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Publisher: Elsevier   (Total: 3160 journals)

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Showing 1 - 200 of 3160 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 35, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 24, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 96, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 27, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 37, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 5)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 7)
Acta Astronautica     Hybrid Journal   (Followers: 421, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 28, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 2)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 10, SJR: 0.18, CiteScore: 1)
Acta Haematologica Polonica     Free   (Followers: 1, SJR: 0.128, CiteScore: 0)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 276, 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: 3, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 27, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 6, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 8)
Acute Pain     Full-text available via subscription   (Followers: 14, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 17, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 8, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 11, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 23)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 167, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 12, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 8, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 28, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 10, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, 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: 14, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 33, 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: 4)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 13)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 28, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 10, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 26, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 20, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.205, CiteScore: 1)
Advances in Dermatology     Full-text available via subscription   (Followers: 15)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 12)
Advances in Digestive Medicine     Open Access   (Followers: 9)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Drug Research     Full-text available via subscription   (Followers: 25)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 29, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 46, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 60, 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: 19, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 10, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 24, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 12, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 23)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 36, 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: 8, SJR: 0.682, CiteScore: 2)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 18, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 11, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 7, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 23)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 17, 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: 5, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 25, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 12)
Advances in Pharmacology     Full-text available via subscription   (Followers: 16, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 10)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 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: 65)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 1, 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: 6)
Advances in Space Research     Full-text available via subscription   (Followers: 403, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 12, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 34, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 18)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 14)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 48, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 359, 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: 11, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 464, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 17, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 42, 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: 57, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 6, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 11)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 10, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 10, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 52, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 6)
American Heart J.     Hybrid Journal   (Followers: 56, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 59, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 44, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 11)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 13, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 34, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 28, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 35, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 48)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 225, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 66, 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: 28, 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: 38, 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: 63, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 19, 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: 5, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 43, SJR: 1.512, CiteScore: 5)
Analytical Biochemistry     Hybrid Journal   (Followers: 188, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 12, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 13)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 23, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)
Animal Behaviour     Hybrid Journal   (Followers: 204, SJR: 1.58, CiteScore: 3)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 0.937, CiteScore: 2)
Animal Reproduction Science     Hybrid Journal   (Followers: 7, SJR: 0.704, CiteScore: 2)

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Journal Cover
American Journal of Pathology
Journal Prestige (SJR): 2.139
Citation Impact (citeScore): 4
Number of Followers: 28  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0002-9440
Published by Elsevier Homepage  [3160 journals]
  • This Month in AJP
    • Abstract: Publication date: Available online 19 March 2019Source: The American Journal of PathologyAuthor(s): Chhavi Chauhan
       
  • Immediate Release of Gastrin-Releasing Peptide Mediates, Delayed
           Radiation-Induced Pulmonary Fibrosis
    • Abstract: Publication date: Available online 18 March 2019Source: The American Journal of PathologyAuthor(s): Robert M. Tighe, Karissa Heck, Erik Soderblom, Shutang Zhou, Anastasiya Birukova, Kenneth Young, Douglas Rouse, Jessica Vidas, Miglena K. Komforti, Christopher B. Toomey, Frank Cuttitta, Mary E. Sunday Radiation-induced pulmonary fibrosis is a progressive, serious condition in many subjects treated for thoracic malignancies or following accidental nuclear exposure. No biomarker exists for identifying the irradiated subjects most susceptible to pulmonary fibrosis. Previously, we determined that gastrin-releasing peptide (GRP) was elevated within days after birth in newborns exposed to hyperoxia that later developed chronic lung disease. The goal of the current study was to test whether radiation exposure triggers GRP release in mice and whether this contributes to RT-induced pulmonary fibrosis in vivo. We determined urine GRP levels and lung GRP immunostaining in mice 0-24 hours post-thoracic radiation (15 Gy). Urine GRP levels were significantly elevated between 24 hours post-radiation; GRP-blocking MoAb 2A11 given minutes post-radiation abrogated urine GRP levels by 6-12 hours and also altered phosphoprotein signaling pathways at 24 hours post-radiation. Strong extracellular GRP immunostaining was observed in lung at 6 hours post-radiation. Mice given one dose of GRP MoAb 2A11 24 hours post-radiation had significantly reduced myofibroblast accumulation and collagen deposition 15 weeks later, indicating protection against lung fibrosis. Therefore, elevation of urine GRP could be predictive of radiation-induced pulmonary fibrosis development. Additionally, transient GRP-blockade could mitigate pulmonary fibrosis in normal lung following therapeutic or accidental radiation exposure.
       
  • Vascular Endothelial Growth Factor–D (VEGF-D) Overexpression and
           Lymphatic Expansion in Murine Adipose Tissue Improves Metabolism in
           Obesity
    • Abstract: Publication date: Available online 13 March 2019Source: The American Journal of PathologyAuthor(s): Adri Chakraborty, Sheridan Barajas, Gabriela M. Lammoglia, Andrea J. Reyna, Thomas S. Morley, Joshua A. Johnson, Philipp E. Scherer, Joseph M. RutkowskiObese adipose tissue expansion is an inflammatory process that results in dysregulated lipolysis, increased circulating lipids, ectopic lipid deposition, and systemic insulin resistance. Lymphatic vessels provide a route of fluid, macromolecule, and immune cell clearance, and lymphangiogenesis increases this capability. Indeed, inflammation-associated lymphangiogenesis is critical in resolving acute and chronic inflammation, but it is largely absent in obese adipose tissue. Enhancing adipose tissue lymphangiogenesis could, therefore, improve metabolism in obesity. To test this hypothesis, transgenic mice with doxycycline-inducible expression of murine vascular endothelial growth factor (VEGF)-D under a tightly controlled Tet-On promoter were crossed with adipocyte-specific adiponectin–reverse tetracycline–dependent transactivator mice (Adipo-VD) to stimulate adipose tissue–specific lymphangiogenesis during 16-week high-fat diet–induced obesity. Adipose VEGF-D overexpression induced de novo lymphangiogenesis in murine adipose tissue, and obese Adipo-VD mice exhibited enhanced glucose clearance, lower insulin levels, and reduced liver triglycerides. On β-3 adrenergic stimulation, Adipo-VD mice exhibited more rapid and increased glycerol flux from adipose tissue, suggesting that the lymphatics are a potential route of glycerol clearance. Resident macrophage crown-like structures were scarce and total F4/80+ macrophages were reduced in obese Adipo-VD s.c. adipose tissue with evidence of increased immune trafficking from the tissue. Augmenting VEGF-D signaling and lymphangiogenesis specifically in adipose tissue, therefore, reduces obesity-associated immune accumulation and improves metabolic responsiveness.
       
  • MRPL35 is up-regulated in colorectal cancer and regulates colorectal
           cancer cell growth and apoptosis
    • Abstract: Publication date: Available online 9 March 2019Source: The American Journal of PathologyAuthor(s): Litao Zhang, Peifen Lu, Lihong Yan, Lijun Yang, Yutao Wang, Junjun Chen, Jie Dai, Yahui Li, Zhiming Kang, Tao Bai, Yanfeng Xi, Jun Xu, Gongqin Sun, Tao Yang Mitochondrial ribosome proteins (MRPs), which are encoded by the nuclear genomic DNA, are important for mitochondrial-encoded protein synthesis and mitochondrial function. Emerging evidence suggests that several MRPs also exhibit important extra-mitochondrial functions, such as involvement in apoptosis, protein biosynthesis, and signal transduction. In this study, we demonstrate a significant role of mitochondrial ribosomal protein L35 in colorectal cancer (CRC). The expression of MRPL35 was higher in CRC tissues than in matched cancer-adjacent tissues and higher in CRC cells than in normal mucosal epithelial cells. Higher MRPL35 expression in CRC tissue correlated with shorter overall survival for CRC patients. In vitro, down-regulation of MRPL35 led to increased production of reactive oxygen species (ROS) together with DNA damage, loss of cell proliferation, G2/M arrest, a decrease in mitochondrial membrane potential, apoptosis, and autophagy induction. MRPL35 knockdown inhibited tumor proliferation in a CRC xenograft nude mouse model. Furthermore, overexpression of MRPL35 or treatment of cells with the ROS scavenger, N-acetyl cysteine (NAC), abrogated ROS production, cell cycle arrest, and apoptosis in vitro. These findings suggest that MRPL35 plays an essential role in the development of CRC and may be a potential therapeutic target for CRC.
       
  • Reviewer Acknowledgment
    • Abstract: Publication date: March 2019Source: The American Journal of Pathology, Volume 189, Issue 3Author(s):
       
  • Mammalian Target of Rapamycin: A Metabolic Rheostat for Regulating Adipose
           Tissue Function and Cardiovascular Health
    • Abstract: Publication date: March 2019Source: The American Journal of Pathology, Volume 189, Issue 3Author(s): Matthew F. Wipperman, David C. Montrose, Antonio M. Gotto, David P. HajjarThe complex relationship between diet and metabolism is an important contributor to cellular metabolism and health. Over the past few decades, a central role for mammalian target of rapamycin (mTOR) in the regulation of multiple cellular processes, including the response to food intake, maintaining homeostasis, and the pathogenesis of disease, has been shown. Herein, we first review our current understanding of the biochemical functions of mTOR and its response to fluctuations in hormone levels, like insulin. Second, we highlight the role of mTOR in lipogenesis, adipogenesis, β-oxidation of lipids, and ketosis of carbohydrates, lipids, and proteins. Special attention is paid to recent advances in mTOR signaling in white versus brown adipose tissues. Finally, we review how mTOR regulates cardiovascular health and disease. Together, these insights define a clearer picture of the connection between mTOR signaling, metabolic health, and disease.
       
  • Correction
    • Abstract: Publication date: March 2019Source: The American Journal of Pathology, Volume 189, Issue 3Author(s):
       
  • TEA domain transcription factor 4 (TEAD4) is the major mediator of Yap
           oncogenic activity in mouse and human hepatoblastoma
    • Abstract: Publication date: Available online 19 February 2019Source: The American Journal of PathologyAuthor(s): Jie Zhang, Pin Liu, Junyan Tao, Pan Wang, Yi Zhang, Xinhua Song, Li Che, Pavel Sumazin, Silvia Ribback, Andras Kiss, Zsuzsa Schaff, Antonio Cigliano, Frank Dombrowski, Carla Cossu, Rosa M. Pascale, Diego F. Calvisi, Satdarshan P. Monga, Xin Chen Hepatoblastoma (HB) is the most common type of pediatric liver cancer. Activation of Yes-associated protein (YAP) has been implicated in HB molecular pathogenesis. The transcriptional co-activator Yap regulates downstream gene expression through interaction with the TEA domain (TEAD) proteins. Nonetheless, YAP also displays functions that are independent of its transcriptional activity. The underlying molecular mechanisms by which Yap promotes HB development remain elusive. In the current study, we demonstrated that blocking TEAD function via the dominant negative form of TEAD2 (dnTEAD2) abolishes Yap-driven HB formation in mice and restrains human HB growth in vitro. When TEAD2 DNA binding domain was fused with VP16 transcriptional activation domain (TEAD2VP16), it synergized with activated β-catenin (ΔN90-β-catenin) to promote HB formation in vivo. Among TEAD genes, silencing of TEAD4 consistently inhibited tumor growth and Yap target gene expression in HB cell lines. Furthermore, TEAD4 mRNA expression was significantly higher in human HB lesions when compared with corresponding non-tumorous liver tissues. Human HB specimens also exhibited strong nuclear immunoreactivity for TEAD4. Altogether, data demonstrate that TEAD-mediated transcriptional activity is both sufficient and necessary for Yap-driven HB development. TEAD4 is the major TEAD isoform and Yap partner in human HB. Targeting TEAD4 may represent an effective treatment option for human HB.
       
  • Epidermis Activated Gsdma3 Enhances Thermogenesis of Brown Adipose Tissue
           through Interleukin-6/Stat3 Signaling
    • Abstract: Publication date: Available online 19 February 2019Source: The American Journal of PathologyAuthor(s): Qin Chen, Peiliang Shi, Dingyu Wang, Qiyao Liu, Xu Li, Yufang Wang, Dayuan Zou, Zan Huang, Xiang Gao, Zhaoyu LinMissense mutations in the Gasdermin-A3 (Gsdma3) gene are associated with skin inflammation and hair loss in mice. However, the physiological function of Gsdma3 remains unclear. Here we reported that mice carrying the Gsdma3 Y344H mutation that encodes a presumptive activated form of Gsdma3, show increased heat production along with lower body fat percentages. Detailed analysis indicated that this metabolic phenotype is mediated by serum interleukin-6–induced up-regulation of thermogenesis in brown adipose tissue. The mutant form of Gsdma3 promotes the expression of interleukin-6 in the epidermis in a JNK signaling–dependent manner. The higher whole-body heat production in AE mice (alopecia and excoriation) could be suppressed by an interleukin-6 receptor/GP130 inhibitor. Our results uncovered Gsdma3/interleukin-6–dependent cross-talk between the skin and brown adipose tissue.
       
  • Genetic strain and sex differences in a hyperoxia-induced mouse model of
           varying severity of bronchopulmonary dysplasia
    • Abstract: Publication date: Available online 19 February 2019Source: The American Journal of PathologyAuthor(s): Sean Leary, Pragnya Das, Devasena Ponnalagu, Harpreet Singh, Vineet BhandariBronchopulmonary dysplasia (BPD) is a disease prevalent in preterm babies with a need for supplemental oxygen resulting in impaired lung development and dysregulated vascularization. Epidemiological studies have shown that males are more prone to BPD and have a delayed recovery compared to females for reasons unknown. Here, we tried to recapitulate mild, moderate, and severe BPD, using two different strains of mice: CD1 (outbred) and C57BL/6 (inbred), in males and females. Aside from higher body weight in the CD1 strain, there were no other gross morphological differences with respect to alveolar development between the two strains. With respect to lung morphology after oxygen exposure, females had less injury with better preservation of alveolar chord length and decreased alveolar protein leak and inflammatory cells in the bronchoalveolar lavage fluid. In addition, housekeeping genes, which are routinely used as loading controls, were expressed differently in males and females. In the BPD mouse model, gonadotropin-releasing hormone was increased in females as compared to males. Specific microRNAs (miR146 and miR34a) were expressed differently in the sexes. In the severe BPD mouse model, administering miR146-mimic to males attenuated lung damage while administering miR-146 inhibitor to females increased pulmonary injury.
       
  • Intrinsic Bone Defects in Cystinotic Mice
    • Abstract: Publication date: Available online 19 February 2019Source: The American Journal of PathologyAuthor(s): Giulia Battafarano, Michela Rossi, Laura Rita Rega, Gianna Di Giovamberardino, Anna Pastore, Matteo D'Agostini, Ottavia Porzio, Nathalie Nevo, Francesco Emma, Anna Taranta, Andrea Del FattoreCystinosis is a rare lysosomal storage disorder caused by loss of function mutations of the CTNS gene, encoding cystinosin, a symporter that mediates cystine efflux from lysosomes. About 95% of patients with cystinosis display renal Fanconi syndrome, short stature, osteopenia, and rickets . In this study, we investigated whether the absence of cystinosin primarily affects bone remodeling activity, apart from the influences of the Fanconi syndrome on bone mineral metabolism. Using micro-computed tomography, histomorphometric and bone serum biomarkers analysis, we evaluated the bone phenotype of one-month–old ctns-/- (KO) male mice without tubulopathy. In vitro study was performed to characterize the effects of cystinosin deficiency on osteoblasts and osteoclasts. Micro-computed tomography analysis showed a reduction of trabecular bone volume, bone mineral density, number and thickness in KO mice compared to wild-type animals; histomorphometric analysis revealed a reduction of osteoblast and osteoclast parameters in tibias of cystinotic mice. Decreased levels of serum P1NP and TRAcP in KO mice confirmed reduced bone remodeling activity. In vitro experiments showed an impairment of ctns-/- osteoblasts and osteoclasts. In conclusion, cystinosin deficiency primarily affects bone cells, leading to a bone loss phenotype of KO mice, independent from renal failure.
       
  • β-Catenin and yes-associated protein 1 cooperate in hepatoblastoma
           pathogenesis
    • Abstract: Publication date: Available online 19 February 2019Source: The American Journal of PathologyAuthor(s): Qian Min, Laura Molina, Jing Li, Adeola O. Adebayo Michael, Jacquelyn O. Russell, Morgan E. Preziosi, Sucha Singh, Minakshi Poddar, Madlen Matz-Soja, Sarangarajan Ranganathan, Aaron W. Bell, Rolf Gebhardt, Frank Gaunitz, Jinming Yu, Junyan Tao, Satdarshan P. Monga Hepatoblastoma (HB), the most common pediatric primary liver neoplasm, show nuclear localization of β-catenin and yes-associated protein1 (YAP1) in almost 80% of the cases. Co-expression of constitutively active S127A-YAP1 and ΔN90 deletion-mutant-β-catenin (YAP1-ΔN90-β-catenin) causes HB in mice. Since heterogeneity in downstream signaling is being identified owing to mutational differences even in β-catenin gene alone, we investigated if co-expression of point-mutants of β-catenin (S33Y or S45Y) with S127A-YAP1 led to similar tumors as YAP1-ΔN90-β-catenin. Co-expression of S33Y/S45Y-β-catenin and S127A-YAP1 led to activation of Yap and Wnt signaling and development of HB with 100% mortality by 13 to 14 weeks. Co-expression with YAP1-S45Y/S33Y-β-catenin of the dominant-negative (dn) TCF4 or dnTEAD2, the respective surrogate transcription factors, prevented HB development. Although histologically similar, HB in YAP1-S45Y/S33Y-β-catenin, unlike YAP1-ΔN90-β-catenin HB were glutamine synthetase (GS)-positive. However, both ΔN90-β-catenin and point-mutant-β-catenin comparably induced GS-luciferase reporter in vitro. Finally, using a previously reported 16-gene signature, it was shown that YAP1-ΔN90-β-catenin HB tumors exhibit genetic similarities with more proliferative, less differentiated, GS-negative HB patient tumors, whereas YAP1-S33Y/S45Y-β-catenin HB exhibit heterogeneity and clustered with both well-differentiated GS-positive and proliferative GS-negative patient tumors. Thus, we demonstrate that β-catenin point mutants can also collaborate with YAP1 in HB development, albeit with distinct molecular profile from the deletion mutant, which may have implications in both biology and therapy.
       
  • Identification of CCDC180 and LRRC4 as Potential Immunohistochemical
           Markers for Liposarcoma Based on Proteomic Analysis Using Formalin-Fixed,
           Paraffin-Embedded Tissue
    • Abstract: Publication date: Available online 18 February 2019Source: The American Journal of PathologyAuthor(s): Tomoyuki Aoyama, Akira Takasawa, Kumi Takasawa, Yusuke Ono, Makoto Emori, Masaki Murata, Takahiro Hayasaka, Naoki Fujitani, Makoto Osanai, Toshihiko Yamashita, Tadashi Hasegawa, Norimasa SawadaRecent technical improvements in both mass spectrometry and protein extraction have made it possible to use formalin-fixed, paraffin-embedded (FFPE) tissues for proteome analysis. In this study, comparable proteome analysis of FFPE tissues revealed multiple candidate marker molecules for differentiating atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) from lipoma. One-hundred and eighty-one unique proteins were identified for ALT/WDL. Of the identified proteins, coiled-coil domain-containing protein 180 (CCDC180) and leucine-rich repeat-containing protein 4 (LRRC4) were studied as candidate markers of ALT/WDL. CCDC180 and LRRC4 immunohistochemistry clearly stained tumor cells of ALT/WDL and dedifferentiated liposarcoma and could differentiate them from lipoma with high accuracy. Cell biological methods were used to further examine the expression of the candidate marker molecules in liposarcoma cells. In liposarcoma cells, knockdown of CCDC180 and LRRC4 inhibited cell proliferation. CCDC180 inhibited cell migration, invasion, and apoptosis resistance in WDL cells. Adipogenic differentiation suppressed the expression of CCDC180 and LRRC4 in WDL cells. These results indicated that LRRC4 and CCDC180 are novel immunohistochemical markers for differentiating ALT/WDLS. Their expression was associated with adipocyte differentiation and contributed to malignant potentials of WDL cells. Proteome analysis using a standard stock of FFPE tissues can reveal novel biomarkers for various diseases, which contributes to the progress of molecular pathology.
       
  • This Month in AJP
    • Abstract: Publication date: Available online 13 February 2019Source: The American Journal of PathologyAuthor(s): Chhavi Chauhan
       
  • Integrated Fourier Transform Infrared Imaging and Proteomics for
           Identification of a Candidate Histochemical Biomarker in Bladder Cancer
    • Abstract: Publication date: Available online 12 February 2019Source: The American Journal of PathologyAuthor(s): Kathrin E. Witzke, Frederik Großerueschkamp, Hendrik Jütte, Melanie Horn, Florian Roghmann, Nicolas von Landenberg, Thilo Bracht, Angela Kallenbach-Thieltges, Heiko Käfferlein, Thomas Brüning, Karin Schork, Martin Eisenacher, Katrin Marcus, Joachim Noldus, Andrea Tannapfel, Barbara Sitek, Klaus GerwertHistopathological differentiation between severe urocystitis with reactive urothelial atypia and carcinoma in situ (CIS) can be difficult, particularly after a treatment that deliberately induces an inflammatory reaction, such as intravesical instillation of Bacillus Calmette-Guèrin. However, precise grading in bladder cancer is critical for therapeutic decision making and thus requires reliable immunohistochemical biomarkers. Herein, an exemplary potential biomarker in bladder cancer was identified by the novel approach of Fourier transform infrared imaging for label-free tissue annotation of tissue thin sections. Identified regions of interest are collected by laser microdissection to provide homogeneous samples for liquid chromatography–tandem mass spectrometry–based proteomic analysis. This approach afforded label-free spatial classification with a high accuracy and without interobserver variability, along with the molecular resolution of the proteomic analysis. Cystitis and invasive high-grade urothelial carcinoma samples were analyzed. Three candidate biomarkers were identified and verified by immunohistochemistry in a small cohort, including low-grade urothelial carcinoma samples. The best-performing candidate AHNAK2 was further evaluated in a much larger independent verification cohort that also included CIS samples. Reactive urothelial atypia and CIS were distinguishable on the basis of the expression of this newly identified and verified immunohistochemical biomarker, with a sensitivity of 97% and a specificity of 69%. AHNAK2 can differentiate between reactive urothelial atypia in the setting of an acute or chronic cystitis and nonmuscle invasive-type CIS.
       
  • Macrophage-Mediated Phagocytosis and Dissolution of Amyloid-Like Fibrils
           in Mice, Monitored by Optical Imaging
    • Abstract: Publication date: Available online 6 February 2019Source: The American Journal of PathologyAuthor(s): Tina Richey, James S. Foster, Angela D. Williams, Anna Bryn Williams, Alexa Stroh, Sallie Macy, Craig Wooliver, R. Eric Heidel, Siva Karthik Varanasi, Elizabeth N. Ergen, Dianne J. Trent, Stephen A. Kania, Stephen J. Kennel, Emily B. Martin, Jonathan S. WallLight chain–associated amyloidosis is characterized by the extracellular deposition of amyloid fibrils in abdominothoracic organs, skin, soft tissue, and peripheral nerves. Phagocytic cells of the innate immune system appear to be ineffective at clearing the material; however, human light chain amyloid extract, injected subcutaneously into mice, is rapidly cleared in a process that requires neutrophil activity. To better elucidate the phagocytosis of light chain fibrils, a potential method of cell-mediated dissolution, amyloid-like fibrils were labeled with the pH-sensitive dye pHrodo red and a near infrared fluorophore. After injecting this material subcutaneously in mice, optical imaging was used to quantitatively monitor phagocytosis and dissolution of fibrils concurrently. Histological evaluation of the residual fibril masses revealed the presence of CD68+, F4/80+, Iba-1- macrophages containing Congo red–stained fibrils as well as neutrophil-associated proteins with no evidence of intact neutrophils. These data suggest an early infiltration of neutrophils followed by extensive phagocytosis of the light chain fibrils by macrophages leading to dissolution of the mass. Optical imaging of this novel murine model, coupled with histological evaluation can be used to study the cellular mechanisms underlying dissolution of synthetic amyloid-like fibrils and human amyloid extracts. In addition, it may serve as a test bed to evaluate investigational opsonizing agents that might serve as therapeutic agents for light chain–associated amyloidosis.
       
  • MBD2 inhibits the malignant characteristic of lung adenocarcinoma through
           the epigenetic modulation of TET1 and mir-200s
    • Abstract: Publication date: Available online 5 February 2019Source: The American Journal of PathologyAuthor(s): Yao-fei Pei, Xiang-nan Xu, Zhi-fei Wang, Fu-wei Wang, Wei-ding Wu, Jun-feng Geng, Xi-qiang Liu It has been reported that disorders of epigenetic modulation play a critical role in carcinogenesis. MBD2 is known to act as an epigenetic modulator in various types of tumors; however, the role of MBD2 in lung adenocarcinoma (LUAD) remains unclear. Here, we demonstrated the down-regulation of MBD2 in LUAD compared with adjacent nontumor tissues. The down-regulation of MBD2 in LUAD was correlated with metastasis and poor survival. Additionally, MBD2 inhibited tumor metastasis by maintaining the expression of the mir-200s, which suppressed the invasive properties of tumors. Also, MBD2 positively correlated with 5-hmC content in mir-200s promoter. The conventional view is that MBD2 acts as a transcriptional suppressor. However, the data revealed that MBD2 may act as transcriptional activator by recruiting TET1 and forming a chromatin-remodeling complex. The MBD2-TET1 complex locates to the TET1 promoter and removes the methyl residues in this region, thereby activating TET1 transcription. TET1 also acted as tumor suppressor in LUAD. Taken together, the data demonstrate the correlation between MBD2, mir-200s, and TET1, and tumor suppressive effect of MBD2 through up-regulation of TET1 and the mir-200s.
       
  • Complement Factor H Mutation W1206R Causes Retinal Thrombosis and Ischemic
           Retinopathy in Mice
    • Abstract: Publication date: Available online 1 February 2019Source: The American Journal of PathologyAuthor(s): Delu Song, Yoshiyasu Ueda, Rupak Bhuyan, Imran Mohammed, Takashi Miwa, Damodar Gullipali, Hangsoo Kim, Lin Zhou, Ying Song, Hannah Schultz, Albert Bargoud, Joshua L. Dunaief, Wen-Chao SongSingle nucleotide polymorphisms and rare mutations in Factor H (FH; official name CFH) are associated with age-related macular degeneration and atypical hemolytic uremic syndrome, a form of thrombotic microangiopathy. Mice with the FH W1206R mutation (FHR/R) share features with human atypical hemolytic uremic syndrome. Here, we report that FHR/R mice exhibited retinal vascular occlusion and ischemia. Retinal fluorescein angiography demonstrated delayed perfusion and vascular leakage in FHR/R mice. Optical coherence tomography imaging of FHR/R mice showed retinal degeneration, edema, and detachment. Histological analysis of FHR/R mice revealed retinal thinning, vessel occlusion, as well as degeneration of photoreceptors and retinal pigment epithelium. Immunofluorescence showed albumin leakage from blood vessels into the neural retina and electron microscopy demonstrated vascular endothelial cell irregularity with narrowing of retinal and choroidal vessels. Knockout of C6, a component of the membrane attack complex, prevented the aforementioned retinal phenotype in FHR/R mice, consistent with membrane attack complex –mediated pathogenesis. Pharmacologic blockade of C5 also rescued retinas of FHR/R mice. This FHR/R mouse strain represents a model for retinal vascular occlusive disorders and ischemic retinopathy. The results suggest complement dysregulation can contribute to retinal vascular occlusion and that an anti-C5 antibody might be helpful for C5-mediated thrombotic retinal diseases.
       
  • Lipopolysaccharide-Induced Increase in Intestinal Permeability Is Mediated
           by TAK-1 Activation of IKK and MLCK/MYLK Gene
    • Abstract: Publication date: Available online 1 February 2019Source: The American Journal of PathologyAuthor(s): Meghali Nighot, Manmeet Rawat, Rana-Al Sadi, Eliseo F. Castillo, Prashant Nighot, Thomas MaLipopolysaccharides (LPS) are a major component of Gram-negative bacterial cell wall and play an important role in promoting intestinal inflammatory responses. Our recent studies have shown that physiologically relevant concentrations of LPS (0 to 2,000 pg/mL) cause an increase in intestinal epithelial tight junction (TJ) permeability without causing cell death. However, the intracellular pathways and the mechanisms that mediate LPS-induced increase in intestinal TJ permeability remain unclear. Our aim was to delineate the intracellular pathways that mediate the LPS-induced increase in intestinal permeability using in vitro and in vivo intestinal epithelial models. LPS-induced increase in intestinal epithelial TJ permeability was preceded by an activation of transforming growth factor-β activating kinase-1 (TAK-1) and canonical NF-κB (p50/p65) pathways. The siRNA silencing of TAK-1 inhibited the activation of NF-κB p50/p65. The siRNA silencing of TAK-1 and p65/p50 subunit inhibited the LPS- induced increase in intestinal TJ permeability and the increase in MLCK expression, confirming the regulatory role of TAK-1 and NF-κB p65/p50 in up-regulating MLCK expression and the subsequent increase in TJ permeability. The data also showed that TLR-4/MyD88 pathway was crucial upstream regulator of TAK-1 and NF-κB p50/p65 activation. In conclusion, activation of TAK-1 by the TLR-4/MyD88 signal transduction pathway and MLCK by NF-κB p65/p50 regulates the LPS-induced increase in intestinal epithelial TJ permeability.
       
  • Semaphorin 3E inhibits house dust mite–induced angiogenesis in a mouse
           model of allergic asthma
    • Abstract: Publication date: Available online 31 January 2019Source: The American Journal of PathologyAuthor(s): Nazanin Tatari, Hesam Movassagh, Lianyu Shan, Latifa Koussih, Abdelilah S. Gounni Increased angiogenesis is a characteristic feature of remodeling in asthmatic airways which stems from the imbalance between pro-angiogenic and anti-angiogenic factors. Surprisingly, the factors regulating this process in allergic asthma are poorly defined. Previously, we showed an important role of semaphorins 3E (Sema3E) in growth factor–induced airway smooth muscle proliferation and migration in vitro, and in down-regulating airway inflammation, Th2/Th17 cytokine response, mucus cell hyperplasia, and airway hyperresponsiveness in vivo. However, the role of Sema3E in airway angiogenesis is not fully understood. Here, we investigated the role of Sema3E in airway angiogenesis using a house dust mite (HDM) murine model of allergic asthma. Intranasal treatment with recombinant Sema3E significantly reduced expression of angiogenesis markers within the airways of HDM-challenged mice compared to untreated mice. HDM-induced expression of VEGF and VEGFR2 protein were substantially diminished upon Sema3E treatment. Interestingly, Sema3E-treated mice displayed an enhanced expression of the negative regulator of angiogenesis, soluble VEGFR1, compared to the untreated mice. These events were reversed in Sema3E-deficient mice at the baseline or upon HDM challenge. Taken together, this study provides the first evidence that Sema3E modulates angiogenesis in allergic asthmatic airways via modulating pro- and anti-angiogenic factors.
       
  • NF-κB and GATA-6 Repress Transcription of Caveolins in Bladder Smooth
           Muscle Hypertrophy
    • Abstract: Publication date: Available online 30 January 2019Source: The American Journal of PathologyAuthor(s): Chellappagounder Thangavel, Cristiano Mendes Gomes, Stephen A. Zderic, Elham Javed, Sankar Addya, Jagmohan Singh, Sreya Das, Ruth Birbe, Robert B. Den, Satish Rattan, Deepak A. Deshpande, Raymond B. Penn, Samuel Chacko, Ettickan BoopathiCaveolins (CAV) are structural proteins of caveolae that function as signaling platforms to regulate smooth muscle contraction. Loss of CAV proteins expression is associated with impaired contraction in obstruction-induced bladder smooth muscle (BSM) hypertrophy. In this study, microarray analysis of bladder RNA revealed down-regulation of CAV1, CAV2, and CAV3 gene transcription in BSM from models of obstructive bladder disease in mice and humans. We identified and characterized regulatory regions responsible for CAV1, CAV2, and CAV3 gene expression in mice with obstruction-induced BSM hypertrophy, and in men with benign prostatic hyperplasia. DNA affinity chromatography and ChIP assays revealed a greater increase in binding of GATA-6 and NF-κB to their cognate binding motifs on CAV1, CAV2, and CAV3 promoters in obstructed BSM relative to that observed in control BSM. Knockout of NF-κB subunits or shRNA-mediated knockdown of GATA-6 or pharmacological inhibition of GATA-6 and NF-κB in BSM increased CAV1, CAV2, and CAV3 transcription and promoter activity. Conversely, overexpression of GATA-6 decreased CAV2 and CAV3 transcription and promoter activity. Collectively, these data provide new insight into the mechanisms by which CAV gene expression is repressed in hypertrophied BSM in obstructive bladder disease.
       
  • Near-comprehensive resequencing of cancer-associated genes in surgically
           resected metastatic liver tumors of gastric cancer
    • Abstract: Publication date: Available online 29 January 2019Source: The American Journal of PathologyAuthor(s): Naoki Ikari, Akiko Serizawa, Shohei Mitani, Masakazu Yamamoto, Toru Furukawa Liver metastasis is a major cause of death in patients with gastric cancer. We evaluated molecular alterations in clinically resected liver metastases of gastric cancer to identify candidate biomarkers and therapeutic targets. Seventy-four patients, including 37 with liver metastasis that underwent gastrectomy and hepatectomy for gastric cancer and 37 without liver metastasis that underwent gastrectomy for gastric cancer, were studied. Next-generation resequencing was performed for 412 cancer-associated genes in metastatic and/or primary tumors from 30 patients and somatic mutations in TP53, LRP1B, PIK3CA, ADAMTS20, PAX7, FN1, FOXO3, WRN, PTEN, ETV4, and RNF213 were found in metastatic tumors. TP53 mutations were studied by Sanger sequencing in remaining patients; the number of patients with TP53 mutations in metastatic tumors was significantly higher among those with liver metastasis (86.5%, 32/37) versus those without liver metastasis (40.5%; 15/37) (P < 0.0001). TP53 mutations in metastatic liver tumors and corresponding primary tumors were identical in 96.9% (31/32), including some patients with heterogeneous primary tumor components. Immunohistochemical analyses showed aberrant p53 expression in tumors with TP53 mutations. In silico functional evaluations indicated functional loss of missense-mutated TP53. Thus, p53 pathway may facilitate the development of biomarkers and therapeutic approaches to treat gastric cancer metastases to the liver.
       
  • High miR-182 Levels Associate with Low-Risk Prostate Cancer
    • Abstract: Publication date: Available online 29 January 2019Source: The American Journal of PathologyAuthor(s): Bethany Baumann, Andrés Martin Acosta, Zachary Richards, Ryan Deaton, Anastasiya Sapatynska, Adam Murphy, Andre Kajdacsy-Balla, Peter H. Gann, Larisa NonnA subset of men with prostate cancer develops aggressive disease. We sought to determine if miR-182, a microRNA with reported oncogenic functions in prostate, associates with biochemical recurrence and aggressive disease. Prostate epithelial miR-182 expression was quantified via in situ hybridization of two prostate tissue microarrays and by laser-capture microdissection of prostate epithelium. MiR-182 was significantly higher in cancer epithelium than adjacent benign epithelium (P < 0.0001). The ratio of cancer to benign miR-182 expression per patient was inversely associated with recurrence in a multivariate logistic regression model (OR=0.18 (95% CI: 0.03 to 0.89), P = 0.044). Correlation of miR-182 with mRNA expression in laser-capture microdissected benign prostate epithelium was used to predict prostatic miR-182 targets. Genes that negatively correlated with miR-182 were enriched for its predicted targets and genes previously identified as up-regulated in prostate cancer metastases. miR-182 expression also negatively correlated with genes previously identified as up-regulated in primary prostate tumors from African-American patients, who are at an increased risk of developing aggressive prostate cancer. Taken together, these results suggest that although miR-182 is expressed at higher levels in localized prostate cancer, its levels are lower in aggressive cancers, suggesting a biphasic role for this microRNA that may be exploited for prognostic and/or therapeutic purposes to reduce prostate cancer progression.
       
  • Correction
    • Abstract: Publication date: February 2019Source: The American Journal of Pathology, Volume 189, Issue 2Author(s):
       
  • A Link between the Gut and Bone: Bone Health Impacted by Changes in Gut
           Microbiota
    • Abstract: Publication date: February 2019Source: The American Journal of Pathology, Volume 189, Issue 2Author(s): Larry J. Suva
       
  • Potential Biomarkers for Primary Open-Angle Glaucoma Identified by Long
           Noncoding RNA Profiling in the Aqueous Humor
    • Abstract: Publication date: Available online 22 January 2019Source: The American Journal of PathologyAuthor(s): Lili Xie, Mao Mao, Cong Wang, Lusi Zhang, Zheng Pan, Jingming Shi, Xuanchu Duan, Songbo Jia, Bing JiangThis study aimed to identify potential biomarkers for primary open-angle glaucoma (POAG) diagnosis. First, lncRNA and message RNA (mRNA) expression profiles in the aqueous humor (AH) from 10 POAG and 10 control patients were accessed by microarray analyses. Moreover, coding–non-coding gene co-expression networks were drawn to predict potential lncRNA functions. LncRNAs-T267384, ENST00000607393, and T342877 expression were further tested by quantitative real-time PCR in AH from 29 POAG and 30 cataract patients, in iris tissues from 16 POAG patients and 10 controls, and in plasma from 49 POAG patients and 55 healthy controls. Finally, ENST00000607393 function was characterized in an in vitro model of cell calcification. Three-thousand six-hundred and twenty-seven lncRNAs and 2,228 mRNAs in the AH of POAG patients were significantly up-regulated and 1,520 lncRNAs and 820 mRNAs were significantly down-regulated. Seven lncRNAs showed positive correlation with glaucoma associated gene, bone morphogenetic protein 2. Moreover, RT-qPCR confirmed that T267384, ENST00000607393, and T342877 expression were significantly higher in the AH from a different cohort of POAG patients. In addition, ENST00000607393 was also significantly higher in the iris and plasma of POAG patients. Last, ENST00000607393 knockdown alleviated calcification of primary human trabecular meshwork cells in vitro. Therefore, lncRNA-T267384, ENST00000607393, and T342877 may be potential biomarkers for POAG diagnosis. ENST00000607393 might be a new therapeutic target for trabecular meshwork calcification.
       
  • The formation and disordered degradation of neutrophil extracellular traps
           in necrotizing lesions of anti-neutrophil cytoplasmic
           antibody–associated vasculitis
    • Abstract: Publication date: Available online 21 January 2019Source: The American Journal of PathologyAuthor(s): Sakiko Masuda, Mayu Nonokawa, Emika Futamata, Yuka Nishibata, Sari Iwasaki, Takahiro Tsuji, Yutaka Hatanaka, Daigo Nakazawa, Satoshi Tanaka, Utano Tomaru, Tamihiro Kawakami, Tatsuya Atsumi, Akihiro Ishizu Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by the production of ANCAs and systemic necrotizing vasculitis in small vessels. Disordered regulation of neutrophil extracellular traps (NETs) is critically involved in the pathogenesis of AAV. NETs are web-like DNA decorated with antimicrobial proteins; they are extruded from activated neutrophils. The principal degradation factor of NETs in vivo is DNase I; however, NETs resistant to DNase I can persist in tissues and lead to the production of ANCAs. Deposition of NETs has been demonstrated in glomerular crescents and necrotizing vasculitis in AAV. Here, the amount of NETs in formalin-fixed, paraffin-embedded tissue sections were examined and the results for AAV were compared with the results for diseases that should be distinguished from AAV. NETs were more abundant in necrotizing vasculitis of AAV than in non-ANCA-associated vasculitis, or in granulomatous angiitis. Pulmonary granulomas in AAV and non–ANCA-associated diseases were further studied. The amount of NETs was significantly greater in necrotizing granulomas of AAV than in granulomas of sarcoidosis without necrosis. Although NETs were formed in necrotizing granulomas of tuberculosis equivalently to those formed in AAV, they were more susceptible to degradation by DNase I than were NETs in AAV. The formation and disordered degradation of NETs in necrotizing lesions are characteristics of AAV, and are possibly related to its pathogenesis.
       
  • Sost haploinsufficiency provokes peracute lethal cardiac tamponade without
           rescuing the osteopenia in a mouse model of excess glucocorticoids
    • Abstract: Publication date: Available online 19 January 2019Source: The American Journal of PathologyAuthor(s): Behzad Javaheri, Eleanor Herbert, Mark Hopkinson, Ahmed Al-Jazzar, Andrew A. Pitsillides Glucocorticoid-induced secondary osteoporosis is the most predictable side-effect of this anti-inflammatory. One of the main mechanisms by which glucocorticoids achieve such deleterious outcome in bone is by antagonizing Wnt/β-catenin signalling. Sclerostin, encoded by Sost gene, is the main negative regulator of the pro-formative and anti-resorptive role of the Wnt signaling pathway in the skeleton. We hypothesized that the partial inactivation of sclerostin function by genetic manipulation will rescue the osteopenia induced by high endogenous glucocorticoid levels. Sost-deficient mice were crossed with an established mouse model of excess glucocorticoids and the effects on bone mass and structure were evaluated. Sost haploinsufficiency did not rescue the low bone mass induced by high glucocorticoids. Intriguingly, the critical manifestation of Sost-deficiency combined with glucocorticoid excess was sporadic, sudden, unprovoked, and non-convulsive death. Detailed histopathological analysis in a wide range of tissues identified peracute haemopericardium and cardiac tamponade to be the cause. These preclinical studies reveal outcomes with direct relevance to ongoing clinical trials exploring the use of anti-sclerostin antibodies as a treatment for osteoporosis. They particularly highlight a potential for increased cardiovascular risk and may inform improved stratification of patients that might otherwise benefit from anti-sclerostin antibody treatment.
       
  • Impaired Annulus Fibrosis Development and Vertebral Fusion Cause Severe
           Scoliosis in Mice with Deficiency of JNK1 and JNK2
    • Abstract: Publication date: Available online 19 January 2019Source: The American Journal of PathologyAuthor(s): Veronica Ulici, Kathryn L. Kelley, Lara Longobardi, Margaret A. McNulty, Eric W. Livingston, Ted A. Bateman, Cheryle A. Séguin, Craig R. Louer, Richard F. LoeserMAP kinases, including JNK, play an important role in the development and function of a large variety of tissues. We analyzed the skeletal phenotype of JNK1 and JNK2 double knockout (dKO) mice (JNK1fl/flCol2-Cre/JNK2-/-) and control genotypes, including single knockouts, at different embryonic and postnatal stages. The JNK1/2 dKO mice displayed a severe scoliotic phenotype that began during development and was grossly apparent around weaning age. Alcian blue staining of embryos (E17.5) showed abnormal fusion of the posterior spinal elements. In the adult mice, fusion of vertebral bodies and of spinous and transverse processes was noted by microCT, Alcian blue/Alizarin red stain and histology. The long bones developed normally and histological sections of the growth plate and articular cartilage did not reveal significant abnormalities. Histological sections of the vertebral column at E15.5 and E17.5 revealed an abnormal organization of the annulus fibrosus in the dKOs, with chondrocyte-like cells and fusion of dorsal processes. Spinal sections in 10-week–old dKO mice showed replacement of intervertebral disc structures (annulus fibrosus and nucleus pulposus) by cartilage and bone tissues, with cells staining for markers of hypertrophic chondrocytes including collagen X and Runx2. These findings demonstrate a requirement for both JNK1 and JNK2 in the normal development of the axial skeleton with loss of JNK signaling resulting in abnormal endochondral bone formation and subsequent severe scoliosis.
       
  • Spexin/NPQ Induces fos and Produces Antinociceptive Effect against
           Inflammatory Pain in the Mouse Model
    • Abstract: Publication date: Available online 19 January 2019Source: The American Journal of PathologyAuthor(s): Shuang-Yu Lv, Binbin Cui, Yanjie Yang, Hua Du, Xiaomei Zhang, Yuchen Zhou, Wenling Ye, Xiaobo Nie, Yang Li, Qun Wang, Wei-Dong Chen, Yan-Dong WangSpexin/NPQ is a novel highly conserved neuropeptide. It has a widespread expression in periphery and central nervous system. However, the effects of central spexin on acute inflammatory pain are still unknown. This study explored the mechanisms and effects of supraspinal spexin on inflammatory pain. The results from the mouse formalin test show that intracerebroventricular (i.c.v.) administration of spexin decreased licking/biting time during the late and early phases. The non-amidated spexin had no effect on pain response. The antinociception of spexin was blocked by galanin receptor 3 antagonist SNAP 37889. The Galr3 and Adcy4 mRNA levels in the brain were increased after injection with spexin. The antinociceptive effects of spexin were completely reversed by opioid receptor antagonist naloxone and κ-opioid receptor antagonist nor-BNI. Spexin up-regulated the dynorphin and κ-opioid receptor gene and protein expression. PCR array assay and real-time PCR analysis show that spexin up-regulated mRNA level of Fos gene. T-5224, the inhibitor of c-Fos/AP-1, blocked the increased mRNA level of Pdyn and Oprk1 induced by spexin. Spexin (2.43 mg/kg, i.c.v.) increased the number of c-Fos–positive neurons in most subsection of periaqueductal gray. In addition, in the acetic acid–induced writhing test, i.c.v. spexin produced antinociceptive effect. Our results indicate that spexin might be a novel neuropeptide with antinociceptive effect against acute inflammatory pain.
       
  • Smad3 suppresses epithelial cell migration and proliferation via the clock
           gene Dec1, which negatively regulates the expression of clock genes Dec2
           and Per1
    • Abstract: Publication date: Available online 19 January 2019Source: The American Journal of PathologyAuthor(s): Fuyuki Sato, Tsuyoshi Otsuka, Akira Kohsaka, Hue Thi Le, Ujjal K. Bhawal, Yasuteru Muragaki Smad3 has circadian expression; however, whether Smad3 affects the expression of clock genes is poorly understood. Here, we investigated the regulatory mechanisms between Smad3 and the clock genes Dec1, Dec2, and Per1. In Smad3 knockout mice, the amplitude of locomotor activity was decreased and Dec1 expression was decreased in the suprachiasmatic nucleus, liver, kidney, and tongue compared with control mice. Conversely, Dec2 and Per1 expression was increased compared with that of control mice. In Smad3 knockout mice, immunohistochemical staining revealed that Dec1 expression decreased, whereas Dec2 and Per1 expression increased in the endothelial cells of the kidney and liver. In NIH3T3 cells, Smad3 overexpression increased Dec1 expression, but decreased Dec2 and Per1 expression. In a wound-healing experiment using Smad3 knockout mice, Dec1 expression decreased in the basal cells of squamous epithelium, promoting wound healing of the mucosa. Finally, the migration and proliferation of Smad3 knockdown squamous carcinoma cells was suppressed by Dec1 overexpression, but promoted by Dec2 overexpression. Dec1 overexpression decreased E-cadherin and proliferating cell nuclear antigen expression, whereas these expression levels were increased by Dec2 overexpression. These results suggest Smad3 is relevant to circadian rhythm and regulates cell migration and proliferation through Dec1, Dec2, and Per1 expression.
       
  • This Month in AJP
    • Abstract: Publication date: Available online 17 January 2019Source: The American Journal of PathologyAuthor(s): Chhavi Chauhan
       
  • Antibiotic Perturbation of Gut Microbiota Dysregulates Osteoimmune Cross
           Talk in Postpubertal Skeletal Development
    • Abstract: Publication date: Available online 16 January 2019Source: The American Journal of PathologyAuthor(s): Jessica D. Hathaway-Schrader, Heidi M. Steinkamp, Michael B. Chavez, Nicole A. Poulides, Joy E. Kirkpatrick, Michael E. Chew, Emily Huang, Alexander V. Alekseyenko, Jose I. Aguirre, Chad M. NovinceCommensal gut microbiota–host immune responses are experimentally delineated via gnotobiotic animal models or alternatively by antibiotic perturbation of gut microbiota. Osteoimmunology investigations in germ-free mice, revealing that gut microbiota immunomodulatory actions critically regulate physiologic skeletal development, highlight that antibiotic perturbation of gut microbiota may dysregulate normal osteoimmunological processes. We investigated the impact of antibiotic disruption of gut microbiota on osteoimmune response effects in postpubertal skeletal development. Sex-matched C57BL/6T mice were administered broad-spectrum antibiotics or vehicle-control from the age of 6 to 12 weeks. Antibiotic alterations in gut bacterial composition and skeletal morphology were sex dependent. Antibiotics did not influence osteoblastogenesis or endochondral bone formation, but notably enhanced osteoclastogenesis. Unchanged Tnf or Ccl3 expression in marrow and elevated tumor necrosis factor-α and chemokine (C-C motif) ligand 3 in serum indicated that the pro-osteoclastic effects of the antibiotics are driven by increased systemic inflammation. Antibiotic-induced broad changes in adaptive and innate immune cells in mesenteric lymph nodes and spleen demonstrated that the perturbation of gut microbiota drives a state of dysbiotic hyperimmune response at secondary lymphoid tissues draining local gut and systemic circulation. Antibiotics up-regulated the myeloid-derived suppressor cells, immature myeloid progenitor cells known for immunosuppressive properties in pathophysiologic inflammatory conditions. Myeloid-derived suppressor cell–mediated immunosuppression can be antigen specific. Therefore, antibiotic-induced broad suppression of major histocompatibility complex class II antigen presentation genes in bone marrow discerns that antibiotic perturbation of gut microbiota dysregulates critical osteoimmune cross talk.
       
  • Development of a Novel Model of Central Retinal Vascular Occlusion and the
           Therapeutic Potential of the Adrenomedullin–Receptor
           Activity–Modifying Protein 2 System
    • Abstract: Publication date: Available online 15 January 2019Source: The American Journal of PathologyAuthor(s): Kazutaka Hirabayashi, Masaaki Tanaka, Akira Imai, Yuichi Toriyama, Yasuhiro Iesato, Takayuki Sakurai, Akiko Kamiyoshi, Yuka Ichikawa-Shindo, Hisaka Kawate, Megumu Tanaka, Kun Dai, Nanqi Cui, Yangxuan Wei, Keisei Nakamura, Shiho Iida, Shuhei Matsui, Akihiro Yamauchi, Toshinori Murata, Takayuki ShindoCentral retinal vein occlusion (CRVO) is an intractable disease that causes visual acuity loss with retinal ischemia, hemorrhage, and edema. In this study, we developed an experimental CRVO model in mice and evaluated the therapeutic potential of the pleiotropic peptide adrenomedullin (ADM) and its receptor activity–modifying protein 2 (RAMP2). The CRVO model, which had phenotypes resembling those seen in the clinic, was produced by combining i.p. injection of Rose bengal, a photoactivator dye enhancing thrombus formation, with laser photocoagulation. Retinal vascular area, analyzed using fluorescein angiography and fluorescein isothiocyanate–perfused retinal flat mounts, was decreased after induction of CRVO but gradually recovered from day 1 to 7. Measurements of retinal thickness using optical coherence tomography and histology revealed prominent edema early after CRVO, followed by gradual atrophy. Reperfusion after CRVO was diminished in Adm and Ramp2 knockout (KO) mice but was increased by exogenous ADM administration. CRVO also increased expression of a coagulation factor, oxidative stress markers, and a leukocyte adhesion molecule in both wild-type and Adm KO mice, and the effect was more pronounced in Adm KO mice. Using retinal capillary endothelial cells, ADM was found to directly suppress retinal endothelial injury. The retinoprotective effects of the Adm-Ramp2 system make it a novel therapeutic target for the treatment of CRVO.
       
  • Liver Regeneration after Acetaminophen Hepatotoxicity: Mechanisms and
           Therapeutic Opportunities
    • Abstract: Publication date: Available online 14 January 2019Source: The American Journal of PathologyAuthor(s): Bharat Bhushan, Udayan ApteAcetaminophen (APAP) overdose is the most common cause of acute liver failure (ALF) in the western world with limited treatment opportunities. For years, the research on APAP overdose has been focused on investigating mechanisms of hepatotoxicity with limited success in advancing therapeutic strategies. Acute liver injury after any insult, including APAP overdose, is followed by compensatory liver regeneration, which promotes recovery and is a critical determinant of the final outcome. Liver regeneration after APAP-induced liver injury is dose-dependent and impaired after severe APAP overdose. Although robust regenerative response is associated with spontaneous recovery and survival, impaired regeneration results in faster progression of injury and death following APAP overdose. APAP hepatotoxicity-induced liver regeneration involves a complex time and dose-dependent interplay of several signaling mediators including growth factors, cytokines, angiogenic factors, and other mitogenic pathways. Compared to the liver injury, which is established before a majority of patients seek medical attention and has proven to be difficult to manipulate, liver regeneration can be potentially modulated even at the late stage of APAP-induced ALF. Despite recent efforts to study mechanisms of liver regeneration after APAP-induced liver injury, more comprehensive research is required in this area, especially regarding factors contributing to impaired regenerative response, to develop novel regenerative therapies for APAP-induced ALF.
       
  • β1 syntrophin supports autophagy initiation and protects against
           cerulein-induced acute pancreatitis
    • Abstract: Publication date: Available online 14 January 2019Source: The American Journal of PathologyAuthor(s): Risheng Ye, Toshiharu Onodera, Pierre-Gilles Blanchard, Christine M. Kusminski, Victoria Esser, Rolf A. Brekken, Philipp E. SchererSyntrophins are a family of proteins forming membrane-anchored scaffolds and serving as adaptors for various transmembrane and intracellular signaling molecules. To understand the physiological roles of β1 syntrophin, one of the least characterized members, we generated mouse models to eliminate β1 syntrophin specifically in the endocrine or exocrine pancreas. β1 syntrophin is dispensable for the morphology and function of insulin-producing β-cells. However, mice with β1 syntrophin deletion in exocrine acinar cells exhibit increased severity of cerulein-induced acute pancreatitis. Reduced expression of cystic fibrosis transmembrane conductance regulator and dilation of acinar lumen are potential predisposition factors. During the disease progression, a relative lack of autophagy is associated with deficiencies in both actin assembly and endoplasmic reticulum nucleation. Our findings reveal for the first time that β1 syntrophin is a critical regulator of actin cytoskeleton and autophagy in pancreatic acinar cells, and is potently protective against cerulein-induced acute pancreatitis.
       
  • Disruption of P2X7 Signaling Increases Susceptibility to Cerebral
           Toxoplasmosis
    • Abstract: Publication date: Available online 14 January 2019Source: The American Journal of PathologyAuthor(s): Aline Cristina Abreu Moreira-Souza, Thuany Prado Rangel, Sthefani Rodrigues Batista da Silva, Vanessa Ribeiro Figliuolo, Luiz Eduardo Baggio Savio, Felipe Schmitz, Christina Takiya, Angela T.S. Wyse, Rossiane Claudia Vommaro, Robson Coutinho-Silva Toxoplasmosis is a neglected disease that affects millions of individuals worldwide. Toxoplasma gondii infection is an asymptomatic disease, with lethal cases occurring mostly in HIV patients and organ transplant recipients. Nevertheless, atypical strains of T. gondii in endemic locations cause severe pathology in healthy individuals. Toxoplasmosis has no cure but it can be controlled by the pro-inflammatory immune response. The P2X7 purinergic receptor is involved in many inflammatory events and has been associated with genes that confer resistance against toxoplasmosis in humans. In vitro studies reported parasite killing following P2X7 receptor activation in various cell types. To understand the contribution of P2X7 during cerebral toxoplasmosis, wild-type and P2rx7 knockout mice were infected orally with T. gondii and their pathological profiles were analyzed. We found that all P2rx7-/- mice died eight weeks post-infection with increased number of cysts and fewer inflammatory infiltrates in their brains. The cytokines interleukin-1β, interleukin-12, tumor necrosis factor-α and reactive oxygen species were absent or reduced in P2rx7-/- mice. Taken together, these data suggest that the P2X7 receptor promotes inflammatory infiltrates, pro-inflammatory cytokines, and reactive oxygen species production in the brain, and that P2X7 signaling mediates major events that confer resistance to cerebral toxoplasmosis.
       
  • Induced Pluripotent Stem Cell–Derived Endothelial Cells: Overview,
           Current Advances, Applications, And Future Directions
    • Abstract: Publication date: Available online 14 January 2019Source: The American Journal of PathologyAuthor(s): Sae Jang, Alexandra Collin de l’Hortet, Alejandro Soto-Gutierrez Endothelial cells are prevalent in our bodies and serve multiple functions. By lining the vasculature, they provide a barrier to tissues and facilitate the transport of molecules and cells. They also maintain hemostasis and modulate blood flow by reacting to chemokines and releasing signal molecules. Thus, endothelial dysfunction leads to a wide variety of diseases, including atherosclerosis and coronary artery disease. In today’s era of stem cell research, induced pluripotent stem cell–derived endothelial cells (iPSC-ECs) have emerged for research and engineering purposes. They are not only tools for studying disease states, but are also a crucial part of efforts to engineer vessel and organ grafts. As the techniques in cell culture, microfluidics, and personalized medicine concomitantly improve, the potential for iPSC-ECs is enormous. We review functions of endothelium in our bodies, the development and uses of iPSC-ECs, and the possible avenues to explore in the future.
       
  • Galectin-3 Inhibits Cancer Metastasis by Negatively Regulating Integrin
           Beta 3 Expression
    • Abstract: Publication date: Available online 14 January 2019Source: The American Journal of PathologyAuthor(s): Yumiko Hayashi, Weizhen Jia, Hiroyasu Kidoya, Fumitaka Muramatsu, Yohei Tsukada, Nobuyuki TakakuraGalectin-3 (Gal-3; gene LGALS3) is a member of the beta-galactose–binding lectin family. Previous studies showed that Gal-3 is expressed in several tissues across species and functions as a regulator of cell proliferation, apoptosis, adhesion, and migration, thus affecting many aspects of events such as angiogenesis and tumorigenesis. Although several reports have suggested that the level of Gal-3 expression correlates positively with tumor progression, here we show that highly metastatic mouse melanoma B16/BL6 cells express less Gal-3 than B16 cells with a lower metastatic potential. It was found that overexpression of Gal-3 in melanoma cells in fact suppresses metastasis. In contrast, knocking out Gal-3 expression in cancer cells promoted cell aggregation mediated through interactions with platelets and fibrinogen in vitro, and increased the number of metastatic foci in vivo. Thus, reduced Gal-3 expression results in the up-regulation of β3 integrin expression, and this contributes to metastatic potential. These findings indicate that changes of Gal-3 expression in cancer cells during tumor progression influences the characteristics of metastatic cells.
       
  • Loss of Wnt secretion by macrophages promotes hepatobiliary injury
           following administration of DDC diet
    • Abstract: Publication date: Available online 2 January 2019Source: The American Journal of PathologyAuthor(s): An Jiang, Hirohisa Okabe, Branimir Popovic, Morgan E. Preziosi, Tirthadipa Pradhan-Sundd, Minakshi Poddar, Sucha Singh, Aaron Bell, Steven G. England, Shanmugam Nagarajan, Satdarshan P. Monga Exposure of mice to a diet containing 3,5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) induces porphyrin accumulation, cholestasis, immune response, and hepatobiliary damage mimicking hepatic porphyria and sclerosing cholangitis. Although β-catenin signaling promotes hepatocyte proliferation, and macrophages are a source of Wnts, the role of macrophage-derived Wnts in modulating hepatobiliary injury/repair remains unresolved. We investigated the effect of macrophage-specific deletion of Wntless (Wls), a cargo protein critical for cellular Wnt secretion, by feeding macrophage-Wls-KO (Mac-KO) and wild-type littermates (WT) a DDC diet for 14 days. DDC exposure induced Wnt11 up-regulation in macrophages. Mac-KO mice on DDC showed increased serum alkaline phosphatase, aspartate aminotransferase, direct bilirubin, and histological evidence of more cell death, inflammation, and ductular reaction. There was impaired hepatocyte proliferation evidenced by Ki-67 immunostaining, which was associated with decreased hepatocyte β-catenin activation and cyclin-D1 in Mac-KO. Mac-KO also showed increased CD45, F4/80, and neutrophil infiltration after DDC diet, along with increased expression of several pro-inflammatory cytokines and chemokines. Gene expression analyses of bone marrow–derived macrophages from Mac-KO mice and F4/80+ macrophages isolated from DDC-fed Mac-KO livers showed pro-inflammatory M1 polarization. In conclusion, this study shows that a lack of macrophage Wnt secretion leads to more DDC-induced hepatic injury due to impaired hepatocyte proliferation and increased M1 macrophages, which promotes immune-mediated cell injury.
       
  • Leptin Receptor as a Potential Target to Inhibit Human Testicular Seminoma
           Growth
    • Abstract: Publication date: Available online 2 January 2019Source: The American Journal of PathologyAuthor(s): Salvatore Panza, Luca Gelsomino, Rocco Malivindi, Vittoria Rago, Ines Barone, Cinzia Giordano, Francesca Giordano, Antonella Leggio, Alessandra Comandè, Angelo Liguori, Saveria Aquila, Daniela Bonofiglio, Sebastiano Andò, Stefania Catalano Although in the last decades, the adipokine leptin and its own receptor have been considered as significant cancer biomarkers, their potential involvement in human testicular seminoma growth and progression remains unexplored. Here, we demonstrated that the expression of leptin and its receptor was significantly higher in human testicular seminoma compared to normal adult testis. Human seminoma cell line TCam-2 also expressed leptin along with the long and the short isoforms of leptin receptor and in response to leptin treatment, showed an enhanced activation of its downstream effectors. In line with these results, leptin stimulation significantly increased proliferation and migration of TCam-2 cells. Treatment of TCam-2 cells with the peptide LDFI, a full leptin receptor antagonist, completely reversed the leptin-mediated effects on cell growth and motility as well as reduced the expression of several leptin-induced target genes. More importantly, the in vivo xenograft experiments revealed that LDFI treatment markedly decreased seminoma tumor growth. Interestingly, LDFI-treated tumors exhibited reduced levels of the proliferation marker Ki-67 as well as a decreased expression of leptin-regulated genes. Taken together, these data identify, for the first time, leptin as a key factor able to affect testicular seminoma behavior highlighting leptin receptor as a potential target for novel potential treatments in this type of cancer.
       
  • Molecular Evaluation of Breast Ductal Carcinoma in Situ with
           Oncotype DX DCIS
    • Abstract: Publication date: Available online 31 December 2018Source: The American Journal of PathologyAuthor(s): Sharon Nofech-Mozes, Wedad Hanna, Eileen Rakovitch A subset of patients with ductal carcinoma in situ of the breast develop ipsilateral invasive breast cancer following breast conserving surgery with or without adjuvant radiotherapy. Risk assessment and PgRediction of adverse outcomes for individual patients based on traditional clinical and pathological parameters are limited. The Oncotype DCIS Score is a commercially available multigene assay that has been independently validated in PgRospective clinical trial and a population-based cohort. The score helps to identify a subset of women age>50 years with unifocal disease that carries
       
  • Enteric murine ganglionitis induced by autoimmune CD8 T cells mimics human
           gastrointestinal dysmotility
    • Abstract: Publication date: Available online 27 December 2018Source: The American Journal of PathologyAuthor(s): Monica Sanchez-Ruiz, Anna Brunn, Manuel Montesinos-Rongen, Claudia Rudroff, Melanie Hartmann, Dirk Schlüter, Gabriele Pfitzer, Martina Deckert Inflammatory bowel diseases frequently cause gastrointestinal dysmotility suggesting that they may also affect the enteric nervous system. So far, the precise mechanisms that lead to gastrointestinal dysmotility in inflammatory bowel diseases have not been elucidated. To determine the impact of CD8 T cells on gastrointestinal motility, transgenic mice expressing ovalbumin on enteric neurons were generated. In these mice, adoptive transfer of ovalbumin-specific OT-I CD8 T cells induced severe enteric ganglionitis. CD8 T cells homed to submucosal and myenteric plexus neurons, 60% of which were lost, clinically resulting in severely impaired gastrointestinal transition. Anti–interferon-γ treatment rescued neurons by preventing their up-regulation of MHC class I antigen, thus, preserving gut motility. These preclinical murine data translated well into human gastrointestinal dysmotility. In a series of 30 colonic biopsies from patients with gastrointestinal dysmotility, CD8 T cell–mediated ganglionitis was detected that was followed by severe loss of enteric neurons (74.8%). Together, the preclinical and clinical data support the concept that autoimmune CD8 T cells play an important pathogenetic role in gastrointestinal dysmotility and may destroy enteric neurons.
       
  • Blocking NF-κB Activation in Ly6c+ Monocytes Attenuates
           Necrotizing Enterocolitis
    • Abstract: Publication date: Available online 27 December 2018Source: The American Journal of PathologyAuthor(s): Elizabeth Managlia, Shirley X.L. Liu, Xiaocai Yan, Xiao-Di Tan, Pauline M. Chou, Terrence A. Barrett, Isabelle G. De PlaenNecrotizing enterocolitis (NEC) is a devastating disease affecting premature infants with intestinal inflammation and necrosis. The neonatal intestinal inflammatory response is rich in macrophages and blood monocyte count is low in human NEC. We previously found that NF-κB mediates the intestinal injury in experimental NEC. However, the role of NF-κB in myeloid cells during NEC remains unclear. Here, IKKβ, a critical kinase mediating NF-κB activation, was deleted in lysozyme M (Lysm)-expressing cells, which were found to be Cd11b+Ly6c+ monocytes but not Cd11b+Ly6c- macrophages in the dam fed neonatal mouse intestine. NEC induced differentiation of monocytes into intestinal macrophages and up-regulation of monocyte recruitment genes (eg, L-selectin) in the macrophage compartment in wild-type mice, but not in pups with IKKβ deletion in Lysm+ cells. Thus NF-κB is required for NEC-induced monocyte activation, recruitment, and differentiation in neonatal intestines. Furthermore, pups with Lysm-IKKβ deletion had improved survival and decreased incidence of severe NEC compared to littermate controls. Decreased NEC severity was not associated with an improved intestinal barrier. In contrast, NEC was unabated in mice with IKKβ deletion in intestinal epithelial cells. Together, these data suggest that recruitment of Ly6c+ monocytes into the intestine, NF-κB activation in these cells, and differentiation of Ly6c+ monocytes into macrophages are critical cellular and molecular events in NEC development to promote disease.
       
  • PPARγ Knockdown Impairs Bone Morphogenetic Protein-2 (BMP2)-Induced
           Critical-Size Bone Defect Repair
    • Abstract: Publication date: Available online 26 December 2018Source: The American Journal of PathologyAuthor(s): Chenchao Wang, Justine Tanjaya, Jia Shen, Soonchul Lee, Bharti Bisht, Hsin Chuan Pan, Shen Pang, Yulong Zhang, Emily A. Berthiaume, Eric Chen, Andrew L. Da Lio, Xinli Zhang, Kang Ting, Shu Guo, Chia Soo The Food and Drug Administration approved clinical dose (1.5 mg/mL) of bone morphogenetic protein-2 (BMP2) has been reported to induce significant adverse effects, including cyst-like adipose-infiltrated abnormal bone formation. These undesirable complications occur due to increased adipogenesis, at the expense of osteogenesis, through BMP2-mediated increases in the master regulatory gene for adipogenesis, peroxisome proliferator activated receptor gamma (PPARγ). Inhibiting PPARγ during osteogenesis has been suggested to drive the differentiation of bone marrow stromal/stem cells (BMSCs) toward an osteogenic, rather than an adipogenic, lineage. We demonstrate that knocking down PPARγ while concurrently administering BMP2 can reduce adipogenesis, but found that it also impairs BMP2-induced osteogenesis and leads to bone non-union in a mouse femoral segmental defect model. Additionally, in vitro studies using the mouse bone marrow stromal cell line M2-10B4 and mouse primary bone marrow stromal cells confirmed that PPARγ knockdown inhibits BMP2-induced adipogenesis; attenuates BMP2-induced cell proliferation, migration, invasion, and osteogenesis; and escalates BMP2-induced cell apoptosis. Importantly, BMP receptor 2 and 1B expression was also significantly inhibited by the combined BMP2 and PPARγ knockdown treatment. These findings indicate that PPARγ is critical for BMP2-mediated osteogenesis during bone repair. Thus, uncoupling BMP2-mediated osteogenesis and adipogenesis using PPARγ inhibition to combat BMP2’s adverse effects may not be feasible.
       
  • Nrf2-mediated expansion of pilosebaceous cells accelerates cutaneous wound
           healing
    • Abstract: Publication date: Available online 26 December 2018Source: The American Journal of PathologyAuthor(s): Sukalp Muzumdar, Hayley Hiebert, Eric Haertel, Maya Ben-Yehuda Greenwald, Wilhelm Bloch, Sabine Werner, Matthias Schäfer The transcription factor Nrf2 is a key regulator of the cellular stress response. Therefore, pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. Here we show that genetic Nrf2 activation in keratinocytes accelerates wound repair. Enhanced proliferation of cells of the pilosebaceous unit peripheral to the wound and a concomitant acceleration of reepithelialization were identified as the underlying mechanism. Nrf2 specifically promoted the expansion of pilosebaceous cells expressing markers of junctional zone and upper isthmus follicular stem cells. This may result, at least in part, from the up-regulation of the direct Nrf2 target epigen and a concomitant increase in epidermal growth factor receptor signaling. The increase in pilosebaceous cells provided a larger pool of keratinocytes that migrate into the wound, resulting in faster wound closure. These results unravel a novel function of Nrf2 in wound repair and suggest the use of NRF2-activating compounds in patients with impaired healing.
       
  • Spatio-Temporally Skewed Activation of PD-1+ T Cells after Epstein Barr
           Virus Infection and Tumor Development in Long-Term Fully Humanized Mice
    • Abstract: Publication date: Available online 26 December 2018Source: The American Journal of PathologyAuthor(s): Simon Danisch, Constanze Slabik, Angela Cornelius, Manuel Albanese, Takanobu Tagawa, Yen-Fu Adam Chen, Nicole Krönke, Britta Eiz-Vesper, Stefan Lienenklaus, Andre Bleich, Sebastian J. Theobald, Andreas Schneider, Arnold Ganser, Constantin von Kaisenberg, Reinhard Zeidler, Wolfgang Hammerschmidt, Friedrich Feuerhake, Renata StripeckeHumanized mice developing functional human T cells endogenously and capable of recognizing cognate HLA-matched tumors are emerging as relevant models for studying human immuno-oncology in vivo. Here, mice transplanted with human CD34+ stem cells and bearing endogenously-developed human T cells for more than 15 weeks were infected with an oncogenic recombinant Epstein Barr virus (EBV), encoding enhanced firefly luciferase (fLuc) and green fluorescent protein. EBV-fLUC was detectable one week after infection by non-invasive optical imaging in the spleen, from where it spread rapidly and systemically. EBV infection resulted into a pronounced immunological skewing regarding the expansion of CD8+ T cells in the blood outnumbering the CD4+ T and CD19+ B cells. Furthermore, within 10 weeks of infections, mice developing EBV-induced tumors had significantly higher absolute numbers of CD8+ T cells in lymphatic tissues than mice controlling tumor development. Tumor outgrowth was paralleled by an up-regulation of the programmed cell death receptor 1 (PD-1) on CD8+ and CD4+ T cells, indicative for T-cell dysfunction. Histopathological examinations and in situ hybridizations for EBV in tumors, spleen, liver, and kidney revealed foci of EBV-infected cells in perivascular regions in close association with PD-1+ infiltrating lymphocytes. The strong spatio-temporal correlation between tumor development and the T cell dysfunctional status seen in this viral oncogenesis humanized model replicates observations obtained in the clinical setting.
       
  • CCNA2 Ablation in Aged Mice Results in Abnormal rRNA Granule
           Accumulation in Hippocampus
    • Abstract: Publication date: Available online 21 December 2018Source: The American Journal of PathologyAuthor(s): Michele Joana Alves, Mustafa Goksel, Behiye Kaya, Hasnaa Mostafa, Patrick Gygli, Julie Stephens, Summer Fair, José Javier Otero, Catherine Miriam Czeisler Mounting evidence in the literature suggests that RNA–RNA binding protein aggregations can disturb neuronal homeostasis and lead to symptoms associated with normal aging as well as dementia. The specific ablation of cyclin A2 in adult neurons results in neuronal polyribosome aggregations and learning and memory deficits. Detailed histological and ultrastructural assays of aged mice revealed that post-mitotic hippocampal pyramidal neurons maintain cyclin A2 expression and that proliferative cells in the dentate subgranular zone express cyclin A2. Cyclin A2 loss early during neural development inhibited hippocampal development through canonical/cell-cycle mechanisms, including prolonged cell cycle timing in embryonic hippocampal progenitor cells. However, in mature neurons, cyclin A2 co-localized with dendritic rRNA. Cyclin A2 ablation in adult hippocampus resulted in decreased synaptic density in the hippocampus as well as in accumulation of rRNA granules in dendrite shafts. We conclude that cyclin A2 functions in a non-canonical/non–cell cycle regulatory role to maintain adult pyramidal neuron ribostasis.
       
  • Dynamin-1-like protein inhibition drives megamitochondria formation as an
           adaptive response in alcohol-induced hepatotoxicity
    • Abstract: Publication date: Available online 14 December 2018Source: The American Journal of PathologyAuthor(s): Elena Palma, Xiaowen Ma, Antonio Riva, Valeria Iansante, Anil Dhawan, Shaogui Wang, Hong-Min Ni, Hiromi Sesaki, Roger Williams, Wen-Xing Ding, Shilpa Chokshi Despite the growing global burden of alcoholic liver diseases, therapeutic options are limited and novel targets are urgently needed. Accumulating evidence suggests that mitochondria adapt in response to ethanol and formation of megamitochondria in the livers of patients is recognized as a hallmark of alcoholic liver diseases. The processes involved in ethanol-induced hepatic mitochondrial changes, the impact on mitochondria-shaping proteins, and the significance of megamitochondria formation remain unknown. In this study, we investigated the mitochondrial and cellular response to alcohol in hepatoma cell line VL-17A. The mitochondrial architecture rapidly changed after 3 or 14 days of ethanol exposure with double-pronged presentation of hyper-fragmentation and megamitochondria and cell growth was inhibited. Dynamin-1-like protein (Drp1) was identified as the main mediator driving these mitochondrial alterations and its genetic inactivation was determined to foster megamitochondria development, preserving the capacity of the cells to grow despite alcohol toxicity. The role of Drp1 in mediating megamitochondria formation in mice with liver-specific inactivation of Drp1 was further confirmed. Finally, when these mice were fed with ethanol, the presentation of hepatic megamitochondria was exacerbated compared to wild type fed with the same diet. Ethanol-induced toxicity was also reduced. Our study demonstrates that megamitochondria formation is mediated by Drp1 and this phenomenon is a beneficial adaptive response during alcohol-induced hepatotoxicity.
       
  • Heparan Sulfate Proteoglycan Synthesis is Dysregulated in Human
           Osteoarthritic Cartilage
    • Abstract: Publication date: Available online 14 December 2018Source: The American Journal of PathologyAuthor(s): Anastasios Chanalaris, Hannah Clarke, Scott E. Guimond, Tonia L. Vincent, Jeremy E. Turnbull, Linda Troeberg Osteoarthritis (OA) is a common degenerative joint disease, characterized by cartilage loss and subchondral bone remodelling in response to abnormal mechanical load. Heparan sulfate (HS) proteoglycans bind to many proteins that regulate cartilage homeostasis, including growth factors, morphogens, proteases, and their inhibitors, and modulate their localization, retention, and biological activity. Changes in HS expression and structure may thus have important consequences for joint health. We analyzed normal and osteoarthritic human knee cartilage, and found HS biosynthesis was markedly disrupted in OA, with 45% of the 38 genes analyzed differentially regulated in diseased cartilage. The expression of several HS core proteins, biosynthesis, and modification enzymes was increased in OA cartilage, whereas the expression of the HS proteoglycans syndecan 4 and betaglycan was reduced. The structure of HS was also altered, with increased levels of 6-O-sulfation in osteoarthritic samples, which correlated with increased expression of HS6ST1, a 6-O-sulfotransferase, and GLCE, an epimerase that promotes 6-O-sulfation. siRNA silencing of HS6ST1 expression in primary OA chondrocytes inhibited ERK phosphorylation in response to FGF2, showing that changes in 6-O-sulfation impact a key cartilage signalling pathway. Given the broad range of homeostatic and repair pathways that HS regulates, these changes in proteoglycan expression and HS structure are likely to have significant effects on joint health and progression of OA.
       
  • Ganglioside synthase knock-out reduces prion disease incubation time in
           mouse models
    • Abstract: Publication date: Available online 13 December 2018Source: The American Journal of PathologyAuthor(s): Atsushi Kobayashi, Zechen Qi, Taishi Shimazaki, Yoshiko Munesue, Tomomi Miyamoto, Norikazu Isoda, Hirofumi Sawa, Keisuke Aoshima, Takashi Kimura, Shirou Mohri, Tetsuyuki Kitamoto, Tadashi Yamashita, Ichiro Miyoshi Localization of the abnormal and normal isoforms of prion proteins to detergent-resistant membrane microdomains, lipid rafts, is important for the conformational conversion. Lipid rafts are enriched in sialic acid–containing glycosphingolipids, namely gangliosides. Alteration in the ganglioside composition of lipid rafts can affect the localization of lipid raft–associated proteins. To investigate the role of gangliosides in the pathogenesis of prion diseases, we performed intracerebral transmission study of a scrapie prion strain Chandler and a Gerstmann-Sträussler-Scheinker syndrome prion strain Fukuoka-1 using various knock-out mouse strains ablated with ganglioside synthase gene, ie, GD2/GM2 synthase, GD3 synthase, or GM3 synthase. Following challenge with the Chandler strain, GD2/GM2 synthase knock-out mice showed 20% reduction of incubation time, reduced prion protein deposition in the brain with attenuated glial reactions, and reduced localization of prion proteins to lipid rafts. These results raise the possibility that the gangliosides may have an important role in prion disease pathogenesis by affecting the localization of prion proteins to lipid rafts.
       
  • Augmenter of liver regeneration protects against ethanol-induced acute
           liver injury by promoting autophagy
    • Abstract: Publication date: Available online 13 December 2018Source: The American Journal of PathologyAuthor(s): Limin Liu, Ping Xie, Wen Li, Yuan Wu, Wei An Alcoholic liver disease is associated with high morbidity and mortality, and treatment options are limited to date. Augmenter of liver regeneration (ALR) may protect against hepatic injury caused by chemical poisons, including ethanol. Autophagy appears to positively influence survival in cases of liver dysfunction, though the mechanisms are poorly understood. Here, we investigated the impact of ALR-induced autophagy in vitro and in vivo in an ethanol-induced model of acute liver injury. Decreased serum levels of alanine aminotransferase and aspartate aminotransferase and reduced histological lesions revealed that mice overexpressing ALR experienced less liver damage than wild-type mice. ALR-knockdown mice suffered more severe liver damage than wild-type. ALR-transfected HepG2 cells showed increased survival rates, improved maintenance of mitochondrial membrane potential, and increased ATP levels following EtOH treatment. The observed protection was associated with up-regulation of autophagy-markers including LC3-II, Beclin-1, and Atg5, and down-regulation of p62 by ALR. Autophagy was inhibited in ALR-knockdown mice and HepG2 cells, and the autophagy inhibitor bafilomycinA1 attenuated the protective effects of ALR. The results showed that p-mTOR was down-regulated when ALR was overexpressed, and up-regulated when ALR was knocked down. These data show that ALR is protective against ethanol-induced acute liver injury by promoting autophagy, probably via repressing the mTOR pathway. These results have potential implications for the clinical treatment of alcoholic liver disease patients.
       
  • LINE-1 retrotransposons become deregulated during the development of
           ovarian cancer precursor lesions
    • Abstract: Publication date: Available online 13 December 2018Source: The American Journal of PathologyAuthor(s): Thomas R. Pisanic, Shiho Asaka, Shiou-Fu Lin, Ting-Tai Yen, Hanru Sun, Asli Bahadirli-Talbott, Tza-Huei Wang, Kathleen H. Burns, Tian-Li Wang, Ie-Ming Shih There is growing evidence that the majority of high-grade serous ovarian carcinomas likely arise from local dissemination of precursor lesions of the fallopian tube. Evolution of these lesions from early “p53 signatures” to latter-stage, serous tubal intraepithelial carcinomas (STICs) is characterized by cytologic atypia, accumulation of somatic mutations, and genomic instability, the etiologies of which remain unclear. Long interspersed element 1 (LINE-1) retrotransposon is expressed in many carcinomas, including high-grade serous ovarian carcinoma, where it contributes to genomic instability; however, the timing of LINE-1 activation during this evolution has yet to be elucidated. In this study, we assessed LINE-1 open reading frame 1 protein expression in 12 p53 signature lesions, 32 STICs, and 112 various types of ovarian cancers via immunohistochemical staining and examined LINE-1 promoter methylation in representative cases. We found that 78% and 57% of STICs, with and without concurrent ovarian carcinomas, respectively, exhibited intense LINE-1 immunoreactivity compared to adjacent, normal-appearing fallopian tube epithelium. Hypomethylation of the LINE-1 promoter was found in all STICs exhibiting overexpression. None of the 12 p53 signatures demonstrated significant LINE-1 expression. In ovarian cancer, 84 (75%) of 112 ovarian carcinomas overexpressed LINE-1. Our results indicate that LINE-1 retrotransposons often become deregulated during progression of ovarian cancer precursor lesions from the p53 signature to STIC stages and remain highly expressed in carcinoma.
       
  • Expression of Bone Morphogenetic Proteins In Multiple Sclerosis Lesions
    • Abstract: Publication date: Available online 13 December 2018Source: The American Journal of PathologyAuthor(s): Carme Costa, Herena Eixarch, Elena Martínez-Sáez, Laura Calvo-Barreiro, Maite Calucho, Zoraida Castro, Arantxa Ortega-Aznar, Santiago Ramón y Cajal, Xavier Montalban, Carmen Espejo Bone morphogenetic proteins (BMPs) are secreted proteins that belong to the transforming growth factor-beta superfamily. In the adult brain, they modulate neurogenesis, favor astrogliogenesis, and inhibit oligodendrogenesis. As BMPs may be involved in the failure of remyelination in multiple sclerosis (MS), we characterized the expression of BMP-2, -4, -5, and -7; BMP type II receptor (BMPRII); and phosphorylated (p)SMAD 1/5/8 in lesions of MS and other demyelinating diseases. Forty-two MS lesions, 12 acute ischemic lesions, eight progressive multifocal leucoencephalopathy lesions, and 10 CNS areas from four non-neuropathological patients were included. Lesions were histologically classified according to the inflammatory activity. The expression of BMP-2, BMP-4, BMP-5, BMP-7, BMPRII, and pSMAD1/5/8 was quantified by immunostaining, and colocalization studies were performed. In MS lesions, astrocytes, microglia/macrophages, and neurons expressed BMP-2, -4, -5, and -7; BMPRII; and pSMAD1/5/8, whereas oligodendrocytes expressed BMP-2 and -7 and pSMAD1/5/8. The percentage of cells that expressed BMPs, BMPRII, and pSMAD1/5/8 correlated with the inflammatory activity of MS lesions, and changes in the percentage of positive cells were more relevant in MS than in other white matter–damaging diseases. These data indicate that BMPs are increased in active MS lesions, suggesting a possible role in MS pathogenesis.
       
  • This Month in AJP
    • Abstract: Publication date: Available online 11 December 2018Source: The American Journal of PathologyAuthor(s): Chhavi Chauhan
       
  • Podocytes: Way to go
    • Abstract: Publication date: Available online 11 December 2018Source: The American Journal of PathologyAuthor(s): Mehmet M. Altintas, Jochen Reiser
       
  • Mild traumatic brain injury in mice beneficially alters lung NK1R and
           structural protein expression to enhance survival after Pseudomonas
           aeruginosa infection
    • Abstract: Publication date: Available online 23 November 2018Source: The American Journal of PathologyAuthor(s): Max Vaickus, Terry Hsieh, Ekaterina Kintsurashvili, Jiyoun Kim, Daniel Kirsch, George Kasotakis, Daniel Remick Mild traumatic brain injury (mTBI) in a murine model increases survival to a bacterial pulmonary challenge compared to blunt tail trauma (TT). We hypothesize Substance P and its receptor, the neurokinin 1 receptor (NK1R; official name TACR1), play a role in the increased survival of mTBI mice. Mice were subjected to mTBI or TT and 48 hours post-trauma, the levels of NK1R mRNA and protein were significantly up-regulated in mTBI lungs. Examination of the lung 48 hours post-injury by microarray showed significant differences in the expression of 433 gene sets between groups, most notably genes related to intercellular proteins. Despite down-regulated gene expression of connective proteins, the presence of an intact pulmonary vasculature was supported by normal histology and BAL protein levels. To determine if these mTBI-induced lung changes benefited in vivo responses, two chemotactic stimuli (a CXCL1 chemokine and a live Pseudomonas aeruginosa infection) were administered 48 hours post-trauma. For both stimuli, mTBI mice recruited more neutrophils to the lung four hours post-instillation (KC: mTBI = 6.3 ± 1.3 vs TT = 3.3 ± .7 neutrophils/mL; Psd: mTBI = 9.4 ± 1.4 vs TT = 5.3 ± 1.1 neutrophils/mL). This study demonstrates that the downstream consequences of mTBI on lung NK1R levels and connective protein expression enhance neutrophil recruitment to a stimulus which may contribute to increased survival.
       
  • Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and
           Visual Impairment
    • Abstract: Publication date: Available online 23 November 2018Source: The American Journal of PathologyAuthor(s): Fabian PS. Yu, Ben Sajdak, Jakub Sikora, Alexander E. Salmon, Murtaza S. Nagree, Jiří Gurka, Iris S. Kassem, Daniel M. Lipinski, Joseph Carroll, Jeffrey A. Medin Farber Disease (FD) is a debilitating lysosomal storage disorder characterized by severe inflammation and neurodegeneration. FD is caused by mutations in the ASAH1 gene resulting in deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency exhibit a broad clinical spectrum. In classical cases, patients develop hepatosplenomegaly, nervous system involvement, and childhood mortality. Ocular manifestations include decreased vision, a grayish appearance to the retina with a cherry red spot, and nystagmus. That said, the full effect of ACDase deficiency on the visual system has not been studied in detail. We previously developed a mouse model that is orthologous for a known patient mutation in Asah1 that recapitulates human FD. Herein we report evidence of a severe ocular pathology in Asah1P361R/P361R mice. Asah1P361R/P361R mice exhibit progressive retinal and optic nerve pathology. Through non-invasive ocular imaging and histopathological analyses of these Asah1P361R/P361R animals, we revealed progressive inflammation, the presence of retinal dysplasia, and significant storage pathology in various cell types in both the retina and optic nerves. Lipidomic analyses of retinal tissues revealed an abnormal accumulation of ceramides and other sphingolipids. Electroretinograms and behavioral tests showed decreased retinal and visual responses. Taken together, these data suggest that ACDase deficiency leads to sphingolipid imbalance, inflammation, dysmorphic retinal and optic nerve pathology, and severe visual impairment.
       
  • Mitotic Catastrophe Causes Podocyte Loss in the Urine of Human Diabetics
    • Abstract: Publication date: Available online 23 November 2018Source: The American Journal of PathologyAuthor(s): Masanori Hara, Kazuhiko Oohara, Dao-Fu Dai, Helen LiapisABSTRACTMitotic catastrophe (MC) is a major cause of podocyte loss in vitro and in vivo. We evaluated urine samples (a total of 184 from diabetic patients n=41) from diabetic patients and determined the presence of podocytes in the urine and studied their characteristics, specifically asking whether apoptosis versus MC is present. We also evaluated diabetic glomeruli in renal biopsies by electron microscopy (n=54). A battery of stains including anti-podocalyxin (PCX) were used. PCX+podocytes (PCX+podo) showed nuclear morphologies such as ai) mononucleated, normal shape (8.7%), ii) large and abnormal shape (3.8 %), iii) multinucleated with or without micronucleoli (31.2%), iv), mitotic spindles (8.2%), v) single nucleus and denucleation combined (10.3%), and vi) denucleation only (37.0%). Large size/abnormal shape, multinucleation, mitotic spindles, and a combination of single nucleus and denucleation were considered as features of MC (53.5%). Dual staining of PCX+podo were positive for Glepp 1 (50%), whereas none of PCX+podo were positive for nephrin, podocin, leucocyte, and parietal epithelial cell markers (cytokeratin 8), annexin V, cleaved caspase-3, and Tunel. Ten percent of PCX+podo were positive for phosphorylated vimentin. Electron microscopy identified cellular and nuclear podocyte changes characteristic of The majority of urine podocytes in diabetic patients show MC and not apoptosis. This non-invasive approach may be clinically useful in determining progressive diabetic nephropathy or response to therapeutic intervention.
       
  • Fibrosis rescue improves cardiac function in dystrophin-deficient mice and
           
    • Abstract: Publication date: Available online 16 November 2018Source: The American Journal of PathologyAuthor(s): Andrea Farini, Aoife Gowran, Pamela Bella, Clementina Sitzia, Alessandro Scopece, Elisa Castiglioni, Davide Rovina, Patrizia Nigro, Chiara Villa, Francesco Fortunato, Giacomo Pietro Comi, Giuseppina Milano, Giulio Pompilio, Yvan Torrente Patients affected by Duchenne muscular dystrophy (DMD) develop a progressive dilated cardiomyopathy characterized by inflammatory cell infiltration, necrosis, and cardiac fibrosis. Standard treatments consider the use of β‐blockers and angiotensin‐converting enzyme inhibitors that are symptomatic and unspecific towards DMD disease. Medications that target DMD cardiac fibrosis are in early stages of development. Here, we demonstrated immunoproteasome dysregulation in affected hearts of mdx mice (murine animal model of DMD) and cardiomyocytes derived from induced pluripotent stem cells of DMD patients. Interestingly, immunoproteasome inhibition ameliorated cardiomyopathy in mdx mice and reduced the development of cardiac fibrosis. Establishing the immunoproteasome inhibition–dependent cardioprotective role suggests the possibility to modulate the immunoproteasome as novel and clinically relevant treatment to rescue dilated cardiomyopathy in DMD patients.
       
  • Retinal Vascular Abnormalities and Microglia Activation in Mice with
           Deficiency in CYP46A1-Mediated Cholesterol Removal
    • Abstract: Publication date: Available online 16 November 2018Source: The American Journal of PathologyAuthor(s): Aicha Saadane, Natalia Mast, George Trichonas, Dibyendu Chakraborty, Sandra Hammer, Julia V. Busik, Maria B. Grant, Irina A. Pikuleva CYP46A1 is the cytochrome P450 enzyme that converts cholesterol to 24-hydroxycholesterol, a cholesterol elimination product and a potent liver X receptor (LXR) ligand. We conducted retinal characterizations of Cyp46a1-/- mice that had normal fasting blood glucose levels but up to 1.8-fold increase in retinal cholesterol. The retina of Cyp46a1-/- mice exhibited venous beading and tortuosity, microglia/macrophage activation, and increased vascular permeability, features commonly associated with diabetic retinopathy. The expression of Lxrα and Lxrβ was increased in both the whole Cyp46a1-/- retina and retinal macroglia/macrophages. The LXR-target genes were affected as well, primarily in activated microglial cells and macrophages. In the latter, the LXR-transactivated genes (Abca1, Abcg1, Apod, Apoe, Mylip, and Arg2) were up-regulated; similarly, there was an up-regulation of the LXR-transrepressed genes (Ccl2, Ptgs2, Cxcl1, Il1b, Il6, Nos2, and Tnfa). For comparison, gene expression was investigated in bone marrow–derived macrophages from Cyp46a1-/- mice as well as retinal and bone marrow–derived macrophages from Cyp27a1-/- and Cyp27a1-/-Cyp46a1-/- mice. CYP46A1 expression was detected in retinal endothelial cells, and this expression was increased in pro-inflammatory environment. Retinal Cyp46a1-/- phosphoproteome revealed altered phosphorylation of 30 different proteins, including tight junction protein ZO-1 and aquaporin 4. Collectively, the data obtained establish metabolic and regulatory significance of CYP46A1 for the retina and suggest pharmacological activation of CYP46A1 as potential therapeutic approach to dyslipidemia-induced retinal damage.
       
  • The danger signal extracellular ATP is involved in the immuno-mediated
           damage of alpha-sarcoglycan deficient muscular dystrophy
    • Abstract: Publication date: Available online 16 November 2018Source: The American Journal of PathologyAuthor(s): Elisabetta Gazzerro, Serena Baratto, Stefania Assereto, Simona Baldassari, Chiara Panicucci, Lizzia Raffaghello, Paolo Scudieri, Davide De Battista, Chiara Fiorillo, Stefano Volpi, Linda Chaabane, Mauro Malnati, Graziella Messina, Santina Bruzzone, Elisabetta Traggiai, Fabio Grassi, Carlo Minetti, Claudio Bruno In muscular dystrophies the muscle membrane fragility results in a tissue-specific increase of danger-associated molecules (DAMPs) and infiltration of inflammatory cells. The DAMP extracellular adenosine triphosphate (eATP) released by dying myofibers steadily activates muscle and immune purinergic receptors exerting dual negative effects: a direct damage linked to altered intracellular calcium homeostasis in muscle cells and an indirect toxicity through the “triggering” of the immune response and inhibition of regulatory T cells. Accordingly, pharmacological and genetic inhibition of eATP signaling improves the phenotype in models of chronic inflammatory diseases. In α-sarcoglycanopathy (LGMD2D), eATP effects may be further amplified since α-sarcoglycan extracellular domain binds eATP and displays an ecto-ATPase activity, thus controlling eATP concentration at the cell surface and attenuating the magnitude and/or the duration of eATP-induced signals. Here we show that in vivo blockade of the eATP/P2X purinergic pathway by a broad spectrum P2XR–antagonist delayed the progression of the dystrophic phenotype in α-sarcoglycan null mice. eATP blockade dampened the muscular inflammatory response and enhanced the recruitment of Foxp3+ immunosuppressive regulatory CD4+ T cells. The improvement of the inflammatory features was associated with increased strength, reduced necrosis and limited expression of pro-fibrotic factors, suggesting that pharmacologic purinergic antagonism, altering the innate and adaptive immune component in the muscle infiltrates, might provide a therapeutic approach to slow disease progression in LGMD2D.
       
  • The atypical chemokine receptor 2 limits progressive fibrosis after acute
           ischemic kidney injury
    • Abstract: Publication date: Available online 16 November 2018Source: The American Journal of PathologyAuthor(s): Moritz Lux, Alexander Blaut, Nuru Eltrich, Andrei Bideak, Martin B. Müller, John M. Hoppe, Hermann-Josef Gröne, Massimo Locati, Volker VielhauerABSTRACTFollowing renal ischemia-reperfusion injury (IRI) resolution of inflammation allows tubular regeneration, whereas ongoing inflammatory injury mediated by infiltrating leukocytes leads to nephron loss and renal fibrosis, typical hallmarks of chronic kidney disease. The atypical chemokine receptor 2 (ACKR2) is a chemokine decoy receptor, that binds and scavenges inflammatory CC-chemokines and reduces local leukocyte accumulation. We hypothesized that ACKR2 limits leukocyte infiltration, inflammation, and fibrotic tissue remodeling after renal IRI, thus preventing progression to chronic kidney disease. Compared to wild-type, Ackr2 deficiency increased CC chemokine ligand 2 levels in tumor necrosis factor–stimulated tubulointerstitial tissue in vitro. In Ackr2-deficient mice with early IRI one or five days after transient renal pedicle clamping tubular injury was similar to wild-type, although accumulation of mononuclear phagocytes increased in postischemic Ackr2-/- kidneys. Regarding long-term outcomes, Ackr2-/- kidneys displayed more tubular injury five weeks after IRI, which was associated with persistently increased renal infiltrates of mononuclear phagocytes, T cells, Ly6Chigh inflammatory macrophages, and inflammation. Moreover, Ackr2 deficiency resulted in substantially aggravated renal fibrosis in Ackr2-/- kidneys five weeks after IRI, as revealed by increased expression of matrix molecules, renal accumulation of αSMA+ myofibroblasts, and bone marrow–derived fibrocytes. ACKR2 plays an important role in limiting persistent inflammation, tubular loss, and renal fibrosis after ischemic acute kidney injury, and thus can prevent progression to chronic renal disease.
       
  • Hepatocyte PPARα enhances liver regeneration after partial
           hepatectomy in mice
    • Abstract: Publication date: Available online 16 November 2018Source: The American Journal of PathologyAuthor(s): Guomin Xie, Shi Yin, Zhen zhen Zhang, Dan Qi, Xia Wang, Donghwan Kim, Tomoki Yagai, Chad N. Brocker, Yan Wang, Frank J. Gonzalez, Hua Wang, Aijuan Qu Peroxisome proliferator–activated receptor α (PPARα) is a key nuclear receptor involved in the control of lipid homeostasis. In rodents, PPARα is also a potent hepaticmitogen. Hepatocyte-specific disruption of PPARα inhibits agonist-induced hepatocyte proliferation; however, little is known about the exact role of PPARα in partial hepatectomy (PHx)-induced liver regeneration. Here, using hepatocyte-specific PPARα-deficient (Ppara△Hep) mice, the function of hepatocyte PPARα in PHx-induced liver regeneration was investigated. PPARα protein level and transcriptional activity were increased in the liver after PHx. Compared with the Pparafl/fl mice, Ppara△Hep mice exhibited significantly reduced hepatocyte proliferation at 32 hours after PHx. Consistently, reduced Ccnd1 and Pcna mRNA and CYCD1 and PCNA protein were observed at 32 hours after PHx in PparaΔHep mice. Furthermore, PparaΔHep mice showed increased hepatic lipid accumulation, and enhanced hepatic triglyceride contents due to impaired hepatic fatty acid β-oxidation when compared with that observed in Pparafl/fl mice. These results indicate that PPARα promotes liver regeneration after PHx, at least partially via regulating the cell cycle and lipid metabolism.
       
  • Tyrosinase is a novel endogenous regulator of developmental and
           inflammatory lymphangiogenesis
    • Abstract: Publication date: Available online 16 November 2018Source: The American Journal of PathologyAuthor(s): Christian Büttner, Thomas Clahsen, Birgit Regenfuss, Marie-Luise Dreisow, Zita Steiber, Felix Bock, André Reis, Claus Cursiefen Lymphangiogenesis is critically involved in tissue fluid balance, graft rejection, and tumor metastasis. Endogenous regulation of lymphangiogenesis is poorly understood. Here we use the lymphatic vessel architecture at the limbal border of the normally avascular cornea, a quantitative trait under strong genetic influence, as a model system to identify new candidate genes regulating lymphangiogenesis. Comparing low-lymphangiogenic BALB/cN versus high-lymphangiogenic C57BL/6N mice, we performed quantitative trait loci analysis of five phenotypes in a large BALB/cN x C57BL/6N intercross (n=795) and identified three to eight genome-wide significant loci, the strongest on chromosome 7 containing Tyrosinase (Tyr). Tyrosinase-negative mice showed significantly increased limbal lymphvascularized areas, a higher number of lymphatic vessel endpoints, and branching points and increased inflammation-induced lymphangiogenesis. These findings confirm that tyrosinase is a novel lymphangiogenesis regulator in developmental and inflammatory lymphangiogenesis. Our findings link melanin synthesis with lymphangiogenesis and open new treatment options in lymphangiogenesis-related diseases.
       
  • Loss of integrin αvβ8 in murine hepatocytes accelerates liver
           regeneration
    • Abstract: Publication date: Available online 16 November 2018Source: The American Journal of PathologyAuthor(s): Stephen N. Greenhalgh, Kylie P. Matchett, Richard S. Taylor, Katherine Huang, John T. Li, Koy Saeteurn, Mhairi C. Donnelly, Eilidh EM. Simpson, Joshua L. Pollack, Amha Atakilit, Kenneth J. Simpson, Jacquelyn J. Maher, John P. Iredale, Dean Sheppard, Neil C. HendersonABSTRACTRecent fate-mapping studies in mice have provided substantial evidence that mature adult hepatocytes are a major source of new hepatocytes following liver injury. In other systems, integrin αvβ8 has a major role in activating transforming growth factor beta (TGFβ), a potent inhibitor of hepatocyte proliferation. We hypothesized that depletion of hepatocyte integrin αvβ8 would increase hepatocyte proliferation and accelerate liver regeneration following injury. Using Itgb8flox/flox;Alb-Cre mice to deplete hepatocyte αvβ8, following partial hepatectomy, hepatocyte proliferation and liver-to-body weight ratio were significantly increased in Itgb8flox/flox;Alb-Cre mice compared to control. Antibody-mediated blockade of hepatocyte αvβ8 in vitro, with assessment of TGFβ signaling pathways by qPCR array, supported the hypothesis that integrin αvβ8 inhibition alters hepatocyte TGFβ signaling towards a pro-regenerative phenotype. A diethylnitrosamine-induced model of hepatocellular carcinoma, employed to examine the possibility that this pro-proliferative phenotype might be oncogenic, revealed no difference in either tumor number or size between Itgb8flox/flox;Alb-Cre and control mice. Immunohistochemistry for integrin αvβ8 in healthy and injured human liver demonstrated that human hepatocytes express integrin αvβ8. Depletion of hepatocyte integrin αvβ8 results in increased hepatocyte proliferation and accelerated liver regeneration following partial hepatectomy in mice. These data demonstrate that targeting integrin αvβ8 may represent a promising therapeutic strategy to drive liver regeneration in patients with a broad range of liver diseases.
       
  • Elevated membrane cholesterol disrupts lysosomal degradation to induce Aβ
           accumulation: the potential mechanism underlying augmentation of Aβ
           pathology by type 2 diabetes mellitus
    • Abstract: Publication date: Available online 15 November 2018Source: The American Journal of PathologyAuthor(s): Shingo Takeuchi, Naoya Ueda, Keiko Suzuki, Nobuhiro Shimozawa, Yasuhiro Yasutomi, Nobuyuki Kimura Endocytic membrane trafficking system is altered in the brains of early-stage Alzheimer disease (AD) patients, and endocytic disturbance affects the metabolism of β-amyloid protein (Aβ), a key molecule in AD pathogenesis. It is widely accepted that type 2 diabetes mellitus (T2DM) is one of the strongest risk factors for development of AD. Supporting this link, experimentally induced T2DM enhances AD pathology in various animal models. Spontaneous T2DM also enhances Aβ pathology with severe endocytic pathology, even in nonhuman primate brains. However, it remains unclear how T2DM accelerates Aβ pathology. Here, we demonstrate that cholesterol metabolism–related protein levels are increased and that membrane cholesterol level is elevated in spontaneous T2DM-affected cynomolgus monkey brains. Moreover, in vitro studies that manipulate cellular cholesterol reveal that elevated membrane cholesterol disrupts lysosomal degradation and enhances chemical-induced endocytic disturbance, resulting in great accumulation of Aβ in Neuro2a cells. These findings suggest that an alteration of cerebral cholesterol metabolism may be responsible for augmentation of Aβ pathology in T2DM-affected brains, which in turn may increase the risk for developing AD.
       
  • Role of endoplasmic reticulum stress in pro-inflammatory
           cytokine–mediated inhibition of trophoblast invasion in placenta-related
           complications of pregnancy
    • Abstract: Publication date: Available online 15 November 2018Source: The American Journal of PathologyAuthor(s): Cheuk-Lun Lee, Jan H.W. Veerbeek, Tirtha K. Rana, Bas B. van Rijn, Graham J. Burton, Hong Wa Yung Shallow extravillous trophoblast (EVT) invasion is central to the pathophysiology of many pregnancy complications. Invasion is mediated partially by matrix metalloproteinases (MMPs). MMP-2 is highly expressed in early pregnancy. MMP activity can be regulated by pro-inflammatory cytokines, which also induce endoplasmic reticulum (ER) stress in other cells. We investigated whether pro-inflammatory cytokines regulate MMP-2 activity through ER stress response pathways in trophoblast, before exploring potential regulatory mechanisms. There was increased immunoreactivity of HSPA5, also known as GRP78, in cells of the placental bed, including EVTs, in cases of early-onset preeclampsia compared to normotensive controls. Treating EVT-like JEG3 and HTR8/SVneo cells with ER stress inducers, tunicamycin and thapsigargin, suppressed MMP2 mRNA and protein expression, secretion, activity, and reduced their invasiveness. A cocktail of pro-inflammatory cytokines, interleukin-1β, tumor necrosis factor-α, and interferon-γ, suppressed MMP-2 activity in JEG-3 cells, and was accompanied by activation of the PERK-EIF2A arm of the ER stress pathway. Knockdown of ATF4, a downstream transcriptional factor of the PERK-EIF2A pathway, by small interference RNA, restored MMP2 expression but not cellular proteins. However, suppression of EIF2A phosphorylation with a PERK inhibitor, GSK2606414, under ER stress, restored MMP-2 protein. ER stress regulates MMP-2 expression at both the transcriptional and translational levels. This study provides the first mechanistic linkage by which pro-inflammatory cytokines may modulate trophoblast invasion through ER stress pathways.
       
  • Inflammatory stress causes N-glycan processing deficiency in
           ocular autoimmune disease
    • Abstract: Publication date: Available online 15 November 2018Source: The American Journal of PathologyAuthor(s): Ashley M. Woodward, Sylvain Lehoux, Flavio Mantelli, Antonio Di Zazzo, Inka Brockhausen, Stefano Bonini, Pablo Argüeso High levels of proinflammatory cytokines have been associated with loss of tissue function in ocular autoimmune diseases but the basis for this relationship remains poorly understood. Here we investigated a new role for tumor necrosis factor (TNF)-α in promoting N-glycan processing deficiency at the surface of the eye through inhibition of N-acetylglucosaminyltransferase expression in the Golgi. Using mass spectrometry, complex-type biantennary oligosaccharides were identified as major N-glycan structures in differentiated human corneal epithelial cells. Remarkably, significant differences were detected between the efficacies of cytokines in regulating the expression of glycogenes responsible for the biosynthesis of N-glycans. TNFα but not interleukin-1β had a profound effect in suppressing the expression of enzymes involved in the Golgi branching pathway, including MGAT1 and 2, which are required for the formation of biantennary structures. This decrease in gene expression correlated with a reduction in enzymatic activity and impaired N-glycan branching. Moreover, patients with ocular mucous membrane pemphigoid were characterized by marginal N-acetylglucosaminyltransferase expression and decreased N-glycan branching in conjunctiva. Together, these data indicate that proinflammatory cytokines differentially influence the expression of N-glycan processing enzymes in the Golgi and set the stage for future studies to explore the pathophysiology of ocular autoimmune diseases.
       
  • Nur77: Key Functions and Therapeutic Prospects in Inflammation-Related
           Lung Diseases
    • Abstract: Publication date: Available online 7 November 2018Source: The American Journal of PathologyAuthor(s): Asoka Banno, Sowmya P. Lakshmi, Aravind T. Reddy, Seong C. Kim, Raju C. ReddyABSTRACTThe transcription factor nuclear receptor 77 (Nur77) belongs to the NR4A subfamily of nuclear hormone receptors. It features an atypical ligand-binding site that precludes canonical ligand binding, leading to the designation “orphan nuclear receptor.” However, recent studies show that small molecules can interact with the receptor and modulate its activity by inducing a conformational change in the Nur77 ligand-binding site. Nur77 expression and activation are rapidly induced by a wide range of physiological and pathological stimuli. Once expressed, Nur77 initiates transcriptional activity and modulates expression of its target genes. Both in vitro and in vivo evidence shows that Nur77 dampens the immune response to pro-inflammatory stimuli such as tumor necrosis factor-α, toll-like receptor ligands, and oxidized lipids, primarily by suppressing NF-κB signaling. Although studies focusing on Nur77’s role in lung pathophysiology are currently incomplete, available data support its involvement in the pathogenesis of several lung diseases including asthma, acute lung injury, and pulmonary fibrosis, and thus suggest a therapeutic potential for Nur77 activation in these diseases. This review addresses the mechanisms that control Nur77 expression and activity as well as its known roles in inflammation-related lung diseases. Evidence regarding the therapeutic potential of Nur77-targeting molecules will also be presented. Although current knowledge is limited, additional rigorous research followed by clinical studies may firmly identify Nur77 as a pharmacological target for inflammation-related lung diseases.
       
  • Pseudoxanthoma Elasticum as a Paradigm of Heritable Ectopic Mineralization
           Disorders: Pathomechanisms and Treatment Development
    • Abstract: Publication date: Available online 7 November 2018Source: The American Journal of PathologyAuthor(s): Qiaoli Li, Koen van de Wetering, Jouni Uitto Ectopic mineralization is a global problem and leading cause of morbidity and mortality. The pathomechanisms of ectopic mineralization are poorly understood. Recent studies on heritable ectopic mineralization disorders with defined gene defects have been helpful in elucidation of the mechanisms of ectopic mineralization in general. The prototype of such disorders is pseudoxanthoma elasticum (PXE), a late-onset, slowly progressing disorder with multi-system clinical manifestations. Other conditions include generalized arterial calcification of infancy (GACI) characterized by severe, early-onset mineralization of the cardiovascular system often with early postnatal demise. In addition, arterial calcification due to CD73 deficiency (ACDC) occurs late in life mostly affecting arteries in the lower extremities in elderly individuals. These three conditions, PXE, GACI, and ACDC, caused by mutations in ABCC6, ENPP1, and NT5E, are characterized by reduced levels of inorganic pyrophosphate (PPi) in plasma. Since PPi is a powerful anti-mineralization factor, it has been postulated that reduced PPi is a major determinant for ectopic mineralization in PXE, GACI, and ACDC. These and related observations on complementary mechanisms of ectopic mineralization have resulted in development of potential treatment modalities for PXE, including administration of bisphosphonates, stable PPi analogs with anti-mineralization activity. It is conceivable that efficient treatments may soon become available for heritable ectopic mineralization disorders with application to common calcification disorders.
       
  • The Accumulation of Heparan Sulfate S-Domains in Kidney Transthyretin
           Deposits Accelerates Fibril Formation and Promotes Cytotoxicity
    • Abstract: Publication date: Available online 7 November 2018Source: The American Journal of PathologyAuthor(s): Hirokazu Kameyama, Kenji Uchimura, Taro Yamashita, Kaori Kuwabara, Mineyuki Mizuguchi, Shang-Cheng Hung, Keiichiro Okuhira, Tomohiro Masuda, Tomoki Kosugi, Takashi Ohgita, Hiroyuki Saito, Yukio Ando, Kazuchika NishitsujiThe highly sulfated domains of heparan sulfate (HS), also called HS S-domains, are made up of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)–] and are selectively remodeled by extracellular endoglucosamine 6-sulfatases (Sulfs). Although HS S-domains are critical for signal transduction of several growth factors, their roles in amyloidoses are not yet fully understood. Here, we found HS S-domains in the kidney of a patient with transthyretin amyloidosis (ATTR amyloidosis). In in vitro assays with cells stably expressing human Sulfs, heparin, a structural analog of HS S-domains, promoted aggregation of TTR in an HS S-domain–dependent manner. Interactions of cells with TTR fibrils and cytotoxicity of these fibrils also depended on HS S-domains at the cell surface. Furthermore, glypican-5 (GPC5), encoded by the susceptibility gene for nephrotic syndrome GPC5, was found to be accumulated in the ATTR amyloidosis kidney. Our study thus provides a novel insight into the pathological roles of HS S-domains in amyloidoses, and we propose that enzymatic remodeling of HS chains by Sulfs may offer an effective approach to inhibiting formation and cytotoxicity of amyloid fibrils.
       
  • Morphologic and Molecular Features of Breast Ductal Carcinoma In Situ
    • Abstract: Publication date: Available online 29 October 2018Source: The American Journal of PathologyAuthor(s): Souzan Sanati Ductal carcinoma in situ (DCIS) encompasses a highly heterogeneous group of lesions that differ with regard to their clinical presentations, histologic features, biomarker profiles, genetic abnormalities, and potential for progression. DCIS is a non-obligatory precursor for invasive carcinoma. With the advent of screening mammography the incidence of DCIS has significantly increased. There is an argument that many of these lesions will not progress to invasive carcinoma within the lifetime of a patient. In addition, many studies have shown enormous heterogeneity within DCIS. There is a need for biomarkers that can stratify patients with DCIS into different prognostic groups based on the biology of the disease. Estrogen and progesterone receptors are the established biomarkers that are used for clinical decision making. In addition, a number of biomarkers such as HER2, p53 tumor suppressor gene, ki67 proliferation marker, and tumor infiltrating lymphocytes have been shown to carry prognostic significance although their use is considered investigational and has not been transferred to clinical practice. On the molecular level low-grade and high-grade DCIS have different molecular alterations and the intrinsic molecular subtypes that exist in invasive carcinoma also exist in DCIS with prognostic implications. In this manuscript we review the morphologic features, prognostic biomarkers, and molecular features of ductal carcinoma in situ.
       
  • Ductal Carcinoma in Situ Biomarkers in a Precision Medicine Era: Current
           and Future Molecular-Based Testing
    • Abstract: Publication date: Available online 29 October 2018Source: The American Journal of PathologyAuthor(s): Kevin Shee, Kristen E. Muller, Jonathan Marotti, Todd W. Miller, Wendy A. Wells, Gregory J. Tsongalis Historically, ductal carcinoma in situ (DCIS) of the breast has been managed aggressively with surgery and radiation due to a risk of progression to invasive ductal carcinoma. However, this treatment paradigm has been challenged by overtreatment concerns and evidence suggesting that DCIS can be stratified according to risk of recurrence, or risk of progression to invasive disease. Traditional methods of risk stratification include histologic grade and hormone receptor status. Recent technological advancements have enabled an era of precision medicine, where DCIS can be molecularly analyzed by tools such as next-generation DNA and RNA sequencing to identify molecular biomarkers for risk stratification. These findings have led to the development of tools such as the Oncotype DXBreast DCIS Score, a gene expression-based assay with the potential to prevent overtreatment in low-risk disease.
       
  • Functional Role of microRNAs in the Progression of Breast Ductal Carcinoma
           in situ
    • Abstract: Publication date: Available online 29 September 2018Source: The American Journal of PathologyAuthor(s): Bethany N. Hannafon, Wei-Qun Ding microRNAs (miRNAs) are small RNAs that influence gene expression by targeting messenger RNAs (mRNAs). Depending on the function of their target genes, miRNAs may regulate the expression of oncogenes and tumor suppressors, thereby contributing to the promotion or inhibition of tumor progression. Ductal carcinoma in situ (DCIS), although often diagnosed as breast cancer, is a potential precursor to invasive ductal carcinoma. Many of the genetic events required for the invasive progression of DCIS occur at the pre-invasive stage, and these events include changes to the expression of miRNAs. Aberrant expression of miRNAs can influence specific oncogenic or tumor suppressive pathways required for breast cancer progression. miRNAs in DCIS have been shown to influence hormone signaling, cell-cell adhesion, epithelial to mesenchymal transition, TGF-β signaling, maintenance of cancer stem cells, and modulation of the extracellular matrix. Additionally, extracellular DCIS miRNAs, such as those found in exosomes, may promote invasive progression by modifying the tumor microenvironment. Here, we review the miRNAs that have been identified in DCIS and how they may contribute to the progression to invasive disease. We also touch on the current state of miRNA therapeutic development, including the current challenges, and discuss the key future perspectives for research into miRNA function for the purpose of miRNA therapeutic development against DCIS.
       
 
 
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