious illness. This study reveals a complex interaction at the surface of epithelial cells, between G. duodenalis and the intestinal mucus layer. Here, we reveal mechanisms whereby G. duodenalis evades and disrupts the first line of host defense by degrading human mucin-2 (MUC2), depleting mucin stores and inducing differential gene expression in the mouse small and large intestines. Human colonic biopsies exposed to G. duodenalis were depleted of mucus and in vivo, mice infected with G. duodenalis had a thinner mucus layer and demonstrated differential Muc2 and Muc5ac mucin gene expression. Infection in Muc2 -/- mice elevated trophozoite colonization in the small intestine and impaired weight gain. In vitro, human LS174T goblet-like cells were depleted of mucus and had elevated levels of MUC2 mRNA expression following G. duodenalis exposure. Importantly, the cysteine protease inhibitor E64 prevented mucus degradation, mucin depletion, and the increase in MUC2 expression. This study demonstrates a novel role for Giardia’s cysteine proteases in pathogenesis, and describes how Giardia’s disruptions of the mucus barrier facilitate bacterial translocation that may contribute to the onset and propagation of disease.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.009
  • Intermittent Glucocorticoid Dosing Improves Muscle Repair and Function in
           Mice with Limb Girdle Muscular Dystrophy
    • Authors: Mattia Quattrocelli; Isabella M. Salamone; Patrick Page; James L. Warner; Alexis R. Demonbreun; Elizabeth M. McNally
      Abstract: Publication date: Available online 18 August 2017
      Source:The American Journal of Pathology
      Author(s): Mattia Quattrocelli, Isabella M. Salamone, Patrick Page, James L. Warner, Alexis R. Demonbreun, Elizabeth M. McNally
      The muscular dystrophies are genetically diverse. Shared pathological features among muscular dystrophies include breakdown, or loss of muscle, and accompanying fibrotic replacement. Novel strategies are needed to enhance muscle repair and function and to slow this pathological remodeling. Glucocorticoid steroids like prednisone are known to delay loss of ambulation in patients with Duchenne Muscular Dystrophy but are accompanied by prominent side effects. However, less is known about the effects of steroid administration in other types of muscular dystrophies, including limb-girdle muscular dystrophies (LGMDs). LGMD 2B is caused by loss of dysferlin, a membrane repair protein, and LGMD 2C is caused by loss of the dystrophin-associated protein, γ-sarcoglycan. Here we assessed the efficacy of steroid dosing on sarcolemmal repair, muscle function, histopathology, and the regenerative capacity of primary muscle cells. We found that in murine models of LGMD 2B and 2C, daily prednisone dosing reduced muscle damage and fibro-inflammatory infiltration. However, daily prednisone dosing also correlated with increased muscle adipogenesis and atrophic remodeling. Conversely, intermittent dosing of prednisone, provided once weekly, enhanced muscle repair and did not induce atrophy or adipogenesis, and was associated with improved muscle function. These data indicate that dosing frequency of glucocorticoid steroids impacts muscle remodeling in non-Duchenne muscular dystrophies, suggesting a positive outcome associated with intermittent steroid dosing in LGMD 2B and 2C muscle.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.017
  • The LIM-Only Protein Fhl2 Attenuates Development of Psoriatic Arthritis by
           Blocking Adam17-Mediated TNF Release
    • Authors: Rafael Leite Dantas; Bent Brachvogel; Tanja Schied; Vera Bergmeier; Boris Skryabin; Thomas Vogl; Stephan Ludwig; Viktor Wixler
      Abstract: Publication date: Available online 18 August 2017
      Source:The American Journal of Pathology
      Author(s): Rafael Leite Dantas, Bent Brachvogel, Tanja Schied, Vera Bergmeier, Boris Skryabin, Thomas Vogl, Stephan Ludwig, Viktor Wixler
      Four and a half LIM domain protein 2 (Fhl2) is an intracellular adaptor molecule with a high protein-protein interaction capacity. It acts as a modulator of several signaling molecules in the cytosol and as a cofactor of transcription in the nucleus. Recent studies suggest the role of Fhl2 in tissue repair and the anti-inflammatory response. Here, we show that Fhl2-deficient mice develop a more severe psoriatic arthritis disease under induction of the inducible human TNF transgene than wild type mice. The disease was accompanied by increased infiltration of activated macrophages and Treg cells in skin and digit joints as well as by increased expression of matrix metalloproteases and bone-specific proteases. The more severe pathogenesis of psoriatic arthritis in Fhl2 knockout mice coincided with enhanced levels of soluble hTNF cytokine, but surprisingly not with transcription of the hTNF transgene. Studying the shedding of cell membrane-bound hTNF by Adam17, a known Fhl2 interacting protein, revealed an enhanced release of TNF in the absence of Fhl2. In summary, our results show that Fhl2 anticipates the emerging inflammation and specifically the development of psoriatic arthritis by impeding the Adam17-mediated release of TNF.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.015
  • Imaging of wound closure of small epithelial lesions in the mouse trachea
    • Authors: Sarah Kretschmer; Mario Pieper; Antje Klinger; Gereon Hüttmann; Peter König
      Abstract: Publication date: Available online 18 August 2017
      Source:The American Journal of Pathology
      Author(s): Sarah Kretschmer, Mario Pieper, Antje Klinger, Gereon Hüttmann, Peter König
      Integrity of the airway epithelium is essential for normal lung function. However, studies analyzing the repair process of small epithelial lesions in pseudostratified airway epithelium are missing. To follow airway-epithelial wound closure over time, we lesioned small areas of the mouse tracheal epithelium (1 to 12 cells) using a femtosecond laser and followed wound closure up to 6 h by autofluorescence multiphoton microscopy. Selected lesions were also examined by scanning and transmission electron microscopy and by staining of F-actin. Most lesions with a size up to 6 cells closed by elongation of the surrounding epithelial cells within 6 h and all damaged cells were extruded from the epithelium. Electron microscopy confirmed that the surrounding epithelial cells directly closed lesions up to six cells. Most lesions larger than six cells did not close in the observation period of 6 h but we observed that basal cells flattened to cover the basement membrane. Delayed wound closure was in part attributable to damage of the basement membrane. Cells facing the lesion exhibited increased F-actin staining indicating active cell movement. Not all cells initially facing the lesion participated directly in wound closure indicating that closure is driven by movement of individual cells rather than a transepithelial coordinated process. Small wounds in the pseudostratified airway epithelium close within hours to preserve epithelial integrity.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.006
  • Magnetic Resonance Imaging and Molecular Characterization of a
           Hormone-Mediated Murine Model of Prostate Enlargement and Bladder Outlet
    • Authors: Erin M. McAuley; Devkumar Mustafi; Brian W. Simons; Rebecca Valek; Marta Zamora; Erica Markiewicz; Sophia Lamperis; Anthony Williams; Brian B. Roman; Chad Vezina; Greg Karczmar; Aytekin Oto; Donald J. Vander Griend
      Abstract: Publication date: Available online 18 August 2017
      Source:The American Journal of Pathology
      Author(s): Erin M. McAuley, Devkumar Mustafi, Brian W. Simons, Rebecca Valek, Marta Zamora, Erica Markiewicz, Sophia Lamperis, Anthony Williams, Brian B. Roman, Chad Vezina, Greg Karczmar, Aytekin Oto, Donald J. Vander Griend
      Urinary complications resulting from benign prostatic hyperplasia (BPH) and bladder outlet obstruction (BOO) continue to be a serious health problem. Novel animal model systems and imaging approaches are needed to understand the mechanisms of disease initiation, and to develop novel therapies for BPH. Long-term administration of both estradiol (E) and testosterone (T) in mice can result in prostatic enlargement and recapitulate several clinical components of lower urinary tract symptoms (LUTS). Here we use longitudinal magnetic resonance imaging (MRI) and histological analyses to quantify changes in prostatic volume, urethral volume, and genitourinary vascularization over time in response to estradiol-induced prostatic enlargement. Our data demonstrate significant prostatic enlargement by 12 weeks post-treatment, with no detectable immune infiltrate by macrophages, T- or B-cell populations. Importantly, the percentage of cell death as measured by TUNEL was significantly decreased in the prostatic epithelium of treated animals as compared to controls. We found no significant change in prostate cell proliferation in treated mice when compared to controls. These studies highlight the utility of MRI to quantify changes in prostatic and urethral volumes over time. In conjunction with histological analyses, this approach has the high potential to enable mechanistic studies of initiation and progression of clinically relevant LUTS. Additionally, this model is tractable for investigation and testing of therapeutic interventions to ameliorate or potentially reverse prostatic enlargement.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.014
  • Stromal expression of activated leukocyte cell adhesion molecule (ALCAM)
           promotes lung tumor growth and metastasis
    • Authors: Ann-Helen Willrodt; Michal Beffinger; Martina Vranova; Darya Protsyuk; Katja Schuler; Maria Jadhav; Mathias Heikenwalder; Maries van den Broek; Lubor Borsig; Cornelia Halin Winter
      Abstract: Publication date: Available online 17 August 2017
      Source:The American Journal of Pathology
      Author(s): Ann-Helen Willrodt, Michal Beffinger, Martina Vranova, Darya Protsyuk, Katja Schuler, Maria Jadhav, Mathias Heikenwalder, Maries van den Broek, Lubor Borsig, Cornelia Halin Winter
      Activated leukocyte cell adhesion molecule (ALCAM) is expressed on various cell types, including leukocytes, endothelial cells and certain tumor cells. While ALCAM expression on tumor cells has been linked with tumor invasion and metastatic spread, the contribution of ALCAM expressed in cells forming the tumor stroma to cancer progression has not been investigated. In this study, we made use of ALCAM-deficient (ALCAM-/-) mice to evaluate the role of ALCAM in lung tumor growth and metastasis. ALCAM-/- mice displayed an altered blood vascular network in the lung and the diaphragm, indicative of an angiogenesis defect. Absence of ALCAM expression by cells forming the stromal tumor microenvironment profoundly impacted lung tumor growth in three different intravenous metastasis models. In the case of Lewis lung carcinoma (LLC), an additional defect in tumor cell homing to the lungs and a resulting reduction in the number of lung tumor nodules was observed. Similarly, when LLC were subcutaneously implanted to study spontaneous tumor cell metastasis, the rate of LLC metastases to the lungs was profoundly reduced in ALCAM-/- mice. Taken together, our work demonstrates for the first time the in vivo contribution of ALCAM to angiogenesis and reveals a novel role of stromally expressed ALCAM in supporting tumor growth and metastatic spread.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.008
  • Discerning Clinical Responses in Breast Cancer Based On Molecular
    • Authors: William B. Coleman; Carey K. Anders
      Abstract: Publication date: Available online 16 August 2017
      Source:The American Journal of Pathology
      Author(s): William B. Coleman, Carey K. Anders
      Breast cancer represents a heterogeneous collection of diseases with disparate clinical behaviors, responses to treatment, and patient outcomes, despite common histopathological features at diagnosis. Examination of molecular signatures of breast cancer (based on complex gene expression patterns) enabled identification of several intrinsic molecular subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 enriched, and basal like. The intrinsic subtypes are associated with measures of clinical aggressiveness, but do not perfectly predict patient outcomes. Several molecular signatures have been developed for prediction and prognostication of breast cancer outcomes. This review describes the molecular classification of breast cancer and the use of predictive/prognostic molecular signatures for guiding treatment decisions in breast cancer patients.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.08.002
  • This Month in AJP
    • Abstract: Publication date: Available online 16 August 2017
      Source:The American Journal of Pathology

      Teaser The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.

      PubDate: 2017-09-06T16:00:52Z
  • Next-Generation Breast Cancer Omics
    • Authors: William B. Coleman
      Abstract: Publication date: Available online 16 August 2017
      Source:The American Journal of Pathology
      Author(s): William B. Coleman
      Teaser This Editorial highlights the reviews in the Breast Cancer Theme Issue that features topics related to next-generation breast cancer omics.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.011
  • Sphingosine kinase-2 deficiency ameliorates kidney fibrosis by
           up-regulating Smad7 in a mouse model of unilateral ureteral obstruction
    • Authors: Stephanie Schwalm; Sandra Beyer; Helena Frey; Riad Haceni; Georgios Grammatikos; Dominique Thomas; Gerd Geisslinger; Liliana Schaefer; Andrea Huwiler; Josef Pfeilschifter
      Abstract: Publication date: Available online 12 August 2017
      Source:The American Journal of Pathology
      Author(s): Stephanie Schwalm, Sandra Beyer, Helena Frey, Riad Haceni, Georgios Grammatikos, Dominique Thomas, Gerd Geisslinger, Liliana Schaefer, Andrea Huwiler, Josef Pfeilschifter
      Kidney fibrosis is a hallmark of chronic kidney disease and leads to extracellular matrix accumulation, organ scarring, and loss of kidney function. In this study, we investigated the role of sphingosine kinase-2 (SPHK2) on the progression of tubular fibrosis by utilizing a mouse unilateral ureteral obstruction (UUO) model. We found that SPHK2 protein and activity are up-regulated in fibrotic renal tissue. Functionally, Sphk2 deficient (Sphk2 -/- ) mice showed an attenuated fibrotic response to UUO compared to wild-type mice as demonstrated by reduced collagen abundance and decreased expression of fibronectin-1, collagen I, α-smooth muscle actin, connective tissue growth factor (CTGF), and plasminogen activator inhibitor (PAI-1). Importantly, these changes were associated with increased expression of the antifibrotic protein Smad7 and higher levels of sphingosine in Sphk2 -/- UUO kidneys. Mechanistically, sphingosine ameliorates transforming growth factor- β–induced collagen accumulation, CTGF, and PAI-1 expression, but enhances Smad7 protein expression in primary kidney fibroblasts. In a complementary approach, in human Sphk2-overexpressing mice, UUO resulted in exacerbated signs of fibrosis with increased collagen accumulation, higher expression levels of fibronectin-1, collagen I, α-smooth muscle actin, CTGF, and PAI-1 but decreased Smad7 expression. SPHK2 plays an important role in kidney fibrogenesis by modulating transforming growth factor-β signaling. Thus, SPHK2 might be an attractive new target for the treatment of fibrosis in chronic kidney disease.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.06.017
  • Thyroid hormone receptor-beta agonist GC-1 inhibits Met-β-catenin
           driven hepatocellular cancer
    • Authors: Elisabetta Puliga; Qian Min; Junyan Tao; Rong Zhang; Tirthadipa Pradhan-Sundd; Minakshi Poddar; Sucha Singh; Amedeo Columbano; Jinming Yu; Satdarshan P. Monga
      Abstract: Publication date: Available online 12 August 2017
      Source:The American Journal of Pathology
      Author(s): Elisabetta Puliga, Qian Min, Junyan Tao, Rong Zhang, Tirthadipa Pradhan-Sundd, Minakshi Poddar, Sucha Singh, Amedeo Columbano, Jinming Yu, Satdarshan P. Monga
      The thyromimetic agent GC-1 induces hepatocyte proliferation via Wnt/β-catenin signaling and may promoting regeneration in both acute and chronic liver insufficiencies. However, β-catenin activation particularly due to mutations in CTNNB1 is seen in a subset of hepatocellular carcinomas (HCC). Thus, it will be critical to address any effect of GC-1 on HCC growth and development, before its use can be advocated to stimulate regeneration in chronic liver diseases. In the current study, we first examine the effect of GC-1 on β-catenin-TCF4 activity in HCC cell lines harboring wild-type or mutated-CTNNB1. Next, we assess the effect of GC-1 on HCC in FVB mice generated by hydrodynamic tail vein injection of hMet-S45Y-β-catenin, using the sleeping beauty transposon-transposase. Four weeks following injection, mice were fed GC-1- (5mg/kg) or basal-diet for 10 or 21 days. GC-1 treatment showed no effect on β-catenin-TCF4 activity in HCC cells, irrespective of CTNNB1 mutations. Treatment with GC-1 for 10 or 21 days led to a significant reduction in tumor burden, associated with decreased tumor cell proliferation, and dramatic decreases in p-Met (Y1234/1235) p-ERK and p-STAT3 without affecting β-catenin and its downstream targets. Conclusion: GC-1 exerts a notable antitumoral effect on hMet-S45Y-β-catenin HCC, by inactivating Met signaling. GC-1 does not promote β-catenin activation in HCC. Thus GC-1 may be safe for use in inducing regeneration during chronic hepatic insufficiency.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.005
  • The role of angiotensin II in parietal epithelial cell proliferation and
           crescent formation in glomerular diseases
    • Authors: Paola Rizzo; Rubina Novelli; Cinzia Rota; Elena Gagliardini; Barbara Ruggiero; Daniela Rottoli; Ariela Benigni; Giuseppe Remuzzi
      Abstract: Publication date: Available online 12 August 2017
      Source:The American Journal of Pathology
      Author(s): Paola Rizzo, Rubina Novelli, Cinzia Rota, Elena Gagliardini, Barbara Ruggiero, Daniela Rottoli, Ariela Benigni, Giuseppe Remuzzi
      Crescentic glomerulonephritis (GN) is a devastating disease with rapidly progressive deterioration in kidney function, which, histologically, manifests as crescent formation in most glomeruli. We previously found that crescents derive from the aberrant proliferation and migration of parietal epithelial cells (PECs)/progenitor cells, and that the angiotensin (ang) II/ang II type-1 (AT1) receptor pathway may participate, together with the stromal cell-derived factor-1 (SDF-1)/CXCR4 axis, in the development of those lesions. Here, we elucidated sequential events and cellular and molecular interactions occurring during crescentic lesion onset and evolution. By analyzing kidney biopsies of patients with extracapillary GN, divided according to the grade of glomerular lesions, we found that the accumulation of macrophages expressing matrix metallopeptidase-12 started manifesting in glomeruli affected by early stage lesions, whereas AT1 receptor expression could not be detected. In glomeruli with advanced lesions, AT1 receptor expression increased markedly, and the up-regulation of SDF-1, and its receptor CXCR7, was documented on podocytes and PECs, respectively. In vitro studies were instrumental to demonstrating the role of ang II in inducing podocyte SDF-1 production, which ultimately activates PECs. The present findings support the possibility that angiotensin-converting enzyme inhibitor treatment might limit PEC activation and reduce the frequency and extension of crescents in extracapillary GN.

      PubDate: 2017-09-06T16:00:52Z
      DOI: 10.1016/j.ajpath.2017.07.004
  • Stellate Cells Orchestrate Concanavalin A–Induced Acute Liver Damage
    • Authors: Richa Rani; Ashish Tandon; Jiang Wang; Sudhir Kumar; Chandrashekhar R. Gandhi
      Abstract: Publication date: Available online 13 July 2017
      Source:The American Journal of Pathology
      Author(s): Richa Rani, Ashish Tandon, Jiang Wang, Sudhir Kumar, Chandrashekhar R. Gandhi
      Concanavalin A (ConA) causes immune cell–mediated liver damage, but the contribution of resident nonparenchymal cells is also evident. Hepatic stellate cells (HSCs) induce hepatic inflammation and immunological reactions; we therefore investigated their role in ConA-induced liver injury. ConA was administered i.v. to control or HSC-depleted mice; hepatic histopathology and cytokines/chemokines were determined after 6 hours. In vitro, the effects of ConA-conditioned HSC medium on hepatocytes were determined. ConA induced robust inflammation, sinusoidal congestion, and extensive midzonal hepatocyte death in control mice, which were strongly minimized in HSC-depleted mice. CD4 and natural killer T cells and neutrophils were markedly reduced in ConA-treated HSC-depleted mice compared to control mice. The increase in cytokines and chemokines implicated in hepatic injury was much higher in ConA-treated control mice than in HSC-depleted mice. In vitro, ConA-treated HSCs showed increased expression of interferon-β, tumor necrosis factor-α, and CXCL1, induced oxidative stress in hepatocytes, and caused hepatocyte apoptosis. ConA induced nuclear translocation of interferon-regulatory factor-1 (IRF1) in hepatocytes in vivo, and ConA/HSC induced a similar effect in cultured hepatocytes. IRF1-knockout mice were resistant to ConA-induced liver damage, and anti–interferon β antibody mitigated ConA/HSC-induced injury. In HSC–nonparenchymal cell (NPC) co-culture, ConA-induced expression of inflammatory cytokines/chemokines was significantly augmented compared to NPCs alone. HSCs play an essential role in ConA-induced liver injury directly via the interferon-β/IRF1 axis, and by modulating properties of other NPCs.

      PubDate: 2017-07-14T18:57:45Z
      DOI: 10.1016/j.ajpath.2017.05.015
  • M1 Macrophage–Induced Endothelial-to-Mesenchymal Transition Promotes
           Infantile Hemangioma Regression
    • Authors: Keith Q. Wu; Christopher S. Muratore; Eui Y. So; Changqi Sun; Patrycja M. Dubielecka; Anthony M. Reginato; Olin D. Liang
      Abstract: Publication date: Available online 12 July 2017
      Source:The American Journal of Pathology
      Author(s): Keith Q. Wu, Christopher S. Muratore, Eui Y. So, Changqi Sun, Patrycja M. Dubielecka, Anthony M. Reginato, Olin D. Liang
      Infantile hemangiomas are benign tumors of vascular endothelial cells (ECs), characterized by three distinct stages: proliferating phase, involuting phase, and involuted phase. The mechanisms that trigger involution of hemangioma into fibro-fatty tissue remain unknown. We report a novel mechanism by which M1-polarized macrophages induce endothelial-to-mesenchymal transition (EndMT) and promote hemangioma regression. M1- but not M2-polarized macrophages induced EndMT in ECs. Tumor necrosis factor-α and, to a lesser extent, IL-1β and interferon-γ were the most potent cytokines produced by the M1 macrophages that induce in vitro EndMT. Western blot analysis and gene expression profiling showed that ECs treated with M1 macrophages, tumor necrosis factor-α, or IL-1β decreased the expression of endothelial markers, whereas mesenchymal markers increased concomitantly. Immunohistochemical staining of patient samples revealed that a significant perivascular infiltration of M1, but not M2, macrophages coincides with endothelial expression of the critical EndMT transcription factors Snail/Slug in involuting hemangiomas. Most strikingly, M1 macrophage–treated ECs isolated from patient hemangiomas (HemECs) but not untreated HemECs readily differentiated into adipocytes on adipogenic induction. Thus, in vitro EndMT and adipogenesis of HemECs have, in part, recapitulated the natural history of hemangioma regression. In conclusion, our findings indicate that EndMT induced by M1 macrophages promotes infantile hemangioma regression and may lead to novel therapeutic treatments for this vascular tumor.

      PubDate: 2017-07-14T18:57:45Z
      DOI: 10.1016/j.ajpath.2017.05.014
  • Short-Term Alcohol Abstinence Improves Antibacterial Defenses of Chronic
           Alcohol-Consuming Mice against Gut Bacteria–Associated Sepsis Caused by
           Enterococcus faecalis Oral Infection
    • Authors: Makiko Kobayashi; Akira Asai; Ichiaki Ito; Sumihiro Suzuki; Kazuhide Higuchi; Fujio Suzuki
      Abstract: Publication date: Available online 11 July 2017
      Source:The American Journal of Pathology
      Author(s): Makiko Kobayashi, Akira Asai, Ichiaki Ito, Sumihiro Suzuki, Kazuhide Higuchi, Fujio Suzuki
      The effects of short-term alcohol abstinence on host antibacterial resistance against Enterococcus faecalis oral infection was investigated in chronic alcohol-consuming mice [mice with 0.1 g/day of 20% ethanol consumption for 12 or 16 weeks (CAC-mice)]. These mice were highly susceptible to the infection; however, after 7 days of alcohol abstinence (aaCAC-mice), their antibacterial resistances were completely restored to the normal mouse level. Normal mice inoculated with CAC-mouse hepatic macrophages were shown to be susceptible to the infection, whereas the same macrophage preparation from aaCAC-mice did not impair the antibacterial resistance of normal mice. aaCAC-mouse liver macrophages protected nonobese diabetic–severe combined immunodeficiency IL-2Rγnull mice exposed to E. faecalis, whereas those from CAC-mice did not. Monocyte-derived (MD) M2b macrophages were predominantly isolated from CAC-mouse livers, but these cells were not significantly isolated from aaCAC-mouse livers. Hepatic MD macrophages from aaCAC-mice switched to M1 macrophages in response to bacterial antigen, whereas the same macrophage preparation from CAC-mice did not. M1 Kupffer cells, M2a Kupffer cells, and MD M2b macrophages were shown to be not bactericidal, whereas E. faecalis was killed effectively by M1 macrophages derived from aaCAC-mouse hepatic MD macrophages. These results indicate that MD M2b macrophages predominantly distributed in the liver are responsible for the impaired resistance of CAC-mice to E. faecalis oral infection, and aaCAC-mice without MD M2b macrophages in the livers are resistant to the infection.

      PubDate: 2017-07-14T18:57:45Z
      DOI: 10.1016/j.ajpath.2017.05.013
  • UV Irradiation of Skin Enhances Glycolytic Flux and Reduces Migration
           Capabilities in Bone Marrow–Differentiated Dendritic Cells
    • Authors: Terence A. McGonigle; Kevin N. Keane; Simon Ghaly; Kim W. Carter; Denise Anderson; Naomi M. Scott; Helen S. Goodridge; Amy Dwyer; Eloise Greenland; Fiona J. Pixley; Philip Newsholme; Prue H. Hart
      Abstract: Publication date: Available online 11 July 2017
      Source:The American Journal of Pathology
      Author(s): Terence A. McGonigle, Kevin N. Keane, Simon Ghaly, Kim W. Carter, Denise Anderson, Naomi M. Scott, Helen S. Goodridge, Amy Dwyer, Eloise Greenland, Fiona J. Pixley, Philip Newsholme, Prue H. Hart
      A systemic immunosuppression follows UV irradiation of the skin of humans and mice. In this study, dendritic cells (DCs) differentiating from the bone marrow of UV-irradiated mice had a reduced ability to migrate toward the chemokine (C-C motif) ligand 21. Fewer DCs also accumulated in the peritoneal cavity of UV-chimeric mice (ie, mice transplanted with bone marrow from UV-irradiated mice) after injection of an inflammatory stimulus into that site. We hypothesized that different metabolic states underpin altered DC motility. Compared with DCs from the bone marrow of nonirradiated mice, those from UV-irradiated mice produced more lactate, used greater amounts of glucose, and had greater glycolytic flux in a bioenergetics stress test. Greater expression of 3-hydroxyanthranilate 3,4-dioxygenase was identified as a potential contributor to increased glycolysis. Inhibition of 3-hydroxyanthranilate 3,4-dioxygenase by 6-chloro-dl-tryptophan prevented both increased lactate production and reduced migration toward chemokine (C-C motif) ligand 21 by DCs differentiated from bone marrow of UV-irradiated mice. UV-induced prostaglandin E2 has been implicated as an intermediary in the effects of UV radiation on bone marrow cells. DCs differentiating from bone marrow cells pulsed in vitro for 2 hours with dimethyl prostaglandin E2 were functionally similar to those from the bone marrow of UV-irradiated mice. Reduced migration of DCs to lymph nodes associated with increased glycolytic flux may contribute to their reduced ability to initiate new immune responses in UV-irradiated mice.

      PubDate: 2017-07-14T18:57:45Z
      DOI: 10.1016/j.ajpath.2017.06.003
  • Regulator of Calcineurin 3 Ameliorates Autoimmune Arthritis by Suppressing
           Th17 Cell Differentiation
    • Authors: Jin-Sil Park; Jeong-Hee Jeong; Jae-Kyeong Byun; Mi-Ae Lim; Eun-Kyung Kim; Sung-Min Kim; Si-Young Choi; Sung-Hwan Park; Jun-Ki Min; Mi-La Cho
      Abstract: Publication date: Available online 10 July 2017
      Source:The American Journal of Pathology
      Author(s): Jin-Sil Park, Jeong-Hee Jeong, Jae-Kyeong Byun, Mi-Ae Lim, Eun-Kyung Kim, Sung-Min Kim, Si-Young Choi, Sung-Hwan Park, Jun-Ki Min, Mi-La Cho
      Regulator of calcineurin 3 (RCAN3), an endogenous regulator of the calcineurin–nuclear factor of activated T cells (NFAT) signaling pathway, inhibits the phosphatase activity of calcineurin, the nuclear translocation of NFAT, and the NFAT downstream pathway. To investigate the effects of RCAN3 on T-cell regulatory function and the development and progression of inflammatory arthritis, we studied the effects of RCAN3 transfection on regulation of Th17 cell differentiation in a murine T-lymphoma cell line and primary splenic CD4+ T cells. Overexpression of RCAN3 suppressed Th17 cell differentiation through the down-regulation of RAR receptor orphan receptor γT mRNA and up-regulation of Foxp3 mRNA. In mice with collagen-induced arthritis, injection of an RCAN3-overexpression vector controlled arthritis development in vivo. Injection of RCAN3 reduced the formation of osteoclasts and expression of inflammatory cytokines in vivo. Antioxidants stimulated the expression of RCAN3 in vitro, and combination therapy with pcDNA-RCAN3 had a synergistic suppressive effect on the development of arthritis. These data suggest that RCAN3 may be an effective treatment for rheumatoid arthritis.

      PubDate: 2017-07-14T18:57:45Z
      DOI: 10.1016/j.ajpath.2017.05.008
  • Laminin-Dependent Interaction between Astrocytes and Microglia
    • Authors: Saptarshi Biswas; Galina Bachay; Julianne Chu; Dale D. Hunter; William J. Brunken
      Abstract: Publication date: Available online 8 July 2017
      Source:The American Journal of Pathology
      Author(s): Saptarshi Biswas, Galina Bachay, Julianne Chu, Dale D. Hunter, William J. Brunken
      Retinal vascular diseases are among the leading causes of acquired blindness. In recent years, retinal microglia have been shown to influence vascular branching density and endothelial cell proliferation. However, how microglial recruitment and activation are regulated during development remains unclear. We hypothesized that microglial recruitment, activation, and down-stream signaling are modulated by components of the mural basement membrane. We used a reverse genetic approach to disrupt laminin expression in the vascular basement membrane and demonstrate that microglia respond to the mural basement membrane in an isoform-specific manner. Microglial density is significantly increased in the laminin γ3-null (Lamc3 −/−) retinal superficial vascular plexus and consequently the vascular branching density is increased. Microglia also respond to astrocyte-derived matrices and become hyperactivated in the Lamc3 −/− retina or when tested in vitro with cell-derived matrix. Pharmacological activation of microglia in the wild-type retina produced an Lamc3 −/−-like vascular phenotype, whereas pharmacological blocking of microglial activation in the Lamc3 −/− retina rescued the wild-type vascular phenotype. On the molecular level, microglial transforming growth factor-β1 expression is down-regulated in the Lamc3 −/− retina, and SMAD signaling decreased in endothelial cells with a consequent increase in endothelial proliferation. The reverse effects were seen in the Lamb2 −/− retina. Together, our results demonstrate a novel mechanism by which laminins modulate vascular branching and endothelial cell proliferation during retinal angiogenesis.

      PubDate: 2017-07-14T18:57:45Z
      DOI: 10.1016/j.ajpath.2017.05.016
  • HIV-Associated Cardiovascular Disease
    • Authors: Lisa Prevedel; Camilla Morocho; Michael V.L. Bennett; Eliseo A. Eugenin
      Abstract: Publication date: Available online 5 July 2017
      Source:The American Journal of Pathology
      Author(s): Lisa Prevedel, Camilla Morocho, Michael V.L. Bennett, Eliseo A. Eugenin
      Chronic HIV infection due to effective antiretroviral treatment has resulted in a broad range of clinical complications, including accelerated heart disease. Individuals with HIV infection have a 1.5 to 2 times higher incidence of cardiovascular diseases than their uninfected counterparts; however, the underlying mechanisms are poorly understood. To explore the link between HIV infection and cardiovascular diseases, we used postmortem human heart tissues obtained from HIV-infected and control uninfected individuals to examine connexin 43 (Cx43) expression and distribution and HIV-associated inflammation. Here, we demonstrate that Cx43 is dysregulated in the hearts of HIV-infected individuals. In all HIV heart samples analyzed, there were areas where Cx43 was overexpressed and found along the lateral membrane of the cardiomyocyte and in the intercalated disks. Areas of HIV tissue with anomalous Cx43 expression and localization also showed calcium overload, sarcofilamental atrophy, and accumulation of collagen. All these changes were independent of viral replication, CD4 counts, inflammation, and type of antiretroviral treatment. Overall, we propose that HIV infection increases Cx43 expression in heart, resulting in tissue damage that likely contributes to the high rates of cardiovascular disease in HIV-infected individuals.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.05.011
  • Characterization of Brown Adipose–Like Tissue in Trauma-Induced
           Heterotopic Ossification in Humans
    • Authors: Elizabeth A. Salisbury; Austin R. Dickerson; Thomas A. Davis; Jonathan A. Forsberg; Alan R. Davis; Elizabeth A. Olmsted-Davis
      Abstract: Publication date: Available online 4 July 2017
      Source:The American Journal of Pathology
      Author(s): Elizabeth A. Salisbury, Austin R. Dickerson, Thomas A. Davis, Jonathan A. Forsberg, Alan R. Davis, Elizabeth A. Olmsted-Davis
      Heterotopic ossification (HO), the abnormal formation of bone within soft tissues, is a major complication after severe trauma or amputation. Transient brown adipocytes have been shown to be a critical regulator of this process in a mouse model of HO. In this study, we evaluated the presence of brown fat within human HO lesions. Most of the excised tissue samples displayed histological characteristics of bone, fibroproliferative cells, blood vessels, and adipose tissue. Immunohistochemical analysis revealed extensive expression of uncoupling protein 1 (UCP1), a definitive marker of brown adipocytes, within HO-containing tissues but not normal tissues. As seen in the brown adipocytes observed during HO in the mouse, these UCP1+ cells also expressed the peroxisome proliferator-activated receptor γ coactivator 1α. However, further characterization showed these cells, like their mouse counterparts, did not express PRDM16, a key factor present in brown adipocytes found in depots. Nor did they express factors present in beige adipocytes. These results identify a population of UCP1+ cells within human tissue undergoing HO that do not entirely resemble either classic brown or beige adipocytes, but rather a specialized form of brown adipocyte-like cells, which have a unique function. These cells may offer a new target to prevent this unwanted bone.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.05.012
  • Retrograde Lymph Flow Leads to Chylothorax in Transgenic Mice with
           Lymphatic Malformations
    • Authors: Maximilian Nitschké; Alexander Bell; Sinem Karaman; Meelad Amouzgar; Joseph M. Rutkowski; Philipp E. Scherer; Kari Alitalo; Donald M. McDonald
      Abstract: Publication date: Available online 3 July 2017
      Source:The American Journal of Pathology
      Author(s): Maximilian Nitschké, Alexander Bell, Sinem Karaman, Meelad Amouzgar, Joseph M. Rutkowski, Philipp E. Scherer, Kari Alitalo, Donald M. McDonald
      Chylous pleural effusion (chylothorax) frequently accompanies lymphatic vessel malformations and other conditions with lymphatic defects. Although retrograde flow of chyle from the thoracic duct is considered a potential mechanism underlying chylothorax in patients and mouse models, the path chyle takes to reach the thoracic cavity is unclear. Herein, we use a novel transgenic mouse model, where doxycycline-induced overexpression of vascular endothelial growth factor (VEGF)-C was driven by the adipocyte-specific promoter adiponectin (ADN), to determine how chylothorax forms. Surprisingly, 100% of adult ADN–VEGF-C mice developed chylothorax within 7 days. Rapid, consistent appearance of chylothorax enabled us to examine the step-by-step development in otherwise normal adult mice. Dynamic imaging with a fluorescent tracer revealed that lymph in the thoracic duct of these mice could enter the thoracic cavity by retrograde flow into enlarged paravertebral lymphatics and subpleural lymphatic plexuses that had incompetent lymphatic valves. Pleural mesothelium overlying the lymphatic plexuses underwent exfoliation that increased during doxycycline exposure. Together, the findings indicate that chylothorax in ADN–VEGF-C mice results from retrograde flow of chyle from the thoracic duct into lymphatic tributaries with defective valves. Chyle extravasates from these plexuses and enters the thoracic cavity through exfoliated regions of the pleural mesothelium.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.05.009
  • Characterization of Normal Murine Carpal Bone Development Prompts
           Re-Evaluation of Pathologic Osteolysis as the Cause of Human Carpal-Tarsal
           Osteolysis Disorders
    • Authors: Syndia Lazarus; Hsu-Wen Tseng; Felicity Lawrence; Maria Ann Woodruff; Emma Letitia Duncan; Allison Robyn Pettit
      Abstract: Publication date: Available online 1 July 2017
      Source:The American Journal of Pathology
      Author(s): Syndia Lazarus, Hsu-Wen Tseng, Felicity Lawrence, Maria Ann Woodruff, Emma Letitia Duncan, Allison Robyn Pettit
      Multicentric carpal–tarsal osteolysis; multicentric osteolysis, nodulosis, and arthropathy; and Winchester syndromes, skeletal dysplasias characterized by carpal/tarsal and epiphyseal abnormalities, are caused by mutations in v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B (MAFB), matrix metalloproteinase 2 (MMP2), and MMP14, respectively; however, the underlying pathophysiology is unclear. Osteoclast-mediated osteolysis has been regarded as the main mechanism, but does not explain the skeletal distribution. We hypothesized that MAFB, MMP-2, and MMP-14 have integral roles in carpal/tarsal and epiphyseal bone development. Normal neonatal mouse forepaws were imaged by micro–computed tomography and examined histologically. Murine forepaw ossification occurred sequentially. Subarticular regions of endochondral ossification showed morphologic and calcification patterns that were distinct from archetypical physeal endochondral ossification. This suggests that two different forms of endochondral ossification occur. The skeletal sites showing the greatest abnormality in the carpal–tarsal osteolysis syndromes are regions of subarticular ossification. Thus, abnormal bone formation in areas of subarticular ossification may explain the site-specific distribution of the carpal–tarsal osteolysis phenotype. MafB, Mmp-2, and Mmp-14 were expressed widely, and tartrate-resistant acid phosphatase staining notably was absent in the subarticular regions of the cartilage anlagen and entheses at a time point most relevant to the human osteolysis syndromes. Thus, abnormal peri-articular skeletal development and modeling, rather than excessive bone resorption, may be the underlying pathophysiology of these skeletal syndromes.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.05.007
  • Increased Circulating and Urinary Levels of Soluble TAM Receptors in
           Diabetic Nephropathy
    • Authors: Peter Ochodnicky; Lionel Lattenist; Mohamed Ahdi; Jesper Kers; Melissa Uil; Nike Claessen; Jaklien C. Leemans; Sandrine Florquin; Joost C.M. Meijers; Victor E.A. Gerdes; Joris J.T.H. Roelofs
      Abstract: Publication date: Available online 29 June 2017
      Source:The American Journal of Pathology
      Author(s): Peter Ochodnicky, Lionel Lattenist, Mohamed Ahdi, Jesper Kers, Melissa Uil, Nike Claessen, Jaklien C. Leemans, Sandrine Florquin, Joost C.M. Meijers, Victor E.A. Gerdes, Joris J.T.H. Roelofs
      TAM receptors (Tyro3, Axl, and Mer) have been implicated in regulation of innate immunity. Circulating levels of TAM receptor soluble forms (sTyro3, sAxl, sMer) are related to autoimmune disorders. We investigated levels of TAM and their ligand protein S in patients with diabetes. Urinary and plasma levels of protein S, sTyro3, sAxl, and sMer were determined by enzyme-linked immunosorbent assay in 126 patients with diabetes assigned to a normoalbuminuric or macroalbuminuric (urinary albumin excretion <30 mg/24 hours and >300 mg/24 hours, respectively) study group and 18 healthy volunteers. TAM and protein S immunostaining was performed on kidney biopsy specimens from patients with diabetic nephropathy (n = 9) and controls (n = 6). TAM expression and shedding by tubular epithelial cells were investigated by PCR and enzyme-linked immunosorbent assay in an in vitro diabetes model. Patients with macroalbuminuria diabetes had higher circulating levels of sMer and more urinary sTyro3 and sMer than normoalbuminuric diabetics. Increased clearance of sTyro3 and sMer was associated with loss of tubular Tyro3 and Mer expression in diabetic nephropathy tissue and glomerular depositions of protein S. During in vitro diabetes, human kidney cells had down-regulation of Tyro3 and Mer mRNA and increased shedding of sTyro3 and sMer. Renal injury in diabetes is associated with elevated systemic and urine levels of sMer and sTyro3. This is the first study reporting excretion of sTAM receptors in the urine, identifying the kidney as a source of sTAM.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.05.004
  • Monocytes Promote Crescent Formation in Anti-Myeloperoxidase
           Antibody–Induced Glomerulonephritis
    • Authors: Anthony Rousselle; Ralph Kettritz; Adrian Schreiber
      Abstract: Publication date: Available online 28 June 2017
      Source:The American Journal of Pathology
      Author(s): Anthony Rousselle, Ralph Kettritz, Adrian Schreiber
      Neutrophils and monocytes express anti-neutrophil cytoplasmic antibody (ANCA) antigens, and activation of these cells by ANCA is central to ANCA-associated vasculitis and necrotizing crescentic glomerulonephritis (NCGN). The importance of neutrophils is established; however, any role of monocytes is less clear. We tested the hypothesis that depletion of CCR2+ inflammatory monocytes and their derivatives would abrogate anti-myeloperoxidase (MPO) antibody–induced NCGN in a mouse model. We used passive anti-MPO antibody transfer for NCGN induction in wild-type mice or mice expressing the CCR2 promoter–controlled diphtheria toxin receptor. Both mouse strains showed similar circulating Ly6Chi and Ly6Clo monocytes and neutrophils at baseline. Diphtheria toxin robustly depleted circulating monocytes only in CCR2 promoter–controlled diphtheria toxin receptor mice, whereas neutrophil numbers were similar. Anti-MPO antibody transfer resulted in nephritic urine by dipstick and albuminuria by enzyme-linked immunosorbent assay, and monocyte depletion had no effect. However, monocyte depletion significantly reduced glomerular necrosis and crescent formation and abrogated monocyte, macrophage, and dendritic cell increase in the affected kidneys, whereas renal neutrophil numbers were not affected. Soluble CD163 increased in serum, but not in urine, with anti-MPO antibody treatment and was completely abolished with monocyte depletion. Our findings establish an important role of monocytes/macrophages for glomerular necrosis and crescent formation in a renal ANCA-associated vasculitis model.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.05.003
  • Adenosine A2a Receptor Blockade Diminishes Wnt/β-Catenin Signaling in a
           Murine Model of Bleomycin-Induced Dermal Fibrosis
    • Authors: Jin Zhang; Carmen Corciulo; Hailing Liu; Tuere Wilder; Mayumi Ito; Bruce Cronstein
      Abstract: Publication date: Available online 28 June 2017
      Source:The American Journal of Pathology
      Author(s): Jin Zhang, Carmen Corciulo, Hailing Liu, Tuere Wilder, Mayumi Ito, Bruce Cronstein
      Adenosine A2a receptor (A2aR) stimulation promotes the synthesis of collagens I and III, and we have recently demonstrated that there is crosstalk between the A2aR and WNT/β-catenin signaling pathway. In in vitro studies, A2aR signaling for collagen III expression was mediated by WNT/β-catenin signaling in human dermal fibroblasts; we further verified whether the crosstalk between A2aR and Wnt/β-catenin signaling was involved in diffuse dermal fibrosis in vivo. Wnt-signaling reporter mice (Tcf/Lef:H2B-GFP) were challenged with bleomycin and treated with the selective A2aR antagonist istradefylline (KW6002) or vehicle. Dermal fibrosis was quantitated and nuclear translocation of β-catenin in fibroblasts was assessed by double-staining for Green fluorescent protein or dephosphorylated β-catenin or β-catenin phosphorylated at Ser552, and vimentin. KW6002 significantly reduced skin thickness, skinfold thickness, breaking tension, dermal hydroxyproline content, myofibroblast accumulation, and collagen alignment in bleomycin-induced dermal fibrosis. Also, there was increased expression of Tcf/Lef:H2B-GFP reporter in bleomycin-induced dermal fibrosis, an effect that was diminished by treatment with KW6002. Moreover, KW6002 significantly inhibited nuclear translocation of Tcf/Lef:H2B-GFP reporter, as well as dephosphorylated β-catenin and β-catenin phosphorylated at Ser552. Our work supports the hypothesis that pharmacologic blockade of A2aR inhibits the WNT/β-catenin signaling pathway, contributing to its capacity to inhibit bleomycin-induced dermal fibrosis.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.05.005
  • Novel Transgenic Mouse Model of Polycystic Kidney Disease
    • Authors: Yusuke Kito; Chiemi Saigo; Tamotsu Takeuchi
      Abstract: Publication date: Available online 27 June 2017
      Source:The American Journal of Pathology
      Author(s): Yusuke Kito, Chiemi Saigo, Tamotsu Takeuchi
      Transmembrane protein 207 (TMEM207) is characterized as an important molecule for invasiveness of gastric signet-ring cell carcinoma cells. To clarify the pathobiological effects of TMEM207, we generated 13 transgenic mouse strains, designated C57BL/6-transgenic (Tg) (ITF-TMEM207), where the mouse Tmem207 is ectopically expressed under the proximal promoter of the murine intestinal trefoil factor gene. A C57BL/6-Tg (ITF-TMEM207) mouse strain unexpectedly exhibited a high incidence of spontaneous kidney cysts with histopathological features resembling human polycystic kidney disease, which were found in approximately all mice within 1 year. TMEM207 immunoreactivity was found in noncystic kidney tubules and in renal cysts of the transgenic mice. The ITF-TMEM207 construct was inserted into Mitf at chromosome 6. Cystic kidney was not observed in other C57BL/6-Tg (ITF-TMEM207) transgenic mouse strains. Although several genetically manipulated animal models exist, this mouse strain harboring a genetic mutation in Mitf and overexpression of Tmem207 protein was not reported as a model of polycystic kidney disease until now. This study demonstrates that the C57BL/6-Tg (ITF-TMEM207) mouse may be a suitable model for understanding human polycystic kidney disease.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.05.002
  • This Month in AJP
    • Abstract: Publication date: Available online 21 June 2017
      Source:The American Journal of Pathology

      Teaser The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.

      PubDate: 2017-07-06T09:22:50Z
  • Loss of Function of P2X7 Receptor Scavenger Activity in Aging Mice
    • Authors: Kirstan A. Vessey; Ben J. Gu; Andrew I. Jobling; Joanna A. Phipps; Ursula Greferath; Mai X. Tran; Michael A. Dixon; Paul N. Baird; Robyn H. Guymer; James S. Wiley; Erica L. Fletcher
      Abstract: Publication date: Available online 17 June 2017
      Source:The American Journal of Pathology
      Author(s): Kirstan A. Vessey, Ben J. Gu, Andrew I. Jobling, Joanna A. Phipps, Ursula Greferath, Mai X. Tran, Michael A. Dixon, Paul N. Baird, Robyn H. Guymer, James S. Wiley, Erica L. Fletcher
      Age-related macular degeneration (AMD) is a leading cause of irreversible, severe vision loss in Western countries. Recently, we identified a novel pathway involving P2X7 receptor scavenger function expressed on ocular immune cells as a risk factor for advanced AMD. In this study, we investigate the effect of loss of P2X7 receptor function on retinal structure and function during aging. P2X7-null and wild-type C57bl6J mice were investigated at 4, 12, and 18 months of age for macrophage phagocytosis activity, ocular histological changes, and retinal function. Phagocytosis activity of blood-borne macrophages decreased with age at 18 months in the wild-type mouse. Lack of P2X7 receptor function reduced phagocytosis at all ages compared to wild-type mice. At 12 months of age, P2X7-null mice had thickening of Bruch membrane and retinal pigment epithelium dysfunction. By 18 months of age, P2X7-null mice displayed phenotypic characteristics consistent with early AMD, including Bruch membrane thickening, retinal pigment epithelium cell loss, retinal functional deficits, and signs of subretinal inflammation. Our present study shows that loss of function of the P2X7 receptor in mice induces retinal changes representing characteristics of early AMD, providing a valuable model for investigating the role of scavenger receptor function and the immune system in the development of this age-related disease.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.04.016
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