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Publisher: Elsevier   (Total: 3163 journals)

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Showing 1 - 200 of 3163 Journals sorted alphabetically
A Practical Logic of Cognitive Systems     Full-text available via subscription   (Followers: 9)
AASRI Procedia     Open Access   (Followers: 14)
Academic Pediatrics     Hybrid Journal   (Followers: 30, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 22, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 88, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 25, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 35, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 5)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 7)
Acta Astronautica     Hybrid Journal   (Followers: 394, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 27, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 2)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.18, CiteScore: 1)
Acta Haematologica Polonica     Free   (Followers: 1, SJR: 0.128, CiteScore: 0)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 244, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 10, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 27, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 6, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 6)
Acute Pain     Full-text available via subscription   (Followers: 15, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 16, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 8, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 9, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 22)
Advanced Cement Based Materials     Full-text available via subscription   (Followers: 3, SJR: 0.732, CiteScore: 3)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 135, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 16, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 8, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 12, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 28, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 10, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 10, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 22, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 14, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 29, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 7, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 3)
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: 27, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 10, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 28, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.205, CiteScore: 1)
Advances in Dermatology     Full-text available via subscription   (Followers: 15)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 8)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 23)
Advances in Ecological Research     Full-text available via subscription   (Followers: 42, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 27, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 43, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 53, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Genetics     Full-text available via subscription   (Followers: 15, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 8, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 21, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 22)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 37, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.682, CiteScore: 2)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 14, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 11, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 21)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 3)
Advances in Oncobiology     Full-text available via subscription   (Followers: 1)
Advances in Organ Biology     Full-text available via subscription   (Followers: 1)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 16, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 6, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 24, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 10)
Advances in Pharmacology     Full-text available via subscription   (Followers: 16, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
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: 5)
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: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 59)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 5)
Advances in Space Research     Full-text available via subscription   (Followers: 385, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 10, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 30, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 17)
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: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 46, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 337, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 10, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 436, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 15, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 43, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 1)
Agriculture and Natural Resources     Open Access   (Followers: 2)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 56, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 6, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 11, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 9)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 10, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 9, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 50, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 6)
American Heart J.     Hybrid Journal   (Followers: 50, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 51, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 44, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 10)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 32, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 26, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 34, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 43)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 203, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 62, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 6, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 27, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 27, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 37, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 6)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 63, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 15, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 5, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 39, SJR: 1.512, CiteScore: 5)
Analytical Biochemistry     Hybrid Journal   (Followers: 174, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 10, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 11)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 23, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)

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Journal Cover
American Journal of Pathology
Journal Prestige (SJR): 2.139
Citation Impact (citeScore): 4
Number of Followers: 27  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0002-9440
Published by Elsevier Homepage  [3163 journals]
  • Visualization of Proliferative Vascular Endothelial Cells in Tumors
           in Vivo by Imaging Their Partner of Sld5-1 Promoter Activity
    • Authors: Daishi Yamakawa; Weizhen Jia; Hiroyasu Kidoya; Shoko Hosojima; Miku Torigata; Li Zhang; Nobuyuki Takakura
      Pages: 1300 - 1314
      Abstract: Publication date: Available online 9 April 2018
      Source:The American Journal of Pathology
      Author(s): Daishi Yamakawa, Weizhen Jia, Hiroyasu Kidoya, Shoko Hosojima, Miku Torigata, Li Zhang, Nobuyuki Takakura
      Vascular endothelial cells (ECs) isolated from tumors characteristically express certain genes. It has recently been suggested that tumor vessel normalization facilitates effective drug delivery into tumors; however, how tumor vessel normalization can be recognized on the basis of the molecules expressed by tumor ECs is not clearly defined. The degree of cell proliferation is an important indicator to characterize the condition of the ECs. Herein, we generated transgenic mice expressing enhanced green fluorescent protein (EGFP) under the transcriptional control of the DNA replication factor partner of Sld5-1 (PSF1; official name GINS1) promoter to assess whether active ECs can be distinguished from dormant ECs. Predictably, ECs in the adult skin exhibited no EGFP signals. However, after s.c. injection of tumor cells, some ECs shifted to EGFP positivity, enabling distinction of EGFP-positive from EGFP-negative cells. We found that only a fraction of the EGFP-negative ECs strongly expressed the glycosylphosphatidylinositol-anchor protein CD109 associated with the phosphatidylinositol 3-kinase pathway. Taken together, these data indicate that areas of vascular normalization in tumors can be detected by CD109 expression, and this provides a window of opportunity for timing chemotherapy.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2018.01.015
      Issue No: Vol. 188, No. 5 (2018)
  • Variations on a Theme by Darwin
    • Authors: Mark E. Sobel
      Pages: 836 - 837
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Mark E. Sobel
      Teaser This Editorial from American Society for Investigative Pathology Executive Officer Emeritus, Dr. Mark E. Sobel, reflects on his time serving the society as Executive Officer (2001 to 2017).

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2018.02.002
  • Adventitial Activation in the Pathogenesis of Injury-Induced Arterial
    • Authors: Jianli Wang; Yuan Wang; Jingjing Wang; Xiaosun Guo; Elsa C. Chan; Fan Jiang
      Pages: 838 - 845
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Jianli Wang, Yuan Wang, Jingjing Wang, Xiaosun Guo, Elsa C. Chan, Fan Jiang
      Transplant vasculopathy is one of the major causes of chronic rejection after solid organ transplantation. The pathogenic mechanisms of transplant vasculopathy are still poorly understood. Herein, we summarize current evidence suggesting that activation of the tunica adventitia may be involved in the pathogenesis of transplant vasculopathy. Adventitia is an early responder to various vascular injuries and plays an integral role in eliciting vascular inflammation and remodeling. Accumulation of macrophages in the adventitia promotes the development of vascular remodeling by releasing a variety of paracrine factors that have profound impacts on vascular mural cells. Targeting adventitial macrophages has been shown to be effective for repressing transplantation-induced arterial remodeling in animal models. Adventitia also fosters angiogenesis, and neovascularization of the adventitial layer may facilitate the transport of inflammatory cells through the arterial wall. Further investigations are warranted to clarify whether inhibiting adventitial oxidative stress and/or adventitial neovascularization are better strategies for preventing transplant vasculopathy.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.002
  • Next-Generation Sequencing to Detect Deletion of RB1 and ERBB4 Genes in
           Chromophobe Renal Cell Carcinoma
    • Authors: Qingqing Liu; Kristine M. Cornejo; Liang Cheng; Lloyd Hutchinson; Mingsheng Wang; Shaobo Zhang; Keith Tomaszewicz; Ediz F. Cosar; Bruce A. Woda; Zhong Jiang
      Pages: 846 - 852
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Qingqing Liu, Kristine M. Cornejo, Liang Cheng, Lloyd Hutchinson, Mingsheng Wang, Shaobo Zhang, Keith Tomaszewicz, Ediz F. Cosar, Bruce A. Woda, Zhong Jiang
      Overlapping morphologic, immunohistochemical, and ultrastructural features make it difficult to diagnose chromophobe renal cell carcinoma (ChRCC) and renal oncocytoma (RO). Because ChRCC is a malignant tumor, whereas RO is a tumor with benign behavior, it is important to distinguish these two entities. We aimed to identify genetic markers that distinguish ChRCC from RO by using next-generation sequencing (NGS). NGS for hotspot mutations or gene copy number changes was performed on 12 renal neoplasms, including seven ChRCC and five RO cases. Matched normal tissues from the same patients were used to exclude germline variants. Rare hotspot mutations were found in cancer-critical genes (TP53 and PIK3CA) in ChRCC but not RO. The NGS gene copy number analysis revealed multiple abnormalities. The two most common deletions were tumor-suppressor genes RB1 and ERBB4 in ChRCC but not RO. Fluorescence in situ hybridization was performed on 65 cases (ChRCC, n = 33; RO, n = 32) to verify hemizygous deletion of RB1 (17/33, 52%) or ERBB4 (11/33, 33%) in ChRCC, but not in RO (0/32, 0%). In total, ChRCCs (23/33, 70%) carry either a hemizygous deletion of RB1 or ERBB4. The combined use of RB1 and ERBB4 fluorescence in situ hybridization to detect deletion of these genes may offer a highly sensitive and specific assay to distinguish ChRCC from RO.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.003
  • A Shared Pattern of β-Catenin Activation in Bronchopulmonary Dysplasia
           and Idiopathic Pulmonary Fibrosis
    • Authors: Jennifer M.S. Sucre; Gail H. Deutsch; Christopher S. Jetter; Namasivayam Ambalavanan; John T. Benjamin; Linda A. Gleaves; Bryan A. Millis; Lisa R. Young; Timothy S. Blackwell; Jonathan A. Kropski; Susan H. Guttentag
      Pages: 853 - 862
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Jennifer M.S. Sucre, Gail H. Deutsch, Christopher S. Jetter, Namasivayam Ambalavanan, John T. Benjamin, Linda A. Gleaves, Bryan A. Millis, Lisa R. Young, Timothy S. Blackwell, Jonathan A. Kropski, Susan H. Guttentag
      Wnt/β-catenin signaling is necessary for normal lung development, and abnormal Wnt signaling contributes to the pathogenesis of both bronchopulmonary dysplasia (BPD) and idiopathic pulmonary fibrosis (IPF), fibrotic lung diseases that occur during infancy and aging, respectively. Using a library of human normal and diseased human lung samples, we identified a distinct signature of nuclear accumulation of β-catenin phosphorylated at tyrosine 489 and epithelial cell cytosolic localization of β-catenin phosphorylated at tyrosine 654 in early normal lung development and fibrotic lung diseases BPD and IPF. Furthermore, this signature was recapitulated in murine models of BPD and IPF. Image analysis of immunofluorescence colocalization demonstrated a consistent pattern of elevated nuclear phosphorylated β-catenin in the lung epithelium and surrounding mesenchyme in BPD and IPF, closely resembling the pattern observed in 18-week fetal lung. Nuclear β-catenin phosphorylated at tyrosine 489 associated with an increased expression of Wnt target gene AXIN2, suggesting that the observed β-catenin signature is of functional significance during normal development and injury repair. The association of specific modifications of β-catenin during normal lung development and again in response to lung injury supports the widely held concept that repair of lung injury involves the recapitulation of developmental programs. Furthermore, these observations suggest that β-catenin phosphorylation has potential as a therapeutic target for the treatment and prevention of both BPD and IPF.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.004
  • Parathyroid Hormone–Related Protein Contributes to Early Healing of Habu
           Snake Venom–Induced Glomerulonephritis in Mice
    • Authors: Mazène Hochane; Denis Raison; Catherine Coquard; Claire Béraud; Sabrina Danilin; Audrey Bethry; Thierry Massfelder; Mariette Barthelmebs
      Pages: 863 - 875
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Mazène Hochane, Denis Raison, Catherine Coquard, Claire Béraud, Sabrina Danilin, Audrey Bethry, Thierry Massfelder, Mariette Barthelmebs
      Proliferative glomerulonephritis is characterized by local inflammation and mesangial cell deterioration, followed by mesangial proliferation and glomerular healing. Parathyroid hormone–related peptide (PTHrP) is a mesangial cytokine-like growth factor implicated in mesangial proliferation and survival. No data are available about its role in glomerulonephritis. Herein, we analyzed the expression and role of PTHrP in glomerular inflammation and healing in an experimental model of glomerulonephritis induced by i.v. injection of Habu snake venom in mice. The temporal analysis showed marked renal damage in the first days after venom injection and the beginning of recovery within 7 days. Glomerular expression of PTHrP (transcript and protein) was observed in the early phase after venom injection (from day 1 to day 3), along with an inflammatory environment. The inactivation of secreted PTHrP with PTHrP-neutralizing antibody (PTH2E11; 120 μg i.p. daily) reduced the markers of local inflammation (expression of macrophage chemotactic protein-1; regulated upon activation, normal T cell expressed and secreted; cyclooxygenase 2; IL-6; and macrophage infiltration) and abolished the expression of PTHrP itself. Moreover, the glomerular cell proliferation was hampered, and the healing process was prevented on day 7 after venom injection. These results show that PTHrP has antinomic actions in glomerulonephritis, participating in both the proinflammatory condition and the healing process. Our work reveals the essential role of PTHrP in early glomerular repair in an experimental model of glomerulonephritis.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.012
  • Pancreatic and Islet Remodeling in Cystic Fibrosis Transmembrane
           Conductance Regulator (CFTR) Knockout Ferrets
    • Authors: Pavana G. Rotti; Weiliang Xie; Ananta Poudel; Yaling Yi; Xingshen Sun; Scott R. Tyler; Aliye Uc; Andrew W. Norris; Manami Hara; John F. Engelhardt; Katherine N. Gibson-Corley
      Pages: 876 - 890
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Pavana G. Rotti, Weiliang Xie, Ananta Poudel, Yaling Yi, Xingshen Sun, Scott R. Tyler, Aliye Uc, Andrew W. Norris, Manami Hara, John F. Engelhardt, Katherine N. Gibson-Corley
      In cystic fibrosis (CF), there is early destruction of the exocrine pancreas, and this results in a unique form of diabetes that affects approximately half of adult CF individuals. An animal model of cystic fibrosis–related diabetes has been developed in the ferret, which progresses through phases of glycemic abnormalities because of islet remodeling during and after exocrine destruction. Herein, we quantified the pancreatic histopathological changes that occur during these phases. There was an increase in percentage ductal, fat, and islet area in CF ferrets over time compared with age-matched wild-type controls. We also quantified islet size, shape, islet cell composition, cell proliferation (Ki-67), and expression of remodeling markers (matrix metalloprotease-7, desmin, and α-smooth muscle actin). Pancreatic ducts were dilated with scattered proliferating cells and were surrounded by activated stellate cells, indicative of tissue remodeling. The timing of islet and duct proliferation, stellate cell activation, and matrix remodeling coincided with the previously published stages of glycemic crisis and inflammation. This mapping of remodeling events in the CF ferret pancreas provides insights into early changes that control glycemic intolerance and subsequent recovery during the evolution of CF pancreatic disease.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.015
  • Comparative Histopathologic Lesions of the Male Reproductive Tract during
           Acute Infection of Zika Virus in AG129 and Ifnar−/− Mice
    • Authors: Chad S. Clancy; Arnaud J. Van Wettere; Venkatraman Siddharthan; John D. Morrey; Justin G. Julander
      Pages: 904 - 915
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Chad S. Clancy, Arnaud J. Van Wettere, Venkatraman Siddharthan, John D. Morrey, Justin G. Julander
      An understanding of the pathogenesis of infection with the Zika virus in the male reproductive tract is vital for the development of vaccines and antivirals that will limit or prevent sexual transmission. Two common immunocompromised mouse strains used in transmission studies—male with genes encoding interferon types I and II receptor gene knockout (IFNAR/IFNGR; AG129) and with interferon type 1 receptor knockout (Ifnar−/−) were infected with a Puerto Rican Zika virus isolate (PRVABC59), and pathology was assessed 5 to 11 days after infection. Virus was detected by immunohistochemistry and quantitative RT-PCR in the testicle and epididymis of AG129 and Ifnar−/− mice, and by immunohistochemistry in the prostate and seminal vesicle of infected AG129 mice. Severe disease manifestations initiating as epididymitis and progressing to orchitis were observed in both models, with more severe inflammation noted in the AG129 mouse strain. Significant inflammation was not observed in any evaluated accessory sex gland at any point during infection. Time–course analysis of infection revealed an increase in the severity of disease within the epididymis of both strains, indicating a potential route of sexual transmission. Male mice with Ifnar−/− may better recapitulate Zika virus in humans and provide insight into the mechanism of sexual transmission, due to milder histopathologic lesions, the presence of histologically normal sperm in epididymal tubules, and an ability to survive the acute phase of disease.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.019
  • miRNA in Rat Liver Sinusoidal Endothelial Cells and Hepatocytes and
           Application to Circulating Biomarkers that Discern Pathogenesis of Liver
    • Authors: Shingo Oda; Masaki Takeuchi; Sho Akai; Yuji Shirai; Koichi Tsuneyama; Tsuyoshi Yokoi
      Pages: 916 - 928
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Shingo Oda, Masaki Takeuchi, Sho Akai, Yuji Shirai, Koichi Tsuneyama, Tsuyoshi Yokoi
      Sinusoidal obstruction syndrome is a serious liver injury caused by toxic injury to liver sinusoidal endothelial cells (LSECs) during clinical chemotherapy. Although circulating miRNAs, such as hepatocyte-specific miR-122-5p and miR-192-5p, have been proposed as potential noninvasive biomarkers of hepatocellular liver injury, these miRNAs may not be specific to damage to other hepatic cell types, including LSECs. We characterized miRNA expression in LSECs and hepatocytes and investigated whether cell type–specific miRNAs in plasma can discern pathogenesis of liver injuries in rats. Comprehensive miRNA expression analyses found that 66 and 12 miRNAs were highly expressed in LSECs and hepatocytes isolated from nontreated rats, respectively. An LSEC-enriched miR-511-3p was relatively liver specific according to public data. For establishing LSEC and hepatocyte injury models, rats were orally treated with monocrotaline and thioacetamide, respectively. In monocrotaline-treated rats, a sinusoidal obstruction syndrome model, LSEC damage was observed 6 hours after dosing, whereas hepatocellular damage was observed after 48 hours. Interestingly, the level of miR-511-3p in plasma was increased as early as 6 hours after monocrotaline dosing, followed by an increase of miR-122-5p after 24 hours. In the thioacetamide-induced hepatocellular injury model, the level of miR-511-3p was not altered in plasma, whereas miR-122-5p levels were increased after 6 hours. In conclusion, we identified miR-511-3p in plasma as a possible biomarker for LSEC damage.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.007
  • Does the Fuhrman or World Health Organization/International Society of
           Urological Pathology Grading System Apply to the Xp11.2 Translocation
           Renal Cell Carcinoma'
    • Authors: Ning Liu; Weidong Gan; Feng Qu; Zhen Wang; Wenyuan Zhuang; Sezim Agizamhan; Linfeng Xu; Juanjuan Yin; Hongqian Guo; Dongmei Li
      Pages: 929 - 936
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Ning Liu, Weidong Gan, Feng Qu, Zhen Wang, Wenyuan Zhuang, Sezim Agizamhan, Linfeng Xu, Juanjuan Yin, Hongqian Guo, Dongmei Li
      The Fuhrman and World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading systems are widely used to predict survival for patients with conventional renal cell carcinoma. To determine the validity of nuclear grading systems (both the Fuhrman and the WHO/ISUP) and the individual components of the Fuhrman grading system in predicting the prognosis of Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC), we identified and followed up 47 patients with Xp11.2 tRCC in our center from January 2007 to June 2017. The Fuhrman and WHO/ISUP grading was reassigned by two pathologists. Nuclear size and shape were determined for each case based on the greatest degree of nuclear pleomorphism using image analysis software. Univariate and multivariate analyses were performed to evaluate the capacity of the grading systems and nuclear parameters to predict overall survival and progression-free survival. On univariate Cox regression analysis, the parameters of nuclear size were associated significantly with overall survival and progression-free survival, whereas the grading systems and the parameters of nuclear shape failed to reach a significant correlation. On multivariate analysis, however, none of the parameters was associated independently with survival. Our findings indicate that neither the Fuhrman nor the WHO/ISUP grading system is applicable to Xp11.2 tRCC. The assessment of nuclear size instead may be novel outcome predictors for patients with Xp11.2 tRCC.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.018
  • Serum Amyloid A1 Is an Epithelial Prorestitutive Factor
    • Authors: Benjamin H. Hinrichs; Jason D. Matthews; Dorothée Siuda; Monique N. O'Leary; Alexandra A. Wolfarth; Bejan J. Saeedi; Asma Nusrat; Andrew S. Neish
      Pages: 937 - 949
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Benjamin H. Hinrichs, Jason D. Matthews, Dorothée Siuda, Monique N. O'Leary, Alexandra A. Wolfarth, Bejan J. Saeedi, Asma Nusrat, Andrew S. Neish
      Several proteins endogenously produced during the process of intestinal wound healing have demonstrated prorestitutive properties. The presence of serum amyloid A1 (SAA1), an acute-phase reactant, within inflamed tissues, where it exerts chemotaxis of phagocytes, is well recognized; however, a putative role in intestinal wound repair has not been described. Herein, we show that SAA1 induces intestinal epithelial cell migration, spreading, and attachment through a formyl peptide receptor 2–dependent mechanism. Induction of the prorestitutive phenotype is concentration and time dependent and is associated with epithelial reactive oxygen species production and alterations in p130 Crk-associated substrate staining. In addition, using a murine model of wound recovery, we provide evidence that SAA1 is dynamically and temporally regulated, and that the elaboration of SAA1 within the wound microenvironment correlates with the influx of SAA1/CD11b coexpressing immune cells and increases in cytokines known to induce SAA expression. Overall, the present work demonstrates an important role for SAA in epithelial wound recovery and provides evidence for a physiological role in the wound environment.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.013
  • Identification and Complete Stereochemical Assignments of the New Resolvin
           Conjugates in Tissue Regeneration in Human Tissues that Stimulate
           Proresolving Phagocyte Functions and Tissue Regeneration
    • Authors: Xavier de la Rosa; Paul C. Norris; Nan Chiang; Ana R. Rodriguez; Bernd W. Spur; Charles N. Serhan
      Pages: 950 - 966
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Xavier de la Rosa, Paul C. Norris, Nan Chiang, Ana R. Rodriguez, Bernd W. Spur, Charles N. Serhan
      Resolvin conjugates in tissue regeneration (RCTRs) are new chemical signals that accelerate resolution of inflammation, infection, and tissue regeneration. Herein, using liquid chromatography–tandem mass spectrometry–based metabololipidomics, we identified RCTRs in human spleen, lymph node, bone marrow, and brain. In human spleen incubated with Staphylococcus aureus, endogenous RCTRs were increased along with conversion of deuterium-labeled docosahexaenoic acid, conferring pathway activation. Physical and biological properties of endogenous RCTRs were matched with those prepared by total organic synthesis. The complete stereochemical assignment of bioactive RCTR1 is 8R-glutathionyl-7S,17S-dihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, RCTR2 is 8R-cysteinylglycinyl-7S,17S-dihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, and RCTR3 is 8R-cysteinyl-7S,17S-dihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid. These stereochemically defined RCTRs stimulated human macrophage phagocytosis, efferocytosis, and planaria tissue generation. Proteome profiling demonstrated that RCTRs regulated both proinflammatory and anti-inflammatory cytokines with human macrophages. In microfluidic chambers, the three RCTRs limited human polymorphonuclear cell migration. In hind-limb ischemia-reperfusion–initiated organ injury, both RCTR2 and RCTR3 reduced polymorphonuclear cell infiltration into lungs. In infectious peritonitis, RCTR1 shortened the resolution intervals. Each RCTR (1 nmol/L) accelerated planaria tissue regeneration by approximately 0.5 days, with direct comparison to both maresin and protectin CTRs. Together, these results identify a new bioactive RCTR (ie, RCTR3) in human tissues and establish the complete stereochemistry and rank-order potencies of three RCTRs in vivo. Moreover, RCTR1, RCTR2, and RCTR3 each exert potent anti-inflammatory and proresolving actions with human leukocytes.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2018.01.004
  • Spliceosome-Associated Protein 130 Exacerbates Alcohol-Induced Liver
           Injury by Inducing NLRP3 Inflammasome–Mediated IL-1β in Mice
    • Authors: Jong-Won Kim; Yoon-Seok Roh; Hyeneui Jeong; Ho-Keun Yi; Min-Ho Lee; Chae-Woong Lim; Bumseok Kim
      Pages: 967 - 980
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Jong-Won Kim, Yoon-Seok Roh, Hyeneui Jeong, Ho-Keun Yi, Min-Ho Lee, Chae-Woong Lim, Bumseok Kim
      Excessive alcohol consumption leads to chronic liver diseases. Macrophage-inducible C-type lectin (Mincle) is a C-type lectin receptor that recognizes spliceosome-associated protein 130 (SAP130) known as an endogenous ligand released from dying cells. The aim was to examine the role of Mincle-SAP130 in the pathogenesis of alcoholic liver disease. Alcohol-induced liver injury was induced in wild-type (WT) and Mincle knockout (KO) mice by using a chronic-binge ethanol-feeding model. Mincle KO mice showed significant lower hepatic steatosis, inflammation with neutrophil infiltration, and fibrosis compared with WT mice after alcohol feeding. In contrast, Mincle activation exacerbated alcohol-induced liver injury. Kupffer cells (KCs) are major sources of Mincle. IL-1β expression was significantly down-regulated in Mincle KO mice compared with that in WT mice after alcohol consumption. Interestingly, expression and production of IL-1β were significantly decreased in SAP130-treated KCs isolated from leucine-rich–containing family pyrin domain containing-3–deficient mice compared with those in WT KCs. Such results were also observed in cells treated with SAP130 plus Syk inhibitor. Furthermore, infiltration of invariant natural killer T cells was decreased in livers of Mincle KO mice. Finally, inhibition of Syk signaling ameliorated alcohol-induced liver injury. Collectively, these results demonstrated that interaction between Mincle and SAP130 may promote the progression of alcoholic liver disease by IL-1β production in KCs and consequently increase inflammatory immune cell infiltration.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.010
  • Combination of a Histone Deacetylase 6 Inhibitor and a Somatostatin
           Receptor Agonist Synergistically Reduces Hepatorenal Cystogenesis in an
           Animal Model of Polycystic Liver Disease
    • Authors: Maria Lorenzo Pisarello; Tatyana V. Masyuk; Sergio A. Gradilone; Anatoliy I. Masyuk; Jingyi F. Ding; Pui-Yuen Lee; Nicholas F. LaRusso
      Pages: 981 - 994
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Maria Lorenzo Pisarello, Tatyana V. Masyuk, Sergio A. Gradilone, Anatoliy I. Masyuk, Jingyi F. Ding, Pui-Yuen Lee, Nicholas F. LaRusso
      Hepatic cystogenesis in polycystic liver disease (PLD) is associated with abnormalities in multiple cellular processes, including elevated cAMP and overexpression of histone deacetylase 6 (HDAC6). Disease progression in polycystic kidney (PCK) rats (an animal model of PLD) is attenuated by inhibition of either cAMP production or HDAC6. Therefore, we hypothesized that concurrent targeting of HDAC6 and cAMP would synergistically reduce cyst growth. Changes in hepatorenal cystogenesis were examined in PCK rats treated with a pan-HDAC inhibitor, panobinostat; three specific HDAC6 inhibitors, ACY-1215, ACY-738, and ACY-241; and a combination of ACY-1215 and the somatostatin receptor analogue, pasireotide. We also assessed effects of ACY-1215 and pasireotide alone and in combination on cell proliferation, cAMP production, and expression of acetylated α-tubulin in vitro in cultured cholangiocytes and the length of primary cilia and the frequency of ciliated cholangiocytes in vivo in PCK rats. Panobinostat and all three HDAC6 inhibitors decreased hepatorenal cystogenesis in PCK rats. ACY-1215 was more effective than other HDAC inhibitors and was chosen for combinational treatment. ACY-1215 + pasireotide combination synergistically reduced cyst growth and increased length of primary cilia in PCK rats. In cultured cystic cholangiocytes, ACY-1215 + pasireotide combination concurrently decreased cell proliferation and inhibited cAMP levels. These data suggest that the combination of drugs that inhibit HDAC6 and cAMP may be an effective therapy for PLD.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.016
  • Hippo Cascade Controls Lineage Commitment of Liver Tumors in Mice and
    • Authors: Shanshan Zhang; Jingxiao Wang; Haichuan Wang; Lingling Fan; Biao Fan; Billy Zeng; Junyan Tao; Xiaolei Li; Li Che; Antonio Cigliano; Silvia Ribback; Frank Dombrowski; Bin Chen; Wenming Cong; Lixin Wei; Diego F. Calvisi; Xin Chen
      Pages: 995 - 1006
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Shanshan Zhang, Jingxiao Wang, Haichuan Wang, Lingling Fan, Biao Fan, Billy Zeng, Junyan Tao, Xiaolei Li, Li Che, Antonio Cigliano, Silvia Ribback, Frank Dombrowski, Bin Chen, Wenming Cong, Lixin Wei, Diego F. Calvisi, Xin Chen
      Primary liver cancer consists mainly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). A subset of human HCCs expresses a ICC-like gene signature and is classified as ICC-like HCC. The Hippo pathway is a critical regulator of normal and malignant liver development. However, the precise function(s) of the Hippo cascade along liver carcinogenesis remain to be fully delineated. The role of the Hippo pathway in a murine mixed HCC/ICC model induced by activated forms of AKT and Ras oncogenes (AKT/Ras) was investigated. The authors demonstrated the inactivation of Hippo in AKT/Ras liver tumors leading to nuclear localization of Yap and TAZ. Coexpression of AKT/Ras with Lats2, which activates Hippo, or the dominant negative form of TEAD2 (dnTEAD2), which blocks Yap/TAZ activity, resulted in delayed hepatocarcinogenesis and elimination of ICC-like lesions in the liver. Mechanistically, Notch2 expression was found to be down-regulated by the Hippo pathway in liver tumors. Overexpression of Lats2 or dnTEAD2 in human HCC cell lines inhibited their growth and led to the decreased expression of ICC-like markers, as well as Notch2 expression. Altogether, this study supports the key role of the Hippo cascade in regulating the differentiation status of liver tumors.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.017
  • Cytokine Signaling Protein 3 Deficiency in Myeloid Cells Promotes Retinal
           Degeneration and Angiogenesis through Arginase-1 Up-Regulation in
           Experimental Autoimmune Uveoretinitis
    • Authors: Mei Chen; Jiawu Zhao; Imran H.A. Ali; Stephen Marry; Josy Augustine; Mohajeet Bhuckory; Aisling Lynch; Adrien Kissenpfennig; Heping Xu
      Pages: 1007 - 1020
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Mei Chen, Jiawu Zhao, Imran H.A. Ali, Stephen Marry, Josy Augustine, Mohajeet Bhuckory, Aisling Lynch, Adrien Kissenpfennig, Heping Xu
      The suppressor of cytokine signaling protein 3 (SOCS3) critically controls immune cell activation, although its role in macrophage polarization and function remains controversial. Using experimental autoimmune uveoretinitis (EAU) as a model, we show that inflammation-mediated retinal degeneration is exaggerated and retinal angiogenesis is accelerated in mice with SOCS3 deficiency in myeloid cells (LysM Cre/+ SOCS3 fl/fl ). At the acute stage of EAU, the population of infiltrating neutrophils was increased and the population of macrophages decreased in LysM Cre/+ SOCS3 fl/fl mice compared with that in wild-type (WT) mice. Real-time RT-PCR showed that the expression of tumor necrosis factor-α, IL-1β, interferon-γ, granulocyte-macrophage colony-stimulating factor, and arginase-1 was significantly higher in the LysM Cre/+ SOCS3 fl/fl EAU retina in contrast to the WT EAU retina. The percentage of arginase-1+ infiltrating cells was significantly higher in the LysM Cre/+ SOCS3 fl/fl EAU retina than that in the WT EAU retina. In addition, bone marrow–derived macrophages and neutrophils from the LysM Cre/+ SOCS3 fl/fl mice express significantly higher levels of chemokine (C-C motif) ligand 2 and arginase-1 compared with those from WT mice. Inhibition of arginase using an l-arginine analog amino-2-borono-6-hexanoic suppressed inflammation-induced retinal angiogenesis without affecting the severity of inflammation. Our results suggest that SOCS3 critically controls the phenotype and function of macrophages and neutrophils under inflammatory conditions and loss of SOCS3 promotes the angiogenic phenotype of the cells through up-regulation of arginase-1.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.021
  • ASK Family Kinases Are Required for Optimal NLRP3 Inflammasome Priming
    • Authors: David E. Place; Parimal Samir; Rajendra Karki; Benoit Briard; Peter Vogel; Thirumala-Devi Kanneganti
      Pages: 1021 - 1030
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): David E. Place, Parimal Samir, Rajendra Karki, Benoit Briard, Peter Vogel, Thirumala-Devi Kanneganti
      Activation of the multimeric inflammasome complex leads to inflammatory responses to biotic and abiotic triggers. The inflammasome sensor, Nod-like receptor family pyrin domain containing 3 (NLRP3), is activated by a range of stimuli and is tightly regulated to restrict excessive inflammation. Because NLRP3 responds broadly to cellular insults and regulates cell death similar to the stress-activated apoptosis signal-regulating kinases 1 and 2 (ASK1/2), we hypothesized that ASK1/2 may regulate NLRP3 activity. Although essential for mediating NLRP3 inflammasome activation, ASK1/2 were not required for NLRC4 or absent in melanoma 2 inflammasome activation. ASK1/2 was required for NLRP3 up-regulation after lipopolysaccharide treatment in primary bone marrow–derived macrophages and lung fibroblasts as well as during infection with Burkholderia thailandensis and influenza virus. Consistent with reduced NLRP3 expression in response to B. thailandensis, caspase-1 cleavage and cell death were reduced in infected bone marrow–derived macrophages, and mice lacking ASK1/2 were resistant to Burkholderia intranasal infection. Single knockouts of either ASK1 or ASK2 showed a partial role for both ASK1 and ASK2 in NLRP3 up-regulation in response to lipopolysaccharide or B. thailandensis, but ASK2 was required primarily to mediate lethal pathology during intranasal infection in vivo. Our findings identify the ASK1/2 complex as a regulator of NLRP3 activation and highlight a larger role for ASK2 in lung infection during B. thailandensis infection.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.006
  • Galectin-3 Enhances Avian H5N1 Influenza A Virus–Induced Pulmonary
           Inflammation by Promoting NLRP3 Inflammasome Activation
    • Authors: Yu-Jung Chen; Sheng-Fan Wang; I-Chun Weng; Ming-Hsiang Hong; Tzu-Han Lo; Jia-Tsrong Jan; Li-Chung Hsu; Huan-Yuan Chen; Fu-Tong Liu
      Pages: 1031 - 1042
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Yu-Jung Chen, Sheng-Fan Wang, I-Chun Weng, Ming-Hsiang Hong, Tzu-Han Lo, Jia-Tsrong Jan, Li-Chung Hsu, Huan-Yuan Chen, Fu-Tong Liu
      Highly pathogenic avian influenza A H5N1 virus causes pneumonia and acute respiratory distress syndrome in humans. Virus-induced excessive inflammatory response contributes to severe disease and high mortality rates. Galectin-3, a β-galactoside-binding protein widely distributed in immune and epithelial cells, regulates various immune functions and modulates microbial infections. Here, we describe galectin-3 up-regulation in mouse lung tissue after challenges with the H5N1 influenza virus. We investigated the effects of endogenous galectin-3 on H5N1 infection and found that survival of galectin-3 knockout (Gal-3KO) mice was comparable with wild-type (WT) mice after infections. Compared with infected WT mice, infected Gal-3KO mice exhibited less inflammation in the lungs and reduced IL-1β levels in bronchoalveolar lavage fluid. In addition, the bone marrow–derived macrophages (BMMs) from Gal-3KO mice exhibited reduced oligomerization of apoptosis-associated speck-like proteins containing caspase-associated recruitment domains and secreted less IL-1β compared with BMMs from WT mice. However, similar levels of the inflammasome component of nucleotide oligomerization domain–like receptor protein 3 (NLRP3) were observed in two genotypes of BMMs. Co-immunoprecipitation data indicated galectin-3 and NLRP3 interaction in BMMs infected with H5N1. An association was also observed between galectin-3 and NLRP3/apoptosis-associated speck-like proteins containing caspase-associated recruitment domain complex. Combined, our results suggest that endogenous galectin-3 enhances the effects of H5N1 infection by promoting host inflammatory responses and regulating IL-1β production by macrophages via interaction with NLRP3.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.014
  • Chd7 Is Critical for Early T-Cell Development and Thymus Organogenesis in
    • Authors: Zhi-Zhi Liu; Zi-Long Wang; Tae-Ik Choi; Wen-Ting Huang; Han-Tsing Wang; Ying-Ying Han; Lou-Yin Zhu; Hyun-Taek Kim; Jung-Hwa Choi; Jin-Soo Lee; Hyung-Goo Kim; Jian Zhao; Yue Chen; Zhuo Lu; Xiao-Li Tian; Bing-Xing Pan; Bao-Ming Li; Cheol-Hee Kim; Hong A. Xu
      Pages: 1043 - 1058
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Zhi-Zhi Liu, Zi-Long Wang, Tae-Ik Choi, Wen-Ting Huang, Han-Tsing Wang, Ying-Ying Han, Lou-Yin Zhu, Hyun-Taek Kim, Jung-Hwa Choi, Jin-Soo Lee, Hyung-Goo Kim, Jian Zhao, Yue Chen, Zhuo Lu, Xiao-Li Tian, Bing-Xing Pan, Bao-Ming Li, Cheol-Hee Kim, Hong A. Xu
      Coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE) syndrome is a congenital disorder affecting multiple organs and mainly caused by mutations in CHD7, a gene encoding a chromatin-remodeling protein. Immunodeficiency and reduced T cells have been noted in CHARGE syndrome. However, the mechanisms underlying T lymphopenia are largely unexplored. Herein, we observed dramatic decrease of T cells in both chd7knockdown and knockout zebrafish embryos. Unexpectedly, hematopoietic stem and progenitor cells and, particularly, lymphoid progenitor cells were increased peripherally in nonthymic areas in chd7-deficient embryos, unlikely to contribute to the T-cell decrease. Further analysis demonstrated that both the organogenesis and homing function of the thymus were seriously impaired. Chd7 might regulate thymus organogenesis through modulating the development of both neural crest cell–derived mesenchyme and pharyngeal endoderm–derived thymic epithelial cells. The expression of foxn1, a central regulator of thymic epithelium, was remarkably down-regulated in the pharyngeal region in chd7-deficient embryos. Moreover, the T-cell reduction in chd7-deficient embryos was partially rescued by overexpressing foxn1, suggesting that restoring thymic epithelium may be a potential therapeutic strategy for treating immunodeficiency in CHARGE syndrome. Collectively, the results indicated that chd7 was critical for thymic development and T-lymphopenia in CHARGE syndrome may be mainly attributed to the defects of thymic organogenesis. The current finding may benefit the diagnosis and therapy of T lymphopenia and immunodeficiency in CHARGE syndrome.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.005
  • Mechanisms of Enhanced Osteoclastogenesis in Alkaptonuria
    • Authors: Giacomina Brunetti; Albina Tummolo; Gabriele D'Amato; Alberto Gaeta; Federica Ortolani; Laura Piacente; Paola Giordano; Silvia Colucci; Maria Grano; Francesco Papadia; Maria F. Faienza
      Pages: 1059 - 1068
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Giacomina Brunetti, Albina Tummolo, Gabriele D'Amato, Alberto Gaeta, Federica Ortolani, Laura Piacente, Paola Giordano, Silvia Colucci, Maria Grano, Francesco Papadia, Maria F. Faienza
      Alkaptonuria (AKU) is a rare disorder characterized by the deficiency of the enzyme homogentisate 1,2-dioxygenase and consequent homogentisate accumulation, which leads to progressive and severe osteoarthopathy starting from the second decade of life. Thus, in AKU patients, bone involvement represents an important clinical issue, which we investigated. Serum levels of receptor activator of NF-κB ligand (RANKL), osteoprotegerin, sclerostin, Dickkopf-1, and bone remodeling markers were measured in nine AKU patients (two children and seven adults) and 22 controls, together with lumbar spine bone mineral density (LS-BMD) and femoral-BMD. In the two AKU children, the average of LS-BMD and femoral-BMD Z-scores were within the normal range, but reduced with respect to the controls. Otherwise, in the adult AKU patients, LS-BMD T-score was inside the normal range, but femoral-BMD T-score reached osteopenic levels. Consistently, in AKU adults, higher RANKL and C-terminal telopeptide of collagen type 1 and lower osteoprotegerin levels were observed than in controls. Otherwise, spontaneous osteoclastogenesis was already evident in peripheral blood mononuclear cell cultures from AKU children, together with a high percentage of circulating osteoclast precursors. Osteoclastogenesis was sustained by the high levels of tumor necrosis factor-α, RANK, RANKL, and LIGHT. In conclusion, the altered osteoclastogenesis was observed already in AKU children, despite the absence of evident injury. Thus, a preventive approach in young patients, targeting osteoclast activity, may prevent the macroscopic bone disease that appears in adult AKU.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.008
  • Long-Term Treatment of Tamoxifen and Raloxifene Alleviates Dystrophic
           Phenotype and Enhances Muscle Functions of FKRP Dystroglycanopathy
    • Authors: Bo Wu; Sapana N. Shah; Peijuan Lu; Lauren E. Bollinger; Anthony Blaeser; Susan Sparks; Amy D. Harper; Qi L. Lu
      Pages: 1069 - 1080
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Bo Wu, Sapana N. Shah, Peijuan Lu, Lauren E. Bollinger, Anthony Blaeser, Susan Sparks, Amy D. Harper, Qi L. Lu
      The third most common form of limb-girdle muscular dystrophies is caused by mutations of the Fukutin-related protein (FKRP) gene, with no effective therapy available. Selective estrogen receptor modulators, tamoxifen and raloxifene, have been widely used for human conditions for their anti-inflammatory, antifibrosis, prevention of bone loss, and muscle building effects (essential features for muscular dystrophy therapies). We evaluated therapeutic values of tamoxifen and raloxifene in FKRPP448L mutant mouse with severe dystrophic phenotype. The mice were treated with the drugs for 1 year through daily gavage. We demonstrate that tamoxifen and raloxifene significantly ameliorated the disease progression. The improvement includes increase in grip force production, extended running time and distance in treadmill test, and enhancement in cardiac and respiratory functions. Significant reduction in muscle pathology includes diminished fibrosis and fiber degeneration. Tamoxifen and raloxifene also significantly mitigated bone loss. Tamoxifen, but not raloxifene, caused severe adverse effects on male reproductive organs. The results demonstrate that tamoxifen and raloxifene hold significant potential for treating FKRP-related muscular dystrophy and probably other muscular dystrophies. Sex-related differential effects of the drugs call for a careful consideration for the drug and dosage selection in male and female patient populations.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.011
  • Protection against the Neurotoxic Effects of β-Amyloid Peptide on
           Cultured Neuronal Cells by Lovastatin Involves Elevated Expression of α7
           Nicotinic Acetylcholine Receptors and Activating Phosphorylation of
           Protein Kinases
    • Authors: Liang Zhao; Yan Xiao; Jin Xiu; Long-Chun Tan; Zhi-Zhong Guan
      Pages: 1081 - 1093
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Liang Zhao, Yan Xiao, Jin Xiu, Long-Chun Tan, Zhi-Zhong Guan
      The treatment of neurodegenerative diseases with statins has drawn increasing attention, but the related molecular mechanisms remain elusive. To examine the pleiotropic cholesterol-independent effects of statins in connection with the treatment of Alzheimer disease, we probed the influence of lovastatin on the metabolism of amyloid precursor protein (APP), expression of nicotinic acetylcholine receptors (nAChRs), and activity of mitogen-activated protein kinase (MAPK) in primary cultured neurons and SH-SY5Y cells overexpressing human APP670/671. Lovastatin attenuated the neurotoxic effects of β-amyloid peptide (Aβ) and affected the metabolism of APP, reducing levels of Aβ1 to Aβ42 and β-site amyloid precursor protein-cleaving enzyme 1; enhancing those of αAPP, disintegrin metalloproteinase domain-containing protein 10, and β-site amyloid precursor protein-cleaving enzyme 2; and up-regulating expression of α7 nAChR and stimulating phosphorylation of extracellular signal-regulated kinase (ERK)1/2. Interestingly, methyllycaconitine, an antagonist of α7 nAChR, attenuated this effect on αAPP, but not on phospho-ERK1/2; whereas U0126, an inhibitor of MAPK/ERK kinase/ERK, blocked both the elevated expression of α7 nAChR and enhanced secretion of αAPP. Our findings indicate that lovastatin up-regulates expression of α7 nAChR by a mechanism involving activation of the MAPK/ERK pathway, which may result in diminished production of Aβ.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.11.020
  • Syndecan-1 Controls Lung Tumorigenesis by Regulating miRNAs Packaged in
    • Authors: Tanyalak Parimon; Rena Brauer; Saundra Y. Schlesinger; Ting Xie; Dianhua Jiang; Lingyin Ge; Ying Huang; Timothy P. Birkland; William C. Parks; David M. Habiel; Cory M. Hogaboam; Sina A. Gharib; Nan Deng; Zhenqui Liu; Peter Chen
      Pages: 1094 - 1103
      Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4
      Author(s): Tanyalak Parimon, Rena Brauer, Saundra Y. Schlesinger, Ting Xie, Dianhua Jiang, Lingyin Ge, Ying Huang, Timothy P. Birkland, William C. Parks, David M. Habiel, Cory M. Hogaboam, Sina A. Gharib, Nan Deng, Zhenqui Liu, Peter Chen
      Syndecan-1 is a transmembrane proteoglycan expressed prominently by lung epithelium and has pleiotropic functions such as regulating cell migration, proliferation, and survival. Loss of syndecan-1 expression by lung cancer cells is associated with higher-grade cancers and worse clinical prognosis. We evaluated the effects of syndecan-1 in various cell-based and animal models of lung cancer and found that lung tumorigenesis was moderated by syndecan-1. We also demonstrate that syndecan-1 (or lack thereof) alters the miRNA cargo carried within exosomes exported from lung cancer cells. Analysis of the changes in miRNA expression identified a distinct shift toward augmented procancer signaling consistent with the changes found in lung adenocarcinoma. Collectively, our work identifies syndecan-1 as an important factor in lung cancer cells that shapes the tumor microenvironment through alterations in miRNA packaging within exosomes.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2017.12.009
  • miRNAs as Biomarkers for Predicting the Progression of Ductal Carcinoma in
    • Authors: Bethany N. Hannafon; Wei-Qun Ding
      Pages: 542 - 549
      Abstract: Publication date: March 2018
      Source:The American Journal of Pathology, Volume 188, Issue 3
      Author(s): Bethany N. Hannafon, Wei-Qun Ding
      Ductal carcinoma in situ (DCIS) is defined as a proliferation of neoplastic cells within the duct of the mammary gland that have not invaded into the surrounding stroma. DCIS is considered a precursor to invasive ductal carcinoma (IDC); however, approximately half of DCIS may progress to IDC, if left untreated. Current research has shown that the genomic and transcriptomic changes are present in DCIS before the emergence of invasive disease, indicating that the malignant nature of the DCIS is defined before invasion. However, important questions remain surrounding the specific changes and processes required for malignant progression and identification of prognostic indicators of aggressiveness. miRNAs are small regulatory RNAs that can modulate gene expression by complementary binding to target mRNAs and inducing translational repression and/or mRNA degradation. In the past decade, research has shown that miRNA expression is dysregulated in IDC and that these changes are already present at the DCIS stage. Therefore, changes in miRNA expression may provide the necessary information to identify a clinical indicator of the aggressiveness of DCIS. Herein, we review the miRNA signatures identified in DCIS, describe how these signatures may be used to predict the aggressiveness of DCIS, and discuss future perspectives for DCIS biomarker discovery.

      PubDate: 2018-03-17T07:53:24Z
      DOI: 10.1016/j.ajpath.2017.11.003
  • Pleiotropic Role of p53 in Injury and Liver Regeneration after
           Acetaminophen Overdose
    • Authors: Prachi Borude; Bharat Bhushan; Sumedha Gunewardena; Jephte Akakpo; Hartmut Jaeschke; Udayan Apte
      Abstract: Publication date: Available online 11 April 2018
      Source:The American Journal of Pathology
      Author(s): Prachi Borude, Bharat Bhushan, Sumedha Gunewardena, Jephte Akakpo, Hartmut Jaeschke, Udayan Apte
      p53 is the major cellular gatekeeper involved in proliferation, cell death, migration, and homeostasis. The role of p53 in pathogenesis of drug-induced liver injury is unknown. We investigated the role of p53 in liver injury and regeneration after acetaminophen (APAP) overdose, the most common cause of acute liver failure in the Western world. Eight-week-old male wild-type (WT) and p53 knockout (p53KO) mice were treated with 300 mg/kg APAP, and the dynamics of liver injury and regeneration were studied over a time course of 0 to 96 hours. Deletion of p53 resulted in a threefold higher liver injury than in WT mice. Interestingly, despite higher liver injury, p53KO mice recovered similarly as the WT mice because of faster liver regeneration. Deletion of p53 did not affect APAP bioactivation and initiation of injury. Microarray analysis revealed that p53KO mice had disrupted metabolic homeostasis and induced inflammatory and proliferative signaling. p53KO mice showed prolonged steatosis correlating with prolonged liver injury. Initiation of liver regeneration in p53KO mice was delayed, but once initiated, cell cycle was significantly faster than WT mice because of sustained AKT, extracellular signal–regulated kinase, and mammalian target of rapamycin signaling. These studies show that p53 plays a pleotropic role after APAP overdose, where it prevents progression of liver injury by maintaining metabolic homeostasis and also regulates initiation of liver regeneration through proliferative signaling.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2018.03.006
  • The Role of Microglia and Peripheral Monocytes in Retinal Damage Following
           Corneal Chemical Injury
    • Authors: Eleftherios I. Paschalis; Fengyang Lei; Chengxin Zhou; Vassiliki Kapoulea; Aristomenis Thanos; Reza Dana; Demetrios Vavvas; James Chodosh; Claes H. Dohlman
      Abstract: Publication date: Available online 6 April 2018
      Source:The American Journal of Pathology
      Author(s): Eleftherios I. Paschalis, Fengyang Lei, Chengxin Zhou, Vassiliki Kapoulea, Aristomenis Thanos, Reza Dana, Demetrios Vavvas, James Chodosh, Claes H. Dohlman
      Eyes that have suffered alkali burn to the surface are excessively susceptible to subsequent severe glaucoma and retinal ganglion cell loss, despite maximal efforts to prevent or slow down the disease. Recently, we have shown in mice and rabbits, that such retinal damage is neither mediated by the alkali itself reaching the retina nor by intraocular pressure elevation. Rather, it is caused by the up-regulation of tumor necrosis factor alpha (TNF-α) that rapidly diffuses posteriorly, causing retinal ganglion cell apoptosis and CD45+ cell activation. Here, we investigated the involvement of peripheral blood monocytes and microglia in retinal damage. Using CX3CR1 +/EGFP ::CCR2 +/RFP reporter mice and bone marrow chimeras, we show that peripheral CX3CR1 + CD45 hi CD11b + MHC-II + monocyte infiltrate into the retina from the optic nerve at 24 hours after the burn and release further TNF-α. A secondary source of peripheral monocyte response originates from a rare population of ‘patrolling’ myeloid CCR2+ cells of the retina that differentiate into CX3CR1+ macrophages within hours after the injury. As a result, CX3CR1 + CD45 lo CD11b + microglia become reactive at 7 days, causing further TNF-α release. Prompt TNF-α inhibition after corneal burn suppresses monocyte infiltration and microglia activation, and protects the retina. This study may prove relevant to other injuries of the central nervous system.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2018.03.005
  • CD147 induces epithelial-to-mesenchymal transition by disassembling
           CAS/E-cadherin/β-catenin complex in human endometriosis
    • Authors: Chaoqun Wang; Jieting Zhang; Kin Lam Fok; Lai Ling Tsang; Mei Ye; Jianni Liu; Fanghong Li; Allan Zijian Zhao; Hsiao Chang Chan; Hao Chen
      Abstract: Publication date: Available online 6 April 2018
      Source:The American Journal of Pathology
      Author(s): Chaoqun Wang, Jieting Zhang, Kin Lam Fok, Lai Ling Tsang, Mei Ye, Jianni Liu, Fanghong Li, Allan Zijian Zhao, Hsiao Chang Chan, Hao Chen
      Epithelial-to-mesenchymal transition (EMT) is postulated to be a prerequisite for the establishment of endometriosis (EMS), a common reproductive disorder in women. Our previous studies have demonstrated the elevated expression of transmembrane glycoprotein CD147 and its pro-survival effect on abnormal cells in endometriosis. Intriguingly, CD147 is known to promote EMT in cancers. However, the involvement of CD147 in EMT during the establishment of endometriosis remains incompletely understood. Here, we showed that CD147 promotes EMT in human endometrial adenocarcinoma cell line Ishikawa (ISK). We identified a novel CD147-interacting partner, cellular apoptosis susceptibility protein (CAS), which stabilized the interaction between E-cadherin (E-cad) and β-catenin (β-cat) by forming CAS/E-cad/β-cat complex. Down-regulation of CAS led to the release and nuclear translocation of β-cat from E-cad, resulting in the overexpression of EMT-promoting gene SNAIL. Interestingly, overexpression of CD147 impaired the interaction between CAS and E-cad and triggered the release of β-cat from CAS/E-cad/β-cat complex, which in turn led to EMT. Furthermore, CAS was down-regulated in EMS with elevated levels of CD147 and nuclear β-cat. These findings suggest a previously undefined role of CAS in regulating EMT and reveal the involvement of a CD147-induced EMT signaling pathway in pathogenic progression of EMS.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2018.03.004
  • This Month in AJP
    • Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4

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

      PubDate: 2018-04-15T09:52:16Z
  • Correction
    • Abstract: Publication date: April 2018
      Source:The American Journal of Pathology, Volume 188, Issue 4

      PubDate: 2018-04-15T09:52:16Z
  • Comprehensive Evaluation of Programmed Death-Ligand 1 Expression in
           Primary and Metastatic Prostate Cancer
    • Authors: Michael C. Haffner; Gunes Guner; Diana Taheri; George J. Netto; Doreen N. Palsgrove; Qizhi Zheng; Liana Benevides Guedes; Kunhwa Kim; Harrison Tsai; David M. Esopi; Tamara Lotan; Rajni Sharma; Alan K. Meeker; Arul M. Chinnaiyan; William G. Nelson; Srinivasan Yegnasubramanian; Jun Luo; Rohit Mehra; Emmanuel S. Antonarakis; Charles G. Drake; Angelo M. De Marzo
      Abstract: Publication date: Available online 22 March 2018
      Source:The American Journal of Pathology
      Author(s): Michael C. Haffner, Gunes Guner, Diana Taheri, George J. Netto, Doreen N. Palsgrove, Qizhi Zheng, Liana Benevides Guedes, Kunhwa Kim, Harrison Tsai, David M. Esopi, Tamara Lotan, Rajni Sharma, Alan K. Meeker, Arul M. Chinnaiyan, William G. Nelson, Srinivasan Yegnasubramanian, Jun Luo, Rohit Mehra, Emmanuel S. Antonarakis, Charles G. Drake, Angelo M. De Marzo
      Antibodies targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-L1) interaction have shown clinical activity in multiple cancer types. PD-L1 protein expression is a clinically validated predictive biomarker of response for such therapies. Prior studies evaluating the expression of PD-L1 in primary prostate cancers have reported highly variable rates of PD-L1 positivity. In addition, limited data exist on PD-L1 expression in metastatic castrate-resistant prostate cancer (mCRPC). Here, we determined PD-L1 protein expression by immunohistochemistry using a validated PD-L1–specific antibody (SP263) in a large and representative cohort of primary prostate cancers and prostate cancer metastases. The study included 539 primary prostate cancers comprising 508 acinar adenocarcinomas, 24 prostatic duct adenocarcinomas, 7 small-cell carcinomas, and a total of 57 cases of mCRPC. PD-L1 positivity was low in primary acinar adenocarcinoma, with only 7.7% of cases showing detectable PD-L1 staining. Increased levels of PD-L1 expression were noted in 42.9% of small-cell carcinomas. In mCRPC, 31.6% of cases showed PD-L1–specific immunoreactivity. In conclusion, in this comprehensive evaluation of PD-L1 expression in prostate cancer, PD-L1 expression is rare in primary prostate cancers, but increased rates of PD-L1 positivity were observed in mCRPC. These results will be important for the future clinical development of programmed cell death protein 1/PD-L1–targeting therapies in prostate cancer.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2018.02.014
  • Selective spatio-temporal vulnerability of central nervous system neurons
           to pathological TAR DNA-binding protein 43 in aged transgenic mice
    • Authors: Annika van Hummel; Gabriella Chan; Julia van der Hoven; Marco Morsch; Stefania Ippati; Lisa Suh; Mian Bi; Prita R. Asih; Wei Siang Lee; Troy A. Butler; Magdalena Przybyla; Glenda M. Halliday; Olivier Piguet; Matthew C. Kiernan; Roger S. Chung; Lars M. Ittner; Yazi D. Ke
      Abstract: Publication date: Available online 22 March 2018
      Source:The American Journal of Pathology
      Author(s): Annika van Hummel, Gabriella Chan, Julia van der Hoven, Marco Morsch, Stefania Ippati, Lisa Suh, Mian Bi, Prita R. Asih, Wei Siang Lee, Troy A. Butler, Magdalena Przybyla, Glenda M. Halliday, Olivier Piguet, Matthew C. Kiernan, Roger S. Chung, Lars M. Ittner, Yazi D. Ke
      Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and fatal disease characterized by muscular atrophy due to loss of upper and lower motor neurons. Histopathologically, the majority of ALS cases present with abnormal cytoplasmic accumulation and aggregation of the nuclear RNA-regulating protein TAR DNA-binding protein 43 (TDP-43). Pathogenic mutations in the TARDBP gene that encodes TDP-43 have been identified in familial ALS. We have previously reported transgenic mice with neuronal expression of human TDP-43 carrying the pathogenic A315T mutation (iTDP-43A315T mice), presenting with early-onset motor deficits in adolescent animals. Here, we analyzed aged iTDP-43A315T mice, focusing on the spatio-temporal profile and progression of neurodegeneration in upper and lower motor neurons. Magnetic resonance imaging and histological analysis revealed a differential loss of upper motor neurons in a hierarchical order as iTDP-43A315T mice aged. Furthermore, we report progressive gait problems, profound motor deficits and muscle atrophy in aged iTDP-43A315T mice. Despite these deficits and TDP-43 pathology in lower motor neurons, stereological analysis did not show cell loss in spinal cords. Taken together, neuronal populations in aging iTDP-43A315T mice show differential susceptibility to the expression of human TDP-43A315T.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2018.03.002
  • Hepatitis C Virus (HCV) Mimics Effects of Glypican-3 (GPC3) on CD81 and
           Promotes Development of Hepatocellular Carcinomas via Activation of Hippo
           Pathway in Hepatocytes
    • Authors: Yuhua Xue; Wendy M. Mars; William Bowen; Aatur D. Singhi; John Stoops; George K. Michalopoulos
      Abstract: Publication date: Available online 22 March 2018
      Source:The American Journal of Pathology
      Author(s): Yuhua Xue, Wendy M. Mars, William Bowen, Aatur D. Singhi, John Stoops, George K. Michalopoulos
      Glypican 3 (GPC3) is over-expressed in hepatocellular carcinomas (HCC). GPC3 binds to CD81. Forced expression of CD81 in a GPC3 expressing HCC cell line caused activation of Hippo, decrease in Ezrin phosphorylation, and decrease in Yap. CD81 is also associated with HCV entry into hepatocytes. Activation of CD81 by agonistic antibody causes activation of spleen kinase (Syk) and phosphorylation of Ezrin, a regulator of Hippo pathway. In cultures of normal hepatocytes, CD81 agonistic antibody led to enhanced phosphorylation of Ezrin and increase in nuclear Yap. HCV E2 protein mimicked GPC3 and led to enhanced Hippo activity and decreased Yap in cultured normal human hepatocytes. HCC tissue microarray revealed lack of expression of CD81 in most HCC, rendering them insusceptible to HCV infection. Activation of CD81 by agonistic antibody suppresses Hippo pathway and increases nuclear Yap. HCV mimics GPC3, causing Hippo activation and decrease in Yap. HCV is thus likely to enhance hepatic neoplasia by acting as “promoter” of growth of early CD81-negative neoplastic hepatocytes which are resistant to HCV infection and thus have a proliferative advantage to clonally expand as they participate in compensatory regeneration for the required maintenance of 100% of liver weight (“hepatostat”).

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2018.02.013
  • Possible Involvement of Human Mast Cells in the Establishment of Pregnancy
           via Killer Cell Ig-Like Receptor 2DL4
    • Authors: Chiyuki Ueshima; Tatsuki R. Kataoka; Masahiro Hirata; Akihiko Sugimoto; Yoshiki Iemura; Sachiko Minamiguchi; Takashi Nomura; Hironori Haga
      Abstract: Publication date: Available online 22 March 2018
      Source:The American Journal of Pathology
      Author(s): Chiyuki Ueshima, Tatsuki R. Kataoka, Masahiro Hirata, Akihiko Sugimoto, Yoshiki Iemura, Sachiko Minamiguchi, Takashi Nomura, Hironori Haga
      The involvement of mast cells in the establishment of pregnancy is unclear. Herein, we found that human mast cells are present in the decidual tissues of parous women and expressed a human-specific protein killer cell Ig-like receptor (KIR) 2DL4, a receptor for human leukocyte antigen G expressed on human trophoblasts. In contrast, decreased numbers of decidual mast cells and reduced KIR2DL4 expression were observed in these cells of infertile women who had undergone long-term corticosteroid treatment. Co-culture of the human mast cell line, LAD2, and human trophoblast cell line, HTR-8/SVneo, accelerated the migration and tube formation of HTR-8/SVneo cells in a KIR2DL4-dependent manner. These observations suggest the possible involvement of human mast cells in the establishment of pregnancy via KIR2DL4 and that long-term corticosteroid treatment may cause infertility by influencing the phenotypes of decidual mast cells.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2018.02.012
  • Parathyroid Hormone–Like Hormone Induces Epithelial-to-Mesenchymal
           Transition of Intestinal Epithelial Cells by Activating the Runt-Related
           Transcription Factor 2
    • Authors: Shuying He; Minmin Xue; Cuiping Liu; Fang Xie; Lan Bai
      Abstract: Publication date: Available online 22 March 2018
      Source:The American Journal of Pathology
      Author(s): Shuying He, Minmin Xue, Cuiping Liu, Fang Xie, Lan Bai
      Epithelial-to-mesenchymal transition (EMT) is a key contributor to fibroblast activation in fibrosis of multiple organs, including the intestine. Parathyroid hormone–like hormone (PTHLH) is an important factor in renal fibrosis and regulates several processes, including EMT. Herein, we investigated the role of PTHLH-induced EMT in intestinal fibrosis associated with Crohn disease. The expression levels of the EMT-related proteins, PTHLH, and parathyroid hormone receptor 1 (PTH1R) in intestinal tissues were determined by immunohistochemistry, and our results revealed that PTHLH and PTH1R were significantly elevated and associated with EMT marker expression. Moreover, neutralizing PTH1R and antagonizing PTHLH bioactivity prevented transforming growth factor-β1–induced EMT. PTH1R can propagate the protein kinase A (PKA) signal and activate downstream nuclear transcription factors, including runt-related transcription factor 2 (Runx2). In addition, lentiviral vector-PTHLH–treated mice were highly sensitive to 2,4,6-trinitrobenzene sulfonic acid, and analysis of the PTHLH-PTH1R axis revealed the involvement of PKA-Runx2 in PTHLH-induced EMT. Our results indicate that PTHLH triggered EMT in intestinal epithelial cells through the PKA-Runx2 pathway, which might serve as a therapeutic target for intestinal fibrosis in Crohn disease.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2018.03.003
  • Tmem30a plays critical roles in ensuring the survival of hematopoietic
           cells and leukemia cells in mice
    • Authors: Ning Li; Yeming Yang; Cailing Liang; Qiang Qiu; Cong Pan; Mengyuan Li; Shengyong Yang; Lijuan Chen; Xianjun Zhu; Yiguo Hu
      Abstract: Publication date: Available online 21 March 2018
      Source:The American Journal of Pathology
      Author(s): Ning Li, Yeming Yang, Cailing Liang, Qiang Qiu, Cong Pan, Mengyuan Li, Shengyong Yang, Lijuan Chen, Xianjun Zhu, Yiguo Hu
      The fundamental structure of eukaryotic cell plasma membrane is the phospholipid bilayer, which contains four major phospholipids. These phospholipids are asymmetrically distributed between the outer and inner leaflets. P4-ATPase flippase complexes play essential roles in ensuring this asymmetry. Here we showed that conditional deletion of Tmem30a, the beta subunit of P4-ATPase flippase complex, caused pancytopenia in mice. Tmem30a deficiency resulted in depletion of lineage-committed blood cells in the peripheral blood, spleen, and bone marrow. Ablation of Tmem30a also caused the depletion of hematopoietic stem cells (HSCs). HSC RNA-seq results revealed that multiple biological processes and signal pathways were involved in the event, including mTOR signaling, genes for HSC stemness, and genes responding to interferons. Our results also revealed that targeting Tmem30a signaling had therapeutic utility in BCR/ABL1-induced chronic myeloid leukemia.

      PubDate: 2018-04-15T09:52:16Z
      DOI: 10.1016/j.ajpath.2018.02.015
  • This Month in AJP
    • Abstract: Publication date: Available online 14 March 2018
      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: 2018-03-17T07:53:24Z
  • Cellular and Metabolic Basis for the Ichthyotic Phenotype in NIPAL4
           (Ichthyin) Deficient Canines
    • Authors: Elizabeth Mauldin; Debra Crumrine Margret Casal Sekyoo Jeong Katerina Vavrova
      Abstract: Publication date: Available online 13 March 2018
      Source:The American Journal of Pathology
      Author(s): Elizabeth A. Mauldin, Debra Crumrine, Margret L. Casal, Sekyoo Jeong, Lukáš Opálka, Katerina Vavrova, Yoshikazu Uchida, Kyungho Park, Brittany Craiglow, Keith A. Choate, Kyong-Oh Shin, Yong-Moon Lee, Gary L. Grove, Joan S. Wakefield, Denis Khnykin, Peter M. Elias
      Mutations in several lipid synthetic enzymes that block fatty acid and ceramide production produce autosomal recessive congenital ichthyosis (ARCI) and associated abnormalities in permeability barrier homeostasis. Yet, the basis for the phenotype in patients with NIPAL4 (ichthyin) mutations (among the most prevalent ARCI) remains unknown. Barrier function was abnormal in an index patient and in canines with homozygous NIPAL4 mutations, attributable to extensive membrane stripping, likely from detergent effects of nonesterified free FFA. Cytotoxicity compromised not only lamellar body secretion, but also formation of the corneocyte lipid envelope (CLE) and attenuation of the cornified envelope (CE), consistent with a previously unrecognized, scaffold function of the CLE. Together, these abnormalities result in failure to form normal lamellar bilayers, accounting for the permeability barrier abnormality and clinical phenotype in NIPAL4 deficiency. Thus, NIPAL4 deficiency represents another lipid synthetic ARCI that converges on the CLE (and CE), compromising their putative scaffold function. Yet, the clinical phenotype only partially improved after normalization of CLE and CE structure with topical acylCer, due to ongoing accumulation of toxic metabolites, further evidence that proximal, cytotoxic metabolites contribute to disease pathogenesis.

      PubDate: 2018-03-17T07:53:24Z
  • Mice Expressing c-MYC in Neural Precursors Develop Choroid Plexus and
           Ciliary Body Tumors
    • Authors: Morgan Shannon; Ryann Fame Kevin Chau Neil Dani Monica Calicchio
      Abstract: Publication date: Available online 13 March 2018
      Source:The American Journal of Pathology
      Author(s): Morgan L. Shannon, Ryann M. Fame, Kevin F. Chau, Neil Dani, Monica L. Calicchio, Gwenaelle S. Géléoc, Hart G.W. Lidov, Sanda Alexandrescu, Maria K. Lehtinen
      Choroid plexus tumors and ciliary body medulloepithelioma are predominantly pediatric neoplasms. Progress in understanding the pathogenesis of these tumors has been hindered by their rarity and lack of models that faithfully recapitulate the disease. Here, we find that endogenous c-Myc is down-regulated in the forebrain neuroepithelium, whose neural plate border domains give rise to anterior choroid plexus and ciliary body. To uncover the consequences of persistent MYC (c-Myc) expression, c-Myc expression was forced in multipotent neural precursors (Nestin-Cre:MYC), which produced a fully penetrant model of choroid plexus carcinoma and ciliary body medulloepithelioma. Nestin-mediated c-Myc expression in choroid plexus epithelial cells leads to the regionalized formation of choroid plexus carcinoma in the posterior domain of the lateral ventricle choroid plexus and fouth ventricle choroid plexus that is accompanied by loss of multiple cilia, up-regulation of protein biosynthetic machinery, and hydrocephalus. Parallel c-Myc expression in the ciliary body leads also to up-regulation of protein biosynthetic machinery. Additionally, c-Myc expression in human choroid plexus tumors increases with aggressiveness of disease. Collectively, our findings expose a select vulnerability of the neuroepithelial lineage to postnatal tumorigenesis and provide a new mouse model for investigating the pathogenesis of these rare pediatric neoplasms.

      PubDate: 2018-03-17T07:53:24Z
  • Imiquimod-Induced Psoriasis-Like Skin Lesions Do Not Accelerate
           Atherosclerosis in Low Density Lipoprotein Receptor–Deficient Mice
    • Authors: Marie Madsen; Peter Riis Hansen; Lars Bo Nielsen; Renata Martins Cardoso; Miranda van Eck; Tanja Xenia Pedersen
      Abstract: Publication date: Available online 12 March 2018
      Source:The American Journal of Pathology
      Author(s): Marie Madsen, Peter Riis Hansen, Lars Bo Nielsen, Renata Martins Cardoso, Miranda van Eck, Tanja Xenia Pedersen
      Psoriasis is a chronic inflammatory skin disorder associated with several comorbidities including atherosclerosis. Disease mechanisms that may affect both psoriasis and atherosclerosis include activation of T helper 1 and T helper 17 cells. Imiquimod application is an established mouse model of psoriasis-like skin inflammation. The cardiac glycoside digoxin inhibits the master transcription factor of T helper 17 differentiation, retinoid acid receptor–related orphan nuclear receptor γt, and attenuates interleukin-17–dependent pathologies in mice. We investigated whether cyclic imiquimod-induced psoriasis-like skin inflammation affects atherosclerosis in low-density lipoprotein receptor–deficient mice, and whether digoxin modifies either disease. Topical imiquimod application increased ear thickness, keratinocyte proliferation, and accumulation of CD3+ T cells in the skin of low-density lipoprotein receptor–deficient mice. Also, imiquimod affected the mice systemically with induction of splenomegaly as well as increased plasma levels of interleukin-17A and serum amyloid A. Overall, imiquimod reduced atherosclerosis in the aortic arch en face, but did not affect atherosclerosis in the aortic root. Digoxin significantly reduced the imiquimod-induced ear thickening, had divergent effects on imiquimod-induced systemic inflammation, and did not affect atherosclerosis. In conclusion, cyclic imiquimod applications can be used for long-term induction of psoriasis-like skin lesions, but attenuates atherosclerosis in low-density lipoprotein–deficient mice. In this model, digoxin reduces skin inflammation, but has no effect on atherosclerosis.

      PubDate: 2018-03-17T07:53:24Z
      DOI: 10.1016/j.ajpath.2018.02.005
  • Bromodomain and Extraterminal (BET) Proteins Regulate Hepatocyte
           Proliferation in Hepatocyte-Driven Liver Regeneration
    • Authors: Jacquelyn O. Russell; Sungjin Ko; Harvinder S. Saggi; Sucha Singh; Minakshi Poddar; Donghun Shin; Satdarshan P. Monga
      Abstract: Publication date: Available online 12 March 2018
      Source:The American Journal of Pathology
      Author(s): Jacquelyn O. Russell, Sungjin Ko, Harvinder S. Saggi, Sucha Singh, Minakshi Poddar, Donghun Shin, Satdarshan P. Monga
      Bromodomain and extraterminal (BET) proteins recruit key components of basic transcriptional machinery to promote gene expression. Aberrant expression and mutations in BET genes have been identified in many malignancies. Small molecule inhibitors of BET proteins like JQ1 have shown efficacy in preclinical cancer models including affecting growth of hepatocellular carcinoma. BET proteins also regulate cell proliferation in nontumor settings. We recently showed that BET proteins regulate cholangiocyte-driven liver regeneration. Here, we studied the role of BET proteins in hepatocyte-driven liver regeneration in partial hepatectomy (PHx) and acetaminophen-induced liver injury models in mice and zebrafish. JQ1 was injected 2 or 16 hours post-PHx in mice to determine effect on hepatic injury, regeneration and signaling. Mice treated with JQ1 after PHx displayed increased liver injury and a near-complete inhibition of hepatocyte proliferation. Levels of Ccnd1 mRNA and Cyclin D1 protein were reduced in 16-hour post-PHx JQ1-injected animals, and even further reduced in 2 hours post-PHx JQ1-injected mice. JQ1-treated zebrafish larvae after acetaminophen-induced injury also displayed notably impaired hepatocyte proliferation. In both models, Wnt signaling was prominently suppressed by JQ1. Our results show that BET proteins regulate hepatocyte proliferation–driven liver regeneration, and Wnt signaling is particularly sensitive to BET protein inhibition.

      PubDate: 2018-03-17T07:53:24Z
      DOI: 10.1016/j.ajpath.2018.02.006
  • Alterations in Placental Gene Expression of Pregnant Women With Chronic
           Chagas Disease
    • Authors: Natalia Anahí Juiz; Irma Torrejón; Marianela Burgos; Ana María Fernanda Torres; Tomás Duffy; Nelly Melina Cayo; Anahí Tabasco; Miriam Salvo; Silvia Andrea Longhi; Alejandro Gabriel Schijman
      Abstract: Publication date: Available online 12 March 2018
      Source:The American Journal of Pathology
      Author(s): Natalia Anahí Juiz, Irma Torrejón, Marianela Burgos, Ana María Fernanda Torres, Tomás Duffy, Nelly Melina Cayo, Anahí Tabasco, Miriam Salvo, Silvia Andrea Longhi, Alejandro Gabriel Schijman
      Infection with Trypanosoma cruzi in women at reproductive age is associated with congenital transmission and adverse pregnancy outcome. The placenta is a key barrier to infection. We characterized gene expression profiles of term placental environment from T. cruzi seropositive (SP) and seronegative (SN) mothers performing RNA-seq. Nine pools of placental RNA paired samples were used: three from SN and six from SP tissues. Each pool consisted of female/male newborns and vaginal/caesarean deliveries binomials. No newborn resulted congenitally infected. T. cruzi satellite DNA quantitative PCR in placental tissues and maternal and neonatal blood, and parasite 18S RT-qPCR from placental RNA were negative, except in three SP women's bloodstream. To identify pathways associated with maternal T. cruzi infection, a gene-set association analysis was implemented: SP placental samples showed overexpression of inflammatory response and lymphocytic activation whereas numerous biosynthetic processes were down-regulated. About 42 genes showed a significant fold-change between SP and SN groups. KISS1 and CGB5 were down-regulated whereas KIF12, HLA-G, PRG2, TAC3, FN1, and ATXN3L were up-regulated. Several expressed genes in SP placentas encode proteins associated to preeclampsia and miscarriage. This first transcriptomics study in human term placental environment shows a placental response that may affect the fetus while protecting it from parasite infection; this host response could be responsible for the low rate of congenital transmission in chronic Chagas disease.

      PubDate: 2018-03-17T07:53:24Z
      DOI: 10.1016/j.ajpath.2018.02.011
  • High MUC2 Mucin Expression and Misfolding Induce Cellular Stress, Reactive
           Oxygen Production, and Apoptosis in Goblet Cells
    • Authors: Adelaide Tawiah; Steve Cornick; France Moreau; Hayley Gorman; Manish Kumar; Sameer Tiwari; Kris Chadee
      Abstract: Publication date: Available online 12 March 2018
      Source:The American Journal of Pathology
      Author(s): Adelaide Tawiah, Steve Cornick, France Moreau, Hayley Gorman, Manish Kumar, Sameer Tiwari, Kris Chadee
      MUC2 mucin is a large glycoprotein produced by goblet cells that forms the protective mucus blanket overlying the intestinal epithelium as the first line of innate host defense. High MUC2 production in inflammatory bowel disease and infectious colitis depletes goblet cells and the mucus layer by an unknown mechanism. Here, we analyzed the effect of high MUC2 biosynthesis on endoplasmic reticulum (ER) stress and apoptosis in goblet cells using a high MUC2-producing human goblet cell line (HT29-H) and a HT29-H clone (HT29-L) silenced for MUC2 expression by lentivirus-mediated shRNA. Goblet cell ER stress and apoptosis were quantified during early onset of dextran sulfate sodium–induced colitis in C57BL/6 and Math1M1GFP mice. Compared with HT29-L and MUC2 nonproducing Caco-2 cells, high MUC2-producing HT29-H cells had significantly increased ER stress and apoptosis after treatment with ER stress–inducing agents. Apoptosis was driven by increased misfolded MUC2 that triggered elevated levels of reactive oxygen species. Correcting MUC2 folding and inhibiting reactive oxygen species alleviated ER stress and rescued cells from apoptosis. During early-onset colitis, mucus hypersecretion caused severe ER stress and apoptosis of goblet cells that preceded absorptive epithelial cell damage. Thus, in gastrointestinal inflammation, high MUC2 biosynthesis and goblet cell apoptosis leads to a dysfunctional epithelial barrier. Enhancing MUC2 folding may help alleviate goblet cell depletion and maintain mucosal integrity.

      PubDate: 2018-03-17T07:53:24Z
      DOI: 10.1016/j.ajpath.2018.02.007
  • Induction of the Hajdu Cheney Syndrome Mutation in CD19 B Cells in Mice
           Alters B-Cell Allocation but Not Skeletal Homeostasis
    • Authors: Jungeun Yu; Stefano Zanotti; Lauren Schilling; Chris Schoenherr; Aris Economides; Archana Sanjay; Ernesto Canalis
      Abstract: Publication date: Available online 12 March 2018
      Source:The American Journal of Pathology
      Author(s): Jungeun Yu, Stefano Zanotti, Lauren Schilling, Chris Schoenherr, Aris Economides, Archana Sanjay, Ernesto Canalis
      Mice harboring Notch2 mutations replicating Hajdu Cheney syndrome (Notch2 tm1.1ECan ) have osteopenia and exhibit an increase in splenic marginal zone B cells with a decrease in follicular B cells. Whether the altered B-cell allocation is responsible for the osteopenia of Notch2 tm1.1ECan mutants is unknown. To determine the effect of NOTCH2 activation in B cells on splenic B-cell allocation and skeletal phenotype, a conditional by inversion (COIN) Hajdu Cheney syndrome allele of Notch2 (Notch2 [ΔPEST]COIN ) was used. Cre recombination generates a permanent Notch2 ΔPEST allele expressing a transcript where sequences coding for the PEST domain are replaced by a STOP codon. CD19-Cre drivers were backcrossed into Notch2 [ΔPEST]COIN/[ΔPEST]COIN to generate CD19-specific Notch2 ΔPEST/ΔPEST mutants and control Notch2 [ΔPEST]COIN/[ΔPEST]COIN littermates. There was an increase in marginal zone B cells and a decrease in follicular B cells in the spleen of CD19 Cre/WT ;Notch2 ΔPEST/ΔPEST mice recapitulating the splenic phenotype of Notch2 tm1.1ECan mice. The effect was reproduced when the NOTCH1 intracellular domain was induced in CD19-expressing cells (CD19 Cre/WT ;Rosa Notch1/WT mice). However, neither CD19 Cre/WT ;Notch2 ΔPEST/ΔPEST nor CD19 Cre/WT ;Rosa Notch1/WT mice had a skeletal phenotype. Moreover, splenectomies in Notch2 tm1.1ECan mice did not reverse their osteopenic phenotype. In conclusion, Notch2 activation in CD19-expressing cells determines B-cell allocation in the spleen but has no skeletal consequences.

      PubDate: 2018-03-17T07:53:24Z
      DOI: 10.1016/j.ajpath.2018.02.010
  • This Month in AJP
    • Abstract: Publication date: March 2018
      Source:The American Journal of Pathology, Volume 188, Issue 3

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

      PubDate: 2018-03-17T07:53:24Z
  • Modeling Idiopathic Pulmonary Fibrosis in Humanized Severe Combined
           Immunodeficiency Mice
    • Authors: David M. Habiel; Milena S. Espindola; Ana L. Coelho; Cory M. Hogaboam
      Abstract: Publication date: Available online 17 February 2018
      Source:The American Journal of Pathology
      Author(s): David M. Habiel, Milena S. Espindola, Ana L. Coelho, Cory M. Hogaboam
      Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease of unknown etiopathogenesis with limited therapeutic options. IPF is characterized by an abundance of fibroblasts and loss of epithelial progenitors, which cumulates in unrelenting fibrotic lung remodeling and loss of normal oxygenation. IPF has been challenging to model in rodents; nonetheless, mouse models of lung fibrosis provide clues as to the natural progression of lung injury and remodeling, but many have not been useful in predicting efficacy of therapeutics in clinical IPF. We provide a detailed methodologic description of various iterations of humanized mouse models, initiated by the i.v. injection of cells from IPF lung biopsy specimens or explants into severe combined immunodeficiency (SCID)/beige or nonobese diabetic SCID γ mice. Unlike cells from normal lung samples, IPF cells promote persistent, nonresolving lung remodeling in SCID mice. Finally, we provide examples and discuss potential advantages and pitfalls of human-specific targeting approaches in a humanized SCID model of pulmonary fibrosis.

      PubDate: 2018-02-25T05:48:06Z
      DOI: 10.1016/j.ajpath.2017.12.020
  • Ebola Virus Localization in the Macaque Reproductive Tract during Acute
           Ebola Virus Disease
    • Authors: Donna L. Perry; Louis M. Huzella; John G. Bernbaum; Michael R. Holbrook; Peter B. Jahrling; Katie R. Hagen; Matthias J. Schnell; Reed F. Johnson
      Abstract: Publication date: Available online 14 February 2018
      Source:The American Journal of Pathology
      Author(s): Donna L. Perry, Louis M. Huzella, John G. Bernbaum, Michael R. Holbrook, Peter B. Jahrling, Katie R. Hagen, Matthias J. Schnell, Reed F. Johnson
      Sexual transmission of Ebola virus (EBOV) has been demonstrated more than a year after recovery from the acute phase of Ebola virus disease (EVD). The mechanisms underlying EBOV persistence and sexual transmission are not currently understood. Using the acute macaque model of EVD, we hypothesized EBOV would infect the reproductive tissues and sought to localize the infection in these tissues using immunohistochemistry and transmission electron microscopy. In four female and eight male macaques that succumbed to EVD between 6 and 9 days after EBOV challenge, we demonstrate widespread EBOV infection of the interstitial tissues and endothelium in the ovary, uterus, testis, seminal vesicle, epididymis, and prostate gland, with minimal associated tissue immune response or organ pathology. Given the widespread involvement of EBOV in the reproductive tracts of both male and female macaques, it is reasonable to surmise that our understanding of the mechanisms underlying sexual transmission of EVD and persistence of EBOV in immune-privileged sites would be facilitated by the development of a nonhuman primate model in which the macaques survived past the acute stage into convalescence.

      PubDate: 2018-02-14T04:44:06Z
      DOI: 10.1016/j.ajpath.2017.11.004
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