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Publisher: Elsevier   (Total: 3034 journals)

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Showing 1 - 200 of 3034 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 19, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 16, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 81, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 23, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 27, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 4)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 5, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 322, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription  
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 200, SJR: 3.683, h-index: 202)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.615, h-index: 21)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.442, h-index: 21)
Acta Oecologica     Hybrid Journal   (Followers: 9, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 22, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 5, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 4, SJR: 0.383, h-index: 19)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 2)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 5, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 4, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 3)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 5)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 20)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 122, SJR: 5.2, h-index: 222)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.265, h-index: 53)
Advanced Powder Technology     Hybrid Journal   (Followers: 16, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.299, h-index: 15)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 24, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 6, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 10, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 21, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 25, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 24, SJR: 0.183, h-index: 23)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.665, h-index: 29)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 8, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 28, SJR: 0.938, h-index: 33)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 16, SJR: 0.223, h-index: 22)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 4)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 39, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 25, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 40, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 3)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 43, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
Advances in Genetics     Full-text available via subscription   (Followers: 15, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 12)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 20, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 24)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 34, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 3, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 4)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
Advances in Life Course Research     Hybrid Journal   (Followers: 7, SJR: 0.764, h-index: 15)
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: 16, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 5, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 21, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 13)
Advances in Pharmacology     Full-text available via subscription   (Followers: 15, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 7, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 58)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 2, SJR: 0.1, h-index: 2)
Advances in Space Research     Full-text available via subscription   (Followers: 337, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Surgery     Full-text available via subscription   (Followers: 6, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 29, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 15)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 43, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 309, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 4, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 7, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 393, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 15, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 30, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 38, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 50, SJR: 1.879, h-index: 120)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.434, h-index: 14)
Air Medical J.     Hybrid Journal   (Followers: 5, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 9, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 5)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access  
Algal Research     Partially Free   (Followers: 8, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 5, SJR: 0.776, h-index: 35)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 6, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 46, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 5)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 3)
American Heart J.     Hybrid Journal   (Followers: 46, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 45, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 34, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 6, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 15, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 30, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 24, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 32, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 44, SJR: 2.023, h-index: 189)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 180, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 54, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 2)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.249, h-index: 88)
American J. of Otolaryngology     Hybrid Journal   (Followers: 23, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 23, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 21, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 33, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 51, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 3)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 2, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 38, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 161, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 8, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 10)
Anesthésie & Réanimation     Full-text available via subscription  
Anesthesiology Clinics     Full-text available via subscription   (Followers: 21, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 151, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
Annales d'Endocrinologie     Full-text available via subscription   (SJR: 0.394, h-index: 30)
Annales d'Urologie     Full-text available via subscription  
Annales de Cardiologie et d'Angéiologie     Full-text available via subscription   (SJR: 0.177, h-index: 13)
Annales de Chirurgie de la Main et du Membre Supérieur     Full-text available via subscription  
Annales de Chirurgie Plastique Esthétique     Full-text available via subscription   (Followers: 2, SJR: 0.354, h-index: 22)
Annales de Chirurgie Vasculaire     Full-text available via subscription   (Followers: 1)

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Journal Cover American Journal of Pathology
  [SJR: 2.653]   [H-I: 228]   [23 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0002-9440
   Published by Elsevier Homepage  [3034 journals]
  • RNA-Binding Proteins in Female Reproductive Pathologies
    • Authors: Kasra Khalaj; Jessica E. Miller; Christian R. Fenn; SooHyun Ahn; Rayana L. Luna; Lindsey Symons; Stephany P. Monsanto; Madhuri Koti; Chandrakant Tayade
      Pages: 1200 - 1210
      Abstract: Publication date: June 2017
      Source:The American Journal of Pathology, Volume 187, Issue 6
      Author(s): Kasra Khalaj, Jessica E. Miller, Christian R. Fenn, SooHyun Ahn, Rayana L. Luna, Lindsey Symons, Stephany P. Monsanto, Madhuri Koti, Chandrakant Tayade
      RNA-binding proteins are key regulatory molecules involved primarily in post-transcriptional gene regulation of RNAs. Post-transcriptional gene regulation is critical for adequate cellular growth and survival. Recent reports have shown key interactions between these RNA-binding proteins and other regulatory elements, such as miRNAs and long noncoding RNAs, either enhancing or diminishing their response to RNA stabilization. Many RNA-binding proteins have been reported to play a functional role in mediation of cytokines involved in inflammation and immune dysfunction, and some have been classified as global post-transcriptional regulators of inflammation. The ubiquitous expression of RNA-binding proteins in a wide variety of cell types and their unique mechanisms of degradative action provide evidence that they are involved in reproductive tract pathologies. Aberrant inflammation and immune dysfunction are major contributors to the pathogenesis and disease pathophysiology of many reproductive pathologies, including ovarian and endometrial cancers in the female reproductive tract. Herein, we discuss various RNA-binding proteins and their unique contributions to female reproductive pathologies with a focus on those mediated by aberrant inflammation and immune dysfunction.

      PubDate: 2017-05-20T14:42:26Z
      DOI: 10.1016/j.ajpath.2017.01.017
       
  • Boosting Inflammation Resolution in Atherosclerosis
    • Authors: Gabrielle Fredman; Ira Tabas
      Pages: 1211 - 1221
      Abstract: Publication date: June 2017
      Source:The American Journal of Pathology, Volume 187, Issue 6
      Author(s): Gabrielle Fredman, Ira Tabas
      Defective inflammation resolution is the underlying cause of prevalent chronic inflammatory diseases, such as arthritis, asthma, cancer, and neurodegenerative and cardiovascular diseases. Inflammation resolution is governed by several endogenous factors, including fatty acid–derived specialized proresolving mediators and proteins, such as annexin A1. Specifically, specialized proresolving mediators comprise a family of mediators that include arachidonic acid–derived lipoxins, omega-3 fatty acid eicosapentaenoic acid–derived resolvins, docosahexaenoic acid–derived resolvins, protectins, and maresins. Emerging evidence indicates that imbalances between specialized proresolving mediators and proinflammatory mediators are associated with several prevalent human diseases, including atherosclerosis. Mechanisms that drive this imbalance remain largely unknown and will be discussed in this review. Furthermore, the concept of dysregulated inflammation resolution in atherosclerosis has been known for several decades. Recently, there has been an explosion of new work with regard to the therapeutic application of proresolving ligands in experimental atherosclerosis. Therefore, this review will highlight recent advances in our understanding of how inflammation resolution may become defective in atherosclerosis and the potential for proresolving therapeutics in atherosclerosis. Last, we offer insight for future implications of the field.

      PubDate: 2017-05-20T14:42:26Z
      DOI: 10.1016/j.ajpath.2017.01.018
       
  • CCN3 Regulates Macrophage Foam Cell Formation and Atherosclerosis
    • Authors: Hong Shi; Chao Zhang; Vinay Pasupuleti; Xingjian Hu; Domenick A. Prosdocimo; Wenconghui Wu; Yulan Qing; Shitong Wu; Haneen Mohammad; Stanton L. Gerson; Bernard Perbal; Philip A. Klenotic; Nianguo Dong; Zhiyong Lin
      Pages: 1230 - 1237
      Abstract: Publication date: June 2017
      Source:The American Journal of Pathology, Volume 187, Issue 6
      Author(s): Hong Shi, Chao Zhang, Vinay Pasupuleti, Xingjian Hu, Domenick A. Prosdocimo, Wenconghui Wu, Yulan Qing, Shitong Wu, Haneen Mohammad, Stanton L. Gerson, Bernard Perbal, Philip A. Klenotic, Nianguo Dong, Zhiyong Lin
      Recent studies implicate the Cyr61, CTGF, Nov (CCN) matricellular signaling protein family as emerging players in vascular biology, with NOV (alias CCN3) as an important regulator of vascular homeostasis. Herein, we examined the role of CCN3 in the pathogenesis of atherosclerosis. In response to a 15-week high-fat diet feeding, CCN3-deficient mice on the atherosclerosis-prone Apoe −/− background developed increased aortic lipid-rich plaques compared to control Apoe −/− mice, a result that was observed in the absence of alterations in plasma lipid content. To address the cellular contributor(s) responsible for the atherosclerotic phenotype, we performed bone marrow transplantation experiments. Transplantation of Apoe; Ccn3 double-knockout bone marrow into Apoe −/− mice resulted in an increase of atherosclerotic plaque burden, whereas transplantation of Apoe −/− marrow to Apoe; Ccn3 double-knockout mice caused a reduction of atherosclerosis. These results indicate that CCN3 deficiency, specifically in the bone marrow, plays a major role in the development of atherosclerosis. Mechanistically, cell-based studies in isolated peritoneal macrophages demonstrated that CCN3 deficiency leads to an increase of lipid uptake and foam cell formation, an effect potentially attributed to the increased expression of scavenger receptors CD36 and SRA1, key factors involved in lipoprotein uptake. These results suggest that bone marrow–derived CCN3 is an essential regulator of atherosclerosis and point to a novel role of CCN3 in modulating lipid accumulation within macrophages.

      PubDate: 2017-05-20T14:42:26Z
      DOI: 10.1016/j.ajpath.2017.01.020
       
  • In Vivo Effects of Long-Term Cigarette Smoke Exposure on Mammary
           Tissue in Mice
    • Authors: Shannon Kispert; Susan Crawford; Grant Kolar; Jane McHowat
      Pages: 1238 - 1244
      Abstract: Publication date: June 2017
      Source:The American Journal of Pathology, Volume 187, Issue 6
      Author(s): Shannon Kispert, Susan Crawford, Grant Kolar, Jane McHowat
      Cigarette smoking is the leading cause of preventable death worldwide and has been linked to the development and progression of cancer. Many cohort studies have described the link between patients with breast cancer and those with long-term smoking history. Despite the claim of correlation, the mechanism by which cigarette smoke alters normal breast epithelial cells and stroma and contributes to tumor cell growth remains undefined. To investigate whether cigarette smoke promotes ductal epithelial cell hyperplasia by stimulating stromal endothelial cell proliferation, we exposed mice to cigarette smoke for 6 months. We observed epithelial proliferation, increased fibrosis, increased vascularity, and mast cell infiltration. This is the first study to look at the in vivo changes in the breast after long-term cigarette smoke exposure and provides a novel insight to understanding how cigarette smoke contributes to early changes that may contribute to tumor formation and progression. In conclusion, this study suggests that cigarette smoke modulates key stromal-epithelial interactions to support increased angiogenesis, desmoplasia, and abnormal ductal epithelial cell growth.

      PubDate: 2017-05-20T14:42:26Z
      DOI: 10.1016/j.ajpath.2017.02.004
       
  • Matrix Metalloproteinase-28 Is a Key Contributor to Emphysema Pathogenesis
    • Authors: Anne M. Manicone; Sina A. Gharib; Ke-Qin Gong; William E. Eddy; Matthew E. Long; Charles W. Frevert; William A. Altemeier; William C. Parks; A. McGarry Houghton
      Pages: 1288 - 1300
      Abstract: Publication date: June 2017
      Source:The American Journal of Pathology, Volume 187, Issue 6
      Author(s): Anne M. Manicone, Sina A. Gharib, Ke-Qin Gong, William E. Eddy, Matthew E. Long, Charles W. Frevert, William A. Altemeier, William C. Parks, A. McGarry Houghton
      Chronic obstructive pulmonary disease (COPD) comprises chronic bronchitis and emphysema, and is a leading cause of morbidity and mortality. Because tissue destruction is the prominent characteristic of emphysema, extracellular proteinases, particularly those with elastolytic ability, are often considered to be key drivers in this disease. Several human and mouse studies have implicated roles for matrix metalloproteinases (MMPs), particularly macrophage-derived proteinases, in COPD pathogenesis. MMP-28 is expressed by the pulmonary epithelium and macrophage, and we have found that it regulates macrophage recruitment and polarization. We hypothesized that MMP-28 has contributory roles in emphysema via alteration of macrophage numbers and activation. Because of the established association of emphysema pathogenesis to macrophage influx, we evaluated the inflammatory changes and lung histology of Mmp28 −/− mice exposed to 3 and 6 months of cigarette smoke. At earlier time points, we found altered macrophage polarization in the smoke-exposed Mmp28 −/− lung consistent with other published findings that MMP-28 regulates macrophage activation. At both 3 and 6 months, Mmp28 −/− mice had blunted inflammatory responses more closely resembling nonsmoked mice, with a reduction in neutrophil recruitment and CXCL1 chemokine expression. By 6 months, Mmp28 −/− mice were protected from emphysema. These results highlight a previously unrecognized role for MMP-28 in promoting chronic lung inflammation and tissue remodeling induced by cigarette smoke and highlight another potential target to modulate COPD.

      PubDate: 2017-05-20T14:42:26Z
      DOI: 10.1016/j.ajpath.2017.02.008
       
  • Tau Antibody Targeting Pathological Species Blocks Neuronal Uptake and
           Interneuron Propagation of Tau in Vitro
    • Authors: Chloe K. Nobuhara; Sarah L. DeVos; Caitlin Commins; Susanne Wegmann; Benjamin D. Moore; Allyson D. Roe; Isabel Costantino; Matthew P. Frosch; Rose Pitstick; George A. Carlson; Christoph Hock; Roger M. Nitsch; Fabio Montrasio; Jan Grimm; Anne E. Cheung; Anthone W. Dunah; Marion Wittmann; Thierry Bussiere; Paul H. Weinreb; Bradley T. Hyman; Shuko Takeda
      Pages: 1399 - 1412
      Abstract: Publication date: June 2017
      Source:The American Journal of Pathology, Volume 187, Issue 6
      Author(s): Chloe K. Nobuhara, Sarah L. DeVos, Caitlin Commins, Susanne Wegmann, Benjamin D. Moore, Allyson D. Roe, Isabel Costantino, Matthew P. Frosch, Rose Pitstick, George A. Carlson, Christoph Hock, Roger M. Nitsch, Fabio Montrasio, Jan Grimm, Anne E. Cheung, Anthone W. Dunah, Marion Wittmann, Thierry Bussiere, Paul H. Weinreb, Bradley T. Hyman, Shuko Takeda
      The clinical progression of Alzheimer disease (AD) is associated with the accumulation of tau neurofibrillary tangles, which may spread throughout the cortex by interneuronal tau transfer. If so, targeting extracellular tau species may slow the spreading of tau pathology and possibly cognitive decline. To identify suitable target epitopes, we tested the effects of a panel of tau antibodies on neuronal uptake and aggregation in vitro. Immunodepletion was performed on brain extract from tau-transgenic mice and postmortem AD brain and added to a sensitive fluorescence resonance energy transfer–based tau uptake assay to assess blocking efficacy. The antibodies reduced tau uptake in an epitope-dependent manner: N-terminal (Tau13) and middomain (6C5 and HT7) antibodies successfully prevented uptake of tau species, whereas the distal C-terminal–specific antibody (Tau46) had little effect. Phosphorylation-dependent (40E8 and p396) and C-terminal half (4E4) tau antibodies also reduced tau uptake despite removing less total tau by immunodepletion, suggesting specific interactions with species involved in uptake. Among the seven antibodies evaluated, 6C5 most efficiently blocked uptake and subsequent aggregation. More important, 6C5 also blocked neuron-to-neuron spreading of tau in a unique three-chamber microfluidic device. Furthermore, 6C5 slowed down the progression of tau aggregation even after uptake had begun. Our results imply that not all antibodies/epitopes are equally robust in terms of blocking tau uptake of human AD-derived tau species.

      PubDate: 2017-05-20T14:42:26Z
      DOI: 10.1016/j.ajpath.2017.01.022
       
  • Deficiency in EP4 Receptor–Associated Protein Ameliorates Abnormal
           Anxiety-Like Behavior and Brain Inflammation in a Mouse Model of Alzheimer
           Disease
    • Authors: Risako Fujikawa; Sei Higuchi; Masato Nakatsuji; Mika Yasui; Taichi Ikedo; Manabu Nagata; Kosuke Hayashi; Masayuki Yokode; Manabu Minami
      Abstract: Publication date: Available online 16 June 2017
      Source:The American Journal of Pathology
      Author(s): Risako Fujikawa, Sei Higuchi, Masato Nakatsuji, Mika Yasui, Taichi Ikedo, Manabu Nagata, Kosuke Hayashi, Masayuki Yokode, Manabu Minami
      Microglia are thought to play key roles in the progression of Alzheimer disease (AD). Overactivated microglia produce proinflammatory cytokines, such as tumor necrosis factor-α, which appear to contribute to disease progression. Previously, we reported that prostaglandin E2 type 4 receptor–associated protein (EPRAP) promotes microglial activation. We crossed human amyloid precursor protein transgenic mice from strain J20+/− onto an EPRAP-deficient background to determine the role of EPRAP in AD. Behavioral tests were performed in 5-month-old male J20+/−EPRAP+/+ and J20+/−EPRAP−/− mice. EPRAP deficiency reversed the reduced anxiety of J20+/− mice but did not affect hyperactivity. No differences in spatial memory were observed between J20+/−EPRAP+/+ and J20+/−EPRAP−/− mice. In comparison with J20+/−EPRAP+/+, J20+/−EPRAP−/− mice exhibited less microglial accumulation and reductions in the Cd68 and tumor necrosis factor-α mRNAs in the prefrontal cortex and hippocampus. No significant differences were found between the two types of mice in the amount of amyloid-β 40 or 42 in the cortex and hippocampus. J20+/−EPRAP−/− mice reversed the reduced anxiety-like behavior and had reduced microglial activation compared with J20+/−EPRAP+/+ mice. Further research is required to identify the role of EPRAP in AD, but our results indicate that EPRAP may be related to behavioral and psychological symptoms of dementia and inflammation in patients with AD.

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

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

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

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

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

      PubDate: 2017-06-14T12:31:45Z
      DOI: 10.1016/j.ajpath.2017.04.003
       
  • Hypoxia-Inducible Factor 1α Signaling Promotes Repair of the Alveolar
           Epithelium after Acute Lung Injury
    • Authors: Jazalle McClendon; Nicole L. Jansing; Elizabeth F. Redente; Aneta Gandjeva; Yoko Ito; Sean P. Colgan; Aftab Ahmad; David W.H. Riches; Harold A. Chapman; Robert J. Mason; Rubin M. Tuder; Rachel L. Zemans
      Abstract: Publication date: Available online 12 June 2017
      Source:The American Journal of Pathology
      Author(s): Jazalle McClendon, Nicole L. Jansing, Elizabeth F. Redente, Aneta Gandjeva, Yoko Ito, Sean P. Colgan, Aftab Ahmad, David W.H. Riches, Harold A. Chapman, Robert J. Mason, Rubin M. Tuder, Rachel L. Zemans
      During acute respiratory distress syndrome, epithelial cells, primarily alveolar type (AT) I cells, die and slough off the basement membrane, resulting in enhanced permeability. ATII cells proliferate and spread onto the denuded basement membrane to reseal the barrier. Repair of the alveolar epithelium is critical for clinical recovery; however, the mechanisms underlying ATII cell proliferation and spreading are not well understood. We hypothesized that hypoxia-inducible factor (HIF)1α promotes proliferation and spreading of ATII cells during repair after lung injury. Mice were treated with intratracheal lipopolysaccharide or hydrochloric acid. HIF activation in ATII cells after injury was demonstrated by increased luciferase activity in oxygen degradation domain–Luc (HIF reporter) mice and expression of the HIF1α target gene GLUT1. ATII cell proliferation during repair after lung injury was attenuated in ATII cell–specific HIF1α knockout (SftpcCreERT2 +/− ;HIF1α f/f ) mice. The HIF target vascular endothelial growth factor promoted ATII cell proliferation in vitro and after lung injury in vivo. In the scratch wound assay of cell spreading, HIF stabilization accelerated, whereas HIF1α shRNA delayed wound closure. SDF1 and its receptor, CXCR4, were found to be HIF1α-regulated genes in ATII cells and were up-regulated during lung injury. Stromal cell-derived factor 1/CXCR4 inhibition impaired cell spreading and delayed the resolution of permeability after lung injury. HIF1α is activated in ATII cells after lung injury and promotes proliferation and spreading during repair.

      PubDate: 2017-06-14T12:31:45Z
      DOI: 10.1016/j.ajpath.2017.04.012
       
  • Platelet-Derived Growth Factor BB Influences Muscle Regeneration in
           Duchenne Muscle Dystrophy
    • Authors: Patricia Piñol-Jurado; Eduard Gallardo; Noemi de Luna; Xavier Suárez-Calvet; Carles Sánchez-Riera; Esther Fernández-Simón; Clara Gomis; Isabel Illa; Jordi Díaz-Manera
      Abstract: Publication date: Available online 12 June 2017
      Source:The American Journal of Pathology
      Author(s): Patricia Piñol-Jurado, Eduard Gallardo, Noemi de Luna, Xavier Suárez-Calvet, Carles Sánchez-Riera, Esther Fernández-Simón, Clara Gomis, Isabel Illa, Jordi Díaz-Manera
      Duchenne muscular dystrophy (DMD) is characterized by a progressive loss of muscle fibers, and their substitution by fibrotic and adipose tissue. Many factors contribute to this process, but the molecular pathways related to regeneration and degeneration of muscle are not completely known. Platelet-derived growth factor (PDGF)-BB belongs to a family of growth factors that regulate proliferation, migration, and differentiation of mesenchymal cells. The role of PDGF-BB in muscle regeneration in humans has not been studied. We analyzed the expression of PDGF-BB in muscle biopsy samples from controls and patients with DMD. We performed in vitro experiments to understand the effects of PDGF-BB on myoblasts involved in the pathophysiology of muscular dystrophies and confirmed our results in vivo by treating the mdx murine model of DMD with repeated i.m. injections of PDGF-BB. We observed that regenerating and necrotic muscle fibers in muscle biopsy samples from DMD patients expressed PDGF-BB. In vitro, PDGF-BB attracted myoblasts and activated their proliferation. Analysis of muscles from the animals treated with PDGF-BB showed an increased population of satellite cells and an increase in the number of regenerative fibers, with a reduction in inflammatory infiltrates, compared with those in vehicle-treated mice. Based on our results, PDGF-BB may play a protective role in muscular dystrophies by enhancing muscle regeneration through activation of satellite cell proliferation and migration.

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

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

      PubDate: 2017-06-14T12:31:45Z
      DOI: 10.1016/j.ajpath.2017.03.015
       
  • Tumor Necrosis Factor-α and IL-17A Activation Induces Pericyte-Mediated
           Basement Membrane Remodeling in Human Neutrophilic Dermatoses
    • Authors: Holly M. Lauridsen; Amanda S. Pellowe; Anand Ramanathan; Rebecca Liu; Kathryn Miller-Jensen; Jennifer M. McNiff; Jordan S. Pober; Anjelica L. Gonzalez
      Abstract: Publication date: Available online 10 June 2017
      Source:The American Journal of Pathology
      Author(s): Holly M. Lauridsen, Amanda S. Pellowe, Anand Ramanathan, Rebecca Liu, Kathryn Miller-Jensen, Jennifer M. McNiff, Jordan S. Pober, Anjelica L. Gonzalez
      Sweet syndrome is a prototypical neutrophilic dermatosis, a class of inflammatory diseases marked by elevated levels of tumor necrosis factor (TNF)-α and IL-17A, pathologic neutrophil recruitment, and microvascular remodeling. Histologic analyses of four matrix proteins—collagen I and IV, laminin, and fibronectin—in the skin biopsies of patients with Sweet syndrome reveal that the basement membrane of dermal postcapillary venules undergoes changes in structure and composition. Increased neutrophil recruitment in vivo was associated with increases in collagen IV, decreases in laminin, and varied changes in fibronectin. In vitro studies using TNF-α and IL-17A were conducted to dissect basement membrane remodeling. Prolonged dual activation of cultured human pericytes with TNF-α and IL-17A augmented collagen IV production, similar to in vivo remodeling. Co-activation of pericytes with TNF-α and IL-17A also elevated fibronectin levels with little direct effect on laminin. However, the expression of fibronectin- and laminin-specific matrix metalloproteinases (MMPs), particularly MMP-3, was significantly up-regulated. Interactions between pericytes and neutrophils in culture yielded even higher levels of active MMPs, facilitating fibronectin and laminin degradation, and likely contributing to the varied levels of detectable fibronectin and the decreases in laminin observed in vivo. These data indicate that pericyte-neutrophil interactions play a role in mediating microvascular changes in neutrophilic dermatosis and suggest that targeting MMP-3 may be effective in protecting vascular wall integrity.

      PubDate: 2017-06-14T12:31:45Z
      DOI: 10.1016/j.ajpath.2017.04.008
       
  • Antifibrotic Actions of Peroxisome Proliferator-Activated Receptor γ
           Ligands in Corneal Fibroblasts Are Mediated by β-Catenin–Regulated
           Pathways
    • Authors: Kye-Im Jeon; Richard P. Phipps; Patricia J. Sime; Krystel R. Huxlin
      Abstract: Publication date: Available online 10 June 2017
      Source:The American Journal of Pathology
      Author(s): Kye-Im Jeon, Richard P. Phipps, Patricia J. Sime, Krystel R. Huxlin
      Wound healing after corneal injury typically involves fibrosis, with transforming growth factor β1 (TGF-β1) as one of its strongest mediators. A class of small molecules—peroxisome proliferator–activated receptor γ (PPARγ) ligands—exert potent antifibrotic effects in the cornea by blocking phosphorylation of p38 mitogen-activated protein kinase (MAPK). However, why this blocks fibrosis remains unknown. Herein, we show that PPARγ ligands (rosiglitazone, troglitazone, and 15-deoxy-Δ12,14-prostaglandin J2) decrease levels of β-catenin. We also show that β-catenin siRNA and the Wingless and integration site-1 (Wnt) inhibitor pyrvinium block the ability of corneal fibroblasts to up-regulate synthesis of α-smooth muscle actin (α-SMA), collagen 1 (COL1), and fibronectin (FN) in response to TGF-β1. Activation of TGF-β receptors and p38 MAPK increased glycogen synthase kinase 3β (GSK3β) bioactivity, whereas a chemical inhibitor of p38 MAPK (SB203580) reduced the phosphorylation of GSK3β, decreasing active β-catenin levels in both cytoplasmic and nuclear fractions. Finally, lithium chloride, a GSK3 inhibitor, also attenuated the TGF-β1–induced increase in α-SMA, COL1, and FN expression. All in all, our results suggest that TGF-β1 stimulation increases active β-catenin concentration in cultured corneal fibroblasts through p38 MAPK regulation of canonical Wnt/β-catenin signaling, increasing α-SMA, COL1, and FN synthesis. Thus, PPARγ ligands, by blocking TGF-β1–induced p38 MAPK phosphorylation, prevent increases in both total and active β-catenin through p38 MAPK-GSK3β signaling.

      PubDate: 2017-06-14T12:31:45Z
      DOI: 10.1016/j.ajpath.2017.04.002
       
  • Endothelium-Independent Primitive Myxoid Vascularization Creates
           Invertebrate-Like Channels to Maintain Blood Supply in Optic Gliomas
    • Authors: Matija Snuderl; Guoan Zhang; Pamela Wu; Tara S. Jennings; Seema Shroff; Valerio Ortenzi; Rajan Jain; Benjamin Cohen; Jason J. Reidy; Mitchell S. Dushay; Jeffrey H. Wisoff; David H. Harter; Matthias A. Karajannis; David Fenyo; Thomas A. Neubert; David Zagzag
      Abstract: Publication date: Available online 9 June 2017
      Source:The American Journal of Pathology
      Author(s): Matija Snuderl, Guoan Zhang, Pamela Wu, Tara S. Jennings, Seema Shroff, Valerio Ortenzi, Rajan Jain, Benjamin Cohen, Jason J. Reidy, Mitchell S. Dushay, Jeffrey H. Wisoff, David H. Harter, Matthias A. Karajannis, David Fenyo, Thomas A. Neubert, David Zagzag
      Optic gliomas are brain tumors characterized by slow growth, progressive loss of vision, and limited therapeutic options. Optic gliomas contain various amounts of myxoid matrix, which can represent most of the tumor mass. We sought to investigate biological function and protein structure of the myxoid matrix in optic gliomas to identify novel therapeutic targets. We reviewed histological features and clinical imaging properties, analyzed vasculature by immunohistochemistry and electron microscopy, and performed liquid chromatography–mass spectrometry on optic gliomas, which varied in the amount of myxoid matrix. We found that although subtypes of optic gliomas are indistinguishable on imaging, the microvascular network of pilomyxoid astrocytoma, a subtype of optic glioma with abundant myxoid matrix, is characterized by the presence of endothelium-free channels in the myxoid matrix. These tumors show normal perfusion by clinical imaging and lack histological evidence of hemorrhage organization or thrombosis. The myxoid matrix is composed predominantly of the proteoglycan versican and its linking protein, a vertebrate hyaluronan and proteoglycan link protein 1. We propose that pediatric optic gliomas can maintain blood supply without endothelial cells by using invertebrate-like channels, which we termed primitive myxoid vascularization. Enzymatic targeting of the proteoglycan versican/hyaluronan and proteoglycan link protein 1 rich myxoid matrix, which is in direct contact with circulating blood, can provide novel therapeutic avenues for optic gliomas of childhood.

      PubDate: 2017-06-14T12:31:45Z
      DOI: 10.1016/j.ajpath.2017.04.004
       
  • Lasting Retinal Injury in a Mouse Model of Blast-Induced Trauma
    • Authors: Najiba Mammadova; Shivani Ghaisas; Gary Zenitsky; Donald S. Sakaguchi; Anumantha G. Kanthasamy; Justin J. Greenlee; M. Heather West Greenlee
      Abstract: Publication date: Available online 9 June 2017
      Source:The American Journal of Pathology
      Author(s): Najiba Mammadova, Shivani Ghaisas, Gary Zenitsky, Donald S. Sakaguchi, Anumantha G. Kanthasamy, Justin J. Greenlee, M. Heather West Greenlee
      Traumatic brain injury due to blast exposure is currently the most prevalent of war injuries. Although secondary ocular blast injuries due to flying debris are more common, primary ocular blast exposure resulting from blast wave pressure has been reported among survivors of explosions, but with limited understanding of the resulting retinal pathologies. Using a compressed air-driven shock tube system, adult male and female C57BL/6 mice were exposed to blast wave pressure of 300 kPa (43.5 psi) per day for 3 successive days, and euthanized 30 days after injury. We assessed retinal tissues using immunofluorescence for glial fibrillary acidic protein, microglia-specific proteins Iba1 and CD68, and phosphorylated tau (AT-270 pThr181 and AT-180 pThr231). Primary blast wave pressure resulted in activation of Müller glia, loss of photoreceptor cells, and an increase in phosphorylated tau in retinal neurons and glia. We found that 300-kPa blasts yielded no detectable cognitive or motor deficits, and no neurochemical or biochemical evidence of injury in the striatum or prefrontal cortex, respectively. These changes were detected 30 days after blast exposure, suggesting the possibility of long-lasting retinal injury and neuronal inflammation after primary blast exposure.

      PubDate: 2017-06-09T16:11:30Z
      DOI: 10.1016/j.ajpath.2017.03.005
       
  • This Month in AJP
    • Abstract: Publication date: Available online 22 May 2017
      Source:The American Journal of Pathology

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

      PubDate: 2017-06-09T16:11:30Z
       
  • Correction
    • Abstract: Publication date: June 2017
      Source:The American Journal of Pathology, Volume 187, Issue 6


      PubDate: 2017-05-20T14:42:26Z
       
  • Activation of Hypoxia Signaling in Stromal Progenitors Impairs Kidney
           Development
    • Authors: Katharina Gerl; Dominik Steppan; Michaela Fuchs; Charlotte Wagner; Carsten Willam; Armin Kurtz; Birgül Kurt
      Abstract: Publication date: Available online 17 May 2017
      Source:The American Journal of Pathology
      Author(s): Katharina Gerl, Dominik Steppan, Michaela Fuchs, Charlotte Wagner, Carsten Willam, Armin Kurtz, Birgül Kurt
      Intrauterine hypoxia is a reason for impaired kidney development. The cellular and molecular pathways along which hypoxia exerts effects on nephrogenesis are not well understood. They are likely triggered by hypoxia-inducible transcription factors (HIFs), and their effects appear to be dependent on the cell compartment contributing to kidney formation. In this study, we investigated the effects of HIF activation in the developing renal stroma, which also essentially modulates nephron development from the metanephric mesenchyme. HIF activation was achieved by conditional deletion of the von Hippel–Lindau tumor suppressor (VHL) protein in the forkhead box FOXD1 cell lineage, from which stromal progenitors arise. The resulting kidneys showed maturation defects associated with early postnatal death. In particular, nephron formation, tubular maturation, and the differentiation of smooth muscle, renin, and mesangial cells were impaired. Erythropoietin expression was strongly enhanced. Codeletion of VHL together with HIF2A but not with HIF1A led to apparently normal kidneys, and the animals reached normal age but were anemic because of low erythropoietin levels. Stromal deletion of HIF2A or HIF1A alone did not affect kidney development. These findings emphasize the relevance of sufficient intrauterine oxygenation for normal renal stroma differentiation, suggesting that chronic activity of HIF2 in stromal progenitors impairs kidney development. Finally, these data confirm the concept that normal stroma function is essential for normal tubular differentiation.

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

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

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

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

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

      PubDate: 2017-05-15T16:37:56Z
      DOI: 10.1016/j.ajpath.2017.02.020
       
  • Selective Activation of Estrogen Receptor α Activation Function-1 Is
           
    • Authors: Maeva Guillaume; Sandra Handgraaf; Aurélie Fabre; Isabelle Raymond-Letron; Elodie Riant; Alexandra Montagner; Alexia Vinel; Melissa Buscato; Natalia Smirnova; Coralie Fontaine; Hervé Guillou; Jean-François Arnal; Pierre Gourdy
      Abstract: Publication date: Available online 11 May 2017
      Source:The American Journal of Pathology
      Author(s): Maeva Guillaume, Sandra Handgraaf, Aurélie Fabre, Isabelle Raymond-Letron, Elodie Riant, Alexandra Montagner, Alexia Vinel, Melissa Buscato, Natalia Smirnova, Coralie Fontaine, Hervé Guillou, Jean-François Arnal, Pierre Gourdy
      Estrogen receptor α (ERα) regulates gene transcription through two activation functions (ERα-AF1 and ERα-AF2). We recently found that the protection conferred by 17β-estradiol against obesity and insulin resistance requires ERα-AF2 but not ERα-AF1. However, the interplay between the two ERα-AFs is poorly understood in vivo and the metabolic influence of a specific ERα-AF1 action remains to be explored. To this end, wild-type, ERα-deficient, or ERα-AF1–deficient ovariectomized female mice were fed a high-fat diet and concomitantly administered with vehicle or tamoxifen, a selective ER modulator that acts as a ERα-AF1 agonist/ERα-AF2 antagonist. In ovariectomized wild-type mice, tamoxifen significantly reduced food intake and totally prevented adiposity, insulin resistance, and steatosis. These effects were abolished in ERα-deficient and ERα-AF1–deficient mice, revealing the specific role of ERα-AF1 activation. Finally, hepatic gene expression changes elicited by tamoxifen in wild-type mice were abrogated in ERα-AF1–deficient mice. The combination of pharmacologic and transgenic approaches thus indicates that selective ERα-AF1 activation by tamoxifen is sufficient to elicit metabolic protection, contrasting with the specific requirement of ERα-AF2 in the metabolic actions of 17β-estradiol. This redundancy in the ability of the two ERα-AFs to separately mediate metabolic prevention strikingly contrasts with the contribution of both ERα-AFs in breast cancer proliferation, shedding new light on the therapeutic potential of selective ER modulation.

      PubDate: 2017-05-15T16:37:56Z
      DOI: 10.1016/j.ajpath.2017.02.013
       
  • Enhanced Tau Aggregation in the Presence of Amyloid β
    • Authors: Rachel E. Bennett; Sarah L. DeVos; Simon Dujardin; Bianca Corjuc; Rucha Gor; Jose Gonzalez; Allyson D. Roe; Matthew P. Frosch; Rose Pitstick; George A. Carlson; Bradley T. Hyman
      Abstract: Publication date: Available online 10 May 2017
      Source:The American Journal of Pathology
      Author(s): Rachel E. Bennett, Sarah L. DeVos, Simon Dujardin, Bianca Corjuc, Rucha Gor, Jose Gonzalez, Allyson D. Roe, Matthew P. Frosch, Rose Pitstick, George A. Carlson, Bradley T. Hyman
      Amyloid plaques and neurofibrillary tangles co-occur in Alzheimer disease, but with different topological and temporal patterns. Whether these two lesions are independent or pathobiologically related is uncertain. For example, amyloid deposition in the neocortex precedes the spread of tau neurofibrillary tangles from the limbic areas to the cortex. We examined the aggregation properties of tau isolated from human cases with early tau pathology (Braak II) with and without plaques. Using a well-established HEK cell biosensor assay, we show that tau from cases with plaques has an enhanced ability to induce tau aggregates compared to tau from cases without plaques. To further explore this effect, we combined mice carrying the APP/PS1 transgene array that develop plaques with rTg4510 mice carrying the P301L mutant human tau transgene that develop extensive tau pathology with age. The resulting APP/PS1-rTg4510 mice had a threefold increase in tau seeding activity over the rTg4510 strain, without change in tau production or extracellular release. Surprisingly, this effect was observed before overt amyloid deposition. The enhancement of tau aggregation was also apparent by an increase in histological measures of tau pathology in young APP/PS1-rTg4510 mice and an increase in high-molecular-weight tau. Overall, these data provide evidence that amyloid β acts to enhance tau pathology by increasing the formation of tau species capable of seeding new aggregates.

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

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

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

      PubDate: 2017-05-10T21:49:03Z
      DOI: 10.1016/j.ajpath.2017.03.007
       
  • miR-24-3p Is Overexpressed in Hodgkin Lymphoma and Protects Hodgkin and
           Reed-Sternberg Cells from Apoptosis
    • Authors: Ye Yuan; Joost Kluiver; Jasper Koerts; Debora de Jong; Bea Rutgers; Fazlyn Reeny Abdul Razak; Martijn Terpstra; Boudewijn Plaat; Ilja M. Nolte; Arjan Diepstra; Lydia Visser; Klaas Kok; Anke van den Berg
      Abstract: Publication date: Available online 20 April 2017
      Source:The American Journal of Pathology
      Author(s): Ye Yuan, Joost Kluiver, Jasper Koerts, Debora de Jong, Bea Rutgers, Fazlyn Reeny Abdul Razak, Martijn Terpstra, Boudewijn Plaat, Ilja M. Nolte, Arjan Diepstra, Lydia Visser, Klaas Kok, Anke van den Berg
      miRNAs play important roles in biological processes, such as proliferation, metabolism, differentiation, and apoptosis, whereas altered expression levels contribute to diseases, such as cancers. We identified miRNAs with aberrant expression in Hodgkin lymphoma (HL) and investigated their role in pathogenesis. Small RNA sequencing revealed 84 significantly differentially expressed miRNAs in HL cell lines as compared to germinal center B cells. Three up-regulated miRNAs—miR-23a-3p, miR-24-3p, and miR-27a-3p—were derived from one primary miRNA transcript. Loss-of-function analyses for these miRNAs and their seed family members resulted in decreased growth on miR-24-3p inhibition in three and of miR-27a/b-3p inhibition in one HL cell line. Apoptosis analysis indicated that the effect of miR-24-3p on cell growth is at least in part caused by an increase of apoptotic cells. Argonaute 2 immunoprecipitation revealed 1142 genes consistently targeted by miRNAs in at least three of four HL cell lines. Furthermore, 52 of the 1142 genes were predicted targets of miR-24-3p. Functional annotation analysis revealed a function related to cell growth, cell death, and/or apoptosis for 15 of the 52 genes. Western blotting of the top five genes showed increased protein levels on miR-24-3p inhibition for CDKN1B/P27kip1 and MYC. In summary, we showed that miR-24-3p is up-regulated in HL and its inhibition impairs cell growth possibly via targeting CDKN1B/P27kip1 and MYC.

      PubDate: 2017-05-05T21:27:41Z
      DOI: 10.1016/j.ajpath.2017.02.016
       
  • Human Effector Memory T Helper Cells Engage with Mouse Macrophages and
           Cause Graft-versus-Host–Like Pathology in Skin of Humanized Mice Used in
           a Nonclinical Immunization Study
    • Authors: Bala S. Sundarasetty; Valery Volk; Sebastian J. Theobald; Susanne Rittinghausen; Dirk Schaudien; Vanessa Neuhaus; Constanca Figueiredo; Andreas Schneider; Laura Gerasch; Adele Mucci; Thomas Moritz; Constantin von Kaisenberg; Loukia M. Spineli; Katherina Sewald; Armin Braun; Henning Weigt; Arnold Ganser; Renata Stripecke
      Abstract: Publication date: Available online 20 April 2017
      Source:The American Journal of Pathology
      Author(s): Bala S. Sundarasetty, Valery Volk, Sebastian J. Theobald, Susanne Rittinghausen, Dirk Schaudien, Vanessa Neuhaus, Constanca Figueiredo, Andreas Schneider, Laura Gerasch, Adele Mucci, Thomas Moritz, Constantin von Kaisenberg, Loukia M. Spineli, Katherina Sewald, Armin Braun, Henning Weigt, Arnold Ganser, Renata Stripecke
      Humanized mice engrafted with human hematopoietic stem cells and developing functional human T-cell adaptive responses are in critical demand to test human-specific therapeutics. We previously showed that humanized mice immunized with long-lived induced–dendritic cells loaded with the pp65 viral antigen (iDCpp65) exhibited a faster development and maturation of T cells. Herein, we evaluated these effects in a long-term (36 weeks) nonclinical model using two stem cell donors to assess efficacy and safety. Relative to baseline, iDCpp65 immunization boosted the output of effector memory CD4+ T cells in peripheral blood and lymph nodes. No weight loss, human malignancies, or systemic graft-versus-host (GVH) disease were observed. However, for one reconstitution cohort, some mice immunized with iDCpp65 showed GVH-like signs on the skin. Histopathology analyses of the inflamed skin revealed intrafollicular and perifollicular human CD4+ cells near F4/80+ mouse macrophages around hair follicles. In spleen, CD4+ cells formed large clusters surrounded by mouse macrophages. In plasma, high levels of human T helper 2–type inflammatory cytokines were detectable, which activated in vitro the STAT5 pathway of murine macrophages. Despite this inflammatory pattern, human CD8+ T cells from mice with GVH reacted against the pp65 antigen in vitro. These results uncover a dynamic cross-species interaction between human memory T cells and mouse macrophages in the skin and lymphatic tissues of humanized mice.

      PubDate: 2017-05-05T21:27:41Z
      DOI: 10.1016/j.ajpath.2017.02.015
       
  • Conditional Deletion of Bmal1 Accentuates Microvascular and Macrovascular
           Injury
    • Authors: Ashay D. Bhatwadekar; Eleni Beli; Diao Yanpeng; Jonathan Chen; Qianyi Luo; Alpha Alex; Sergio Caballero; James M. Dominguez; Tatiana E. Salazar; Julia V. Busik; Mark S. Segal; Maria B. Grant
      Abstract: Publication date: Available online 19 April 2017
      Source:The American Journal of Pathology
      Author(s): Ashay D. Bhatwadekar, Eleni Beli, Diao Yanpeng, Jonathan Chen, Qianyi Luo, Alpha Alex, Sergio Caballero, James M. Dominguez, Tatiana E. Salazar, Julia V. Busik, Mark S. Segal, Maria B. Grant
      The brain and muscle aryl hydrocarbon receptor nuclear translocator–like protein (BMAL)-1 constitutes a major transcriptional regulator of the circadian clock. Here, we explored the impact of conditional deletion of Bmal1 in endothelium and hematopoietic cells in murine models of microvascular and macrovascular injury. We used two models of Bmal1 fx/fx;Tek-Cre mice, a retinal ischemia/reperfusion model and a neointimal hyperplasia model of the femoral artery. Eyes were enumerated for acellular capillaries and were stained for oxidative damage markers using nitrotyrosine immunohistochemistry. LSK (lineage-negative, spinocerebellar ataxia type 1 protein homolog–positive, proto-oncogene c-Kit–positive) cells were quantified and proliferation assessed. Hematopoiesis is influenced by innervation to the bone marrow, which we assessed using IHC analysis. The number of acellular capillaries increased threefold, and nitrotyrosine staining increased 1.5-fold, in the retinas of Bmal1 fx/fx;Tek-Cre mice. The number of LSK cells from the Bmal1 fx/fx;Tek-Cre mice decreased by 1.5-fold and was accompanied by a profound decrease in proliferative potential. Bmal1 fx/fx;Tek-Cre mice also exhibited evidence of bone marrow denervation, demonstrating a loss of neurofilament-200 staining. Injured femoral arteries showed a 20% increase in neointimal hyperplasia compared with similarly injured wild-type controls. Our study highlights the importance of the circadian clock in maintaining vascular homeostasis and demonstrates that specific deletion of BMAL1 in endothelial and hematopoietic cells results in phenotypic features similar to those of diabetes.

      PubDate: 2017-05-05T21:27:41Z
      DOI: 10.1016/j.ajpath.2017.02.014
       
  • Interferon-γ Released by Activated CD8+ T Lymphocytes Impairs the Calcium
           Resorption Potential of Osteoclasts in Calcified Human Aortic Valves
    • Authors: Edit Nagy; Yang Lei; Eduardo Martínez-Martínez; Simon C. Body; Florian Schlotter; Michael Creager; Alexander Assmann; Kamal Khabbaz; Peter Libby; Göran K. Hansson; Elena Aikawa
      Abstract: Publication date: Available online 19 April 2017
      Source:The American Journal of Pathology
      Author(s): Edit Nagy, Yang Lei, Eduardo Martínez-Martínez, Simon C. Body, Florian Schlotter, Michael Creager, Alexander Assmann, Kamal Khabbaz, Peter Libby, Göran K. Hansson, Elena Aikawa
      Calcium content in patients with calcific aortic valve disease (CAVD) correlates with the severity of stenosis. In CAVD, activated T lymphocytes localize with osteoclast regions; however, the functional consequences of this association remain unknown. We hypothesized that CD8+ T cells modulate calcification in CAVD. Explanted CAVD valves (n = 52) dissected into noncalcified and calcified portions were subjected to mRNA extraction, real-time quantitative PCR, enzyme-linked immunosorbent assay, and immunohistochemical analyses. Compared with noncalcified portions, calcified regions exhibited significantly elevated transcripts for CD8, interferon (IFN)-γ, CXCL9, Perforin 1, Granzyme B, and heat shock protein 60. Osteoclast-associated receptor activator of NK-κB ligand (RANKL), tartrate-resistant acid phosphatase (TRAP), and osteoclast-associated receptor increased significantly, whereas Cathepsin K remained unchanged. The stimulation of tissue segments with phorbol-12-myristate-13-acetate and ionomycin resulted in IFN-γ release, recapitulating CAVD microenvironment. Real-time quantitative PCR detected signature mRNAs for CD8+ T-cell activation (Perforin 1, Granzyme B). In stimulated versus unstimulated organoid cultures, elevated IFN-γ reduced the mRNAs encoding for RANKL, TRAP, and Cathepsin K. Molecular imaging showed increased calcium signal intensity in stimulated versus unstimulated parts. Human CD14+ monocytes treated either with recombinant human IFN-γ or with conditioned media-derived IFN-γ exhibited low levels of Cathepsin K, TRAP, RANK, and tumor necrosis factor receptor-associated factor 6 mRNAs, whereas concentrations of the T-cell co-activators CD80 and CD86 increased in parallel with reduced osteoclast resorptive function, effects abrogated by neutralizing anti–IFN-γ antibodies. CD8+ cell–derived IFN-γ suppresses osteoclast function and may thus favor calcification in CAVD.

      PubDate: 2017-05-05T21:27:41Z
      DOI: 10.1016/j.ajpath.2017.02.012
       
  • This Month in AJP
    • Abstract: Publication date: Available online 19 April 2017
      Source:The American Journal of Pathology


      PubDate: 2017-05-05T21:27:41Z
       
  • Divergent Function of Programmed Death-Ligand 1 in Donor Tissue versus
           Recipient Immune System in a Murine Model of Bronchiolitis Obliterans
    • Authors: Katharina Schütte-Nütgen; Olaf Boenisch; Hakima Harrach; Alicia Casey; Indira Guleria; Nader Najafian; Mohamed H. Sayegh; Craig J. Gerard; Meera Subramaniam
      Abstract: Publication date: Available online 17 April 2017
      Source:The American Journal of Pathology
      Author(s): Katharina Schütte-Nütgen, Olaf Boenisch, Hakima Harrach, Alicia Casey, Indira Guleria, Nader Najafian, Mohamed H. Sayegh, Craig J. Gerard, Meera Subramaniam
      Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential effects on T-cell function, depending on the clinical setting and/or immunological environment. Given the impact of T cells on bronchiolitis obliterans (BO) in lung transplantation, we used an established tracheal transplant model inducing BO-like lesions to investigate the impact of PD-L1 on alloimmune responses and histopathological outcome in BO. In contrast to other transplant models in which PD-L1 generally shows protective functions, we demonstrated that PD-L1 has divergent effects depending on its location in donor versus recipient tissue. Although PD-L1 deficiency in donor tissue worsened histopathological outcome, and increased systemic inflammatory response, recipient PD-L1 deficiency induced opposite effects. Mechanistic studies revealed PD-L1–deficient recipients were hyporesponsive toward alloantigen, despite increased numbers of CD8+ effector T cells. The function of PD-L1 on T cells after unspecific stimulation was dependent on both cell type and strength of stimulation. This novel function of recipient PD-L1 may result from the high degree of T-cell activation within the highly immunogenic milieu of the transplanted tissue. In this model, both decreased T-cell alloimmune responses and the reduction of BO in PD-L1–deficient recipients suggest a potential therapeutic role of selectively blocking PD-L1 in the recipient. Further investigation is warranted to determine the impact of this finding embedded in the complex pathophysiological context of BO.

      PubDate: 2017-05-05T21:27:41Z
      DOI: 10.1016/j.ajpath.2017.02.007
       
  • Local Group 2 Innate Lymphoid Cells Promote Corneal Regeneration after
           Epithelial Abrasion
    • Authors: Jun Liu; Chengju Xiao; Hanqing Wang; Yunxia Xue; Dong Dong; Cuipei Lin; Fang Song; Ting Fu; Zhaorui Wang; Jiansu Chen; Hongwei Pan; Yangqiu Li; Dongqing Cai; Zhijie Li
      Abstract: Publication date: Available online 15 April 2017
      Source:The American Journal of Pathology
      Author(s): Jun Liu, Chengju Xiao, Hanqing Wang, Yunxia Xue, Dong Dong, Cuipei Lin, Fang Song, Ting Fu, Zhaorui Wang, Jiansu Chen, Hongwei Pan, Yangqiu Li, Dongqing Cai, Zhijie Li
      Corneal injuries and infections are the leading cause of blindness worldwide. Thus, understanding the mechanisms that control healing of the damaged cornea is critical for the development of new therapies to promptly restore vision. Innate lymphoid cells (ILCs) are a recently identified heterogeneous cell population that has been reported to orchestrate immunity and promote tissue repair in the lungs and skin after injury. However, whether ILCs can modulate the repair process in the cornea remains poorly understood. We identified a population of cornea-resident group 2 ILCs (ILC2s) in mice that express CD127, T1/ST2, CD90, and cKit. This cell population was relatively rare in corneas at a steady state but increased after corneal epithelial abrasion. Moreover, ILC2s were maintained and expanded locally at a steady state and after wounding. Depletion of this cell population caused a delay in corneal wound healing, whereas supplementation of ILC2s through adoptive transfer partially restored the healing process. Further investigation revealed that IL-25, IL-33, and thymic stromal lymphopoietin had critical roles in corneal ILC2 responses and that CCR2− corneal macrophages were an important producer of IL-33 in the cornea. Together, these results reveal the critical role of cornea-resident ILC2s in the restoration of corneal epithelial integrity after acute injury and suggest that ILC2 responses depend on local induction of IL-25, IL-33, and thymic stromal lymphopoietin.

      PubDate: 2017-05-05T21:27:41Z
      DOI: 10.1016/j.ajpath.2017.02.010
       
  • Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in
           ABCC6-Deficient Mice
    • Authors: Viola Pomozi; Christopher Brampton; Koen van de Wetering; Janna Zoll; Bianca Calio; Kevin Pham; Jesse B. Owens; Joel Marh; Stefan Moisyadi; András Váradi; Ludovic Martin; Carolin Bauer; Jeanette Erdmann; Zouhair Aherrahrou; Olivier Le Saux
      Abstract: Publication date: Available online 14 April 2017
      Source:The American Journal of Pathology
      Author(s): Viola Pomozi, Christopher Brampton, Koen van de Wetering, Janna Zoll, Bianca Calio, Kevin Pham, Jesse B. Owens, Joel Marh, Stefan Moisyadi, András Váradi, Ludovic Martin, Carolin Bauer, Jeanette Erdmann, Zouhair Aherrahrou, Olivier Le Saux
      Soft tissue calcification occurs in several common acquired pathologies, such as diabetes and hypercholesterolemia, or can result from genetic disorders. ABCC6, a transmembrane transporter primarily expressed in liver and kidneys, initiates a molecular pathway inhibiting ectopic calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into pyrophosphate (PPi), a major calcification inhibitor. Heritable mutations in ABCC6 underlie the incurable calcification disorder pseudoxanthoma elasticum and some cases of generalized arterial calcification of infancy. Herein, we determined that the administration of PPi and the bisphosphonate etidronate to Abcc6 −/− mice fully inhibited the acute dystrophic cardiac calcification phenotype, whereas alendronate had no significant effect. We also found that daily injection of PPi to Abcc6 −/− mice over several months prevented the development of pseudoxanthoma elasticum–like spontaneous calcification, but failed to reverse already established lesions. Furthermore, we found that the expression of low amounts of the human ABCC6 in liver of transgenic Abcc6 −/− mice, resulting in only a 27% increase in plasma PPi levels, led to a major reduction in acute and chronic calcification phenotypes. This proof-of-concept study shows that the development of both acute and chronic calcification associated with ABCC6 deficiency can be prevented by compensating PPi deficits, even partially. Our work indicates that PPi substitution represents a promising strategy to treat ABCC6-dependent calcification disorders.

      PubDate: 2017-05-05T21:27:41Z
      DOI: 10.1016/j.ajpath.2017.02.009
       
  • Exposure of the Amino Terminus of Tau Is a Pathological Event in Multiple
           Tauopathies
    • Authors: Benjamin Combs; Nicholas M. Kanaan
      Abstract: Publication date: Available online 14 April 2017
      Source:The American Journal of Pathology
      Author(s): Benjamin Combs, Nicholas M. Kanaan
      Pathological changes to the tau protein, including conformational changes and aggregation, are major hallmarks of a group of neurodegenerative disorders known as tauopathies. Among the conformational changes are alterations involving the extreme amino terminus of the protein, known as the phosphatase-activating domain (PAD). Aberrant PAD exposure induces a signaling cascade that leads to disruption of axonal transport, a critical function for neuronal survival. Conformational display of PAD is an early marker of pathological tau in Alzheimer disease (AD), but its role in other tauopathies has yet to be firmly established. We used a relatively novel N-terminal, conformation-sensitive antibody, TNT2, to determine whether misfolding in the amino terminus (ie, PAD exposure) occurs in non-AD tauopathies. We found that TNT2 specifically labeled pathological tau in post-mortem human brain tissue from Pick disease, progressive supranuclear palsy, corticobasal degeneration, and chronic traumatic encephalopathy, but did not label nonpathological, parenchymal tau. Tau13, another N-terminal antibody, was not sensitive to pathological N-terminal conformations. Tau13 did not readily distinguish between normal (ie, parenchymal tau) and pathological tau species and showed a range of effectiveness at identifying tau pathologies in the non-AD tauopathies. These findings demonstrate that the conformational display of the PAD in tau represents a common pathological event in many tauopathies.

      PubDate: 2017-05-05T21:27:41Z
      DOI: 10.1016/j.ajpath.2017.01.019
       
  • Toll-Like Receptor 4–Independent Carbon Tetrachloride–Induced Fibrosis
           and Lipopolysaccharide-Induced Acute Liver Injury in Mice
    • Authors: Sudhir Kumar; Jiang Wang; Shiva Kumar Shanmukhappa; Chandrashekhar R. Gandhi
      Abstract: Publication date: Available online 13 April 2017
      Source:The American Journal of Pathology
      Author(s): Sudhir Kumar, Jiang Wang, Shiva Kumar Shanmukhappa, Chandrashekhar R. Gandhi
      Gram-negative bacterial endotoxin lipopolysaccharide (LPS) is implicated in acute and chronic liver injury; its effects are mediated predominantly via the membrane receptor Toll-like receptor 4 (TLR4). However, TLR4-independent effects of LPS may play important role in hepatic pathophysiology. We investigated carbon tetrachloride (CCl4)–induced fibrosis and LPS-induced acute liver injury in wild-type (WT) and B6.B10ScN-Tlr4 lps-del /JthJ [TLR4-knockout (KO)] mice. Effects of LPS on fibrogenic hepatic stellate cells (HSCs) from WT and TLR4-KO mice were assessed in vitro. CCl4 produced similar fibrosis and necroinflammation and increased the mRNA and protein expression of cytokines and chemokines in WT and TLR4-KO mice. However, circulating LPS concentration did not increase in CCl4-treated mice. Interestingly, LPS down-modulated α-smooth muscle actin (activated HSC marker) and collagen 1 in both WT and TLR4-KO HSCs. LPS induced similar activation of NF-κB, and stimulated the expression of cytokines and chemokines in WT and TLR4-KO HSCs. Finally, LPS caused similar inflammation and injury in previously untreated WT and TLR4-KO mice. The results provide evidence of the TLR4/LPS-independent mechanisms of liver fibrosis and also indicate that TLR4 is not entirely critical to LPS-induced acute liver injury. The results further indicate that LPS signaling in activated HSCs might be a mechanism of limiting liver fibrosis.

      PubDate: 2017-05-05T21:27:41Z
      DOI: 10.1016/j.ajpath.2017.01.021
       
  • Mechanisms of Retinal Damage after Ocular Alkali Burns
    • Authors: Eleftherios I. Paschalis; Chengxin Zhou; Fengyang Lei; Nathan Scott; Vassiliki Kapoulea; Marie-Claude Robert; Demetrios Vavvas; Reza Dana; James Chodosh; Claes H. Dohlman
      Abstract: Publication date: Available online 13 April 2017
      Source:The American Journal of Pathology
      Author(s): Eleftherios I. Paschalis, Chengxin Zhou, Fengyang Lei, Nathan Scott, Vassiliki Kapoulea, Marie-Claude Robert, Demetrios Vavvas, Reza Dana, James Chodosh, Claes H. Dohlman
      Alkali burns to the eye constitute a leading cause of worldwide blindness. In recent case series, corneal transplantation revealed unexpected damage to the retina and optic nerve in chemically burned eyes. We investigated the physical, biochemical, and immunological components of retinal injury after alkali burn and explored a novel neuroprotective regimen suitable for prompt administration in emergency departments. Thus, in vivo pH, oxygen, and oxidation reduction measurements were performed in the anterior and posterior segment of mouse and rabbit eyes using implantable microsensors. Tissue inflammation was assessed by immunohistochemistry and flow cytometry. The experiments confirmed that the retinal damage is not mediated by direct effect of the alkali, which is effectively buffered by the anterior segment. Rather, pH, oxygen, and oxidation reduction changes were restricted to the cornea and the anterior chamber, where they caused profound uveal inflammation and release of proinflammatory cytokines. The latter rapidly diffuse to the posterior segment, triggering retinal damage. Tumor necrosis factor-α was identified as a key proinflammatory mediator of retinal ganglion cell death. Blockade, by either monoclonal antibody or tumor necrosis factor receptor 1 and 2 gene knockout, reduced inflammation and retinal ganglion cell loss. Intraocular pressure elevation was not observed in experimental alkali burns. These findings illuminate the mechanism by which alkali burns cause retinal damage and may have importance in designing therapies for retinal protection.

      PubDate: 2017-05-05T21:27:41Z
      DOI: 10.1016/j.ajpath.2017.02.005
       
  • Dysferlinopathy Promotes an Intramuscle Expansion of Macrophages with a
           Cyto-Destructive Phenotype
    • Authors: Jea-Hyun Baek; Gina M. Many; Frances J. Evesson; Vicki R. Kelley
      Abstract: Publication date: Available online 13 April 2017
      Source:The American Journal of Pathology
      Author(s): Jea-Hyun Baek, Gina M. Many, Frances J. Evesson, Vicki R. Kelley
      Dysferlinopathies are a group of muscular dystrophies resulting from a genetic deficiency in Dysf. Macrophages, highly plastic cells capable of mediating tissue repair and destruction, are prominent within dystrophic skeletal muscles of dysferlinopathy patients. In this study, we hypothesized that Dysf-deficient muscle promotes recruitment, proliferation, and skewing of macrophages toward a cyto-destructive phenotype in dysferlinopathy. To track macrophage dynamics in dysferlinopathy, we adoptively transferred enhanced green fluorescent protein–labeled monocytes into Dysf-deficient BLA/J mice with age-related (2 to 10 months) muscle disease and Dysf-intact (C57BL/6 [B6]) mice. We detected an age- and disease-related increase in monocyte recruitment into Dysf-deficient muscles. Moreover, macrophages recruited into muscle proliferated locally and were skewed toward a cyto-destructive phenotype. By comparing Dysf-deficient and -intact monocytes, our data showed that Dysf in muscle, but not in macrophages, mediate intramuscle macrophage recruitment and proliferation. To further elucidate macrophage mechanisms related to dysferlinopathy, we investigated in vitro macrophage-myogenic cell interactions and found that Dysf-deficient muscle i) promotes macrophage proliferation, ii) skews macrophages toward a cyto-destructive phenotype, and iii) is more vulnerable to macrophage-mediated apoptosis. Taken together, our data suggest that the loss of Dysf expression in muscle, not macrophages, promotes the intramuscle expansion of cyto-destructive macrophages likely to contribute to dysferlinopathy. Identifying pathways within the Dysf-deficient muscle milieu that regulate cyto-destructive macrophages will potentially uncover therapeutic strategies for dysferlinopathies.

      PubDate: 2017-05-05T21:27:41Z
      DOI: 10.1016/j.ajpath.2017.02.011
       
  • Tight Junction Proteins Claudin-1 and Occludin Are Important for Cutaneous
           Wound Healing
    • Authors: Thomas Volksdorf; Janina Heilmann; Sabine A. Eming; Kathrin Schawjinski; Michaela Zorn-Kruppa; Christopher Ueck; Sabine Vidal-y-Sy; Sabine Windhorst; Manfred Jücker; Ingrid Moll; Johanna M. Brandner
      Abstract: Publication date: Available online 12 April 2017
      Source:The American Journal of Pathology
      Author(s): Thomas Volksdorf, Janina Heilmann, Sabine A. Eming, Kathrin Schawjinski, Michaela Zorn-Kruppa, Christopher Ueck, Sabine Vidal-y-Sy, Sabine Windhorst, Manfred Jücker, Ingrid Moll, Johanna M. Brandner
      Tight junction (TJ) proteins are known to be involved in proliferation and differentiation. These processes are essential for normal skin wound healing. Here, we investigated the TJ proteins claudin-1 and occludin in ex vivo skin wound healing models and tissue samples of acute and chronic human wounds and observed major differences in localization/expression of these proteins, with chronic wounds often showing a loss of the proteins at the wound margins and/or in the regenerating epidermis. Knockdown experiments in primary human keratinocytes showed that decreased claudin-1 expression resulted in significantly impaired scratch wound healing, with delayed migration and reduced proliferation. Activation of AKT pathway was significantly attenuated after claudin-1 knockdown, and protein levels of extracellular signal–related kinase 1/2 were reduced. For occludin, down-regulation had no impact on wound healing in normal scratch assays, but after subjecting the cells to mechanical stress, which is normally present in wounds, wound healing was impaired. For both proteins we show that most of these actions are independent from the formation of barrier-forming TJ structures, thus demonstrating nonbarrier-related functions of TJ proteins in the skin. However, for claudin-1 effects on scratch wound healing were more pronounced when TJs could form. Together, our findings provide evidence for a role of claudin-1 and occludin in epidermal regeneration with potential clinical importance.

      PubDate: 2017-05-05T21:27:41Z
      DOI: 10.1016/j.ajpath.2017.02.006
       
 
 
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