Publisher: Elsevier   (Total: 3204 journals)

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Showing 1 - 200 of 3204 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 39, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 27, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 106, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 29, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 46, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 8)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 6)
Acta Astronautica     Hybrid Journal   (Followers: 451, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 30, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 3)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 11, SJR: 0.18, CiteScore: 1)
Acta Histochemica     Hybrid Journal   (Followers: 5, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 342, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 3, SJR: 1.793, CiteScore: 6)
Acta Psychologica     Hybrid Journal   (Followers: 26, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access   (Followers: 1)
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 7, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 8)
Acute Pain     Full-text available via subscription   (Followers: 15, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 18, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 14, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 22)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 198, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 13, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 20, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 30, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 12, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 12, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 24, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 15, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 35, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 6)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 14)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 29, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 11, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 11, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 27, SJR: 1.562, CiteScore: 3)
Advances in Clinical Radiology     Full-text available via subscription   (Followers: 2)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 21, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 15, SJR: 0.205, CiteScore: 1)
Advances in Cosmetic Surgery     Full-text available via subscription   (Followers: 2)
Advances in Dermatology     Full-text available via subscription   (Followers: 16)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 14)
Advances in Digestive Medicine     Open Access   (Followers: 14)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Drug Research     Full-text available via subscription   (Followers: 26)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 31, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 9)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 51, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 2)
Advances in Family Practice Nursing     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 70, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Genetics     Full-text available via subscription   (Followers: 21, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 8, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 26, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 26)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 4, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 39, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 10, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 10, SJR: 0.682, CiteScore: 2)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 21, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 17, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 9, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 5, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 26)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Pathology     Hybrid Journal   (Followers: 1)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 5)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Ophthalmology and Optometry     Full-text available via subscription   (Followers: 1)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 18, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 6, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 27, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 19)
Advances in Pharmacology     Full-text available via subscription   (Followers: 17, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 10, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 10)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 6)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 71)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 7, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 3, SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 7)
Advances in Space Research     Full-text available via subscription   (Followers: 435, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 6)
Advances in Surgery     Full-text available via subscription   (Followers: 13, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 36, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 20)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 15)
Advances in Virus Research     Full-text available via subscription   (Followers: 6, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 57, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 399, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 12, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 481, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 18, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 32, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 47, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 4)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 58, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 6, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 8, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 12)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 2)
Alexandria Engineering J.     Open Access   (Followers: 2, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 11, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 12, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 56, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 5, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 5, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 59, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 67, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 48, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 13)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 17, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 41, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 35, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 37, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 51)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics & Gynecology MFM     Hybrid Journal   (Followers: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 276, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 68, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 33, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 29, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 39, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 7)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 69, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 27, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription   (Followers: 1)
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 6, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 44, SJR: 1.512, CiteScore: 5)
Analytica Chimica Acta : X     Open Access  
Analytical Biochemistry     Hybrid Journal   (Followers: 224, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 13, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 14)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 25, SJR: 0.683, CiteScore: 2)

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Similar Journals
Journal Cover
American Journal of Pathology
Journal Prestige (SJR): 2.139
Citation Impact (citeScore): 4
Number of Followers: 33  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0002-9440
Published by Elsevier Homepage  [3204 journals]
  • Loss of Roundabout Guidance Receptor 2 (Robo2) in Podocytes Protects Adult
           Mice from Glomerular Injury by Maintaining Podocyte Foot
           Process Structure
    • Abstract: Publication date: Available online 24 March 2020Source: The American Journal of PathologyAuthor(s): Anna Pisarek-Horowitz, Xueping Fan, Sudhir Kumar, Hila M. Rasouly, Richa Sharma, Hui Chen, Kathryn Coser, Crystal T. Bluette, Dinesh Hirenallur-Shanthappa, Sarah R. Anderson, Hongying Yang, Laurence H. Beck, Ramon G. Bonegio, Joel M. Henderson, Stephen P. Berasi, David J. Salant, Weining Lu
       
  • Pathogenesis of intradermal staphylococcal infections: rabbit experimental
           approach to natural Staphylococcus aureus skin infections
    • Abstract: Publication date: Available online 20 March 2020Source: The American Journal of PathologyAuthor(s): Asunción Muñoz-Silvestre, Mariola Penadés, Laura Selva, Sara Pérez-Fuentes, Elena Moreno-Grua, Ana García-Quirós, Juan J. Pascual, Alberto Arnau-Bonachera, Agustín Barragán, Juan M. Corpa, David Viana
       
  • The Thyromimetic, GC-1, Alters Bile Acid Metabolism in a Mouse Model of
           Hepatic Cholestasis
    • Abstract: Publication date: Available online 20 March 2020Source: The American Journal of PathologyAuthor(s): Karis Kosar, Pamela Cornuet, Sucha Singh, Silvia Liu, Kari Nejak-Bowen
       
  • The cross-talk between lncRNA-SNHG7/microRNA-181/cbx7 modulates malignant
           character in lung adenocarcinoma
    • Abstract: Publication date: Available online 20 March 2020Source: The American Journal of PathologyAuthor(s): Yao-fei Pei, Yi He, Li-zhen Hu, Bing Zhou, He-yun Xu, Xi-qiang Liu
       
  • Spontaneous development of hepatocellular carcinoma and B-cell lymphoma in
           mosaic and heterozygous Brca2 and Cdkn1a interacting protein (Bccip)
           knockout mice
    • Abstract: Publication date: Available online 20 March 2020Source: The American Journal of PathologyAuthor(s): Huimei Lu, Caiyong Ye, Xing Feng, Jingmei Liu, Mantu Bhaumik, Bing Xia, Chen Liu, Zhiyuan Shen
       
  • γ-Secretase activity is associated with Braak Senile Plaque stages
    • Abstract: Publication date: Available online 20 March 2020Source: The American Journal of PathologyAuthor(s): Nobuto Kakuda, Haruyasu Yamaguchi, Kohei Akazawa, Saori Hata, Toshiharu Suzuki, Hiroyuki Hatsuta, Shigeo Murayama, Satoru Funamoto, Yasuo Ihara
       
  • Constitutive STAT3 serine phosphorylation promotes
           Helicobacter-mediated gastric disease
    • Abstract: Publication date: Available online 19 March 2020Source: The American Journal of PathologyAuthor(s): Jesse J. Balic, Mohamed I. Saad, Ruby Dawson, Alice J. West, Louise McLeod, Alison C. West, Kimberley D’Costa, Virginie Deswaerte, Anouk Dev, William Sievert, Daniel J. Gough, Prithi S. Bhathal, Richard L. Ferrero, Brendan J. Jenkins
       
  • Hyaluronidase-2 Regulates RhoA Signalling, Myofibroblast Contractility and
           other Key Pro-fibrotic Myofibroblast Functions
    • Abstract: Publication date: Available online 19 March 2020Source: The American Journal of PathologyAuthor(s): Adam C. Midgley, Emma Woods, Robert Jenkins, Charlotte Brown, Usman Khalid, Rafael Chavez, Vincent Hascall, Robert Steadman, Aled O. Phillips, Soma Meran
       
  • Genome-Wide Screens Identify Group A Streptococcus Surface Proteins
           Promoting Female Genital Tract Colonization and Virulence
    • Abstract: Publication date: Available online 19 March 2020Source: The American Journal of PathologyAuthor(s): Luchang Zhu, Randall J. Olsen, Stephen B. Beres, Matthew Ojeda Saavedra, Samantha L. Kubiak, Concepcion C. Cantu, Leslie Jenkins, Prasanti Yerramilli, Layne Pruitt, Amelia R.L. Charbonneau, Andrew S. Waller, James M. Musser
       
  • Apoptotic cell-directed resolution of lung inflammation requires myeloid
           αv integrin-mediated induction of regulatory T lymphocytes
    • Abstract: Publication date: Available online 19 March 2020Source: The American Journal of PathologyAuthor(s): Ailiang Zhang, Adam Lacy-Hulbert, Stephen Anderton, Christopher Haslett, John Savill
       
  • Return of Individual Research Results: A Guide for Biomedical Researchers
           Utilizing Human Biospecimens
    • Abstract: Publication date: Available online 19 March 2020Source: The American Journal of PathologyAuthor(s): Mark E. Sobel, Jennifer C. Dreyfus, Kelsey Dillehay McKillip, Christi Kolarcik, William A. Muller, Melanie J. Scott, Gene P. Siegal, Kristine Wadosky, Timothy J. O’Leary
       
  • Immunogradient indicators for anti-tumor response assessment by automated
           tumor-stroma interface zone detection
    • Abstract: Publication date: Available online 17 March 2020Source: The American Journal of PathologyAuthor(s): Allan Rasmusson, Dovile Zilenaite, Ausrine Nestarenkaite, Renaldas Augulis, Aida Laurinaviciene, Valerijus Ostapenko, Tomas Poskus, Arvydas Laurinavicius
       
  • Specific deletion of p16INK4a with retention of p19ARF enhances the
           development of invasive oral squamous cell carcinoma
    • Abstract: Publication date: Available online 16 March 2020Source: The American Journal of PathologyAuthor(s): Kazuhisa Ishida, Hiroyuki Tomita, Tomohiro Kanayama, Kei Noguchi, Ayumi Niwa, Masaya Kawaguchi, Masafumi Miyai, Mikiko Matsuo, Yuko Imaizumi, Keizo Kato, Yuichiro Hatano, Akihiro Hirata, Hideshi Okada, Toshiyuki Shibata, Akira Hara
       
  • CHRONIC KIDNEY DISEASE: A VICARIOUS RELATION TO PREMATURE CELL
           SENESCENCE'
    • Abstract: Publication date: Available online 16 March 2020Source: The American Journal of PathologyAuthor(s): Michael S. Goligorsky
       
  • Complement membrane attack complex: new roles, mechanisms of action, and
           therapeutic targets
    • Abstract: Publication date: Available online 16 March 2020Source: The American Journal of PathologyAuthor(s): Catherine B. Xie, Dan Jane-wit, Jordan S. Pober
       
  • Current concepts of osteomyelitis: from pathological mechanisms to
           advanced research methods.
    • Abstract: Publication date: Available online 16 March 2020Source: The American Journal of PathologyAuthor(s): Marloes Imke Hofstee, Gowrishankar Muthukrishnan, Gerald James Atkins, Martijn Riool, Keith Thompson, Mario Morgenstern, Martin James Stoddart, Robert Geoff Richards, Sebastian Antonius Johannes Zaat, Thomas Fintan Moriarty
       
  • Podocytopathy and Nephrotic Syndrome in Mice with Podocyte-Specific
           Deletion of the Asah1 Gene: Role of Ceramide Accumulation in Glomeruli
    • Abstract: Publication date: Available online 16 March 2020Source: The American Journal of PathologyAuthor(s): Guangbi Li, Jason Kidd, Cristin Kaspar, Sara Dempsey, Owais M. Bhat, Sarah Camus, Joseph K. Ritter, Todd W.B. Gehr, Erich Gulbins, Pin-Lan Li
       
  • Sympathetic Nerves Positively Regulate Eosinophil-Driven Allergic
           Conjunctivitis via α1-Adrenergic Receptor Signaling
    • Abstract: Publication date: Available online 16 March 2020Source: The American Journal of PathologyAuthor(s): Jun Liu, Shuoya Huang, Fanying Li, Mingjuan Wu, Jingxin He, Yunxia Xue, Ting Fu, Ruoxun Yu, Xinwei Chen, Yuming Wang, Zhijie Li
       
  • Induction of steatohepatitis and liver tumorigenesis by enforced Snail
           expression in hepatocytes
    • Abstract: Publication date: Available online 15 March 2020Source: The American Journal of PathologyAuthor(s): Shizuka Miura, Atsushi Suzuki
       
  • H2 histamine receptor Vivo-Morpholino treatment ameliorates large bile
           duct damage in mice deficient in ATP binding cassette subfamily B member 4
           (Abcb4-/-) via down-regulation of cAMP/ERK signaling
    • Abstract: Publication date: Available online 3 March 2020Source: The American Journal of PathologyAuthor(s): Lindsey Kennedy, Vik Meadows, Konstantina Kyritsi, Linh Pham, Debjyoti Kundu, Rewa Kulkarni, Karla Cerritos, Jennifer Demieville, Laura Hargrove, Shannon Glaser, Tianhao Zhou, Victoria Jaeger, Gianfranco Alpini, Heather Francis
       
  • Oxidative phosphorylation promotes primary melanoma invasion
    • Abstract: Publication date: Available online 3 March 2020Source: The American Journal of PathologyAuthor(s): Amel Salhi, Alexander C. Jordan, Irineu Illa Bochaca, Allison Izsak, Farbod Darvishian, Yariv Houvras, Keith M. Giles, Iman Osman
       
  • BAG3P215L/KO Mice as a Model of BAG3P209L
           Myofibrillar Myopathy
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s): Rebecca Robertson, Talita C. Conte, Marie-Josée Dicaire, Vladimir V. Rymar, Abbas F. Sadikot, Robert J. Bryson-Richardson, Josée N. Lavoie, Erin O'Ferrall, Jason C. Young, Bernard Brais
       
  • The Immune Response in Nonmetastatic Axillary Lymph Nodes Is Associated
           with the Presence of Axillary Metastasis and Breast Cancer Patient Outcome
           
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s): Carlos López, Ramon Bosch, Guifre Orero, Anna Korzynska, Marcial García-Rojo, Gloria Bueno, María del Milagro Fernández-Carrobles, Albert Gibert-Ramos, Lukasz Roszkowiak, Cristina Callau, Laia Fontoura, Maria-Teresa Salvadó, Tomás Álvaro, Joaquín Jaén, Albert Roso-Llorach, Montserrat Llobera, Julia Gil, Montserrat Onyos, Benoît Plancoulaine, Jordi Baucells
       
  • miR-218 Expressed in Endothelial Progenitor Cells Contributes to the
           Development and Repair of the Kidney Microvasculature
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s): Xiaojie Wang, Jialing Liu, Wenqing Yin, Farhiya Abdi, Paul D. Pang, Quynh-Anh Fucci, Molly Abbott, Steven L. Chang, Graeme Steele, Ankit Patel, Yutaro Mori, Aifeng Zhang, Shikai Zhu, Tzong-Shi Lu, Adam S. Kibel, Bin Wang, Kenneth Lim, Andrew M. Siedlecki
       
  • Coordinated Targeting of Galanin Receptors on Cholangiocytes and Hepatic
           Stellate Cells Ameliorates Liver Fibrosis in Multidrug Resistance Protein
           2 Knockout Mice
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s): Anca D. Petrescu, Stephanie Grant, Elaina Williams, Gabriel Frampton, Natalie Parks, Hanna Blaney, Marcus Davies, Rebekah John, Evan H. Reinhart, Matthew McMillin, Sharon DeMorrow
       
  • Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Regulates Epidermal
           Keratinization under Psoriatic Skin Inflammation
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s): Tatsuya Ogawa, Yosuke Ishitsuka, Sae Inoue, Yoshiyuki Nakamura, Akimasa Saito, Naoko Okiyama, Yasuhiro Fujisawa, Junichi Furuta, Rei Watanabe, Manabu Fujimoto
       
  • Hyperlipidemia Affects Tight Junctions and Pump Function in the Corneal
           Endothelium
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s): Jinghua Bu, Jingwen Yu, Yang Wu, Xiaoxin Cai, Kechun Li, Liying Tang, Nan Jiang, M. Vimalin Jeyalatha, Minjie Zhang, Huimin Sun, Hui He, Andrew J. Quantock, Yongxiong Chen, Zuguo Liu, Wei Li
       
  • An Animal Model Further Uncovers the Role of Mutant Braf V600E during
           Papillary Thyroid Cancer Development
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s): Bernd Koelsch, Sarah Theurer, Magdalena Staniszewska, Jacqueline Heupel, Amelie Koch, Svenja Mergener, Franziska Walk, Christine Fischer, Andrea Kutritz, Kurt W. Schmid, Andrea Kindler-Röhrborn
       
  • Distinct Chronic Post-Viral Lung Diseases upon Infection with Influenza or
           Parainfluenza Viruses Differentially Impact Superinfection Outcome
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s): Geyon L. Garcia, Alex Valenzuela, Tomaz Manzoni, Andrew E. Vaughan, Carolina B. López
       
  • Endothelial Cell Calcium Signaling during Barrier Function and
           Inflammation
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s): Prarthana J. Dalal, William A. Muller, David P. Sullivan
       
  • Recent Developments in Vascular Adventitial Pathobiology: The Dynamic
           Adventitia as a Complex Regulator of Vascular Disease
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s): Maria G. Tinajero, Avrum I. Gotlieb
       
  • This Month in AJP
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s):
       
  • Correction
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s):
       
  • Reviewer Acknowledgment
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s):
       
  • miR-431 Promotes Metastasis of Pancreatic Neuroendocrine Tumors by
           Targeting DAB2 Interacting Protein, a Ras GTPase Activating Protein Tumor
           Suppressor
    • Abstract: Publication date: March 2020Source: The American Journal of Pathology, Volume 190, Issue 3Author(s): Tiantian Zhang, Soyoung Choi, Tuo Zhang, Zhengming Chen, Yudan Chi, Shixia Huang, Jenny Z. Xiang, Yi-Chieh Nancy Du
       
  • Endoplasmic Reticulum Stress Signaling in Cancer Cells
    • Abstract: Publication date: Available online 27 February 2020Source: The American Journal of PathologyAuthor(s): Scott A. Oakes
       
  • Haploinsufficiency of Casitas B-Lineage Lymphoma Augments the Progression
           of Colon Cancer in the Background of Adenomatous Polyposis Coli
           Inactivation
    • Abstract: Publication date: Available online 26 February 2020Source: The American Journal of PathologyAuthor(s): Sean Richards, Joshua Walker, Masako Nakanishi, Mostafa Belghasem, Chimera Lyle, Nkiruka Arinze, Marc A. Napoleon, Jonathan D. Ravid, Nicholas Crossland, Qing Zhao, Daniel Rosenberg, Nader Rahimi, Vipul C. Chitalia
       
  • Adrenomedullin Is Necessary to Resolve Hyperoxia-Induced Experimental
           Bronchopulmonary Dysplasia and Pulmonary Hypertension in Mice
    • Abstract: Publication date: Available online 21 February 2020Source: The American Journal of PathologyAuthor(s): Renuka T. Menon, Amrit Kumar Shrestha, Corey L. Reynolds, Roberto Barrios, Kathleen M. Caron, Binoy ShivannaBronchopulmonary dysplasia (BPD)–associated pulmonary hypertension (PH) is an infantile lung disease characterized by aberrant angiogenesis and impaired resolution of lung injury. Adrenomedullin (AM) signals through calcitonin receptor–like receptor and receptor activity–modifying protein 2 and modulates lung injury initiation. However, its role in lung injury resolution and the mechanisms by which it regulates angiogenesis remain unclear. Consequently, we hypothesized that AM resolves hyperoxia-induced BPD and PH via endothelial nitric oxide synthase (NOS3). AM-sufficient (ADM+/+) or -deficient (ADM+/−) mice were exposed to normoxia or hyperoxia through postnatal days (PNDs) 1 to 14, and the hyperoxia-exposed mice were allowed to recover in normoxia for an additional 56 days. Lung injury and development and PH were quantified at different time points. Human pulmonary microvascular endothelial cells were also used to examine the effects of AM signaling on the NOS3 pathway and angiogenesis. Lung blood vessels and NOS3 expression decreased and the extent of hyperoxia-induced BPD and PH increased in ADM+/− mice compared with ADM+/+ mice. Hyperoxia-induced apoptosis and PH resolved by PND14 and PND70, respectively, in ADM+/+ mice but not in ADM+/− mice. Knockdown of ADM, calcitonin receptor–like receptor, and receptor activity–modifying protein 2 in vitro decreased NOS3 expression, nitric oxide generation, and angiogenesis. Furthermore, NOS3 knockdown abrogated the angiogenic effects of AM. Collectively, these results indicate that AM resolves hyperoxic lung injury via NOS3.
       
  • Erythropoietin Receptor Signaling Supports Retinal Function after Vascular
           Injury
    • Abstract: Publication date: Available online 21 February 2020Source: The American Journal of PathologyAuthor(s): Colin A. Bretz, Aaron B. Simmons, Eric Kunz, Aniket Ramshekar, Carson Kennedy, Ivan Cardenas, M. Elizabeth HartnettThe investigation of erythropoietin (EPO) has expanded to include potential nonhematopoietic roles in neural and retinal diseases, including diabetic retinopathy. However, it remains unclear how EPO functions to support the neural retina. Transgenic mice with hypoactive EPO receptor (EPOR) signaling (hWtEPOR) were compared with littermate control mice (WT) to test the role of EPOR signaling under normal conditions and after vascular injury and regrowth into the retina. Although retinal function tested with OptoMotry and electroretinography was comparable to adult (8-week–old) littermate WT mice, hWtEPOR mice had thinner inner and outer plexiform layers and a greater number of amacrine cells. Injury and repair caused by the oxygen-induced retinopathy model reduced visual acuity thresholds, reduced electroretinography amplitudes, and thinned the outer plexiform and inner nuclear layers of both WT and hWtEPOR 8-week–old mice. In hWtEPOR compared with WT mice, scotopic a-wave amplitudes were reduced by injury, despite no change in outer nuclear layer thickness; and peripheral rod, but not cone number, was reduced. Scotopic b-waves were reduced in injured hWtEPOR mice compared with WT, and rod bipolar cell ectopic neurites were increased in both genotypes after injury, suggesting a potential reparative process to preserve connectivity and the b-wave. Normal EPOR signaling appeared important because ectopic neurites and b-waves were lower in the hWtEPOR than WT injured mice.
       
  • Placental overexpression of soluble CORIN in preeclampsia
    • Abstract: Publication date: Available online 19 February 2020Source: The American Journal of PathologyAuthor(s): Séverine A. Degrelle, Audrey Chissey, Alain Stepanian, Thierry Fournier, Jean Guibourdenche, Laurent Mandelbrot, Vassilis Tsatsaris Preeclampsia (PE) is a hypertensive disease of pregnancy associated with substantial maternal and fetal morbidity and mortality. CORIN is a transmembrane type II serine protease expressed in cardiomyocytes that converts pro-atrial natriuretic peptide (pro-ANP) into ANP, a cardiac hormone that regulates blood pressure. High levels of soluble CORIN have been reported in preeclampsia and are supposed to be cardiac in origin. We hypothesized that during pregnancy soluble CORIN is released by the syncytiotrophoblast and that increased levels of soluble CORIN in preeclampsia originate from placenta. Three-hundred and ninety-five patients (181 PE patients and 194 controls) were analyzed. High levels of soluble CORIN were confirmed in maternal blood from preeclamptic pregnancies compared to controls. Differentiated primary villous cytotrophoblasts showed that CORIN was expressed (mRNA and protein levels) and secreted by trophoblastic cells, mostly by the syncytiotrophoblast . Finally, placental explants demonstrated a significant increase in CORIN production and secretion in PE cases compared to controls. This study demonstrates that CORIN is secreted by trophoblastic cells and that high levels of soluble CORIN in preeclampsia have a placental origin.
       
  • Identification of lacrimal gland postganglionic innervation and its
           regulation of tear secretion
    • Abstract: Publication date: Available online 19 February 2020Source: The American Journal of PathologyAuthor(s): Kai Jin, Toshihiro Imada, Ryuji Hisamura, Masataka Ito, Haruki Toriumi, Kenji F. Tanaka, Shigeru Nakamura, Kazuo Tsubota Tear fluid secreted from the exocrine lacrimal gland (LG) has an essential role in maintaining a homeostatic environment for a healthy ocular surface. It is known that tear secretion is regulated by both the sympathetic and parasympathetic components of the autonomic nervous system, although the contribution of each component is not fully understood. Here, to investigate LG innervation, we identified sympathetic and parasympathetic postganglionic nerves, specifically innervating the mouse LG, by injecting a retrograde neuronal tracer into the LG. Interruption of neural stimuli to the LG by the denervation of these postganglionic nerves immediately and chronically decreased tear secretion, leading to LG atrophy along with destruction of the lobular structure. This investigation also found that parasympathetic, but not sympathetic, innervation was involved in these alterations.
       
  • Knockdown of long non-coding RNAs of maternally expressed 3 (lncRNA-MEG3)
           alleviates hyperoxia-induced lung injury via inhibiting
           thioredoxin-interacting protein (TXNIP)-mediated pyroptosis by binding to
           microRNA miR-18a
    • Abstract: Publication date: Available online 19 February 2020Source: The American Journal of PathologyAuthor(s): Dong-Mei Zou, Shao-Ming Zhou, Long-Hui Li, Jian-Li Zhou, Zan-Mei Tang, Shao-Hua Wang Long-term hyperoxia exposure may cause lung damage, with characteristic inflammation. Long non-coding RNA of maternally expressed 3 (lncRNA-MEG3) is up-regulated in lung tissues exposed to hyperoxia; however, the underlying mechanism is unclear. Hyperoxia-induced cells and mouse models were used to study these mechanisms. Molecular assays were used to detect cell viability, cytotoxicity, and expression of microRNA miR-18a, MEG3, and inflammatory cytokines. The interaction among MEG3, miR-18a, and thioredoxin-interacting protein (TXNIP) was verified and pyroptosis-related proteins analyzed. The in vivo model was established by exposing MEG3 knockdown mice to hyperoxia. Hemotoxylin and eosin staining was used to assess pathological alterations of lung tissues. Hyperoxia suppressed cell viability, induced cell damage, and exacerbated the secretion of interleukin IL1B and IL18. Hyperoxia inhibited miR-18a, with increased expression of MEG3, TXNIP, and NOD-like receptor family pyrin domain containing 3 (NLRP3). MEG3 aggravated TXNIP expression by binding to miR-18a. Knockdown of MEG3 rescued hyperoxia-induced pyroptosis by up-regulating miR-18a. Furthermore, knockdown of MEG3 inhibited NLRP3 inflammasome activity and caspase-1 signaling by miR-18a. In vivo knockdown of MEG3 and overexpression of miR-18a relieved hyperoxia-induced lung injury via restraining NLRP3 inflammasome-mediated pyroptosis, whereas miR-18a inhibition reversed these effects. In conclusion, knockdown of MEG3 inhibits pyroptosis to alleviate hyperoxia lung injury by suppressing NLRP3 inflammasome and caspase-1 signaling via regulating miR-18a–TXNIP axis.
       
  • Fibroblast activation protein regulates lesion burden and the
           fibro-inflammatory response in Apoe-deficient mice in a sexually dimorphic
           manner
    • Abstract: Publication date: Available online 19 February 2020Source: The American Journal of PathologyAuthor(s): James Monslow, Leslie Todd, John E. Chojnowski, Priya K. Govindaraju, Richard K. Assoian, Ellen Puré Fibroblast activation protein (FAP) has been established as an inducible and mesenchymal cell-specific mediator of disease progression in cancer and fibrosis. Atherosclerosis is a fibro-inflammatory disease, and FAP was previously reported to be up-regulated in human atherosclerotic plaques compared to normal vessel. Here, we investigated the spatial and temporal distribution of Fap expressing cells in a murine model of atherosclerosis and used a genetic approach to determine if and how Fap impacted disease progression. Fap was found to be expressed predominantly on vascular smooth muscle cells in lesions of athero-prone Apoe-/- mice. Global deletion of Fap (Fap-/-) in Apoe-/- mice accelerated atherosclerotic disease progression in both males and females, with the effect observed earlier in males. Sex-specific effects on lesion morphology were observed. Relative levels of extracellular matrix, fibrotic, and inflammatory cell content were comparable in lesions in male mice regardless of Fap status. In contrast, lesions in Fap-/- female mice were characterized by a more-fibrotic composition due to a reduction in inflammation, specifically a reduction in Mox macrophages. Combined, these data suggest that Fap restrains the progression of atherosclerosis and it may contribute to the sexually dimorphic susceptibility to atherosclerosis by regulating the balance between inflammation—an indicator of vulnerability to plaque rupture, and fibrosis—an indicator of plaque stability.
       
  • Toll-like receptor-4 antagonist (+)-naltrexone protects against
           carbamyl-platelet activating factor (Cpaf)-induced preterm labor in mice
    • Abstract: Publication date: Available online 18 February 2020Source: The American Journal of PathologyAuthor(s): Hanan H. Wahid, Peck Yin Chin, David J. Sharkey, Kerrilyn R. Diener, Mark R. Hutchinson, Kenner C. Rice, Lachlan M. Moldenhauer, Sarah A. Robertson Spontaneous preterm labor is frequently caused by an inflammatory response in the gestational tissues elicited by either infectious or sterile agents. In sterile preterm labor, the key regulators of inflammation are not identified, but platelet activating factor (PAF) is implicated as a potential rate-limiting effector agent. Since toll-like receptor 4 (TLR4) can amplify PAF signaling, we evaluated whether TLR4 contributes to inflammation and fetal loss in a mouse model of PAF-induced sterile preterm labor, and whether a small molecule TLR4 inhibitor (+)-naltrexone can mitigate adverse PAF-induced effects. Administration of carbamyl-PAF (cPAF) caused preterm labor and fetal loss in wild-type mice but not in TLR4-deficient (Tlr4-/-) mice. Treatment with (+)-naltrexone prevented preterm delivery and alleviated fetal demise in utero elicited after cPAF administered by intraperitoneal or intrauterine routes. Pups born after cPAF and (+)-naltrexone treatment exhibited comparable rates of postnatal survival and growth to carrier-treated controls. (+)-Naltrexone suppressed the cPAF-induced expression of inflammatory cytokine genes, Il1b, Il6, and Il10 in the decidua, Il6, Il12b, and Il10 in the myometrium, and Il1b and Il6 in the placenta. These data demonstrate that TLR4 antagonist (+)-naltrexoneinhibits the inflammatory cascade induced by cPAF, preventing preterm birth and perinatal death. Inhibition of TLR4 signaling warrants further investigation as a candidate strategy for fetal protection and delaying preterm birth elicited by sterile stimuli.
       
  • Cortactin expression in hematopoietic cells: implications for
           hematological malignancies
    • Abstract: Publication date: Available online 18 February 2020Source: The American Journal of PathologyAuthor(s): Ramón Castellanos-Martínez, Karina Elizabeth Jiménez-Camacho, Michael Schnoor Cortactin is an actin-binding protein expressed in virtually all cell types. It regulates several cell functions including adhesion and migration. Cortactin overexpression is associated with increased metastasis formation and worse outcome in different types of solid tumors, thus highlighting a critical role of cortactin in cancer progression. Mechanistically, this is due to increased invadopodia formation and matrix metalloproteinase secretion. Cortactin has been until recently considered absent in hematopoietic cells because these cells express the cortactin homolog hematopoietic cell-specific lyn substrate-1. However, many recent reports describe functional expression of cortactin in different hematopoietic cells such as macrophages, dendritic cells, and lymphocytes. Of note, cortactin is strongly overexpressed in leukemic cell lines and primary patient-derived leukemic cells. In B-cell chronic lymphocytic leukemia this is associated with poor prognosis and increased chemotaxis; whereas in B-cell acute lymphoblastic leukemia, high cortactin levels correlate with treatment failure and relapse. Moreover, cortactin has been proposed as a diagnostic marker for non-Hodgkin B-cell lymphomas. This review summarizes current knowledge on cortactin expression in hematopoietic cells and discusses the functional implications for different hematological malignancies.
       
  • Sweet and sticky: selective recruitment of monocyte subsets by endothelial
           N-glycans
    • Abstract: Publication date: Available online 18 February 2020Source: The American Journal of PathologyAuthor(s): Kellie Regal-McDonald, Rakesh P. Patel Monocyte rolling, adhesion, and transmigration across the endothelium is mediated by specific interactions between surface adhesion molecules. This process is fundamental to innate immunity and to inflammatory disease, including atherosclerosis where monocyte egress into the intimal space is central to formation of fatty plaques. Monocytes are a heterogeneous population of three distinct subsets of cells, all of which play different roles in atherosclerosis progression. However, it is not well understood how interactions between different monocyte subsets and the endothelium are regulated. Further, it is appreciated that endothelial adhesion molecules are heavily N-glycosylated, but beyond regulating protein trafficking to the cell surface, whether and if so how, these N-glycans contribute to monocyte recruitment is not known. This review discusses how changes in endothelial N-glycosylation may impact vascular and monocytic inflammation. It will also discuss how regulating N-glycoforms on the endothelial surface may allow for the recruitment of specific monocyte subsets to sites of inflammation, and how further understanding in this area may lead to the development of glyco-specific therapeutics in the treatment of cardiovascular disease.
       
  • Phenotypic characterization and comparison of Phe508del and cystic
           fibrosis transmembrane conductance regulator (CFTR) knockout rat models of
           cystic fibrosis generated by CRISPR/Cas9 gene editing
    • Abstract: Publication date: Available online 18 February 2020Source: The American Journal of PathologyAuthor(s): Alexandra McCarron, Patricia Cmielewski, Nicole Reyne, Chantelle McIntyre, John Finnie, Fiona Craig, Nathan Rout-Pitt, Juliette Delhove, John E. Schjenken, Hon Yeung Chan, Bernadette Boog, Emma Knight, Rodney C. Gilmore, Wanda K. O'Neal, Richard C. Boucher, David Parsons, Martin Donnelley Animal models of cystic fibrosis (CF) are essential for investigating disease mechanisms and trialling potential therapeutics. This study generated two CF rat models using clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated protein 9 (Cas9) gene editing. One rat model carries the common human Phe508del (ΔF508) CF transmembrane conductance regulator (CFTR) mutation, whereas the second is a CFTR knockout model. Phenotype was characterized using a range of functional and histological assessments including nasal potential difference to measure electrophysiological function in the upper airways, RNAscope in situ hybridization and quantitative PCR to assess CFTR mRNA expression in the lungs, immunohistochemistry to localize CFTR protein in the airways, and histopathological assessments in a range of tissues. Both rat models revealed a range of CF manifestations including reduced survival, intestinal obstruction, bioelectric defects in the nasal epithelium, histopathological changes in the trachea, large intestine, and pancreas, and abnormalities in the development of the male reproductive tract. The CF rat models presented here will prove useful for longitudinal assessments of pathophysiology and therapeutics.
       
  • Toll-like receptor 5 signaling ameliorates liver fibrosis by inducing
           interferon β–modulated interleukin-1 receptor antagonist in mice
    • Abstract: Publication date: Available online 21 January 2020Source: The American Journal of PathologyAuthor(s): Zixiong Zhou, Jong-Won Kim, Jing Qi, Seong Kug Eo, Chae Woong Lim, Bumseok Kim Bacterial flagellin, recognized by cell surface of toll-like receptor (TLR) 5, is a potent activator of many types of cells, leading to the activation of innate or adaptive immunity, which are pivotal in regulating fibrotic process. However, the exact role of TLR5 signaling in hepatic fibrogenesis remains unclear, and this study aims to elucidate its underlying mechanisms. Flagellin was injected to hepatotoxin- and cholestasis-induced liver fibrosis murine models. Flagellin-induced TLR5 activation significantly decreased the severity of liver fibrosis. Interestingly, the expression levels of interleukin-1 receptor antagonist (IL1RN) and interferon (IFNB) markedly increased in fibrotic livers upon flagellin treatment. Consistently, in vivo activation of TLR5 signaling markedly increased IFNB and IL1RN expression in the livers. Notably, flagellin injection significantly exacerbated the severity of liver fibrosis in IFN-α/β receptor-1 (IFNAR1) knockout mice. Furthermore, hepatic expression of IL1RN in the fibrotic livers of IFNAR1 knockout mice was significantly lower than those of wild-type mice. In support of these findings, flagellin-mediated IL1RN production is not sufficient to alleviate the severity of hepatic fibro-inflammatory responses in IFNAR1-deficient milieu. Finally, hepatic stellate cells treated with IL1RN showed significantly decreased cellular activation and its associated fibrogenic responses. Collectively, manipulation of TLR5 signaling may be a promising therapeutic strategy for the treatment of liver fibrosis.
       
  • Inflammation and DNA methylation–dependent down-regulation of miR-34b-5p
           mediates c-MYC expression and CRL4DCAF4 E3 ligase activity in
           colitis-associated cancer
    • Abstract: Publication date: Available online 21 January 2020Source: The American Journal of PathologyAuthor(s): Chunmei Yang, Wenzhu Lu, Hongbo He, Hong Liu microRNAs (miRNAs), a well-known group of noncoding RNAs, contribute to the pathogenesis of multiple diseases, including colitis-associated cancer (CAC). Our recent findings indicate that proinflammatory cytokines up-regulate c-MYC level, which subsequently activates Cullin 4A and 4B (CUL4A/4B) and CRL4DCAF4 E3 ligases and promotes ubiquitination of suppression of tumorigenicity 7 (STM7) in CAC. Here, we identified and proved that miR-34b-5p can directly target c-MYC. In vitro oncogenic phenotype analyses and in vivo tumor formation assay indicated that miR-34b-5p overexpression could markedly decrease cell proliferation, colony formation, cell invasion, and tumor volumes. Overexpression of c-MYC in vitro could reverse the oncogenic phenotypes caused by miR-34b-5p up-regulation. Additionally, the down-regulation of miR-34b-5p in CAC was dependent on the coregulation of the inflammatory microenvironment and DNA methylation. Collectively, our findings demonstrate that intracellular inflammation and DNA hypermethylation suppress miR-34b-5p expression, which limits its inhibitory effect on c-MYC and initiates the downstream events, including the induction of CRL4DCAF4 E3 ligase activity. The activated CRL4DCAF4 E3 ligase ubiquitinates ST7 and results in its degradation, eventually leading to the CAC tumorigenesis.
       
  • Thrombin-Induced Decidual Colony-Stimulating Factor-2 Promotes
           Abruption-Related Preterm Birth by Weakening Fetal Membranes
    • Abstract: Publication date: February 2020Source: The American Journal of Pathology, Volume 190, Issue 2Author(s): Rachel G. Sinkey, Ozlem Guzeloglu-Kayisli, Sefa Arlier, Xiaofang Guo, Nihan Semerci, Robert Moore, Asli Ozmen, Kellie Larsen, Chinedu Nwabuobi, Deepak Kumar, John J. Moore, Lynn F. Buckwalder, Frederick Schatz, Umit A. Kayisli, Charles J. LockwoodPreterm premature rupture of membranes (PPROM) and thrombin generation by decidual cell–expressed tissue factor often accompany abruptions. Underlying mechanisms remain unclear. We hypothesized that thrombin-induced colony-stimulating factor-2 (CSF-2) in decidual cells triggers paracrine signaling via its receptor (CSF2R) in trophoblasts, promoting fetal membrane weakening and abruption-associated PPROM. Decidua basalis sections from term (n = 10), idiopathic preterm birth (PTB; n = 8), and abruption-complicated pregnancies (n = 8) were immunostained for CSF-2. Real-time quantitative PCR measured CSF2 and CSF2R mRNA levels. Term decidual cell (TDC) monolayers were treated with 10−8 mol/L estradiol ± 10−7 mol/L medroxyprogesterone acetate (MPA) ± 1 IU/mL thrombin pretreatment for 4 hours, washed, and then incubated in control medium with estradiol ± MPA. TDC-derived conditioned media supernatant effects on fetal membrane weakening were analyzed. Immunostaining localized CSF-2 primarily to decidual cell cytoplasm and cytotrophoblast cell membranes. CSF-2 immunoreactivity was higher in abruption-complicated or idiopathic PTB specimens versus normal term specimens (P 
       
  • Quantitative Proteomics of the Endothelial Secretome Identifies RC0497 as
           Diagnostic of Acute Rickettsial Spotted Fever Infections
    • Abstract: Publication date: February 2020Source: The American Journal of Pathology, Volume 190, Issue 2Author(s): Yingxin Zhao, Rong Fang, Jing Zhang, Yueqing Zhang, Jeremy Bechelli, Claire Smalley, Gustavo Valbuena, David H. Walker, José A. Oteo, Allan R. BrasierMediterranean spotted fever is a reemerging acute tick-borne infection produced by the α-proteobacterium, Rickettsia conorii. Rickettsia conorii infects vascular endothelial cells producing disseminated plasma leakage, manifesting as nonspecific fever, headache, and maculopapular rash. Because there are no available tests of early infection, Mediterranean spotted fever is often undiagnosed and untreated, resulting in significant mortality. To address this critical need, we have applied a quantitative proteomics pipeline for analyzing the secretome of primary human umbilical vein endothelial cells. Of the 104 proteins whose abundance changed significantly in the R. conorii–infected human umbilical vein endothelial cells’ secretome, 46 proteins were up-regulated: 45 were host secreted proteins (including cytokines), and 1 was a rickettsial protein, the putative N-acetylmuramoyl-l-alanine amidase RC0497. Proteins with sequence highly homologous to RC0497 were found to be shared by many species of the spotted fever group rickettsiae, but not typhus group rickettsiae. Quantitative targeted proteomics studies of plasma from a mouse model of sublethal and lethal R. conorii identified RC0497 in the blood, and its circulating levels were proportionally associated with infection outcome. Finally, the presence of RC0497 in the serum samples from a cohort of humans presenting with acute rickettsioses was confirmed. The detection of RC0497 has the potential to be a sensitive and specific marker for acute rickettsial spotted rickettsioses.
       
  • This Month in AJP
    • Abstract: Publication date: Available online 16 December 2019Source: The American Journal of PathologyAuthor(s):
       
  • Partitioning-Defectiveness-6–Ephrin-B1 Interaction Is Regulated by
           Nephrin-Mediated Signal and Is Crucial in Maintaining Slit Diaphragm of
           Podocyte
    • Abstract: Publication date: Available online 16 December 2019Source: The American Journal of PathologyAuthor(s): Sayuri Takamura, Yoshiyasu Fukusumi, Ying Zhang, Ichiei Narita, Hiroshi KawachiEphrin-B1 plays a critical role at slit diaphragm. Partitioning-defectiveness (Par)-6 is down-regulated in podocyte of ephrin-B1 knockout mouse, suggesting that Par-6 is associated with ephrin-B1. Par polarity complex, consisting of Par-6, Par-3, and atypical protein kinase C, is essential for tight junction formation. In this study, the expression of Par-6 was analyzed in the normal and nephrotic syndrome model rats, and the molecular association of Par-6, Par-3, ephrin-B1, and nephrin was assessed with the human embryonic kidney 293 cell expression system. Par-6 was concentrated at slit diaphragm. Par 6 interacted with ephrin-B1 but not with nephrin, and Par-3 interacted with nephrin but not with ephrin-B1. The complexes of Par-6–ephrin-B1 and Par-3–nephrin were linked via extracellular sites of ephrin-B1 and nephrin. The Par-6–ephrin-B1 complex was delinked from the Par-3–nephrin complex, and Par-6 and ephrin-B1 were clearly down-regulated already at early phase of nephrotic model. The alteration of Par-6/ephrin-B1 advanced that of Par-3/nephrin. Stimulation to nephrin phosphorylated not only nephrin but also ephrin-B1, and consequently inhibited the interaction between ephrin-B1 and Par-6. Par-6 appeared at presumptive podocyte of early developmental stage and moved to basal area at capillary loop stage to participate in slit diaphragm formation at the final stage. Par-6–ephrin-B1 interaction is crucial for formation and maintenance of slit diaphragm of podocyte.
       
  • Characterization of an Adapted Murine Model of Intrauterine
           Inflammation–Induced Preterm Birth
    • Abstract: Publication date: Available online 16 December 2019Source: The American Journal of PathologyAuthor(s): Hannah C. Zierden, Jairo I. Ortiz Ortiz, Peter Dimitrion, Victoria Laney, Sabrine Bensouda, Nicole M. Anders, Morgan Scardina, Thuy Hoang, Brigitte M. Ronnett, Justin Hanes, Irina Burd, Mala Mahendroo, Laura M. EnsignPreterm birth (PTB) affects nearly 15 million infants each year. Of these PTBs,>25% are a result of inflammation or infection. Animal models have improved our understanding of the mechanisms leading to PTB. Prior work has described induction of intrauterine inflammation in mice with a single injection of lipopolysaccharide (LPS). Herein, we have improved the reproducibility and potency of LPS in the model using two injections distal to the cervix. IVIS imaging revealed more uniform distribution of Evans Blue Dye using a double distal injection (DDI) approach compared with a single proximal injection (SPI). Endotoxin concentrations in vaginal lavage fluid from SPI dams were significantly higher than from DDI dams. At equivalent LPS doses, DDI consistently induced more PTB than SPI, and DDI showed a linear dose-response, whereas SPI did not. Gene expression in myometrial tissue revealed increased levels of inflammatory markers in dams that received LPS DDI compared with LPS SPI. The SPI group showed more significant overexpression in cervical remodeling genes, likely due to the leakage of LPS from the uterine horns through the cervix. The more reliable PTB induction and uniform uterine exposure provided by this new model will be useful for further studying fetal outcomes and potential therapeutics for the prevention of inflammation-induced PTB.
       
  • Collagen VI Deficiency Results in Structural Abnormalities in the Mouse
           Lung
    • Abstract: Publication date: Available online 13 December 2019Source: The American Journal of PathologyAuthor(s): Jared A. Mereness, Soumyaroop Bhattacharya, Yue Ren, Qian Wang, Christopher S. Anderson, Kathy Donlon, Andrew M. Dylag, Jeannie Haak, Alessia Angelin, Paolo Bonaldo, Thomas J. MarianiCollagen VI (COL6) is known for its role in a spectrum of congenital muscular dystrophies, which are often accompanied by respiratory dysfunction. However, little is known regarding the function of COL6 in the lung. We confirmed the presence of COL6 throughout the basement membrane region of mouse lung tissue. Lung structure and organization were studied in a previously described Col6a1−/− mouse, which does not produce detectable COL6 in the lung. The Col6a1−/− mouse displayed multiple histopathologic alveolar and airway abnormalities. The airspaces of Col6a1−/− lungs appeared simplified, with larger (29%; P 
       
  • Src Kinase Is Biphosphorylated at Y416/Y527 and Activates the CUB-Domain
           Containing Protein 1/Protein Kinase C δ Pathway in a Subset of
           Triple-Negative Breast Cancers
    • Abstract: Publication date: Available online 13 December 2019Source: The American Journal of PathologyAuthor(s): Luke J. Nelson, Heather J. Wright, Nguyen B. Dinh, Kevin D. Nguyen, Olga V. Razorenova, F. Scott HeinemannTargeted therapeutics are needed for triple-negative breast cancer (TNBC). In this study, we investigated the activation of Src family of cytoplasmic tyrosine kinases (SFKs) and two SFK substrates—CUB-domain containing protein 1 (CDCP1) and protein kinase C δ (PKCδ)—in 56 formalin-fixed, paraffin-embedded (FFPE) TNBCs. Expression of SFK phosphorylated at Y416 (SFK_pY416+) in tumor cells was strongly associated with phosphorylation of CDCP1 and PKCδ (CDCP1_ pY743+ and PKCδ_pY311+), as assessed by immunohistochemistry, indicating increased SFK activity in situ. To enable biochemical analysis, protein extraction from FFPE tissue was optimized. Cleaved CDCP1 isoform (70 kDa) was expressed to a varying degree in all samples but only phosphorylated in TNBC tumor cells that expressed SFK_pY416. Interestingly, active SFK was found to be biphosphorylated (SFK_pY416+/pY527+). Biphosphorylated active SFK was observed more frequently in FOXA1− TNBCs. In addition, in SFK_pY416− samples, FOXA1+ TNBC tended to be SFK_pY527+ (classic inactive SFK), and FOXA1− TNBC tended to be SFK_pY527− (SFK poised for activation). Strong SFK_pY416 staining was also observed in tumor-infiltrating lymphocytes in a subset of TNBCs with high tumor-infiltrating lymphocyte content. This report will facilitate protein biochemical analysis of FFPE tumor samples and justifies the development of therapies targeting the SFK/CDCP1/PKCδ pathway for TNBC treatment.
       
  • Amplification of 7p12 Is Associated with Pathologic Nonresponse to
           Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer
    • Abstract: Publication date: Available online 13 December 2019Source: The American Journal of PathologyAuthor(s): Renate Pichler, Andrea K. Lindner, Eva Compérat, Peter Obrist, Georg Schäfer, Tilman Todenhöfer, Wolfgang Horninger, Zoran Culig, Gerold UntergasserPathologic downstaging (pDS) to neoadjuvant chemotherapy (NAC) is one of the most important predictors of survival in muscle-invasive bladder cancer (MIBC). The use of NAC is limited as pDS is only achieved in 30% to 40% of cases and predictive biomarkers are still lacking. We performed a comprehensive immunomolecular biomarker analysis to characterize the role of immune cells and inhibitory checkpoints, genome-wide frequencies of copy number alterations, mutational signatures in whole exome, and tumor mutational burden in predicting NAC response. Our retrospective study included 23 primary MIBC patients who underwent NAC, followed by radical cystectomy. pDS to NAC was a significant prognostic factor for better recurrence-free survival (P 
       
  • Inflammation and Ectopic Fat Deposition in the Aging Murine Liver Is
           Influenced by CCR2
    • Abstract: Publication date: Available online 13 December 2019Source: The American Journal of PathologyAuthor(s): Elizabeth C. Stahl, Evan R. Delgado, Frances Alencastro, Samuel T. LoPresti, Patrick D. Wilkinson, Nairita Roy, Martin J. Haschak, Clint D. Skillen, Satdarshan P. Monga, Andrew W. Duncan, Bryan N. BrownAging is associated with inflammation and metabolic syndrome, which manifests in the liver as nonalcoholic fatty liver disease (NAFLD). NAFLD can range in severity from steatosis to fibrotic steatohepatitis and is a major cause of hepatic morbidity. However, the pathogenesis of NAFLD in naturally aged animals is unclear. Herein, we performed a comprehensive study of lipid content and inflammatory signature of livers in 19-month–old aged female mice. These animals exhibited increased body and liver weight, hepatic triglycerides, and inflammatory gene expression compared with 3-month–old young controls. The aged mice also had a significant increase in F4/80+ hepatic macrophages, which coexpressed CD11b, suggesting a circulating monocyte origin. A global knockout of the receptor for monocyte chemoattractant protein (CCR2) prevented excess steatosis and inflammation in aging livers but did not reduce the number of CD11b+ macrophages, suggesting changes in macrophage accumulation precede or are independent from chemokine (C-C motif) ligand–CCR2 signaling in the development of age-related NAFLD. RNA sequencing further elucidated complex changes in inflammatory and metabolic gene expression in the aging liver. In conclusion, we report a previously unknown accumulation of CD11b+ macrophages in aged livers with robust inflammatory and metabolic transcriptomic changes. A better understanding of the hallmarks of aging in the liver will be crucial in the development of preventive measures and treatments for end-stage liver disease in elderly patients.
       
  • p53-Regulated Long Noncoding RNA PRECSIT Promotes Progression of Cutaneous
           Squamous Cell Carcinoma via STAT3 Signaling
    • Abstract: Publication date: Available online 12 December 2019Source: The American Journal of PathologyAuthor(s): Minna Piipponen, Liisa Nissinen, Pilvi Riihilä, Mehdi Farshchian, Markku Kallajoki, Juha Peltonen, Sirkku Peltonen, Veli-Matti KähäriLong noncoding RNAs (lncRNAs) have emerged as putative biomarkers and therapeutic targets in cancer. The role of lncRNA LINC00346 in cutaneous squamous carcinoma (cSCC) was examined. The expression of LINC00346 was up-regulated in cSCC cells compared with normal human epidermal keratinocytes. Elevated expression of LINC00346 was noted in tumor cells in cSCC tissue sections in vivo, as compared with cSCC in situ, and actinic keratosis by RNA in situ hybridization; and the expression in seborrheic keratosis and normal skin was very low. Immunohistochemical analysis of cSCC tissue sections and functional assays of cSCC cells in culture showed that LINC00346 expression is down-regulated by p53. Knockdown of LINC00346 inhibited invasion of cSCC cells in culture and suppressed growth of human cSCC xenografts in vivo. Knockdown of LINC00346 inhibited expression of activated STAT3 and resulted in down-regulation of the expression of matrix metalloproteinase (MMP)-1, MMP-3, MMP-10, and MMP-13. Based on these observations LINC00346 was named p53 regulated carcinoma-associated STAT3-activating long intergenic non-protein coding transcript (PRECSIT). These results identify PRECSIT as a new p53-regulated lncRNA, which promotes progression of cSCC via STAT3 signaling.
       
  • Angiocrine Hgf signaling controls physiologic organ and body size and
           dynamic hepatocyte proliferation to prevent liver damage during
           regeneration
    • Abstract: Publication date: Available online 27 November 2019Source: The American Journal of PathologyAuthor(s): Xue-jun Zhang, Victor Olsavszky, Yuhan Yin, Baocai Wang, Thomas Engleitner, Rupert Öllinger, Kai Schledzewski, Philipp-Sebastian Koch, Roland Rad, Roland M. Schmid, Helmut Friess, Sergij Goerdt, Norbert Hüser, Cyrill Géraud, Guido von Figura, Daniel HartmannAbstractLiver sinusoidal endothelial cells (LSEC) control organ functions, metabolism, and development through the secretion of angiokines. LSEC express hepatocyte growth factor (Hgf), which is involved in prenatal development, metabolic homeostasis, and liver regeneration. This study aimed to elucidate the precise contribution of LSEC-derived Hgf in physiologic homeostasis and liver regeneration. Stab2-iCretg/wt;Hgffl/fl (HgfΔLSEC) mice were generated to abrogate Hgf expression selectively in LSEC from early fetal development onwards, to study global development, metabolic and endothelial zonation, and organ functions as well as liver regeneration in response to 70% partial hepatectomy (PH). Although zonation and liver-to-body weight ratios were not altered, total body weight, and total liver weight were reduced in HgfΔLSEC. Necrotic organ damage was more marked in HgfΔLSEC mice and regeneration was delayed 72h after PH. This was associated with decreased hepatocyte proliferation at 48h after PH. Molecularly, HgfΔLSEC mice showed down-regulation of Hgf/c-MET signaling and decreased expression of Deptor in hepatocytes. In vitro knock-down of Deptor was associated with decreased proliferation. Therefore, angiocrine Hgf controls hepatocyte proliferation and susceptibility to necrosis following partial hepatectomy via the Hgf/c-Met axis involving Deptor to prevent excessive organ damage.
       
  • Necroptosis in the Pathophysiology of Disease
    • Abstract: Publication date: Available online 26 November 2019Source: The American Journal of PathologyAuthor(s): Mitri K. Khoury, Kartik Gupta, Sarah R. Franco, Bo LiuOver the past 15 years, elegant studies have demonstrated that under certain conditions, programmed cell death resembles necrosis and depends on a unique molecular pathway with no overlap with apoptosis. This form of regulated necrosis is represented by necroptosis, in which the receptor interacting protein kinase 3 (RIPK3) and its substrate MLKL play a crucial role. With the development of knockout mouse models and molecular inhibitors unique to necroptotic proteins, this cell-death has been found to occur virtually in all tissues and diseases evaluated. There are different immunologic consequences depending on whether cells die through apoptosis or necroptosis. Therefore, distinguishing between these two forms of cell death may be critical during pathological evaluations. In this review, we provide an understanding of necroptotic cell-death and highlight diseases in which necroptosis has been found to play a role. We also discuss the inhibitors of necroptosis and the ways these inhibitors have been used in pre-clinical models of diseases. These two discussions offer an understanding of the role of necroptosis in diseases and will foster efforts to pharmacologically target this unique yet pervasive form of programmed cell-death in the clinic.
       
  • miRNA-149* suppresses liver cancer progression by down-regulating TRADD
           protein expression
    • Abstract: Publication date: Available online 26 November 2019Source: The American Journal of PathologyAuthor(s): Qingqing Feng, Hongli Zhang, Xiaobo Nie, Yuanqiang Li, Wei-Dong Chen, Yan-Dong WangAbstractLiver cancer is the third leading cause of cancer-related death worldwide. Here we show that microRNA-149* (miR-149*) serves as a novel tumor suppressor for liver tumorigenesis. Mice with genetic deletion of miR-149* (miR-149*-/- mice), which caused loss of both miR-149 and miR-149*, were considerably more susceptible to acute liver injury and hepatic carcinogenesis induced by diethylnitrosamine than wild-type mice, accompanied by increased compensatory proliferation and up-regulated gene expression of certain inflammatory cytokines. miR-149* mimics dramatically impaired liver cancer cell proliferation and migration in vitro, and blocked liver cancer progression in a xenograft model. Furthermore, miR-149* strongly suppressed NF-κB signaling and repressed tumor necrosis factor receptor type 1–associated DEATH domain protein expression in NF-κB signaling pathway. These results reveal that miR-149*, as a novel liver tumor suppressor, may serve as a potential therapeutic target for liver cancer treatment.
       
  • Effect of Inhibition of Colony Stimulating Factor 1 Receptor on Choroidal
           Neovascularization in Mice
    • Abstract: Publication date: Available online 26 November 2019Source: The American Journal of PathologyAuthor(s): Petra Schwarzer, Despina Kokona, Andreas Ebneter, Martin S. ZinkernagelAbstractNeovascular age-related macular degeneration is one of the leading causes of blindness. Microglia and macrophages play critical role in choroidal neovascularization (CNV) and may therefore be potential targets to modulate the disease course. This study evaluated the effect of the colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX5622 on experimental laser-induced CNV. A 98% reduction of retinal microglia cells was observed in the retina one week after initiation of PLX5622 treatment, preventing accumulation of macrophages within the laser site and leading to a reduction of leukocytes within the choroid after CNV induction. Mice treated with PLX5622 had a significantly faster decrease of the CNV lesion size as revealed by in vivo imaging and immunohistochemistry from day 3 to day 14 compared to untreated mice. Several inflammatory modulators, such as CCL9, granulocyte-macrophage colony-stimulating factor, ssoluble tumor necrosis factor receptor-I, interleukin-1α, and matrix metallopeptidase-2 were elevated in the acute phase of the disease when microglia were ablated with PLX5622, whereas other cytokines (eg, interferon-γ, interleukin-4, and interleukin-10) were reduced. Our results suggest that CSF-1R inhibition may be a novel therapeutic target in patients with neovascular age-related macular degeneration.
       
  • Glucagon Like Peptide-1 Receptor Agonism Improves Nephrotoxic Serum
           Nephritis by Inhibiting T Cell Proliferation
    • Abstract: Publication date: Available online 22 November 2019Source: The American Journal of PathologyAuthor(s): Foteini Moschovaki Filippidou, Alexander H. Kirsch, Matthias Thelen, Máté Kétszeri, Katharina Artinger, Ida Aringer, Corinna Schabhüttl, Agnes A. Mooslechner, Bianca Frauscher, Marion Pollheimer, Tobias Niedrist, Andreas Meinitzer, Daniel J. Drucker, Thomas R. Pieber, Philipp Eller, Alexander R. Rosenkranz, Akos Heinemann, Kathrin EllerGlucagon like peptide (GLP)-1 analogs such as liraglutide improved albuminuria in patients with type 2 diabetes in large randomized controlled trials. One of the suspected mechanisms is the anti-inflammatory potential of GLP-1 receptor (Glp1r) agonism. Thus, we tested the anti-inflammatory action of Glp1r-agonism in a non-diabetic, T-cell–mediated murine model of nephrotoxic serum nephritis (NTS). The role of Glp1r in NTS was evaluated by using Glp1r −/− mice or C57BL/6 mice treated with liraglutide. In vitro, murine T cells were stimulated in the presence of liraglutide or vehicle. Glp1r −/− mice displayed increased renal infiltration of neutrophils and T cells after induction of NTS. Splenocyte proliferation and TH1 cytokine transcription were increased in spleen and lymph nodes of Glp1r −/−. Liraglutide treatment significantly improved the renal outcome of NTS in C57BL/6 mice by decreasing renal infiltration and proliferation of T cells, which resulted in decreased macrophage infiltration. In vitro, T cells stimulated in the presence of liraglutide showed decreased proliferation of TH1 and TH17 cells. Liraglutide blocked glycolysis in T cells and decreased their Glut1 mRNA expression. Together, Glp1r agonism protects mice from a T-cell–dependent glomerulonephritis model by inhibition of T cell proliferation possibly by interacting with their metabolic program. This mechanism may explain in part the reno-protective effects of Glp1r agonism in diabetic nephropathy.
       
  • Next-generation sequencing reveals potential predictive biomarkers and
           targets of therapy for urothelial carcinoma in situ of the urinary bladder
           
    • Abstract: Publication date: Available online 15 November 2019Source: The American Journal of PathologyAuthor(s): Stefan Garczyk, Nadina Ortiz-Brüchle, Ursula Schneider, Isabella Lurje, Karolina Guricova, Nadine Therese Gaisa, Eva Lorsy, Katharina Lindemann-Docter, Axel Heidenreich, Ruth KnüchelAbstractBacillus Calmette-Guérin instillation following removal of the tumor is the first-line of treatment for urothelial carcinoma in situ (CIS), the precursor lesion of most muscle-invasive bladder cancers. Bacillus Calmette-Guérin therapy fails in>50% of cases and second-line radical cystectomy is associated with overtreatment and drastic lifestyle consequences. Given the need for alternative bladder-preserving therapies, we identified genomic alterations (GAs) in urothelial CIS having the potential to predict response to targeted therapies. Laser-capture microdissection was applied to isolate 30 samples (25 CIS and five muscle controls) from 26 fresh-frozen cystectomy specimens. Targeted next-generation sequencing of 31 genes was performed. The panel comprised genes frequently affected in muscle-invasive bladder cancer of non-papillary origin, focusing on potentially actionable GAs described to predict response to approved targeted therapies or drugs that are in registered clinical trials. Ninety-two percent of CIS patients harbored at least one potentially actionable GA, which were were identified in TP53/cell cycle pathway–related genes (eg, TP53, MDM2) in 72%, genes encoding chromatin-modifying proteins (eg, ARID1A, KDM6A) in 68%, DNA damage repair genes (eg, BRCA2, ATM) in 60%, and PI3K/MAPK pathway genes (eg, ERBB2, FGFR1) in 36% of the cases. These data might help guide the selection of targeted therapies to be investigated in future clinical CIS trials, and may provide a basis for future mechanistic studies of urothelial CIS pathogenesis.
       
  • Mycobacterial Trehalose 6,6’-Dimycolate Induced M1-Type Inflammation
    • Abstract: Publication date: Available online 14 November 2019Source: The American Journal of PathologyAuthor(s): Thao K.T. Nguyen, John d’Aigle, Luis Chinea, Zainab Niaz, Robert L. Hunter, Shen-An Hwang, Jeffrey K. ActorAbstractMurine models of Mycobacterium tuberculosis (Mtb) infection demonstrate progression of M1-like (pro-inflammatory) and M2-like (anti-inflammatory) macrophage morphology following primary granuloma formation. The Mtb cell wall cording factor, trehalose 6,6’-dimycolate (TDM), is a physiologically-relevant and useful molecule for modeling early macrophage-mediated events during establishment of the tuberculosis-induced granuloma pathogenesis. Here we show that TDM is a major driver of the early M1-like macrophage response as seen during initiation of the granulomas of primary pathology. Pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-12p40 are produced in lung tissue after administration of TDM to mice. Furthermore, CD11b+CD45+ macrophages with a high surface expression of the M1-like markers CD38 and CD86 were found present in regions of pathology in lungs of mice at 7 days post TDM introduction. Conversely, only low phenotypic marker expression of M2-like markers CD206 and EGR-2 were present on macrophages. These findings suggest that TDM plays a role in establishment of the M1-like shift in the microenvironment during primary tuberculosis.
       
  • Cecal tumorigenesis in AhR-deficient mice depends on cecum-specific MAPK
           pathway activation and inflammation
    • Abstract: Publication date: Available online 14 November 2019Source: The American Journal of PathologyAuthor(s): Hisanori Matoba, Masaya Takamoto, Chifumi Fujii, Masatomo Kawakubo, Eriko Kasuga, Tomio Matsumura, Tatsuya Natori, Ken Misawa, Shun’ichiro Taniguchi, Jun NakayamaAbstractThe aryl hydrocarbon receptor (AhR) is a transcription factor known as a dioxin receptor. Recently, Ahr-/- mice were revealed to develop cecal tumors with inflammation and Wnt/β-catenin pathway activation. However, whether β-catenin degradation is AhR-dependent remains unclear. To determine whether other signaling pathways function in Ahr-/- cecal tumorigenesis, we investigated histological characteristics of the tumors, cytokine/chemokine production in tumors and Ahr-/- peritoneal macrophages. AhR expression was also assessed in human colorectal carcinomas. Ten of the 28 Ahr-/- mice developed cecal lesions by 50 weeks of age, an incidence significantly lower than previously reported. Cecal lesions of Ahr-/- mice developed from serrated hyperplasia to adenoma/dysplasia-like neoplasia with enhanced proliferation. Macrophage and neutrophil infiltration into the lesions was also observed early in serrated hyperplasia, although adjacent mucosa was devoid of inflammation. Il1b, Il6, Ccl2, and Cxcl5 were up-regulated at lesion sites, while only IL-6 production increased in Ahr-/- peritoneal macrophages following LPS+ATP stimulation. Neither c-Myc up-regulation nor β-catenin nuclear translocation was observed unlike previously reported. Interestingly, enhanced phosphorylation of Erk, Src, and EGFR, and Amphiregulin up-regulation at Ahr-/- lesion sites were detected. In human serrated lesions, however, AhR expression in epithelial cells was up-regulated despite morphological similarity to Ahr-/- cecal lesions. Our results suggest novel mechanisms underlying Ahr-/- cecal tumorigenesis, depending primarily on cecum-specific MAPK pathway activation and inflammation.
       
  • Thrombospondin-1 exacerbates acute liver failure and hepatic
           encephalopathy pathology in mice by activating transforming growth factor
           beta 1
    • Abstract: Publication date: Available online 14 November 2019Source: The American Journal of PathologyAuthor(s): Brandi Jefferson, Malaika Ali, Stephanie Grant, Gabriel Frampton, Michaela Ploof, Sarah Andry, Sharon DeMorrow, Matthew McMillinAbstractSevere hepatic insults can lead to acute liver failure and the development of hepatic encephalopathy (HE). Transforming growth factor beta 1 (TGFβ1) has been demonstrated to contribute to HE from acute liver failure; however, TGFβ1 must be activated to bind its receptor and generate downstream effects. One protein that can activate TGFβ1 is thrombospondin-1 (TSP-1). Therefore, the aim of this study was to assess the role of TSP-1 in acute liver failure and HE pathogenesis. C57Bl/6 or TSP-1 knockout (TSP-1-/-) mice were injected with azoxymethane (AOM) to induce acute liver failure and HE. Liver damage, neurological decline, and molecular analyses of TSP-1 and TGFβ1 signaling were performed. AOM-treated mice had elevated TSP-1 and TGFβ1 mRNA and protein expression in the liver. TSP-1-/- mice administered AOM had reduced liver injury as assessed by histology and serum transaminases compared to C57Bl/6 AOM-treated mice. TSP-1-/- mice treated with AOM had reduced TGFβ1 signaling which was associated with less hepatic cell death as assessed by TUNEL staining and cleaved caspase 3 expression. TSP-1-/- AOM-treated mice had a reduced rate of neurological decline, less cerebral edema and a decrease in microglia activation in comparison to C57Bl/6 mice treated with AOM. Taken together, TSP-1 is an activator of TGFβ1 signaling during AOM-induced acute liver failure and contributes to both liver pathology and HE progression.
       
 
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