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Publisher: Elsevier   (Total: 3042 journals)

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Showing 1 - 200 of 3042 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 20, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 17, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 82, 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: 27, 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: 327, 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  
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: 204, 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: 9, 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)
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: 20)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 127, 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: 16, 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: 20, 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: 24, 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 Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 4)
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 Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 47, 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: 12)
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 Human Factors/Ergonomics     Full-text available via subscription   (Followers: 25)
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: 4)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
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: 16, 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: 59)
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: 339, 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: 6, 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: 15)
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: 308, 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: 402, 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: 38, 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: 50, 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: 6)
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)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 7, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 48, 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: 44, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 37, 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: 34, 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: 179, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 55, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 2)
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: 23, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 25, 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: 10)
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: 38, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 158, 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  
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: 152, 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   (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]   [25 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0002-9440
   Published by Elsevier Homepage  [3042 journals]
  • Pathomechanisms of Altered Wound Healing in Recessive Dystrophic
           Epidermolysis Bullosa
    • Authors: Francesca Cianfarani; Giovanna Zambruno; Daniele Castiglia; Teresa Odorisio
      Pages: 1445 - 1453
      Abstract: Publication date: July 2017
      Source:The American Journal of Pathology, Volume 187, Issue 7
      Author(s): Francesca Cianfarani, Giovanna Zambruno, Daniele Castiglia, Teresa Odorisio
      Individuals with recessive dystrophic epidermolysis bullosa (RDEB), a rare genetic skin disease, carry mutations in the COL7A1 gene that codes for type VII collagen, an extracellular matrix component of the basement membrane zone forming the anchoring fibrils. As a consequence, RDEB individuals manifest unremitting skin blistering that evolves into chronic wounds, inflammation, and fibrosis. These features play a central role in the development of more severe disease complications, such as mitten deformities of hands and feet and aggressive epithelial cancers. Despite being recognized as a central clinical issue for RDEB, wound healing impairment has been only marginally investigated. Recently, studies with disease mouse models started to shed light on the molecular mechanisms underlying the altered healing response of RDEB. In turn, alterations found in RDEB skin cell behavior fostered the understanding of mechanisms that may be responsible for defective skin repair. This review summarizes findings related to healing impairment in RDEB, and highlights therapeutic strategies for ameliorating healing.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.03.003
       
  • Numerous Ontogenetic Roads to Mantle Cell Lymphoma
    • Authors: Evi Pouliou; Aliki Xochelli; George Kanellis; Evangelia Stalika; Lesley-Ann Sutton; Alba Navarro; Andreas Agathangelidis; Kypros Dimosthenous; Achilles Anagnostopoulos; Efstratios Patsouris; Penelope Korkolopoulou; Christer Sundstrom; Paolo Ghia; Maurilio Ponzoni; Birgitta Sander; Elias Campo; Richard Rosenquist; Anastasia Hadzidimitriou; Kostas Stamatopoulos; Theodora Papadaki
      Pages: 1454 - 1458
      Abstract: Publication date: July 2017
      Source:The American Journal of Pathology, Volume 187, Issue 7
      Author(s): Evi Pouliou, Aliki Xochelli, George Kanellis, Evangelia Stalika, Lesley-Ann Sutton, Alba Navarro, Andreas Agathangelidis, Kypros Dimosthenous, Achilles Anagnostopoulos, Efstratios Patsouris, Penelope Korkolopoulou, Christer Sundstrom, Paolo Ghia, Maurilio Ponzoni, Birgitta Sander, Elias Campo, Richard Rosenquist, Anastasia Hadzidimitriou, Kostas Stamatopoulos, Theodora Papadaki
      To obtain insight into the ontogeny of mantle cell lymphoma (MCL), we assessed 206 patients from a morphological, immunohistochemical, and immunogenetic perspective. Our series included nodal (n = 151), extranodal (n = 28), and primary splenic (n = 27) MCL cases. Skewing of the immunoglobulin heavy variable (IGHV) gene repertoire was noted, with only four IGHV genes accounting for 46% of cases and approximately 70% of cases (107/154) bearing an imprint of somatic hypermutation (SHM) ranging from minimal to pronounced. Interestingly, a distinctive immunophenotypic and immunogenetic profile was identified for primary splenic MCL, which was enriched for DBA.44-positive cases (P < 0.001) and used the IGHV1-8 gene more frequently (P = 0.02) compared to nodal or extranodal cases, alluding to distinct immunopathogenetic and antigen selection processes. Expression of CD27 (considered a marker of activated B cells) was generally dissociated from SHM and was more prevalent in cases with no or minimal/borderline SHM. These findings support the idea that antigen drive is relevant for most MCL cases, although the specific antigens and the precise location of affinity maturation remain to be elucidated. Moreover, they raise the intriguing hypothesis of multiple cellular origins for MCL.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.02.017
       
  • A New Animal Model of Gastric Lymphomagenesis
    • Authors: Pauline Floch; Julien Izotte; Julien Guillemaud; Elodie Sifré; Pierre Costet; Benoit Rousseau; Amandine Marine Laur; Alban Giese; Victoria Korolik; Francis Mégraud; Pierre Dubus; Michael Hahne; Philippe Lehours
      Pages: 1473 - 1484
      Abstract: Publication date: July 2017
      Source:The American Journal of Pathology, Volume 187, Issue 7
      Author(s): Pauline Floch, Julien Izotte, Julien Guillemaud, Elodie Sifré, Pierre Costet, Benoit Rousseau, Amandine Marine Laur, Alban Giese, Victoria Korolik, Francis Mégraud, Pierre Dubus, Michael Hahne, Philippe Lehours
      APRIL is a member of the tumor necrosis factor cytokine family involved in the regulation of B-cell immunity. We present a study of the infection by Helicobacter species of transgenic (Tg) C57BL6 mice, ectopically expressing the human form of APRIL. Wild-type (WT) and APRIL Tg mice were infected with Helicobacter felis and Helicobacter pylori and compared with noninfected animals. Mice were euthanized 18 months after infection, and inflammatory responses and histologic alterations were analyzed. Flow cytometry results revealed that WT-infected mice had less leukocyte infiltration than APRIL Tg-infected mice. In WT-infected mice, infiltrates in gastric tissues were predominantly composed of T cells, mainly CD4+ for H. pylori and CD8+ for H. felis. In APRIL Tg-infected mice, leukocyte infiltrates were composed of B cells with few CD4+ T cells for both species. B cells expressed B surface markers compatible with a marginal zone origin. These results were confirmed by immunohistochemistry. B cells in particular were involved in lymphoepithelial lesions, a hallmark of gastric MALT lymphoma. Monoclonality was observed in a few infiltrates in the presence of lymphoepithelial lesions. These results confirm the importance of APRIL in the development of gastric lymphoid infiltrates induced by Helicobacter species in vivo. We believe that APRIL Tg mice infected by Helicobacter species may represent a novel animal model of gastric lymphomagenesis.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.03.004
       
  • Semaphorin 3E Alleviates Hallmarks of House Dust Mite–Induced
           Allergic Airway Disease
    • Authors: Hesam Movassagh; Lianyu Shan; Jonathan S. Duke-Cohan; Andrew J. Halayko; Jude E. Uzonna; Abdelilah S. Gounni
      Pages: 1566 - 1576
      Abstract: Publication date: July 2017
      Source:The American Journal of Pathology, Volume 187, Issue 7
      Author(s): Hesam Movassagh, Lianyu Shan, Jonathan S. Duke-Cohan, Andrew J. Halayko, Jude E. Uzonna, Abdelilah S. Gounni
      Semaphorins are an essential family of guidance cues ubiquitously expressed in various organs, which play diverse developmental, homeostatic, and pathological roles. Semaphorin 3E (Sema3E), initially identified as a neuronal chemorepellent, is involved in the regulation of cell migration, proliferation, and angiogenesis. However, expression and function of Sema3E in allergic asthma has not been extensively investigated. We determined the expression of Sema3E in the airways and its effect on airway inflammation, hyperresponsiveness, and remodeling as pathological features of allergic asthma provoked by house dust mite in vivo. Our data indicate that exposure to house dust mite markedly reduces Sema3E expression in mouse airways. More important, replenishment of Sema3E by intranasal administration of exogenous Sema3E protects mice from allergic asthma by reducing eosinophilic inflammation, serum IgE level, and T helper cell 2/T helper cell 17 cytokine response. The regulatory effect of Sema3E on cytokine response was sustained on allergen recall response in the lymph nodes and spleen. Furthermore, goblet cell hyperplasia, collagen deposition, and airway hyperresponsiveness were significantly diminished on Sema3E treatment. The inhibitory effect of Sema3E was associated with a reduction of pulmonary CD11b+ conventional dendritic cells and regulation of CD4+ T-cell cytokine response. Collectively, our data represent a novel approach to treating allergic asthma via regulation of immune response to house dust mite.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.03.008
       
  • Potential Therapeutic Action of Adiponectin in Duchenne Muscular Dystrophy
    • Authors: Michel Abou-Samra; Raphaël Boursereau; Sophie Lecompte; Laurence Noel; Sonia M. Brichard
      Pages: 1577 - 1585
      Abstract: Publication date: July 2017
      Source:The American Journal of Pathology, Volume 187, Issue 7
      Author(s): Michel Abou-Samra, Raphaël Boursereau, Sophie Lecompte, Laurence Noel, Sonia M. Brichard
      Adiponectin (ApN) is a hormone that exhibits anti-inflammatory effects on skeletal muscle exposed to acute and chronic inflammation. We have previously tested the implication of ApN in Duchenne muscular dystrophy (DMD) using mdx mice, a model of DMD, and by generating transgenic mdx mice overexpressing ApN. We showed that ApN can act as a preventive agent and delay disease progression by reducing muscle inflammation/injury and improving force/myogenesis. Herein, we took an opposite approach and crossed mdx mice with ApN knockout mice, to obtain mdx mice with ApN depletion. The aims were to test whether ApN deficiency could worsen the mdx phenotype and whether ApN supplementation can reverse several muscle abnormalities once the disease is settled. mdx-knockout mice exhibited lower muscle force/endurance as well as increased muscle damage when compared to regular mdx mice. Local administration of the ApN gene significantly reduced the expression of several oxidative stress/inflammatory markers and increased the expression of myogenic markers in the skeletal muscle. Finally, the presence of ApN markedly reduced the activity of NF-κB, a key player in muscle inflammation and myogenesis. ApN proves to be a powerful protector of the skeletal muscle capable of reversing the disease progression, thus making it a potential therapeutic agent for DMD.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.02.018
       
  • Testosterone Differentially Affects T Cells and Neurons in Murine and
           Human Models of Neuroinflammation and Neurodegeneration
    • Authors: Megan G. Massa; Christina David; Stefanie Jörg; Johannes Berg; Barbara Gisevius; Sarah Hirschberg; Ralf A. Linker; Ralf Gold; Aiden Haghikia
      Pages: 1613 - 1622
      Abstract: Publication date: July 2017
      Source:The American Journal of Pathology, Volume 187, Issue 7
      Author(s): Megan G. Massa, Christina David, Stefanie Jörg, Johannes Berg, Barbara Gisevius, Sarah Hirschberg, Ralf A. Linker, Ralf Gold, Aiden Haghikia
      The high female-to-male sex ratio of multiple sclerosis (MS) prevalence has continuously confounded researchers, especially in light of male patients' accelerated disease course at later stages of MS. Although multiple studies have concentrated on estrogenic mechanisms of disease modulation, fairly little attention has been paid to androgenic effects in a female system, and even fewer studies have attempted to dissociate hormonal effects on the neurodegenerative and neuroinflammatory processes of MS. Herein, we demonstrate the differential effects of hormone treatment on the acute inflammatory and chronic neurodegenerative phases of murine experimental autoimmune encephalomyelitis. Although s.c. treatment with testosterone and aromatase inhibitor applied beginning on the day of immunization ameliorated initial course of disease, similar treatment administered therapeutically exacerbated chronic disease course. Spinal cord analyses of axonal densities reflected the clinical scores of the chronic phase. In vitro, testosterone treatment not only decreased Th1 and Th17 differentiation in an aromatase-independent fashion, but also exacerbated cell death in induced pluripotent stem cell–derived primary human neurons under oxidative stress conditions in an aromatase inhibitor–dependent manner. Thus, through the alleviation of inflammatory processes and the exacerbation of neurodegenerative processes, androgens may contribute to the epidemiologic sex differentials observed in MS prevalence and course.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.03.006
       
  • Gene Expression Differences between Ductal Carcinoma in Situ with and
           without Progression to Invasive Breast Cancer
    • Authors: Shusma C. Doebar; Anieta M. Sieuwerts; Vanja de Weerd; Hans Stoop; John W.M. Martens; Carolien H.M. van Deurzen
      Pages: 1648 - 1655
      Abstract: Publication date: July 2017
      Source:The American Journal of Pathology, Volume 187, Issue 7
      Author(s): Shusma C. Doebar, Anieta M. Sieuwerts, Vanja de Weerd, Hans Stoop, John W.M. Martens, Carolien H.M. van Deurzen
      To understand the molecular alterations driving the progression of ductal carcinoma in situ (DCIS), we compared patients with pure DCIS and patients with DCIS and synchronous invasive breast cancer (IBC). Twelve patients with extensive pure DCIS were included as a representation of indolent lesions with limited invasive capacity. These cases were matched with 12 patients with a limited DCIS component and IBC, representing lesions with a high invasive potential. Matching included age and surrogate DCIS subtypes. Gene expression profiling was performed on DCIS cells to identify transcriptional differences between these two groups. The identified genes were validated by immunohistochemistry. Nine genes showed significantly different expression. Most of these genes were highly expressed in DCIS samples with IBC, including PLAU (P = 0.002), COL1A1 (P = 0.006), KRT81 (P = 0.009), S100A7 (P = 0.015), SCGB1D2 (P = 0.023), KRT18 (P = 0.029), and NOTCH3 (P = 0.044), whereas EGFR and CXCL14 showed a higher expression in cases with pure DCIS (P = 0.015 and P = 0.028, respectively). This difference was only significant for SCGB1D2 (P = 0.009). Hierarchical clustering revealed distinct clustering of patients with and without invasion. Patients with pure DCIS have a different gene expression pattern as compared to patients with DCIS and synchronous IBC. These genes may pinpoint to driver pathway(s) that play an important role in DCIS progression.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.03.012
       
  • 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
       
  • Western Diet–Induced Dysbiosis in Farnesoid X Receptor Knockout Mice
           Causes Persistent Hepatic Inflammation after Antibiotic Treatment
    • Authors: Prasant K. Jena; Lili Sheng; Hui-Xin Liu; Karen M. Kalanetra; Annie Mirsoian; William J. Murphy; Samuel W. French; Viswanathan V. Krishnan; David A. Mills; Yu-Jui Yvonne Wan
      Abstract: Publication date: Available online 12 July 2017
      Source:The American Journal of Pathology
      Author(s): Prasant K. Jena, Lili Sheng, Hui-Xin Liu, Karen M. Kalanetra, Annie Mirsoian, William J. Murphy, Samuel W. French, Viswanathan V. Krishnan, David A. Mills, Yu-Jui Yvonne Wan
      Patients who have liver cirrhosis and liver cancer also have reduced farnesoid X receptor (FXR). The current study analyzes the effect of diet through microbiota that affect hepatic inflammation in FXR knockout (KO) mice. Wild-type and FXR KO mice were on a control (CD) or Western diet (WD) for 10 months. In addition, both CD- and WD-fed FXR KO male mice, which had hepatic lymphocyte and neutrophil infiltration, were treated by vancomycin, polymyxin B, and Abx (ampicillin, neomycin, metronidazole, and vancomycin). Mice were subjected to morphological analysis as well as gut microbiota and bile acid profiling. Male WD-fed FXR KO mice had the most severe steatohepatitis. FXR KO also had reduced Firmicutes and increased Proteobacteria, which could be reversed by Abx. In addition, Abx eliminated hepatic neutrophils and lymphocytes in CD-fed, but not WD-fed, FXR KO mice. Proteobacteria and Bacteroidetes persisted in WD-fed FXR KO mice even after Abx treatment. Only polymyxin B could reduce hepatic lymphocytes in WD-fed FXR KO mice. The reduced hepatic inflammation by antibiotics was accompanied by decreased free and conjugated secondary bile acids as well as changes in gut microbiota. Our data revealed that Lactococcus, Lactobacillus, and Coprococcus protect the liver from inflammation.

      PubDate: 2017-07-14T18:57:45Z
      DOI: 10.1016/j.ajpath.2017.04.019
       
  • 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
       
  • Inhibition of Early Growth Response 1 in the Hippocampus Alleviates
           Neuropathology and Improves Cognition in an Alzheimer Model with Plaques
           and Tangles
    • Authors: Xike Qin; Yunling Wang; Hemant K. Paudel
      Abstract: Publication date: Available online 20 June 2017
      Source:The American Journal of Pathology
      Author(s): Xike Qin, Yunling Wang, Hemant K. Paudel
      A sporadic form of Alzheimer disease (AD) and vascular dementia share many risk factors, and their pathogenic mechanisms are suggested to be related. Transcription factor early growth response 1 (Egr-1) regulates various vascular pathologies and is up-regulated in both AD brains and AD mouse models; however, its role in AD pathogenesis is unclear. Herein, we report that silencing of Egr-1 in the hippocampus by shRNA reduces tau phosphorylation, amyloid-β (Aβ) pathology, and improves cognition in the 3xTg-AD mouse model. Egr-1 silencing does not affect levels of cyclin-dependent protein kinase 5 (Cdk5), glycogen synthase kinase 3β, PP1, or PP2A, but reduces p35 subunit of Cdk5. Egr-1 silencing also reduces levels of β-secretase 1 (BACE-1) and BACE-1–cleaved amyloid precursor protein (APP) metabolites (sAPPβ, C99, Aβ40, and Aβ42) but has no effect on presenilin 1 and presenilin 2. In hippocampal primary neurons, Egr-1 binds to BACE-1 and CDK5R1 promoters, enhances tau phosphorylation, activates Cdk5 and BACE-1, and accelerates amyloidogenic APP processing. Blocking Cdk5 action blocks Egr-1–induced tau phosphorylation but has no effect on BACE-1 activation and amyloidogenic APP processing. Blocking BACE-1 action, on the other hand, blocks Egr-1–induced amyloidogenic APP processing but does not affect tau phosphorylation. Egr-1 regulates tau phosphorylation and Aβ synthesis in the brain by respectively controlling activities of Cdk5 and BACE-1, suggesting that Egr-1 is a potential therapeutic candidate for the treatment of AD.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.04.018
       
  • Elevated CD26 Expression by Skin Fibroblasts Distinguishes a Profibrotic
           Phenotype Involved in Scar Formation Compared to Gingival Fibroblasts
    • Authors: Wesley Mah; Guoqiao Jiang; Dylan Olver; Corrie Gallant-Behm; Colin Wiebe; David A. Hart; Leeni Koivisto; Hannu Larjava; Lari Häkkinen
      Abstract: Publication date: Available online 20 June 2017
      Source:The American Journal of Pathology
      Author(s): Wesley Mah, Guoqiao Jiang, Dylan Olver, Corrie Gallant-Behm, Colin Wiebe, David A. Hart, Leeni Koivisto, Hannu Larjava, Lari Häkkinen
      Compared to skin, wound healing in oral mucosa is faster and produces less scarring, but the mechanisms involved are incompletely understood. Studies in mice have linked high expression of CD26 to a profibrotic fibroblast phenotype, but this has not been tested in models more relevant for humans. We hypothesized that CD26 is highly expressed by human skin fibroblasts (SFBLs), and this associates with a profibrotic phenotype distinct from gingival fibroblasts (GFBLs). We compared CD26 expression in human gingiva and skin and in gingival and hypertrophic-like scar-forming skin wound healing in a pig model, and used three-dimensional cultures of human GFBLs and SFBLs. In both humans and pigs, nonwounded skin contained abundantly CD26-positive fibroblasts, whereas in gingiva they were rare. During skin wound healing, CD26-positive cells accumulated over time and persisted in forming hypertrophic-like scars, whereas few CD26-positive cells were present in the regenerated gingival wounds. Cultured human SFBLs displayed significantly higher levels of CD26 than GFBLs. This was associated with an increased expression of profibrotic genes and transforming growth factor-β signaling in SFBLs. The profibrotic phenotype of SFBLs partially depended on expression of CD26, but was independent of its catalytic activity. Thus, a CD26-positive fibroblast population that is abundant in human skin but not in gingiva may drive the profibrotic response leading to excessive scarring.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.04.017
       
  • 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
       
  • RNA Interference Reveals the Coregulatory Effects of Cylindromatosis on
           Apoptosis and Necroptosis of Photoreceptor Cells in Experimental Retinal
           Detachment
    • Authors: Kai Dong; Linfeng Han; Jingwen Liu; Fenghua Wang; Xiaodong Sun
      Abstract: Publication date: Available online 17 June 2017
      Source:The American Journal of Pathology
      Author(s): Kai Dong, Linfeng Han, Jingwen Liu, Fenghua Wang, Xiaodong Sun
      Inhibiting only cell apoptosis or necroptosis in photoreceptor cells does not protect them against death after traumatic retinal detachment. This study was designed to evaluate the coregulatory effects of the deubiquitinating enzyme cylindromatosis on the apoptosis and necroptosis of photoreceptor cells in experimental retinal detachment. Lentivirus Cyld shRNA was generated and used to suppress cylindromatosis expression in Sprague-Dawley rats. Three weeks after injection of lentivirus Cyld shRNA, retinal detachment surgery was performed. Transmission electron microscopy, propidium iodide staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, electroretinography, and determination of ubiquitination and phosphorylation of receptor-interacting protein 1 were performed to detect the apoptosis and necroptosis of photoreceptor cells. Knockdown of cylindromatosis expression led to inhibition of caspase 8 activity, a decrease in the number of apoptotic photoreceptor cells, and an increase in the ubiquitination level of receptor-interacting protein 1. In addition, the number of necroptotic cells decreased and the phosphorylation level of receptor-interacting protein 1 decreased dramatically; significant protective effects of RNA interference–mediated suppression of cylindromatosis expression on electroretinogram wave were observed. Cylindromatosis coregulates the apoptosis and necroptosis of photoreceptor cells by regulating the ubiquitination of receptor-interacting protein 1 after retinal detachment.

      PubDate: 2017-07-06T09:22:50Z
      DOI: 10.1016/j.ajpath.2017.04.015
       
  • Deficiency in EP4 Receptor–Associated Protein Ameliorates Abnormal
           Anxiety-Like Behavior and Brain Inflammation in a Mouse Model of Alzheimer
           Disease
    • Authors: Risako Fujikawa; Sei Higuchi; Masato Nakatsuji; Mika Yasui; Taichi Ikedo; Manabu Nagata; Kosuke Hayashi; Masayuki Yokode; Manabu Minami
      Abstract: Publication date: Available online 16 June 2017
      Source:The American Journal of Pathology
      Author(s): Risako Fujikawa, Sei Higuchi, Masato Nakatsuji, Mika Yasui, Taichi Ikedo, Manabu Nagata, Kosuke Hayashi, Masayuki Yokode, Manabu Minami
      Microglia are thought to play key roles in the progression of Alzheimer disease (AD). Overactivated microglia produce proinflammatory cytokines, such as tumor necrosis factor-α, which appear to contribute to disease progression. Previously, we reported that prostaglandin E2 type 4 receptor–associated protein (EPRAP) promotes microglial activation. We crossed human amyloid precursor protein transgenic mice from strain J20+/− onto an EPRAP-deficient background to determine the role of EPRAP in AD. Behavioral tests were performed in 5-month-old male J20+/−EPRAP+/+ and J20+/−EPRAP−/− mice. EPRAP deficiency reversed the reduced anxiety of J20+/− mice but did not affect hyperactivity. No differences in spatial memory were observed between J20+/−EPRAP+/+ and J20+/−EPRAP−/− mice. In comparison with J20+/−EPRAP+/+, J20+/−EPRAP−/− mice exhibited less microglial accumulation and reductions in the Cd68 and tumor necrosis factor-α mRNAs in the prefrontal cortex and hippocampus. No significant differences were found between the two types of mice in the amount of amyloid-β 40 or 42 in the cortex and hippocampus. J20+/−EPRAP−/− mice reversed the reduced anxiety-like behavior and had reduced microglial activation compared with J20+/−EPRAP+/+ mice. Further research is required to identify the role of EPRAP in AD, but our results indicate that EPRAP may be related to behavioral and psychological symptoms of dementia and inflammation in patients with AD.

      PubDate: 2017-06-19T12:57:34Z
      DOI: 10.1016/j.ajpath.2017.04.010
       
  • Cathepsin K in Lymphangioleiomyomatosis
    • Authors: Arundhati Dongre; Debbie Clements; Andrew J. Fisher; Simon R. Johnson
      Abstract: Publication date: Available online 15 June 2017
      Source:The American Journal of Pathology
      Author(s): Arundhati Dongre, Debbie Clements, Andrew J. Fisher, Simon R. Johnson
      Lymphangioleiomyomatosis (LAM) is a rare disease in which clonal LAM cells infiltrate the lungs and lymphatics. In association with recruited fibroblasts, LAM cells form nodules adjacent to lung cysts. It is hypothesized that LAM nodule–derived proteases lead to cyst formation. On protease gene–expression profiling in whole-lung tissue, cathepsin K was 40-fold overexpressed in LAM compared with control lungs (P ≤ 0.0001). Immunohistochemistry confirmed cathepsin K protein in LAM nodules but not in control lungs. Cathepsin K gene expression and protein and protease activity were detected in LAM-associated fibroblasts but not in LAM cell line 621-101. In lung nodules, cathepsin K immunoreactivity predominantly co-localized with LAM-associated fibroblasts. In vitro, extracellular cathepsin K activity was minimal at pH 7.5 but was significantly enhanced in fibroblast cultures at pH 7 and 6. 621-101 cells reduced extracellular pH by 0.5 units over 24 hours. Acidification was dependent on 621-101 mechanistic target of rapamycin activity and net hydrogen ion transporters, particularly sodium bicarbonate co-transporters and carbonic anhydrases, which were also expressed in LAM lung tissue. In LAM cell–fibroblast co-cultures, acidification paralleled cathepsin K activity, and both were inhibited by sodium bicarbonate co-transporter (P ≤ 0.0001) and carbonic anhydrase inhibitor (P = 0.0021). Our findings suggest that cathepsin K activity is dependent on LAM cell–fibroblast interactions; inhibitors of extracellular acidification may be potential therapies for LAM.

      PubDate: 2017-06-19T12:57:34Z
      DOI: 10.1016/j.ajpath.2017.04.014
       
  • Macrophages Regulate Unilateral Ureteral Obstruction-Induced Renal
           Lymphangiogenesis through C-C Motif Chemokine Receptor 2-Dependent
           Phosphatidylinositol 3-Kinase-AKT–Mechanistic Target of Rapamycin
           Signaling and Hypoxia-Inducible Factor-1α/Vascular Endothelial Growth
           Factor-C Expression
    • Authors: Yan-Chao Guo; Meng Zhang; Fa-Xi Wang; Guang-Chang Pei; Fei Sun; Ying Zhang; Xiaoyu He; Yi Wang; Jia Song; Feng-Ming Zhu; Nuruliarizki S. Pandupuspitasari; Jing Liu; Kun Huang; Ping Yang; Fei Xiong; Shu Zhang; Qilin Yu; Ying Yao; Cong-Yi Wang
      Abstract: Publication date: Available online 13 June 2017
      Source:The American Journal of Pathology
      Author(s): Yan-Chao Guo, Meng Zhang, Fa-Xi Wang, Guang-Chang Pei, Fei Sun, Ying Zhang, Xiaoyu He, Yi Wang, Jia Song, Feng-Ming Zhu, Nuruliarizki S. Pandupuspitasari, Jing Liu, Kun Huang, Ping Yang, Fei Xiong, Shu Zhang, Qilin Yu, Ying Yao, Cong-Yi Wang
      Lymphangiogenesis occurs during renal fibrosis in patients with chronic kidney diseases and vascular endothelial growth factor (VEGF)-C is required for the formation of lymphatic vessels; however, the underlying mechanisms remain unclear. We demonstrate that macrophages can regulate unilateral ureteral obstruction (UUO)-induced renal lymphangiogenesis by expressing high levels of VEGF-C by C-C motif chemokine receptor 2 (CCR2)-mediated signaling. Mice deficient in Ccr2 manifested repressed lymphangiogenesis along with attenuated renal injury and fibrosis after UUO induction. The infiltrated macrophages after UUO induction generated a microenvironment in favor of lymphangiogenesis, which likely depended on Ccr2 expression. Mechanistic studies revealed that CCR2 is required for macrophages to activate phosphatidylinositol 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) signaling in response to its ligand monocyte chemoattractant protein 1 stimulation, whereas hypoxia-inducible factor (HIF)-1α is downstream of PI3K-AKT-mTOR signaling. HIF-1α directly bound to the VEGF-C promoter to drive its expression to enhance lymphangiogenesis. Collectively, we characterized a novel regulatory network in macrophages, in which CCR2 activates PI3K-AKT-mTOR signaling to mediate HIF-1α expression, which then drives VEGF-C expression to promote lymphangiogenesis.

      PubDate: 2017-06-19T12:57:34Z
      DOI: 10.1016/j.ajpath.2017.04.007
       
  • Modeling Esophagitis Using Human Three-Dimensional Organotypic Culture
           System
    • Authors: Dorottya Laczkó; Fang Wang; F. Bradley Johnson; Nirag Jhala; András Rosztóczy; Gregory G. Ginsberg; Gary W. Falk; Anil K. Rustgi; John P. Lynch
      Abstract: Publication date: Available online 13 June 2017
      Source:The American Journal of Pathology
      Author(s): Dorottya Laczkó, Fang Wang, F. Bradley Johnson, Nirag Jhala, András Rosztóczy, Gregory G. Ginsberg, Gary W. Falk, Anil K. Rustgi, John P. Lynch
      Esophagitis, whether caused by acid reflux, allergic responses, graft-versus-host disease, drugs, or infections, is a common condition of the gastrointestinal tract affecting nearly 20% of the US population. The instigating agent typically triggers an inflammatory response. The resulting inflammation is a risk factor for the development of esophageal strictures, Barrett esophagus, and esophageal adenocarcinoma. Research into the pathophysiology of these conditions has been limited by the availability of animal and human model systems. Three-dimensional organotypic tissue culture (OTC) is an innovative three-dimensional multicellular in vitro platform that recapitulates normal esophageal epithelial stratification and differentiation. We hypothesized that this platform can be used to model esophagitis to better understand the interactions between immune cells and the esophageal epithelium. We found that human immune cells remain viable and respond to cytokines when cultured under OTC conditions. The acute inflammatory environment induced in the OTC significantly affected the overlying epithelium, inducing a regenerative response marked by increased cell proliferation and epithelial hyperplasia. Moreover, oxidative stress from the acute inflammation induced DNA damage and strand breaks in epithelial cells, which could be reversed by antioxidant treatment. These findings support the importance of immune cell–mediated esophageal injury in esophagitis and confirms the utility of the OTC platform to characterize the underlying molecular events in esophagitis.

      PubDate: 2017-06-19T12:57:34Z
      DOI: 10.1016/j.ajpath.2017.04.013
       
  • Role of AKT Hyperactivation and the Potential of AKT-Targeted Therapy in
           Diffuse Large B-Cell Lymphoma
    • Authors: Jinfen Wang; Zijun Y. Xu-Monette; Kausar J. Jabbar; Qi Shen; Ganiraju C. Manyam; Alexandar Tzankov; Carlo Visco; Jing Wang; Santiago Montes-Moreno; Karen Dybkær; Wayne Tam; Govind Bhagat; Eric D. Hsi; J. Han van Krieken; Maurilio Ponzoni; Andrés J.M. Ferreri; Shi Wang; Michael B. Møller; Miguel A. Piris; L. Jeffrey Medeiros; Yong Li; Lan V. Pham; Ken H. Young
      Abstract: Publication date: Available online 13 June 2017
      Source:The American Journal of Pathology
      Author(s): Jinfen Wang, Zijun Y. Xu-Monette, Kausar J. Jabbar, Qi Shen, Ganiraju C. Manyam, Alexandar Tzankov, Carlo Visco, Jing Wang, Santiago Montes-Moreno, Karen Dybkær, Wayne Tam, Govind Bhagat, Eric D. Hsi, J. Han van Krieken, Maurilio Ponzoni, Andrés J.M. Ferreri, Shi Wang, Michael B. Møller, Miguel A. Piris, L. Jeffrey Medeiros, Yong Li, Lan V. Pham, Ken H. Young
      AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found high levels of p-AKT nuclear expression, observed in 24.3% of the study cohort, were associated with significantly worse progression-free survival and Myc and Bcl-2 overexpression. However, multivariate analysis indicated that AKT hyperactivation was not an independent factor. miRNA profiling analysis demonstrated that 63 miRNAs directly or indirectly related to the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway were differentially expressed between DLBCLs with high and low p-AKT nuclear expression. We further targeted the AKT signaling using a highly selective AKT inhibitor MK-2206 in 26 representative DLBCL cell lines and delineated signaling alterations using a reverse-phase protein array. MK-2206 treatment inhibited lymphoma cell viability, and MK-2206 sensitivity correlated with AKT activation status in DLBCL cells. On MK-2206 treatment, p-AKT levels and downstream targets of AKT signaling were significantly decreased, however, likely because of the decreased feedback repression; Rictor and phosphatidylinositol 3-kinase expression and other compensatory pathways were also induced. This study demonstrates the clinical and therapeutic implication values of AKT hyperactivation in DLBCL and suggests that AKT inhibitors need to be combined with other targeted agents for DLBCL to achieve optimal clinical efficacy.

      PubDate: 2017-06-19T12:57:34Z
      DOI: 10.1016/j.ajpath.2017.04.009
       
  • Cigarette Smoke Regulates Calcium-Independent Phospholipase A2 Metabolic
           Pathways in Breast Cancer
    • Authors: Shannon Kispert; Theresa Schwartz; Jane McHowat
      Abstract: Publication date: Available online 12 June 2017
      Source:The American Journal of Pathology
      Author(s): Shannon Kispert, Theresa Schwartz, Jane McHowat
      Phospholipase A2 (PLA2)–dependent pathways are important in the regulation of cell proliferation, differentiation, motility, and immune responses, and can be dysregulated during tumor development and progression. We show herein, for the first time, that cigarette smoking leads to an increase in platelet-activating factor (PAF) content and PAF receptor expression in human breast cancer cells and tissue. PAF production could be abrogated in triple-negative breast cancer cells by inhibition of calcium-independent PLA2 (iPLA2). We also demonstrate that cigarette smoke induces the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 and reduces 15-hydroxyprostaglandin dehydrogenase, resulting in prostaglandin E2 release in human breast cancer. Increased cyclooxygenase-2 expression and prostaglandin E2 release could be abrogated in metastatic breast cancer cells by inhibition of iPLA2. These studies indicate that iPLA2-dependent metabolic pathways play an important role in tumor initiation or progression in smokers, representing novel therapeutic targets for breast cancer patients who smoke.

      PubDate: 2017-06-14T12:31:45Z
      DOI: 10.1016/j.ajpath.2017.04.003
       
  • Platelet-Derived Growth Factor BB Influences Muscle Regeneration in
           Duchenne Muscle Dystrophy
    • Authors: Patricia Piñol-Jurado; Eduard Gallardo; Noemi de Luna; Xavier Suárez-Calvet; Carles Sánchez-Riera; Esther Fernández-Simón; Clara Gomis; Isabel Illa; Jordi Díaz-Manera
      Abstract: Publication date: Available online 12 June 2017
      Source:The American Journal of Pathology
      Author(s): Patricia Piñol-Jurado, Eduard Gallardo, Noemi de Luna, Xavier Suárez-Calvet, Carles Sánchez-Riera, Esther Fernández-Simón, Clara Gomis, Isabel Illa, Jordi Díaz-Manera
      Duchenne muscular dystrophy (DMD) is characterized by a progressive loss of muscle fibers, and their substitution by fibrotic and adipose tissue. Many factors contribute to this process, but the molecular pathways related to regeneration and degeneration of muscle are not completely known. Platelet-derived growth factor (PDGF)-BB belongs to a family of growth factors that regulate proliferation, migration, and differentiation of mesenchymal cells. The role of PDGF-BB in muscle regeneration in humans has not been studied. We analyzed the expression of PDGF-BB in muscle biopsy samples from controls and patients with DMD. We performed in vitro experiments to understand the effects of PDGF-BB on myoblasts involved in the pathophysiology of muscular dystrophies and confirmed our results in vivo by treating the mdx murine model of DMD with repeated i.m. injections of PDGF-BB. We observed that regenerating and necrotic muscle fibers in muscle biopsy samples from DMD patients expressed PDGF-BB. In vitro, PDGF-BB attracted myoblasts and activated their proliferation. Analysis of muscles from the animals treated with PDGF-BB showed an increased population of satellite cells and an increase in the number of regenerative fibers, with a reduction in inflammatory infiltrates, compared with those in vehicle-treated mice. Based on our results, PDGF-BB may play a protective role in muscular dystrophies by enhancing muscle regeneration through activation of satellite cell proliferation and migration.

      PubDate: 2017-06-14T12:31:45Z
      DOI: 10.1016/j.ajpath.2017.04.011
       
  • Osteocyte Regulation of Receptor Activator of NF-κB
           Ligand/Osteoprotegerin in a Sheep Model of Osteoporosis
    • Authors: Thaqif El Khassawna; Felix Merboth; Deeksha Malhan; Wolfgang Böcker; Diaa E.S. Daghma; Sabine Stoetzel; Stefanie Kern; Fathi Hassan; Dirk Rosenbaum; Judith Langenstein; Natali Bauer; Anja Schlagenhauf; Angela Rösen-Wolff; Felix Schulze; Markus Rupp; Dirk Hose; Anja Secklinger; Anita Ignatius; Hans-Joachim Wilke; Katrin S. Lips; Christian Heiss
      Abstract: Publication date: Available online 12 June 2017
      Source:The American Journal of Pathology
      Author(s): Thaqif El Khassawna, Felix Merboth, Deeksha Malhan, Wolfgang Böcker, Diaa E.S. Daghma, Sabine Stoetzel, Stefanie Kern, Fathi Hassan, Dirk Rosenbaum, Judith Langenstein, Natali Bauer, Anja Schlagenhauf, Angela Rösen-Wolff, Felix Schulze, Markus Rupp, Dirk Hose, Anja Secklinger, Anita Ignatius, Hans-Joachim Wilke, Katrin S. Lips, Christian Heiss
      Osteoporosis induction in a sheep model by steroid administration combined with ovariectomy recapitulates decreased bone formation and substandard matrix mineralization in patients. Recently, the role of osteocytes has been frequently addressed, with focus on their role in osteoclastogenesis. However, the quantification of receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) signaling in osteocytes was not studied in sheep. The current study reproduced the sheep model of osteoporosis to study the RANKL/OPG ratio correlation to the method of osteoporosis induction. We investigated the induction of osteoporosis after 8 months using 31 female merino land sheep divided into four groups: control, ovariectomy, ovariectomy with dietary limitation, and ovariectomy with dietary limitation and steroid injection. In accordance to previous reports, the present study showed trabecular thinning, higher numbers of apoptotic osteocytes, and imbalanced metabolism, leading to defective mineralization. The global RANKL/OPG ratio in the spine after 8 months of steroid and dietary treatment was not different from that of the control. Interestingly, assessment of the osteocyte-specific RANKL/OPG ratio showed that the steroid-induced osteoporosis in its late progressive phase stimulates RANKL expression in osteocytes. Sclerostin is suggested to induce RANKL expression in osteocytes. The findings of this study can contribute to further explain the success of sclerostin antibodies in treating osteoporotic patients despite increased osteocyte-expressed RANKL.

      PubDate: 2017-06-14T12:31:45Z
      DOI: 10.1016/j.ajpath.2017.04.005
       
  • Differentiation Affects the Release of Exosomes from Colon Cancer Cells
           and Their Ability to Modulate the Behavior of Recipient Cells
    • Authors: Donatella Lucchetti; Federica Calapà; Valentina Palmieri; Caterina Fanali; Federica Carbone; Alfredo Papa; Ruggero De Maria; Marco De Spirito; Alessandro Sgambato
      Abstract: Publication date: Available online 12 June 2017
      Source:The American Journal of Pathology
      Author(s): Donatella Lucchetti, Federica Calapà, Valentina Palmieri, Caterina Fanali, Federica Carbone, Alfredo Papa, Ruggero De Maria, Marco De Spirito, Alessandro Sgambato
      Exosomes are involved in intercellular communication. We previously reported that sodium butyrate–induced differentiation of HT29 colon cancer cells is associated with a reduced CD133 expression. Herein, we analyzed the role of exosomes in the differentiation of HT29 cells. Exosomes were prepared using ultracentrifugation. Gene expression levels were evaluated by real-time PCR. The cell proliferation rate was assessed by MTT assay and with the electric cell-substrate impedance sensing system, whereas cell motility was assessed using the scratch test and confocal microscopy. Sodium butyrate–induced differentiation of HT29 and Caco-2 cells increased the levels of released exosomes and their expression of CD133. Cell differentiation and the decrease of cellular CD133 expression levels were prevented by blocking multivesicular body maturation. Exosomes released by HT29 differentiating cells carried increased levels of miRNAs, induced an increased proliferation and motility of both colon cancer cells and normal fibroblasts, increased the colony-forming efficiency of cancer cells, and reduced the sodium butyrate–induced differentiation of HT29 cells. Such effects were associated with an increased phosphorylation level of both Src and extracellular signal regulated kinase proteins and with an increased expression of epithelial-to-mesenchymal transition–related genes. Release of exosomes is affected by differentiation of colon cancer cells; exosomes might be used by differentiating cells to get rid of components that are no longer necessary but might continue to exert their effects on recipient cells.

      PubDate: 2017-06-14T12:31:45Z
      DOI: 10.1016/j.ajpath.2017.03.015
       
  • Lasting Retinal Injury in a Mouse Model of Blast-Induced Trauma
    • Authors: Najiba Mammadova; Shivani Ghaisas; Gary Zenitsky; Donald S. Sakaguchi; Anumantha G. Kanthasamy; Justin J. Greenlee; M. Heather West Greenlee
      Abstract: Publication date: Available online 9 June 2017
      Source:The American Journal of Pathology
      Author(s): Najiba Mammadova, Shivani Ghaisas, Gary Zenitsky, Donald S. Sakaguchi, Anumantha G. Kanthasamy, Justin J. Greenlee, M. Heather West Greenlee
      Traumatic brain injury due to blast exposure is currently the most prevalent of war injuries. Although secondary ocular blast injuries due to flying debris are more common, primary ocular blast exposure resulting from blast wave pressure has been reported among survivors of explosions, but with limited understanding of the resulting retinal pathologies. Using a compressed air-driven shock tube system, adult male and female C57BL/6 mice were exposed to blast wave pressure of 300 kPa (43.5 psi) per day for 3 successive days, and euthanized 30 days after injury. We assessed retinal tissues using immunofluorescence for glial fibrillary acidic protein, microglia-specific proteins Iba1 and CD68, and phosphorylated tau (AT-270 pThr181 and AT-180 pThr231). Primary blast wave pressure resulted in activation of Müller glia, loss of photoreceptor cells, and an increase in phosphorylated tau in retinal neurons and glia. We found that 300-kPa blasts yielded no detectable cognitive or motor deficits, and no neurochemical or biochemical evidence of injury in the striatum or prefrontal cortex, respectively. These changes were detected 30 days after blast exposure, suggesting the possibility of long-lasting retinal injury and neuronal inflammation after primary blast exposure.

      PubDate: 2017-06-09T16:11:30Z
      DOI: 10.1016/j.ajpath.2017.03.005
       
  • This Month in AJP
    • Abstract: Publication date: Available online 22 May 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: 2017-06-09T16:11:30Z
       
  • Activation of Hypoxia Signaling in Stromal Progenitors Impairs Kidney
           Development
    • Authors: Katharina Gerl; Dominik Steppan; Michaela Fuchs; Charlotte Wagner; Carsten Willam; Armin Kurtz; Birgül Kurt
      Abstract: Publication date: Available online 17 May 2017
      Source:The American Journal of Pathology
      Author(s): Katharina Gerl, Dominik Steppan, Michaela Fuchs, Charlotte Wagner, Carsten Willam, Armin Kurtz, Birgül Kurt
      Intrauterine hypoxia is a reason for impaired kidney development. The cellular and molecular pathways along which hypoxia exerts effects on nephrogenesis are not well understood. They are likely triggered by hypoxia-inducible transcription factors (HIFs), and their effects appear to be dependent on the cell compartment contributing to kidney formation. In this study, we investigated the effects of HIF activation in the developing renal stroma, which also essentially modulates nephron development from the metanephric mesenchyme. HIF activation was achieved by conditional deletion of the von Hippel–Lindau tumor suppressor (VHL) protein in the forkhead box FOXD1 cell lineage, from which stromal progenitors arise. The resulting kidneys showed maturation defects associated with early postnatal death. In particular, nephron formation, tubular maturation, and the differentiation of smooth muscle, renin, and mesangial cells were impaired. Erythropoietin expression was strongly enhanced. Codeletion of VHL together with HIF2A but not with HIF1A led to apparently normal kidneys, and the animals reached normal age but were anemic because of low erythropoietin levels. Stromal deletion of HIF2A or HIF1A alone did not affect kidney development. These findings emphasize the relevance of sufficient intrauterine oxygenation for normal renal stroma differentiation, suggesting that chronic activity of HIF2 in stromal progenitors impairs kidney development. Finally, these data confirm the concept that normal stroma function is essential for normal tubular differentiation.

      PubDate: 2017-05-20T14:42:26Z
      DOI: 10.1016/j.ajpath.2017.03.014
       
  • Knockdown of Hepatic Gonadotropin-Releasing Hormone by Vivo-Morpholino
           Decreases Liver Fibrosis in Multidrug Resistance Gene 2 Knockout Mice by
           Down-Regulation of miR-200b
    • Authors: Konstantina Kyritsi; Fanyin Meng; Tianhao Zhou; Nan Wu; Julie Venter; Heather Francis; Lindsey Kennedy; Paolo Onori; Antonio Franchitto; Francesca Bernuzzi; Pietro Invernizzi; Kelly McDaniel; Romina Mancinelli; Domenico Alvaro; Eugenio Gaudio; Gianfranco Alpini; Shannon Glaser
      Abstract: Publication date: Available online 12 May 2017
      Source:The American Journal of Pathology
      Author(s): Konstantina Kyritsi, Fanyin Meng, Tianhao Zhou, Nan Wu, Julie Venter, Heather Francis, Lindsey Kennedy, Paolo Onori, Antonio Franchitto, Francesca Bernuzzi, Pietro Invernizzi, Kelly McDaniel, Romina Mancinelli, Domenico Alvaro, Eugenio Gaudio, Gianfranco Alpini, Shannon Glaser
      Hepatic fibrosis occurs during the progression of primary sclerosing cholangitis (PSC) and is characterized by accumulation of extracellular matrix proteins. Proliferating cholangiocytes and activated hepatic stellate cells (HSCs) participate in the promotion of liver fibrosis during cholestasis. Gonadotropin-releasing hormone (GnRH) is a trophic peptide hormone synthesized by hypothalamic neurons and the biliary epithelium and exerts its biological effects on cholangiocytes by interaction with the receptor subtype (GnRHR1) expressed by cholangiocytes and HSCs. Previously, we demonstrated that administration of GnRH to normal rats increased intrahepatic biliary mass (IBDM) and hepatic fibrosis. Also, miR-200b is associated with the progression of hepatic fibrosis; however, the role of the GnRH/GnRHR1/miR-200b axis in the development of hepatic fibrosis in PSC is unknown. Herein, using the mouse model of PSC (multidrug resistance gene 2 knockout), the hepatic knockdown of GnRH decreased IBDM and liver fibrosis. In vivo and in vitro administration of GnRH increased the expression of miR-200b and fibrosis markers. The GnRH/GnRHR1 axis and miR-200b were up-regulated in human PSC samples. Cetrorelix, a GnRHR1 antagonist, inhibited the expression of fibrotic genes in vitro and decreased IBDM and hepatic fibrosis in vivo. Inhibition of miR-200b decreased the expression of fibrosis genes in vitro in cholangiocyte and HSC lines. Targeting the GnRH/GnRHR1/miR-200b axis may be key for the management of hepatic fibrosis during the progression of PSC.

      PubDate: 2017-05-15T16:37:56Z
      DOI: 10.1016/j.ajpath.2017.03.013
       
  • Megakaryocytes in Myeloproliferative Neoplasms Have Unique Somatic
           Mutations
    • Authors: Belinda B. Guo; Richard J. Nigel Allcock; Bob Mirzai; Jacques A. Jacobus Malherbe; Fizzah A. Choudry; Mattia Frontini; Hun Chuah; James Liang; Simon E. Kavanagh; Rebecca Howman; Willem H. Ouwehand; Kathryn A. Fuller; Wendy N. Erber
      Abstract: Publication date: Available online 11 May 2017
      Source:The American Journal of Pathology
      Author(s): Belinda B. Guo, Richard J. Nigel Allcock, Bob Mirzai, Jacques A. Jacobus Malherbe, Fizzah A. Choudry, Mattia Frontini, Hun Chuah, James Liang, Simon E. Kavanagh, Rebecca Howman, Willem H. Ouwehand, Kathryn A. Fuller, Wendy N. Erber
      Myeloproliferative neoplasms (MPNs) are a group of related clonal hemopoietic stem cell disorders associated with hyperproliferation of myeloid cells. They are driven by mutations in the hemopoietic stem cell, most notably JAK2 V617F, CALR, and MPL. Clinically, they have the propensity to progress to myelofibrosis and transform to acute myeloid leukemia. Megakaryocytic hyperplasia with abnormal features are characteristic, and it is thought that these cells stimulate and drive fibrotic progression. The biological defects underpinning this remain to be explained. In this study we examined the megakaryocyte genome in 12 patients with MPNs to determine whether there are somatic variants and whether there is any association with marrow fibrosis. We performed targeted next-generation sequencing for 120 genes associated with myeloid neoplasms on megakaryocytes isolated from aspirated bone marrow. Eleven of the 12 patients had genomic defects in megakaryocytes that were not present in nonmegakaryocytic hemopoietic marrow cells from the same patient. The greatest allelic burden was in patients with increased reticulin deposition. The megakaryocyte-unique mutations were predominantly in genes that regulate chromatin remodeling, chromosome alignment, and stability. These findings show that genomic abnormalities are present in megakaryocytes in MPNs and that these appear to be associated with progression to bone marrow fibrosis.

      PubDate: 2017-05-15T16:37:56Z
      DOI: 10.1016/j.ajpath.2017.03.009
       
  • Cyst-Like Osteolytic Formations in Recombinant Human Bone Morphogenetic
           Protein-2 (rhBMP-2) Augments Sheep Spinal Fusion
    • Authors: Hsin Chuan Pan; Soonchul Lee; Kang Ting; Jia Shen; Chenchao Wang; Alan Nguyen; Emily A. Berthiaume; Janette N. Zara; A. Simon Turner; Howard B. Seim; Jin Hee Kwak; Xinli Zhang; Chia Soo
      Abstract: Publication date: Available online 11 May 2017
      Source:The American Journal of Pathology
      Author(s): Hsin Chuan Pan, Soonchul Lee, Kang Ting, Jia Shen, Chenchao Wang, Alan Nguyen, Emily A. Berthiaume, Janette N. Zara, A. Simon Turner, Howard B. Seim, Jin Hee Kwak, Xinli Zhang, Chia Soo
      Multiple case reports using recombinant human bone morphogenetic protein-2 (rhBMP-2) have reported complications. However, the local adverse effects of rhBMP-2 application are not well documented. In this report we show that, in addition to promoting lumbar spinal fusion through potent osteogenic effects, rhBMP-2 augmentation promotes local cyst-like osteolytic formations in sheep trabecular bones that have undergone anterior lumbar interbody fusion. Three months after operation, conventional computed tomography showed that the trabecular bones of the rhBMP-2 application groups could fuse, whereas no fusion was observed in the control group. Micro–computed tomography analysis revealed that the core implant area's bone volume fraction and bone mineral density increased proportionately with rhBMP-2 dose. Multiple cyst-like bone voids were observed in peri-implant areas when using rhBMP-2 applications, and these sites showed significant bone mineral density decreases in relation to the unaffected regions. Biomechanically, these areas decreased in strength by 32% in comparison with noncystic areas. Histologically, rhBMP-2–affected void sites had an increased amount of fatty marrow, thinner trabecular bones, and significantly more adiponectin- and cathepsin K-positive cells. Despite promoting successful fusion, rhBMP-2 use in clinical applications may result in local adverse structural alterations and compromised biomechanical changes to the bone.

      PubDate: 2017-05-15T16:37:56Z
      DOI: 10.1016/j.ajpath.2017.03.010
       
  • The Cellular Retinoic Acid Binding Protein 2 Promotes Survival of
           Malignant Peripheral Nerve Sheath Tumor Cells
    • Authors: Susan Fischer-Huchzermeyer; Anna Dombrowski; Christian Hagel; Victor Felix Mautner; Jens Schittenhelm; Anja Harder
      Abstract: Publication date: Available online 11 May 2017
      Source:The American Journal of Pathology
      Author(s): Susan Fischer-Huchzermeyer, Anna Dombrowski, Christian Hagel, Victor Felix Mautner, Jens Schittenhelm, Anja Harder
      Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive neoplasms that commonly occur in patients with neurofibromatosis type 1 (NF1). Effective chemotherapy is not available. To characterize a therapeutic target for treatment, we investigated the role of cellular retinoic acid binding protein 2 (CRABP2) in MPNST in vitro. CRABP2 is a transcriptional co-activator of retinoic acid signaling. Although overexpression of CRABP2 is described in several cancers, it has not yet been studied in MPNSTs. We investigated CRABP2 expression in cultured Schwann cells and formalin-fixed, paraffin-embedded specimens of human peripheral nerve sheath tumors. A transient knockdown of CRABP2 was established in human NF1-associated MPNST cell lines (S462, T265, NSF1), and functional effects on viability, proliferation, apoptosis, and cytotoxicity were monitored. Finally, a 45-pathway reporter assay was performed in knockdown cells. Expression of CRABP2 was found in epithelium, fibroblasts, and tumor Schwann cells of skin, neurofibromas, and MPNSTs. In contrast, normal skin Schwann cells (NF1 +/−, NF1 −/−) did not express CRABP2. In the absence of retinoic acid, MPNST cells depleted of CRABP2 had reduced viability and proliferation, induction of apoptosis and cytotoxicity, and up-regulation of the type 1 interferon pathway. These data suggest a retinoic acid–independent, non–tumor suppressor role of CRABP2 for the survival of MPNST cells in vitro. Targeting CRABP2 overexpression may represent a unique approach for the treatment of human MPNSTs.

      PubDate: 2017-05-15T16:37:56Z
      DOI: 10.1016/j.ajpath.2017.02.021
       
  • Purkinje Cells Are More Vulnerable to the Specific Depletion of Cathepsin
           D Than to That of Atg7
    • Authors: Masato Koike; Masahiro Shibata; Takehiko Sunabori; Junji Yamaguchi; Kenji Sakimura; Masaaki Komatsu; Keiji Tanaka; Yasuo Uchiyama
      Abstract: Publication date: Available online 11 May 2017
      Source:The American Journal of Pathology
      Author(s): Masato Koike, Masahiro Shibata, Takehiko Sunabori, Junji Yamaguchi, Kenji Sakimura, Masaaki Komatsu, Keiji Tanaka, Yasuo Uchiyama
      Neurologic phenotypes of cathepsin D (CTSD)-deficient mice, a murine model of neuronal ceroid lipofuscinoses, indicate the importance of CTSD for the maintenance of metabolism in central nervous system neurons. To further understand the role of CTSD in central nervous system neurons, we generated mice with a CTSD deficiency specifically in the Purkinje cells (PCs) (CTSD Flox/Flox ;GRID2-Cre) and compared their phenotypes with those of PC-selective Atg7-deficient (Atg7 Flox/Flox ;GRID2-Cre) mice. In both strains of mice, PCs underwent degeneration, but the CTSD-deficient PCs disappeared more rapidly than their Atg7-deficient counterparts. When CTSD-deficient PCs died, the neuronal cell bodies became shrunken, filled with autophagosomes and autolysosomes, and had nuclei with dispersed small chromatin fragments. The dying Atg7-deficient PCs also showed similar ultrastructures, indicating that the neuronal cell death of CTSD- and Atg7-deficient PCs was distinct from apoptosis. Immunohistochemical observations showed the formation of calbindin-positive axonal spheroids and the swelling of vesicular GABA transporter–positive presynaptic terminals that were more pronounced in Atg7-deficient PCs than in CTSD-deficient PCs. An accumulation of tubular vesicles may have derived from the smooth endoplasmic reticulum; nascent autophagosome-like structures with double membranes was a common feature in the swollen axons of these PCs. These results suggested that PCs were more vulnerable to CTSD deficiency in lysosomes than to autophagy impairment, and this vulnerability does not depend on the severity of axonal swelling.

      PubDate: 2017-05-15T16:37:56Z
      DOI: 10.1016/j.ajpath.2017.02.020
       
  • Enhanced Tau Aggregation in the Presence of Amyloid β
    • Authors: Rachel E. Bennett; Sarah L. DeVos; Simon Dujardin; Bianca Corjuc; Rucha Gor; Jose Gonzalez; Allyson D. Roe; Matthew P. Frosch; Rose Pitstick; George A. Carlson; Bradley T. Hyman
      Abstract: Publication date: Available online 10 May 2017
      Source:The American Journal of Pathology
      Author(s): Rachel E. Bennett, Sarah L. DeVos, Simon Dujardin, Bianca Corjuc, Rucha Gor, Jose Gonzalez, Allyson D. Roe, Matthew P. Frosch, Rose Pitstick, George A. Carlson, Bradley T. Hyman
      Amyloid plaques and neurofibrillary tangles co-occur in Alzheimer disease, but with different topological and temporal patterns. Whether these two lesions are independent or pathobiologically related is uncertain. For example, amyloid deposition in the neocortex precedes the spread of tau neurofibrillary tangles from the limbic areas to the cortex. We examined the aggregation properties of tau isolated from human cases with early tau pathology (Braak II) with and without plaques. Using a well-established HEK cell biosensor assay, we show that tau from cases with plaques has an enhanced ability to induce tau aggregates compared to tau from cases without plaques. To further explore this effect, we combined mice carrying the APP/PS1 transgene array that develop plaques with rTg4510 mice carrying the P301L mutant human tau transgene that develop extensive tau pathology with age. The resulting APP/PS1-rTg4510 mice had a threefold increase in tau seeding activity over the rTg4510 strain, without change in tau production or extracellular release. Surprisingly, this effect was observed before overt amyloid deposition. The enhancement of tau aggregation was also apparent by an increase in histological measures of tau pathology in young APP/PS1-rTg4510 mice and an increase in high-molecular-weight tau. Overall, these data provide evidence that amyloid β acts to enhance tau pathology by increasing the formation of tau species capable of seeding new aggregates.

      PubDate: 2017-05-15T16:37:56Z
      DOI: 10.1016/j.ajpath.2017.03.011
       
  • Lymphoepithelioma-Like Carcinoma in Liver
    • Authors: Ismail Labgaa; Ashley Stueck; Stephen C. Ward
      Abstract: Publication date: Available online 10 May 2017
      Source:The American Journal of Pathology
      Author(s): Ismail Labgaa, Ashley Stueck, Stephen C. Ward
      Liver cancer, primarily encompassing hepatocellular carcinoma and intrahepatic cholangiocarcinoma, has become the second cause of worldwide cancer-related death during the past two decades. Lymphoepithelioma-like carcinomas (LELCs) are defined as tumors composed of undifferentiated epithelial cells with a prominent lymphoid infiltrate, and can arise in the liver as hepatocellular or cholangiocarcinoma forms. Patients with liver LELC display distinctive demographics and tumor characteristics. LELCs also appear to be associated with strikingly better outcomes compared to typical liver cancers, with 5-year survival rates of 57% to 100% versus 12% to 68%, respectively. Liver LELCs represent a unique model of immune response in liver cancer. Data on LELCs of the liver remain limited, and future comprehensive studies are needed to further elucidate this disease, which could ultimately offer precious insights for immunotherapeutic strategies in liver cancer.

      PubDate: 2017-05-15T16:37:56Z
      DOI: 10.1016/j.ajpath.2017.02.022
       
  • miR-375 Regulates Invasion-Related Proteins Vimentin and L-Plastin
    • Authors: Lizandra Jimenez; Jihyeon Lim; Berta Burd; Thomas Harris; Thomas J. Ow; Nicole Kawachi; Thomas Belbin; Ruth Angeletti; Michael B. Prystowsky; Geoffrey Childs; Jeffrey E. Segall
      Abstract: Publication date: Available online 10 May 2017
      Source:The American Journal of Pathology
      Author(s): Lizandra Jimenez, Jihyeon Lim, Berta Burd, Thomas Harris, Thomas J. Ow, Nicole Kawachi, Thomas Belbin, Ruth Angeletti, Michael B. Prystowsky, Geoffrey Childs, Jeffrey E. Segall
      Invasion is a hallmark of advanced head and neck squamous cell carcinoma (HNSCC). We previously determined that low relative miR-375 expression was associated with poor patient prognosis. HNSCC cells with increased miR-375 expression have lower invasive properties and impaired invadopodium activity. Using stable isotope labeling with amino acids in cell culture and reverse-phase liquid chromatography mass spectrometry, we assessed the impact of miR-375 expression on protein levels in UM-SCC-1 cells. Increased miR-375 expression was associated with down-regulation of proteins involved in cellular assembly and organization, death and survival, and movement. Two invasion-associated proteins, vimentin and L-plastin, were strongly down-regulated by miR-375. Luciferase reporter assays demonstrated that high miR-375 expression reduced vimentin promoter activity, suggesting that vimentin is an indirect target of miR-375. Runt-related transcription factor 1 (RUNX1) is a potential miR-375 direct target, and its knockdown reduced vimentin and L-plastin expression. Data in The Cancer Genome Atlas HNSCC database showed a significant inverse correlation between miR-375 expression and RUNX1, vimentin, and L-plastin RNA expression. These clinical correlations validate our in vitro model findings and support a mechanism in which miR-375 suppresses RUNX1 levels, resulting in reduced vimentin and L-plastin expression. Furthermore, knockdown of RUNX1, L-plastin, and vimentin resulted in significant reductions in cell invasion in vitro, indicating the functional significance of miR-375 regulation of specific proteins involved in HNSCC invasion.

      PubDate: 2017-05-10T21:49:03Z
      DOI: 10.1016/j.ajpath.2017.02.019
       
  • miR-21 Promotes Fibrogenesis in Peritoneal Dialysis
    • Authors: Melisa Lopez-Anton; Mark Lambie; Manuel Lopez-Cabrera; Claus P. Schmitt; Vicente Ruiz-Carpio; Maria Bartosova; Betti Schaefer; Simon Davies; Timothy Stone; Robert Jenkins; Philip R. Taylor; Nicholas Topley; Timothy Bowen; Donald Fraser
      Abstract: Publication date: Available online 9 May 2017
      Source:The American Journal of Pathology
      Author(s): Melisa Lopez-Anton, Mark Lambie, Manuel Lopez-Cabrera, Claus P. Schmitt, Vicente Ruiz-Carpio, Maria Bartosova, Betti Schaefer, Simon Davies, Timothy Stone, Robert Jenkins, Philip R. Taylor, Nicholas Topley, Timothy Bowen, Donald Fraser
      Peritoneal dialysis (PD) is a life-saving form of renal replacement therapy for those with end-stage kidney disease. Mesothelial cells (MCs) line the peritoneal cavity and help define peritoneal response to treatment-associated injury, a major reason for treatment failure. miRNAs are important regulators, but their roles in peritoneal fibrosis are largely unknown. In this study, miR-21 was one of the most abundant miRNAs in primary MCs, and was up-regulated by the profibrotic cytokine transforming growth factor-β1 and in PD effluent-derived MCs exhibiting mesenchymal phenotypic change. Increased miR-21 was found in peritoneal membrane biopsy specimens from PD patients compared to healthy controls (PD biocompatible, 5.86×, P = 0.0001; PD conventional, 7.09×, P < 0.0001, n = 11 per group). In PD effluent from a cohort of 230 patients, miR-21 was higher in those receiving the therapy long-term compared to new starters (n = 230, miR-21 3.26×, P = 0.001) and associated with icodextrin use (R = 0.52; 95% CI, 0.20–0.84), peritonitis count (R = 0.16; 95% CI, 0.03–0.29), and dialysate cytokines. miR-21 down-regulated programmed cell death 4 and programmed cell death 4 protein was decreased in peritoneal membrane biopsy specimens from PD patients compared to healthy controls. New miR-21 targets were identified that may be important during PD fibrogenesis. These data identify miR-21 as an important effector of fibrosis in the peritoneal membrane, and a promising biomarker in the dialysis effluent for membrane change in patients receiving PD.

      PubDate: 2017-05-10T21:49:03Z
      DOI: 10.1016/j.ajpath.2017.03.007
       
 
 
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