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Publisher: Elsevier   (Total: 3183 journals)

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Showing 1 - 200 of 3183 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 37, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 26, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 100, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 28, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 39, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 6)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 7)
Acta Astronautica     Hybrid Journal   (Followers: 437, 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: 3)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 11, SJR: 0.18, CiteScore: 1)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 302, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 25, 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: 7, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 8)
Acute Pain     Full-text available via subscription   (Followers: 15, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 17, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, 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: 182, 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: 9, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 17, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 29, 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: 11, 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: 15, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 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: 5)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 14)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 29, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 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: 13)
Advances in Digestive Medicine     Open Access   (Followers: 12)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Drug Research     Full-text available via subscription   (Followers: 26)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 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: 50, 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: 65, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Genetics     Full-text available via subscription   (Followers: 21, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 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: 26, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 24)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 3, 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: 9, 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: 20, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 12, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 8, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 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: 5)
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: 18, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 26, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 17)
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: 9, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 10)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 6)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 66)
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: 419, 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: 13, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 37, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 20)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 15)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 53, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 385, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 12, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 472, 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: 45, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 4)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 58, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 7, 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: 2, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 11, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 10, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 54, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 6, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 6, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 58, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 63, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 46, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 12)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 36, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 29, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 36, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 51)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 249, 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: 32, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 28, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 39, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 7)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 66, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 24, 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: 44, SJR: 1.512, CiteScore: 5)
Analytica Chimica Acta : X     Open Access  
Analytical Biochemistry     Hybrid Journal   (Followers: 209, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 13, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 14)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 25, SJR: 0.683, CiteScore: 2)
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: 217, SJR: 1.58, CiteScore: 3)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 6, SJR: 0.937, CiteScore: 2)
Animal Reproduction Science     Hybrid Journal   (Followers: 7, SJR: 0.704, CiteScore: 2)

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Similar Journals
Journal Cover
American Journal of Pathology
Journal Prestige (SJR): 2.139
Citation Impact (citeScore): 4
Number of Followers: 32  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0002-9440
Published by Elsevier Homepage  [3183 journals]
  • Identification of Metabolic Changes in Ileum, Jejunum, Skeletal Muscle,
           Liver, and Lung in a Continuous I.V. Pseudomonas aeruginosa Model of
           Sepsis Using Nontargeted Metabolomics Analysis
    • Abstract: Publication date: September 2019Source: The American Journal of Pathology, Volume 189, Issue 9Author(s): Amro Ilaiwy, Gabriella A.M. ten Have, James R. Bain, Michael J. Muehlbauer, Sara K. O'Neal, Jessica M. Berthiaume, Traci L. Parry, Nicolaas E. Deutz, Monte S. WillisSepsis is a multiorgan disease affecting the ileum and jejunum (small intestine), liver, skeletal muscle, and lung clinically. The specific metabolic changes in the ileum, jejunum, liver, skeletal muscle, and lung have not previously been investigated. Live Pseudomonas aeruginosa, isolated from a patient, was given via i.v. catheter to pigs to induce severe sepsis. Eighteen hours later, ileum, jejunum, medial gastrocnemius skeletal muscle, liver, and lung were analyzed by nontargeted metabolomics analysis using gas chromatography/mass spectrometry. The ileum and the liver demonstrated significant changes in metabolites involved in linoleic acid metabolism: the ileum and lung had significant changes in the metabolism of valine/leucine/isoleucine; the jejunum, skeletal muscle, and liver had significant changes in arginine/proline metabolism; and the skeletal muscle and lung had significant changes in aminoacyl-tRNA biosynthesis, as analyzed by pathway analysis. Pathway analysis also identified changes in metabolic pathways unique for different tissues, including changes in the citric acid cycle (jejunum), β-alanine metabolism (skeletal muscle), and purine metabolism (liver). These findings demonstrate both overlapping metabolic pathways affected in different tissues and those that are unique to others and provide insight into the metabolic changes in sepsis leading to organ dysfunction. This may allow therapeutic interventions that focus on multiple tissues or single tissues once the relationship of the altered metabolites/metabolism to the underlying pathogenesis of sepsis is determined.
  • This Month in AJP
    • Abstract: Publication date: Available online 21 August 2019Source: The American Journal of PathologyAuthor(s):
  • Proresolving mediators LXB4 and RvE1 regulate inflammation in stromal
           cells from patients with shoulder tendon tears
    • Abstract: Publication date: Available online 19 August 2019Source: The American Journal of PathologyAuthor(s): Stephanie G. Dakin, Romain A. Colas, Kim Wheway, Bridget Watkins, Louise Appleton, Jonathan Rees, Stephen Gwilym, Christopher Little, Jesmond Dalli, Andrew J. CarrABSTRACTTendon stromal cells isolated from patients with chronic shoulder rotator-cuff tendon tears show dysregulated resolution responses. Current therapies do not address the biological processes concerned with persistent tendon inflammation; therefore, new therapeutic approaches targeting tendon stromal cells are required. We determined if two specialized pro-resolving mediators (SPM) LXB4 and RvE1, modulate the bioactive lipid mediator profiles of interleukin (IL)-1β–stimulated tendon cells derived from patients with shoulder tendon tears and healthy volunteers. We also determined if LXB4 or RvE1 treatments moderated the pro-inflammatory phenotype of tendon tear stromal cells. Incubation of IL-1β–treated patient-derived tendon cells in LXB4 or RvE1 up-regulated concentrations of SPM. RvE1 treatment of diseased tendon stromal cells increased 15-epi-LXB4 and regulated PGF2α. LXB4 or RvE1 also induced expression of the SPM biosynthetic enzymes 12-liopxygeanse (ALOX12), and ALOX15. RvE1 treatment up-regulated proresolving receptor ERV1 compared to vehicle-treated cells. Incubation in LXB4 or RvE1 moderated the proinflammatory phenotype of patient-derived tendon tear cells, regulating markers of tendon inflammation, including Podoplanin, CD90, pSTAT-1, and IL-6. LXB4 and RvE1 counter-regulate inflammatory processes in tendon stromal cells, supporting the role of these molecules as potential therapeutics to resolve tendon inflammation.
  • A new role for the spleen: aggravation of the systemic inflammatory
           response in rats with severe acute pancreatitis
    • Abstract: Publication date: Available online 17 August 2019Source: The American Journal of PathologyAuthor(s): Rui Zhou, Jian Zhang, Wangjun Bu, Wei Zhang, Baojun Duan, Xianwei Wang, Libo Yao, Zongfang Li, Jun Li Little is known about the role of the spleen in mediating systemic inflammatory responses in severe acute pancreatitis (SAP). Here, we investigated the role played by the spleen in rats after SAP induction. Splenectomy was performed at designated time points after SAP induction. Pancreatic tissue and serum samples were collected and subjected to histological, immunohistochemical, and immunological analyses. Following SAP induction, the splenic immune response was enhanced during SAP progression, as shown by the increased diameter of the splenic periarterial lymphatic sheath and the thickness of the splenic marginal zone. Rats with splenectomy developed acute pancreatitis more slowly than rats without splenectomy. Additionally, pancreatic tissues of rats with splenectomy contained lower levels of serum amylase, tumor necrosis factor-α, and interleukin-6 and exhibited less acinar cell death, leucocyte infiltration, and interstitial oedema than those of rats without splenectomy. Compared with splenectomy alone, cotreatment with splenectomy and the administration of splenic cells originating from a rat with SAP 12 h after induction increased systemic inflammation in SAP rats. Splenic factors exacerbated SAP-associated liver and lung injury and accentuated intestinal mucosal barrier dysfunction. Splenectomy altered the serum cytokine profile in rats with SAP. In a rat model of SAP, the spleen exacerbated the systematic inflammatory responses and injury to multiple organs, indicating a new role for the spleen in SAP.
  • The Inability of the Choroid to Revascularize in Oxygen-Induced
           Retinopathy Results from Increased P53/mir-Let-7b Activity
    • Abstract: Publication date: Available online 17 August 2019Source: The American Journal of PathologyAuthor(s): Tianwei Ellen Zhou, Tang Zhu, José Carlos Rivera, Samy Omri, Houda Tahiri, Isabelle Lahaie, Raphaël Rouget, Maëlle Wirth, Stanley Nattel, Gregory Lodygensky, Gerardo Ferbeyre, Mohammad Nezhady, Michel Desjarlais, Patrick Hamel, Sylvain ChemtobRetinopathy of prematurity (ROP) is characterized by an initial retinal avascularisation, followed by pathologic neovascularization. Recently, choroidal thinning has also been detected in children formerly diagnosed with ROP; a similar sustained choroidal thinning is observed in ROP models. But the mechanism underlying the lack of choroidal revascularization remains unclear, and was investigated in an oxygen-induced retinopathy (OIR) model. In OIR, evidence of senescence was detected, preceded by oxidative stress in the choroid and the retinal pigment epithelium. This was associated with a global reduction of pro-angiogenic factors, including insulin-like growth factor 1 receptor (Igf1R). Coincidentally, tumor suppressor p53 was highly expressed in the OIR retinae. Curtailing p53 activity resulted in reversal of senescence, normalization of Igf1r expression, and preservation of choroidal integrity. OIR-induced down-regulation of Igf1r was mediated at least partly by microRNA (miRNA) let-7b as i) let-7b expression was augmented throughout and beyond the period of oxygen exposure, ii) let-7b directly targeted Igf1r mRNA, and iii) p53 knock-down blunted let-7b expression, restored Igf1r expression, and elicited choroidal revascularization. Finally, restoration of Igf1r expression rescued choroid thickness. Altogether, this study uncovers a significant mechanism for defective choroidal revascularization in OIR, revealing a new role for p53/let-7b/IGF-1R axis in the retina. Future investigations on this (and connected) pathway could further our understanding of other degenerative choroidopathies, such as geographic atrophy.
  • N-acetylcysteine resolves placental inflammatory-vasculopathic changes in
           mice consuming a high fat diet
    • Abstract: Publication date: Available online 17 August 2019Source: The American Journal of PathologyAuthor(s): Lyda Williams, Emmanuel S. Burgos, Patricia M. Vuguin, Clarence R. Manuel, Ryan Pekson, Swapna Munnangi, Sandra E. Reznik, Maureen J. Charron The mechanism by which poor maternal nutrition can impact the long-term health of offspring is poorly understood. In mice, we previously demonstrated maternal high fat diet (HFD) exposure results in reduced fetal growth regardless of maternal genotype. Here, we test our hypothesis that maternal HFD-induced inflammation contributes to metabolic disease susceptibility of the offspring via alterations in the placenta. The effect of maternal genotype, diet, and treatment with the anti-inflammatory compound N-acetylcysteine (NAC) on placental morphology was investigated. Placentas from wild type (WT) dams maintained on a HFD, but not those heterozygous (+/-) for Glut4 (Slc2a4) on the same diet, demonstrated an increase in decidual inflammation and vasculopathy occurring together. NAC administration resulted in amelioration of HFD-induced decidual vasculopathy independent of offspring genotype and sex. Consistent with these morphologic improvements, placentas from HFD dams treated with NAC demonstrated decreased mRNA and immunostaining of interleukin-1β and MCP1, decreased mRNA of inflammatory genes, and increased mRNA of Vegfa. These results strongly suggest consumption of a HFD results in vascular changes in placenta reflected by alterations in expression of pivotal vascular developmental markers and inflammatory genes all of which are ameliorated by NAC. These placental changes play a key role in the increased programmed metabolic disease of HFD-exposed offspring.
  • Myeloid-Derived Lymphatic Endothelial Cell Progenitors Significantly
           Contribute to Lymphatic Metastasis in Clinical Breast Cancer
    • Abstract: Publication date: Available online 15 August 2019Source: The American Journal of PathologyAuthor(s): Lisa Volk-Draper, Radhika Patel, Nihit Bhattarai, Jie Yang, Andrew Wilber, David DeNardo, Sophia RanLymphatic metastasis is a high impact prognostic factor for mortality of breast cancer (BC) patients, and directly depends on tumor-associated lymphatic vessels. We previously reported that lipopolysaccharide-induced inflammatory lymphangiogenesis is strongly promoted by myeloid-derived lymphatic endothelial cell progenitors (M-LECP) derived from the bone marrow (BM). As BC recruit massive numbers of pro-vascular myeloid cells, we hypothesized that M-LECP, within this recruited population, are specifically programmed to promote tumor lymphatics that increase lymph node metastasis. In support of this hypothesis, high levels of M-LECP were found in peripheral blood and tumor tissues of BC patients. Moreover, the density of M-LECP and lymphatic vessels positive for myeloid marker proteins strongly correlated with patient node status. It was also established that tumor M-LECP co-express lymphatic-specific, stem/progenitor and M2-type macrophage markers that indicate their BM hematopoietic-myeloid origin and distinguish them from mature lymphatic endothelial cells, tumor-infiltrating lymphoid cells, and tissue-resident macrophages. Using four orthotopic BC models, we show that mouse M-LECP are similarly recruited to tumors and integrate into pre-existing lymphatics. Finally, we demonstrate that adoptive transfer of in vitro differentiated M-LECP, but not naïve or non-differentiated BM cells, significantly increased metastatic burden in ipsilateral lymph nodes. These data support a causative role of BC-induced lymphatic progenitors in tumor lymphangiogenesis and suggest molecular targets for their inhibition.
  • Prostate Cancer- The Role of Inflammation and Chemokines
    • Abstract: Publication date: Available online 14 August 2019Source: The American Journal of PathologyAuthor(s): Aradhana Rani, Prokar Dasgupta, John J. MurphyProstate cancer (PC) is a leading cause of death in men. Inflammation is one of the initiating processes whereby cells are trafficked into the tumor microenvironment by specific cytokines termed chemokines. This recruitment is complex and involves diverse leucocyte subsets with pro-cancer and anti-cancer functions. Chemokines promote/abrogate proliferation of cancerous cells, block/aid apoptosis and are instrumental/detrimental in cancer cell migration required for metastasis. Chemokines guide the release/transport of immune cells that serve as chaperones at sites of inflammation and following subsequent activation, lead to an immune response. The variety of immune cells recruited at the site of tumor initiation possess unique functions and the plethora of chemokines released by each cell derived from a progenitor cell activated under a defined set of conditions dictates its specific role in cancer progression/regression. Geographic consequences that govern the climate and endemic diseases along with the associated evolutionary effects which at times protect populations from one disease could lead to genetic variations that determine a role for ethnicity and race in PC risk and susceptibility. Dysregulated expression or an imbalance in the homeostatic mechanisms associated with chemokines is implicated in PC. This review discusses the role of inflammation and chemokines in PC.
  • The serotype-specific role of RocA polymorphisms in the pathogenesis of
           invasive group A streptococcal infections
    • Abstract: Publication date: Available online 14 August 2019Source: The American Journal of PathologyAuthor(s): Stephan Brouwer, Mark J. Walker
  • KH-Type Splicing Regulatory Protein Controls Colorectal Cancer Cell Growth
           and Modulates the Tumor Microenvironment
    • Abstract: Publication date: Available online 9 August 2019Source: The American Journal of PathologyAuthor(s): Francesco Caiazza, Katarzyna Oficjalska, Miriam Tosetto, James J. Phelan, Sinéad Noonan, Petra Martin, Kate Killick, Laura Breen, Fiona O’Neill, Blathnaid Nolan, Simon Furney, Robert Power, David Fennelly, Charles S. Craik, Jacintha O’Sullivan, Kieran Sheahan, Glen A. Doherty, Elizabeth J. RyanKH-type splicing regulatory protein (KHSRP) is a multifunctional nucleic acid binding protein implicated in key aspects of cancer cell biology: inflammation and cell-fate determination. However, the role KHSRP plays in colorectal cancer (CRC) tumorigenesis remains largely unknown. Using a combination of in silico analysis of large datasets, ex vivo analysis of protein expression in patients, and mechanistic studies using in vitro models of CRC, we investigated the oncogenic role of KHSRP. We demonstrated KHSRP expression in the epithelial and stromal compartments of both primary and metastatic tumors. Elevated expression was found in tumor versus matched normal tissue, and these findings were validated in larger independent cohorts in silico. KHSRP expression was a prognostic indicator of worse overall survival (HR=3.74, 95% CI = 1.43 to 22.97, P = 0.0138). Mechanistic data in CRC cell line models supported a role of KHSRP in driving epithelial cell proliferation in both a primary and metastatic setting, through control of the G1/S transition. Additionally, KHSRP promoted a pro-angiogenic extracellular environment by regulating the secretion of oncogenic proteins involved in diverse cellular processes such as migration and response to cellular stress. Our study provides novel mechanistic insight into the tumor-promoting effects of KHSRP in CRC.
  • Localization and regulation of polymeric immunoglobulin receptor (PIgR) in
           healthy and diseased human kidney
    • Abstract: Publication date: Available online 9 August 2019Source: The American Journal of PathologyAuthor(s): Krzysztof M. Krawczyk, Helén Nilsson, Jenny Nyström, David Lindgren, Karin Leandersson, Karl Swärd, Martin E. Johansson The polymeric immunoglobulin receptor (PIgR) constitutes an important part of the immune system by mediating transcytosis of dimeric IgA into mucosal fluids. Although well studied in organs such as the intestine, the regulation and localization of PIgR in human kidney are incompletely characterized. Here, using immunohistochemistry we show that in healthy human kidneys, PIgR is expressed by the progenitor-like tubular scattered cells of the proximal tubules and by parietal epithelial cells of glomeruli. We further show that proximal tubular expression of PIgR becomes widespread during kidney disease, correlating to elevated levels of urinary secretory IgA as determined by ELISA. Urinary secretory IgA levels also correlated to the degree of tubular fibrosis, plasma creatinine, and urea levels. In addition, primary tubular cells were cultured to study the function and regulation of PIgR in vitro. Cellular PIgR expression was induced by conditioned medium from activated human leukocytes, as well as by inflammatory cytokines, whereas transforming growth factor-β1 caused decreased expression. Furthermore, IFNγ increased the transcytosis of dimeric IgA in cultured tubular cells. Finally, a correlation study of mRNA data from the Genotype-Tissue Expression portal indicated that PIGR mRNA expression in kidney correlates to the expression of TNFSF13, a cytokine involved in plasma cell class switching to IgA. These results indicate that PIgR induction is an integral part of the injury phenotype of renal tubular cells.
  • Dichotomous Role of Plasmin in Regulation of Macrophage Function after
           Acetaminophen Overdose
    • Abstract: Publication date: Available online 2 August 2019Source: The American Journal of PathologyAuthor(s): Katherine Roth, Jenna Strickland, Nikita Joshi, Meihong Deng, Rebekah Kennedy, Cheryl E. Rockwell, James P. Luyendyk, Timothy R. Billiar, Bryan L. Copple Kupffer cells and monocyte-derived macrophages are critical for liver repair after acetaminophen (APAP) overdose. These cells produce pro-mitogenic cytokines and growth factors, and phagocytose dead cell debris, a process that is critical for resolution of inflammation. The factors that regulate these dynamic functions of macrophages after APAP overdose, however, are not fully understood. We tested the hypothesis that the fibrinolytic enzyme, plasmin, is a key regulator of macrophage function after APAP-induced liver injury. In these studies, inhibition of plasmin in mice with tranexamic acid delayed up-regulation of proinflammatory cytokines after APAP overdose. In culture, plasmin directly, and in synergy with high-mobility group B1, stimulated Kupffer cells and bone-marrow–derived macrophages to produce cytokines by a mechanism that required NF-κB. Inhibition of plasmin in vivo also prevented trafficking of monocyte-derived macrophages into necrotic lesions after APAP overdose. This prevented phagocytic removal of dead cells, prevented maturation of monocyte-derived macrophages into F4/80-expressing macrophages, and prevented termination of proinflammatory cytokine production. Our studies reveal further that phagocytosis is an important stimulus for cessation of pro-inflammatory cytokine production as treatment of proinflammatory, monocyte-derived macrophages, isolated from APAP-treated mice, with necrotic hepatocytes decreased expression of pro-inflammatory cytokines. Collectively, these studies demonstrate that plasmin is an important regulator of macrophage function after APAP overdose.
  • Tumor-promoting activity of long non-coding RNA LINC00466 in lung
           adenocarcinoma via microRNA-144–regulated HOXA10 axis
    • Abstract: Publication date: Available online 2 August 2019Source: The American Journal of PathologyAuthor(s): Tiangang Ma, Yanbing Hu, Yingxue Guo, Bingdi Yan Previous investigations have implicated long non-coding RNAs (lncRNAs) in lung adenocarcinoma, which is an aggressive disease with poor prognosis and high mortality. Through the alteration of lung adenocarcinoma–related lncRNA and microRNA (miRNA) based on microarray analysis, our aim was to understand that the role of LINC00466 and miR-144 in lung adenocarcinoma progression. The relationship among LINC00466, miR-144, and HOXA10 was also verified. Moreover, to examine whether the LINC00466/miR-144/HOXA10 axis contributed to the cellular processes in lung adenocarcinoma, A549 and XWLC-05 cells were transduced with siRNA (si)-LINC00466, si-HOXA10, or miR-144 mimic plasmids. Highly expressed LINC00466 and HOXA10 and lowly expressed miR-144 were eventually revealed in lung adenocarcinoma tissues. HOXA10 was down-regulated in response to the overexpression of miR-144, whereas inhibition of LINC00466 decreased its binding to miR-144, thereby up-regulating miR-144, which in turn halted the lung adenocarcinoma progression. LINC00466 silencing or miR-144 up-regulation exerted an inhibitory role in the tumorigenicity, invasion, migration, and proliferation, and also promoted apoptosis of lung adenocarcinoma cells. Furthermore, tumor formation was inhibited by knockdown of LINC00466 or overexpression of miR-144. Taken together, LINC00466 could restrain the miR-144 expression to up-regulate HOXA10 and therefore promote lung adenocarcinoma.
  • Integrated Molecular Analysis of Papillary Renal Cell Carcinoma and
           Precursor Lesions Unfolds Evolutionary Process from Kidney Progenitor-Like
    • Abstract: Publication date: Available online 2 August 2019Source: The American Journal of PathologyAuthor(s): Rola M. Saleeb, Mina Farag, Qiang Ding, Michelle Downes, Georg Bjarnason, Fadi Brimo, Pamela Plant, Fabio Rotondo, Zsuzsanna Lichner, Antonio Finelli, George M. Yousef Papillary renal cell carcinoma (PRCC) is the most common type of RCC in end-stage kidney disease (ESKD). Papillary adenoma (PA) is a small benign lesion morphologically similar to PRCC and is suggested by some to be its precursor. PA is also very prevalent in ESKD. The evolution of PAs to PRCCs and their relationship to ESKD is poorly understood. One-hundred and forty PAs, normal kidneys, ESKDs, and PRCCs were analyzed. Previously described markers of renal tubular progenitor cells were performed using immunohistochemistry and quantified with digital analysis (n=140). Progenitor cells were significantly increased in ESKD (P < 0.0001) and PAs (P = 0.02) in comparison to the normal kidney. Pathway analysis using global miRNA (n=12) and chromosomal Copy number variations (n=21) revealed a common developmental theme between PA and the PRCCs. Whole exome next-generation sequencing (n=12) showed a KMT2C specific pathogenic mutation among all PAs and PRCCs. KMT2C is a Chr 7 epigenetic regulator implicated in development and oncogenesis. Collectively results show a possible connection of PRCCs to PA and progenitor-like cell population, which are increased in response to renal tubular injury. Additionally, each PRCC histological subtype had its own set of mutational changes indicating divergence from a common precursor. The study reports previously unknown biological aspects of PRCC development; and could influence current surveillance criteria and early detection strategies of PRCC tumors.
  • Double-stranded RNA is a novel molecular target in osteomyelitis
           pathogenesis: a translational avian model for human bacterial
           chondronecrosis with osteomyelitis
    • Abstract: Publication date: Available online 2 August 2019Source: The American Journal of PathologyAuthor(s): Elizabeth Greene, Joshua Flees, Ahmed Dhamad, Adnan Alrubaye, Stephen Hennigan, Jason Pleimann, Mark Smeltzer, Sue Murray, Jennifer Kugel, James Goodrich, Avril Robertson, Robert Wideman, Douglas Rhoads, Sami Dridi Osteomyelitis remains a serious inflammatory bone disease that affects millions of individuals worldwide and for which there is no effective treatment. In spite of scientific evidence that Staphylococcus bacteria are the most common causative species for human bacterial chondronecrosis with osteomyelitis (BCO), much remains to be understood about the underlying virulence mechanisms. Here we show increased levels of dsRNA in infected bone in a Staphylococcus-induced chicken BCO model and in human osteomyelitis samples. Administration of synthetic (Poly:IC) or genetic (Alu) dsRNA induces human osteoblast cell death. Similarly, infection with Staphylococcus isolated from chicken BCO induces dsRNA accumulation and cell death in human osteoblast cell cultures. Both dsRNA administration and Staphylococcus infection activate NLRP3 inflammasome and increases IL18 and IL1B gene expression in human osteoblasts. Pharmacological inhibition with Ac-YVAD-cmk of caspase 1, a critical component of the NLRP3 inflammasome, prevents DICER1 dysregulation-, and dsRNA-induced osteoblast cell death. NLRP3 inflammasome and its components are also activated in bone from BCO chickens and humans with osteomyelitis, compared to their healthy counterparts. These findings provide a rationale for the use of chicken BCO as a human-relevant spontaneous animal model for osteomyelitis, and identify dsRNA as a new treatment target for this debilitating bone pathogenesis.
  • Blockade of Lymphangiogenesis Shapes Tumor-Promoting Adipose Tissue
    • Abstract: Publication date: Available online 29 July 2019Source: The American Journal of PathologyAuthor(s): Marek Wagner, Eli Sihn Steinskog, Helge WiigTumor-associated lymphangiogenesis correlates with lymph node metastasis and poor outcome in several human malignancies. Additionally, the presence of functional lymphatic vessels regulates the formation of tumor inflammatory and immune microenvironments. Although lymphatic structures are often found deeply integrated into the fabric of adipose tissue, the impact of lymphangiogenesis on tumor-associated adipose tissue has not yet been investigated. Using K14-VEGFR3-Ig mice that constitutively express soluble VEGFR3-Ig in the skin, scavenging VEGF-C and VEGF-D, the role of lymphangiogenesis in the generation of an inflammatory response within tumor-associated adipose tissue was studied. Macrophages expressing the hyaluronan receptor LYVE-1 were found within peritumoral adipose tissue from melanoma-bearing K14-VEGFR3-Ig mice, which were further enriched with alternatively activated macrophages based on surface marker CD301/CLEC10A expression. The blockade of lymphangiogenesis also resulted in accumulation of the cytokine interleukin-6, which correlated with enhanced macrophage proliferation of the alternatively activated phenotype. Furthermore, melanomas co-implanted with freshly isolated adipose tissue macrophages grew more robustly when compared with melanomas growing alone. In human cutaneous melanomas, adipocyte-selective FABP4 transcripts closely correlated with gene signatures of CLEC10A and were associated with poor overall survival. These data suggest that the blockade of pathways regulating lymphatic vessel formation shapes an inflammatory response within tumor-associated adipose tissue by facilitating accumulation of tumor-promoting alternatively activated macrophages.
  • Polymorphisms in RocA Contribute to the Molecular Pathogenesis of Serotype
           M28 Group A Streptococcus
    • Abstract: Publication date: Available online 29 July 2019Source: The American Journal of PathologyAuthor(s): Paul E. Bernard, Priyanka Kachroo, Jesus M. Eraso, Luchang Zhu, Jessica E. Madry, Sarah E. Linson, Matthew Ojeda Saavedra, Concepcion Cantu, James M. Musser, Randall J. OlsenTwo-component systems (TCSs) are signal transduction proteins that enable bacteria to respond to external stimuli by altering the global transcriptome. Accessory proteins interact with TCSs to fine-tune their activity. In group A streptococcus (GAS), RocA is an accessory protein that functions with the control of virulence regulator/sensor TCS, which regulates approximately 15% of the GAS transcriptome. Whole-genome sequencing analysis of serotype M28 GAS strains collected from invasive infections in humans identified a higher number of missense (amino acid altering) and nonsense (protein truncating) polymorphisms in rocA than expected. We hypothesized that polymorphisms in RocA alter the global transcriptome and virulence of serotype M28 GAS. We used naturally-occurring clinical isolates with rocA polymorphisms (n=48), an isogenic rocA deletion mutant strain, and five isogenic rocA polymorphism mutant strains to perform genome-wide transcript analysis (RNA-seq), in vitro virulence factor assays, and mouse and nonhuman primate pathogenesis studies to test this hypothesis. Results demonstrated that polymorphisms in rocA result in either a subtle transcriptome change causing a wild-type–like virulence phenotype, or a substantial transcriptome change leading to a significantly increased virulence phenotype. Each polymorphism had a unique effect on the global GAS transcriptome. Taken together, our data show that naturally-occurring polymorphisms in one gene encoding an accessory protein can significantly alter the global transcriptome and virulence phenotype of GAS, an important human pathogen.
  • The Origin of Follicular Bile Acids in the Human Ovary
    • Abstract: Publication date: Available online 29 July 2019Source: The American Journal of PathologyAuthor(s): Ruxandra A. Nagy, Harry Hollema, Daniela Andrei, Angelika Jurdzinski, Folkert Kuipers, Annemieke Hoek, Uwe J.F. TietgeBile acids (BA) are present in ovarian follicular fluid (FF) and have been linked to embryo development. However, information on the source of ovarian BA is scarce. Therefore, we aimed to explore local ovarian synthesis and BA transport from blood into FF. BA levels were determined in matching FF and serum from women who underwent in vitro fertilization. In vitro BA production by human mural (MCG) and cumulus granulosa cells (CGC) was measured by mass spectrometry. Gene and protein expression were quantified in human MCG and CGC and in human ovarian tissue by quantitative PCR and Western blot/immunohistochemistry, respectively. There was a significant correlation between the levels of BA in blood and FF (rs=0.186, P = 0.027). Interestingly, levels of FF BA were almost double those in blood (P < 0.001) with a higher percentage of primary BA, indicating that, in addition to passive diffusion, other sources of ovarian BA might exist. The key BA synthesis enzyme CYP7A1 was absent in MGC and CGC, and there was no evidence of BA production in vitro. Therefore, local ovarian BA production is unlikely. However, common BA importers (NTCP, ASBT) and an exporter (ABCC3) were identified in GC, theca cells, and the oocyte. In summary, these results suggest that passive and active transport of BA from blood into FF constitute sources of FF BA.
  • Activation of PINK1-Parkin–Mediated Mitophagy Degrades Mitochondrial
           Quality Control Proteins in Fuchs Endothelial Corneal Dystrophy
    • Abstract: Publication date: Available online 27 July 2019Source: The American Journal of PathologyAuthor(s): Takashi Miyai, Shivakumar Vasanth, Geetha Melangath, Neha Deshpande, Varun Kumar, Anne-Sophie Benischke, Yuming Chen, Marianne O. Price, Francis W. Price, Ula V. JurkunasCorneal endothelium (CE) is a monolayer of mitochondria-rich cells, critical for maintaining corneal transparency compatible with clear vision. Fuchs endothelial corneal dystrophy (FECD) is a heterogeneous genetically complex disorder, where oxidative stress plays a key role in the rosette formation during the degenerative loss of CE. Increased mitochondrial fragmentation along with excessive mitophagy activation has been detected in FECD; however, the mechanism of aberrant mitochondrial dynamics in CE cell loss is poorly understood. Here, we investigate the role of oxidative stress in mitophagy activation in FECD. Immunoblotting of FECD ex vivo specimens revealed an accumulation of PINK1 and phospho-Parkin (Ser65) along with loss of total Parkin and total Drp1. Similarly, modeling of rosette formation with menadione (MN), led to phospho-Parkin accumulation in fragmented mitochondria resulting in mitophagy-induced mitochondrial clearance, albeit possibly in a PINK1 independent manner. Loss of PINK1, phospho-Drp1 and total Drp1 was prominent after MN-induced oxidative stress, but not after mitochondrial depolarization by carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Moreover, MN-induced mitophagy led to degradation of Parkin along with sequestration of Drp1 and PINK1 that was rescued by mitophagy inhibition. This study shows that in FECD intracellular oxidative stress induces Parkin-mediated mitochondrial fragmentation where endogenous Drp1 and PINK1 are sequestered and degraded by mitophagy during degenerative loss of post-mitotic cells of ocular tissue.
  • Mechanisms of ERBB3 Action in Human Neoplasia
    • Abstract: Publication date: Available online 25 July 2019Source: The American Journal of PathologyAuthor(s): Laurel Black, Jody Fromm Longo, Steven L. CarrollIt is well established that the epidermal growth factor receptor, ERBB2/HER2 and, to a lesser extent, ERBB4/HER4 promote the pathogenesis of many types of human cancers. In contrast, the role that ERBB3/HER3, the fourth member of the ERBB family of receptor tyrosine kinases, plays in these diseases is poorly understood and, until recently, underappreciated. In large part, this was because early structural and functional studies suggested that ERBB3 had little, if any, intrinsic tyrosine kinase activity and thus was unlikely to be an important therapeutic target. Since then, however, numerous publications have demonstrated an important role for ERBB3 in carcinogenesis, metastasis, and acquired drug resistance. Further, somatic ERBB3 mutations are frequently encountered in many types of human cancers. Dysregulation of ERBB3 trafficking as well as cooperation with other receptor tyrosine kinases further enhances ERBB3’s role in tumorigenesis and drug resistance. As a result of these advances in our understanding of the structure and biochemistry of ERBB3, and a growing focus on the development of precision and combinatorial therapeutic regimens, ERBB3 is increasingly considered to be an important therapeutic target in human cancers. In this review, we discuss the unique structural and functional features of ERBB3 and how this information is being used to develop effective new therapeutic agents that target ERBB3 in human cancers.
  • Antitumor Activity of a Novel Fibroblast Growth Factor Receptor (FGFR)
           Inhibitor for Intrahepatic Cholangiocarcinoma
    • Abstract: Publication date: Available online 24 July 2019Source: The American Journal of PathologyAuthor(s): Chiara Raggi, Karim Fiaccadori, Mirella Pastore, Margherita Correnti, Benedetta Piombanti, Elisa Forti, Nadia Navari, Giovanni Abbadessa, Terence Hall, Annarita Destro, Luca Di Tommaso, Massimo Roncalli, Fanyin Meng, Shannon Glaser, Elisabetta Rovida, Caterina Peraldo-Neia, Paula Olaizola, Jesus M. Banales, Alessio Gerussi, Alessandra ElveviFibroblast growth factor receptor 2 (FGFR2) might have an important role in the pathogenesis and biology of cholangiocarcinoma (CCA). We examined FGFR expression in CCA tumor specimens obtained from patients and CCA cell lines, and then determined the effects of the novel FGFR inhibitor, derazantinib (DZB, formally ARQ 087), which is currently in clinical phase 2 trials for intrahepatic CCA. DZB inhibited the growth of CCA cell lines in a dose-dependent manner, and ERK1/2 and AKT. It also activated apoptotic and cell growth arrest signaling. DZB reduced the in vitro invasiveness and the expression of key epithelial-to-mesenchymal transition genes. The in vitro data correlated with the expression of FGFRs in human CCA specimens by immunohistochemistry (FGFR1 30% and FGFR2 65% positive), and the CCA cell lines assayed by Western blot analysis. These correlated in vitro studies suggest that FGFR may play an important role in the pathogenesis and biology of CCA. Our findings support the notion that FGFR inhibitors, like DZB, should be further evaluated at the clinical stage as targeted therapy for CCA treatment.
  • Correction
    • Abstract: Publication date: August 2019Source: The American Journal of Pathology, Volume 189, Issue 8Author(s):
  • Silencing of LAMC2 Reverses Epithelial-Mesenchymal Transition and Inhibits
           Angiogenesis in Cholangiocarcinoma via Inactivation of the Epidermal
           Growth Factor Receptor Signaling Pathway
    • Abstract: Publication date: August 2019Source: The American Journal of Pathology, Volume 189, Issue 8Author(s): Yao-Fei Pei, Jie Liu, Jian Cheng, Wei-Ding Wu, Xi-Qiang LiuCholangiocarcinoma (CCA) is a malignant cancer that is associated with high mortality rates. The relationship between laminin γ 2 chain gene (LAMC2) and epidermal growth factor receptor (EGFR) has been previously documented in gastric cancer and oral squamous cell carcinoma. This study investigates the role of LAMC2 in epithelial-mesenchymal transition (EMT) and angiogenesis in CCA and explores the underlying mechanism(s). Differentially expressed genes related to CCA were initially screened using a microarray analysis, and the interaction between LAMC2 and the EGFR signaling pathway was identified. To determine the regulatory effects of LAMC2 on CCA progression, LAMC2 was silenced or overexpressed and the EGFR signaling pathway was activated or blocked. Subsequently, the regulation effects of LAMC2 were evaluated on the expression of EMT markers, invasion and migration of CCA cells, as well as microvessel density in nude mice. Microarray analysis demonstrated that highly expressed LAMC2 is linked to CCA development, which involves the EGFR signaling pathway. When LAMC2 expression was increased, the EGFR signaling pathway and EMT were activated in CCA tissues. Silencing of LAMC2 as well as EGFR signaling pathway inhibition led to suppression of EMT, cell invasion, and migration abilities in vitro, as well as angiogenesis in vivo. This study demonstrates that LAMC2 silencing suppresses the activity of the EGFR signaling pathway, thus functioning as a tumor suppressor in CCA.
  • Notch Signaling in Osteogenesis, Osteoclastogenesis, and Angiogenesis
    • Abstract: Publication date: August 2019Source: The American Journal of Pathology, Volume 189, Issue 8Author(s): Zhengliang Luo, Xifu Shang, Hao Zhang, Guangxi Wang, Patrick A. Massey, Shane R. Barton, Christopher G. Kevil, Yufeng DongSkeletal tissue development and regeneration in mammals are intricate, multistep, and highly regulated processes. Various signaling pathways have been implicated in the regulation of these processes, including Notch. Notch signaling is a highly conserved, intercellular signaling pathway that regulates cell proliferation and differentiation, determines cell fate decision, and participates in cellular process in embryonic and adult tissue. Here, we review recent data showing the regulation of Notch signaling in osteogenesis, osteoclastogenesis, and angiogenesis. These processes are cell-context–dependent via direct or indirect mechanisms. Furthermore, Notch signaling may be highly beneficial for efficient coupling of osteogenesis and angiogenesis for tissue engineering and skeletal repair, which is critical to develop clinically therapeutic options.
  • Obesity-Associated Extracellular Matrix Remodeling Promotes a Macrophage
           Phenotype Similar to Tumor-Associated Macrophages
    • Abstract: Publication date: Available online 16 July 2019Source: The American Journal of PathologyAuthor(s): Nora L. Springer, Neil M. Iyengar, Rohan Bareja, Akanksha Verma, Maxine Jochelson, Dilip D. Giri, Xi Kathy Zhou, Olivier Elemento, Andrew J. Dannenberg, Claudia FischbachObesity is associated with adipose inflammation, defined by macrophages encircling dead adipocytes, as well as extracellular matrix (ECM) remodeling and increased risk of breast cancer. Whether ECM affects macrophage phenotype in obesity is uncertain. A better understanding of this relationship could be strategically important to reduce cancer risk or improve outcomes in the obese. Utilizing clinical samples, computational approaches, and in vitro decellularized ECM models, this study quantified the relative abundance of pro (M1)- and anti (M2)-inflammatory macrophages in human breast adipose tissue, determined molecular similarities between obesity and tumor-associated macrophages, and assessed the regulatory effect of obese versus lean ECM on macrophage phenotype. Our results suggest that breast adipose tissue contains more M2-biased than M1-biased macrophages across all body mass index (BMI) categories. Obesity further increased M2-biased macrophages but did not affect M1-biased macrophage density. Gene Set Enrichment Analysis (GSEA) suggested that breast tissue macrophages from obese versus lean women are more similar to tumor-associated macrophages (TAMs). These changes positively correlated with adipose tissue interstitial fibrosis, and in vitro experiments indicated that obese ECM directly stimulates M2-biased macrophage functions. However, mammographic density cannot be used as a clinical indicator of these changes. Collectively, these data suggest that obesity-associated interstitial fibrosis promotes a macrophage phenotype similar to TAMs, which may contribute to the link between obesity and breast cancer.
  • LRRC8A Expression Influences Growth of Esophageal Squamous Cell Carcinoma
    • Abstract: Publication date: Available online 16 July 2019Source: The American Journal of PathologyAuthor(s): Tomoki Konishi, Atsushi Shiozaki, Toshiyuki Kosuga, Michihiro Kudou, Katsutoshi Shoda, Tomohiro Arita, Hirotaka Konishi, Shuhei Komatsu, Takeshi Kubota, Hitoshi Fujiwara, Kazuma Okamoto, Mitsuo Kishimoto, Eiichi Konishi, Yoshinori Marunaka, Eigo OtsujiThe volume-regulated anion channel is composed of leucine-rich repeat–containing protein A (LRRC8A), and is activated by hypotonic conditions to implement the process of regulatory volume decrease. The role of LRRC8A in regulating genes related to progression of esophageal squamous cell carcinoma (ESCC) was investigated, as well as the prognostic significance of LRRC8A expression in this tumor. Knockdown experiments were conducted using ESCC cell lines and LRRC8A siRNA to assess the influence of this protein on tumor function. In addition, the gene expression profile of ESCC was determined by microarray analysis. Immunohistochemistry was performed on 64 primary tumor samples from ESCC patients receiving radical esophagectomy. It was found that depletion of LRRC8A decreased cell proliferation and migration, and also promoted apoptosis. Microarray data demonstrated G1/S checkpoint regulation and up-regulation or down-regulation of PI3K/AKT signaling, MMP, and integrin signaling–related genes (including p21, p27, MMP1, and ITGAV) in LRRC8A-depleted cells. Immunohistochemistry showed that LRRC8A expression was related to the pT and pN categories, and strong LRRC8A expression was correlated with a worse prognosis of ESCC. These findings indicate that LRRC8A modulates tumor progression by influencing cell cycle, apoptosis, and migration, providing new insights into its function as an effector or biomarker of ESCC.
  • This Month in AJP
    • Abstract: Publication date: Available online 15 July 2019Source: The American Journal of PathologyAuthor(s):
  • Penetration of CD8+ Cytotoxic T Cells into Large Target, Tissue Cysts of
           Toxoplasma gondii, Leads to Its Elimination
    • Abstract: Publication date: Available online 10 July 2019Source: The American Journal of PathologyAuthor(s): Ashish Tiwari, Rancie Hannah, Jenny Lutshumba, Eri Ochiai, Louis M. Weiss, Yasuhiro SuzukiCD8+ cytotoxic T cells kill target cells through direct cell-cell contact. However, it remains unclear how these T cells eliminate a target of large mass. We investigated how CD8+ T cells remove tissue cysts of Toxoplasma gondii, which can grow to the size of>50 μm in diameter within infected cells. Notably, immunohistologic analyses in the brains of infected mice visualized the presence of numbers of CD8+ immune T cells that had migrated halfway through the cyst wall as well as T cells located fully within the cysts. Perforin was required for their invasion and cyst elimination. Cysts invaded by the T cells displayed morphologic deterioration and destruction. Within these deteriorated cysts, granular structures intensely positive for granzyme B were detected in association with T. gondii bradyzoites. Furthermore, the bradyzoites within the destroyed cysts were located within accumulated ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia and Ly6C+ macrophages, suggesting that these phagocytes had phagocytosed those organisms for their eradication. The present study uncovered a previously unappreciated capability of CD8+ cytotoxic T cells to penetrate into a large target, T. gondii cysts, for their elimination. This invasive capability of CD8+ cytotoxic T cells in collaboration with phagocytes appears to be a powerful effector mechanism that functions against not only T. gondii cysts but also other large targets, including solid cancers.
  • Liver-Specific but Not Retina-Specific Hepcidin Knockout Causes Retinal
           Iron Accumulation and Degeneration
    • Abstract: Publication date: Available online 6 July 2019Source: The American Journal of PathologyAuthor(s): Bailey H. Baumann, Wanting Shu, Ying Song, Jacob Sterling, Zbynek Kozmik, Samira Littleton-Lakhal, Joshua L. DunaiefThe liver secretes hepcidin (Hepc) into the bloodstream to reduce blood iron levels. Hepc accomplishes this by triggering degradation of the only known cellular iron exporter ferroportin in the gut, macrophages, and the liver. We previously demonstrated that systemic HepcKO mice, which have high serum iron, develop retinal iron overload and degeneration. However, it was unclear whether this is caused by high blood iron levels or alternatively, due to retinal iron influx that would normally be regulated by retina-produced Hepc. To address this question, retinas of liver-specific (LS) and retina-specific (RS) HepcKO mice were studied. LS-Hepc KO mice had elevated blood and RPE iron levels and increased free (labile) iron levels in the retina despite an intact blood-retinal barrier. This led to RPE hypertrophy associated with lipofuscin-laden lysosome accumulation. Photoreceptors also degenerated focally. In contrast, there was no change in retinal or RPE iron levels or degeneration in the RS-HepcKO mice. These data indicate that high blood iron levels can lead to retinal iron accumulation and degeneration. High blood iron levels can occur in patients with hereditary hemochromatosis or result from use of iron supplements or multiple blood transfusions. Our results suggest that high blood iron levels may cause or exacerbate retinal disease.
  • Repeated Exposure to Streptococcus pneumoniae Exacerbates Chronic
           Obstructive Pulmonary Disease
    • Abstract: Publication date: Available online 18 June 2019Source: The American Journal of PathologyAuthor(s): Xuxu Gou, Qiao Zhang, Sunil More, Gayan Bamunuarachchi, Yurong Liang, Faizan Haider Khan, Rachel Maranville, Emily Zuniga, Changzheng Wang, Lin LiuStreptococcus pneumoniae (S. pneumoniae) is commonly found in patients with chronic obstructive pulmonary disease (COPD) and is linked to acute exacerbation of COPD. However, current clinical therapy neglects asymptomatic insidious S. pneumoniae colonization. We studied the roles of repeated exposure to S. pneumonia in COPD progression using a mouse model. C57BL/6J mice were intranasally inoculated with S. pneumoniae ST262 every four weeks with or without cigarette smoke (CS) exposure up to 20 weeks to maintain persistent S. pneumoniae (SP) presence in the lower airways. SP enhanced CS-induced inflammatory cell infiltration at 12 to 20 weeks of exposure. SP also increased CS-induced release of inflammatory cytokines, including interleukin-1β, tumor necrosis factor-α, interleukin-12 (p70), and interleukin-5 at 20 weeks of exposure. Moreover, a combination of CS and SP caused alveolar epithelial injury, a decline in lung function, and an increased expression of platelet activating factor receptor and bacterial load. Our results suggest that repeated exposure to S. pneumonia in lower airways exacerbates CS-induced COPD.
  • The Protective Role of Natriuretic Peptide Receptor 2 against High Salt
           Injury in the Renal Papilla
    • Abstract: Publication date: Available online 18 June 2019Source: The American Journal of PathologyAuthor(s): George J. Dugbartey, Breandan Quinn, Lingfeng Luo, Deanne M. Mickelsen, Sara K. Ture, Craig N. Morrell, Jan Czyzyk, Marvin M. Doyley, Chen Yan, Bradford C. Berk, Vyacheslav A. KorshunovMutations in natriuretic peptide receptor 2 (Npr2) gene cause a rare form of short-limbed dwarfism, but its physiologic effects have not been well studied. Human and mouse genetic data suggest that Npr2 in the kidney plays a role in salt homeostasis. Here, we described anatomical changes within renal papilla of Npr2 knockout (Npr2−/−) mice. Dramatic reduction was found in diuresis and albuminuria was evident after administration of 1% NaCl in drinking water in Npr2−/− and heterozygous (Npr2+/−) mice compared to their wild-type (Npr2+/+) littermates. There was indication of renal epithelial damage accompanied by high numbers of red blood cells and inflammatory cells (Mac2) and an increase of renal epithelial damage marker (TIM-1) in Npr2−/− mice. Addition of 1% NaCl tended to increase apoptotic cells (cleaved Caspase 3) in the renal papilla of Npr2−/− mice. In vitro, genetic silencing of the Npr2 abolished protective effects of C-type natriuretic peptide, a ligand for Npr2, against death of M-1 kidney epithelial cells exposed to 360mM NaCl. Finally, significantly lower levels of expression of the NPR2 protein were detected in renal samples of hypertensive compared to normotensive human subjects. Taken together, these findings suggest that Npr2 is essential to protect renal epithelial cells from high concentrations of salt and prevent kidney injury.
  • Müller Cell–Localized GPR81 (HCA1) Regulates Inner Retinal Vasculature
           via Norrin/Wnt Pathways
    • Abstract: Publication date: Available online 18 June 2019Source: The American Journal of PathologyAuthor(s): Ankush Madaan, Prabhas Chaudhari, Mathieu Nadeau-Vallée, David Hamel, Tang Zhu, Grant Mitchell, Mark Samuels, Sheetal Pundir, Rabah Dabouz, Colin Wayne Howe Cheng, Mohammad Ali Mohammad Nezhady, Jean-Sébastien Joyal, José Carlos Rivera, Sylvain ChemtobIschemic retinopathies (IRs) are characterized by a progressive microvascular degeneration followed by a post-ischemic aberrant neovascularization. To reinstate vascular supply and metabolic equilibrium to the ischemic tissue during IRs, a dysregulated production of growth factors and metabolic intermediates occurs, promoting retinal angiogenesis. Glycolysis-derived lactate highly produced during ischemic conditions has been associated with tumor angiogenesis and wound healing. Lactate exerts its biologic effects via a G-protein–coupled receptor 81 (GPR81) in several tissues; however, its physiological functions and mechanisms of action in the retina remain poorly understood. Here we show that GPR81 localized predominantly in Müller cells governs deep vascular complex formation during development and in ischemic retinopathy. Lactate-stimulated GPR81 Müller cells produce numerous angiogenic factors including Wnt ligands and particularly Norrin, which contributes significantly in triggering inner retinal blood vessel formation. Conversely, GPR81-null mice retina shows reduced inner vascular network formation associated with low levels of Norrin (and Wnt ligands). Lactate accumulation during IR, selectively activates GPR81-Erk1/2-Norrin signaling to accelerate inner retinal vascularization in WT animals, but not in retina of GPR81-null mice. Altogether, we reveal that lactate via GPR81-Norrin participates in inner vascular network development, and in restoration of the vasculature in response to injury. These findings suggest a new potential therapeutic target to alleviate ischemic diseases.
  • Corneal Sensory Experience via TRPV1 Accelerates the Maturation
           of Neonatal Tearing
    • Abstract: Publication date: Available online 18 June 2019Source: The American Journal of PathologyAuthor(s): Kai Jin, Toshihiro Imada, Shigeru Nakamura, Yusuke Izuta, Erina Oonishi, Michiko Shibuya, Hisayo Sakaguchi, Hirotaka Tanabe, Masataka Ito, Kimiaki Katanosaka, Kazuo TsubotaTearing maturates rapidly after birth, and external environmental challenges play a key role in promoting lacrimal functional maturation. However, little is known about the facilitative factors underlying this developmental process or the potential of application of these factors to treat hypofunction of the lacrimal gland. In this study, eye-opening and the subsequent ocular surface sensory experience, which is thought to be involved in postnatal maturation of lacrimal function, were investigated. Our results demonstrated that eye-opening after birth is essential for the maturation of neonatal tearing. The maturation process of lacrimal function is dependent on the ocular surface sensory experience via transient receptor potential cation channel subfamily member 1 after birth. This study provides, for the first time, important evidence of the sensory experience of the ocular surface in relation to the maturation of functional tear secretion during the postnatal period.
  • microRNA-24 Is Elevated in Ulcerative Colitis Patients and Regulates
           Intestinal Epithelial Barrier Function
    • Abstract: Publication date: Available online 18 June 2019Source: The American Journal of PathologyAuthor(s): Artin Soroosh, Carl Robert Rankin, Christos Polytarchou, Zulfiqar Ali Lokhandwala, Ami Patel, Lin Chang, Charalabos Pothoulakis, Dimitrios Iliopoulos, David Miguel PaduaInflammatory bowel disease is characterized by high levels of inflammation and loss of barrier integrity in the colon. The intestinal barrier is a dynamic network of proteins that encircle intestinal epithelial cells. microRNAs regulate protein-coding genes. In this study, microRNA-24 was found to be elevated in colonic biopsies and blood samples from ulcerative colitis (UC) patients compared to healthy controls. In the colon of UC patients, microRNA-24 is localized to intestinal epithelial cells which prompted an investigation of intestinal epithelial barrier function. Two intestinal epithelial cell lines were used to study the effect of miR-24 overexpression on barrier integrity. Overexpression of microRNA-24 in both cell lines led to diminished transepithelial electrical resistance and increased dextran flux, suggesting an effect on barrier integrity. Overexpression of microRNA-24 did not induce apoptosis or affect cell proliferation, suggesting that the effect of microRNA-24 on barrier function was due to an effect on cell-cell junctions. Although the tight junctions in cells overexpressing microRNA-24 appeared normal, microRNA-24 overexpression led to a decrease in the tight junction–associated protein cingulin. Loss of cingulin compromised barrier formation;cingulin levels negatively correlated with disease severity in UC patients. Together, these data suggest that microRNA-24 is a significant regulator of intestinal barrier that may be important in the pathogenesis of UC.
  • Detection and classification of novel renal histological phenotypes using
           deep neural networks
    • Abstract: Publication date: Available online 18 June 2019Source: The American Journal of PathologyAuthor(s): Susan Sheehan, Seamus Mawe, Rachel E. Cianciolo, Ron Korstanje, J. Matthew Mahoney With the advent and increased accessibility of deep neural networks (DNNs), complex properties of histological images can be rigorously and reproducibly quantified. We used DNN-based transfer learning to analyze histological images of Periodic acid-Schiff–stained renal sections from a cohort of mice with different genotypes. We demonstrate that DNN-based machine learning has strong generalization performance on multiple histological image processing tasks. The neural network extracted quantitative image features and used them as classifiers to look for differences between mice of different genotypes. Excellent performance was observed at segmenting glomeruli from non-glomerular structure and subsequently predict the genotype of the animal based on glomerular quantitative image features. The DNN-based genotype classifications highly correlate with mesangial matrix expansion scored by a pathologist, which differed in these animals. Additionally, by analyzing non-glomeruli images, the neural network identified novel histological features that differed by genotype, including the presence of vacuoles, nuclear count, and proximal tubule brush border integrity, which was validated with immunohistological staining. These features were not identified in systematic pathological examination. Our study demonstrates the power of DNNs to extract biologically relevant phenotypes and serve as a platform for discovering novel phenotypes. These results highlight the synergistic possibilities for pathologists and DNNs to radically scale up our ability to generate novel mechanistic hypotheses in disease.
  • Involvement of α-Melanocyte-Stimulating Hormone-Thromboxane A2 System on
           Itching in Atopic Dermatitis
    • Abstract: Publication date: Available online 18 June 2019Source: The American Journal of PathologyAuthor(s): Tsugunobu Andoh, Chihiro Akasaka, Kyoko Shimizu, Jung-Bum Lee, Yoko Yoshihisa, Tadamichi Shimizuα-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone involved in cutaneous pigmentation in atopic dermatitis (AD) with severe itching. α-MSH elicits itch-related responses in mice. We therefore investigated whether α-MSH was involved in itching in AD. In the skin of AD patients and mice with atopy-like dermatitis, α-MSH and the prohormone convertase 2, which is the key processing enzyme for the production of α-MSH, were distributed mainly in keratinocytes. In the skin of mice with dermatitis, α-MSH receptors (MC1R and MC5R) were expressed at the mRNA level and were distributed in the dermis. In the dorsal root ganglion (DRG) of mice with dermatitis, mRNAs encoding MC1 and MC3∼5 were also expressed. MC1R antagonist agouti-signaling protein inhibited spontaneous scratching in mice with dermatitis. In healthy mice, intradermal α-MSH elicited itch-associated responses, which were inhibited by TP thromboxane (TX) receptor antagonist ONO-3708. In mouse keratinocytes, α-MSH increased the production of TXA2, which was inhibited by adenylyl cyclase inhibitor SQ-22536 and Ca2+ chelator EGTA. In mouse keratinocytes treated with siRNA for MC1R and/or MC5R, α-MSH–induced TXA2 production was decreased. α-MSH increased intracellular Ca2+ ion concentration in DRG neurons and keratinocytes. These results suggest that α-MSH is involved in itching during AD and may elicit itching through the direct action of primary afferents and TXA2 production by keratinocytes.
  • The Expression of Yes-Associated Protein (YAP) Maintains Putative Cancer
           Stemness and Is Associated with Poor Prognosis in Intrahepatic
    • Abstract: Publication date: Available online 18 June 2019Source: The American Journal of PathologyAuthor(s): Kensuke Sugiura, Takashi Mishima, Shigetsugu Takano, Hideyuki Yoshitomi, Katsunori Furukawa, Tsukasa Takayashiki, Satoshi Kuboki, Mamoru Takada, Masaru Miyazaki, Masayuki OhtsukaIntrahepatic cholangiocarcinoma (ICC) is resistant to most chemotherapeutic agents. Yes-associated protein (YAP) is related to tumor progression; however, its role in ICC remains unknown. We investigated the mechanism underlying YAP-mediated cancer progression by focusing on the property of cancer stem cells (CSCs) in ICC. Immunohistochemistry results revealed the positive YAP expression in 37 of 52 resected ICC cases. Those with positive YAP expression showed poor prognosis in Kaplan-Meier analysis (P = 0.023). YAP expression was associated with vimentin and the putative CSC marker, OV-6. The knockdown of YAP expression using specific small-interfering RNAs in ICC cells decreased OCT4 expression in Western blotting, and OV-6 and CD133 expression in flow cytometry analysis. Verteporfin, a YAP inhibitor, decreased N-cadherin and OCT4 expression in Western blotting. In vitro sphere formation and anoikis resistance assays revealed the impairment in CSC property and anoikis resistance in response to the decrease in YAP expression. Verteporfin treatment activated the protein kinase B/mechanistic target of rapamycin (mTOR) signal pathway and dramatically impaired interleukin-6–stimulated signal transducer and activator of transcription-3 phosphorylation in ICC cells. The combination of verteporfin and rapamycin, an inhibitor of mTOR phosphorylation, inhibited cell proliferation and tumor growth. In conclusion, verteporfin regulates multiple signaling pathways and in combination with rapamycin, might be a promising therapeutic strategy for ICC treatment.
  • Invasive Ductular Reaction
    • Abstract: Publication date: Available online 14 June 2019Source: The American Journal of PathologyAuthor(s): David B. Wilson, David A. Rudnick
  • This Month in AJP
    • Abstract: Publication date: Available online 14 June 2019Source: The American Journal of PathologyAuthor(s): Chhavi Chauhan
  • Neutral Sphingomyelinase 2 (SMPD3)-Deficiency in Mice Causes
           Chondrodysplasia with Unimpaired Skeletal Mineralization
    • Abstract: Publication date: Available online 12 June 2019Source: The American Journal of PathologyAuthor(s): Wilhelm Stoffel, Ina Hammels, Britta Jenke, Inga Schmidt-Soltau, Anja NiehoffSMPD3 deficiency in the neutral sphingomyelinase (Smpd3−/−) mouse results in a novel form of juvenile dwarfism, suggesting smpd3 as polygenetic determinant of body-height. SMPD3 controls homeostasis of the sphingomyelin cycle in the Golgi-compartment, essential for membrane remodeling, initiating multiform vesicle formation and transport in the Golgi secretory pathway. Using the unbiased Smpd3−/− genetic model, this study shows that the perturbed Golgi secretory pathway of chondrocytes of the epiphyseal growth zone leads to dysproteostasis, skeletal growth inhibition, malformation, and chondrodysplasia, but revealed unimpaired mineralization in primary and secondary enchondral ossification centers. This has been elaborated by biochemical analyses and immuno-histochemistry of long bones of Smpd3−/− mice. A more precise definition of the microarchitecture and three dimensional structure of the bone was asserted by peripheral quantitative computed tomography, high resolution microcomputed tomography, and less precise by dual-energy X-ray absorptiometry for osteodensitometry. Ablation of the Smpd3-locus as part of a 980 kb-deletion on chromosome 8 in the fro/fro mutant, generated by chemical mutagenesis, is held responsible for skeletal hypomineralization, osteoporosis, multiple fractures of long bones, which are hallmarks of human osteogenesis imperfecta (OI). The phenotype of the genetically unbiased Smpd3−/− mouse, described here, precludes the proposed role of Smpd3 as a candidate gene of human OI, but suggests SMPD3-deficiency as the pathogenetic basis of a novel form of chondrodysplasia.
  • Diverse Consequences in Liver Injury in Mice with Different Autophagy
           Functional Status Treated with Alcohol
    • Abstract: Publication date: Available online 11 June 2019Source: The American Journal of PathologyAuthor(s): Shengmin Yan, Jun Zhou, Xiaoyun Chen, Zheng Dong, Xiao-Ming YinAlcoholic fatty liver disease is often complicated by other pathological insults, such as viral infection or high fat diet. Autophagy plays a homeostatic role in the liver but can be compromised by alcohol, high fat diet, or viral infection, which in turn affect the disease process caused by these etiologies. To understand the full impact of autophagy modulation on alcohol-induced liver injury, several genetic models of autophagy deficiency, which have different levels of functional alterations, were examined following acute binge or chronic-plus-binge treatment. Alcohol given in either mode to the liver-specific inducible Atg7-deficient mice shortly after the induction of Atg7 deletion had an elevated liver injury, indicating the protective role of autophagy. Constitutive hepatic Atg7 deficient mice, in which Atg7 was deleted in embryos, were more susceptible to chronic-plus-binge but not to acute alcohol treatment. Constitutive hepatic Atg5 deficient mice, in which Atg5 was deleted in embryos, were more prone to acute alcohol treatment, but liver injury were surprisingly improved in the chronic-plus-binge regime. A prolonged autophagy deficiency may complicate the hepatic response to alcohol treatment, likely in part due to endogenous liver injury. The complexity of the relationship between autophagy deficiency and alcohol-induced liver injury can thus be affected by the timing of autophagy dysfunction, the exact autophagy gene being affected, and the alcohol treatment regime.
  • Dynamic Regulation of Caveolin-1 Phosphorylation and Caveolae Formation by
           mTORC2 in Bladder Cancer Cells
    • Abstract: Publication date: Available online 11 June 2019Source: The American Journal of PathologyAuthor(s): Andrew M. Hau, Sounak Gupta, Mariah Z. Leivo, Kazufumi Nakashima, Jesus Macias, Weidong Zhou, Alex Hodge, Julie Wulfkuhle, Brian Conkright, Krithika Bhuvaneshwar, Shruti Rao, Subha Madhavan, Emanuel F. Petricoin, Donna E. HanselThe mammalian target of rapamycin and associated PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway is commonly up-regulated in cancer, including bladder cancer. The mammalian target of rapamycin complex 2 (mTORC2) is a major regulator of bladder cancer cell migration and invasion, but the mechanisms by which mTORC2 regulates these processes are unclear. A discovery mass-spectrometry (MS) and reverse-phase protein array (RPPA)-based proteomics dual approach was used to identify novel mTORC2 phosphoprotein targets in actively invading cancer cells. mTORC2 targets included focal adhesion kinase, proto-oncogene tyrosine-protein kinase Src, and caveolin-1 (Cav-1), among others. Functional testing shows that mTORC2 regulates Cav-1 localization and dynamic phosphorylation of Cav-1 on Y14. Regulation of Cav-1 activity by mTORC2 also alters the abundance of caveolae, which are specialized lipid raft invaginations of the plasma membrane associated with cell signaling and membrane compartmentalization. Our results demonstrate a unique role for mTORC2-mediated regulation of caveolae formation in actively migrating cancer cells.
  • Pathology Image Analysis Using Segmentation Deep Learning Algorithms
    • Abstract: Publication date: Available online 11 June 2019Source: The American Journal of PathologyAuthor(s): Shidan Wang, Donghan M. Yang, Ruichen Rong, Xiaowei Zhan, Guanghua XiaoWith the rapid development of image scanning techniques and visualization software, whole slide imaging (WSI) is becoming a routine diagnostic method. Accelerating clinical diagnosis from pathology images and automating image analysis efficiently and accurately remain significant challenges. Recently, deep learning algorithms have shown great promise in pathology image analysis, such as in tumor region identification, metastasis detection and patient prognosis. Many machine learning algorithms, including convolutional neural networks, have been proposed to automatically segment pathology images. Among these algorithms, segmentation deep learning algorithms such as fully-convolutional networks stand out for their accuracy, computational efficiency, and generalizability. Thus, deep learning–based pathology image segmentation has become an important tool in WSI analysis. In this review, we describe the pathology image segmentation process using deep learning algorithms in detail. The goals are to provide quick guidance for implementing deep learning into pathology image analysis, and to provide some potential ways of further improving segmentation performance. Although there have been previous reviews on using machine learning methods in digital pathology image analysis, to our knowledge, this is the first in-depth review of the applications of deep learning algorithms for segmentation in WSI analysis.
  • Expression Profiling Reveals Involvement of WNT Pathway in the Malignant
           Progression of Sessile Serrated Adenomas
    • Abstract: Publication date: Available online 11 June 2019Source: The American Journal of PathologyAuthor(s): Mahra Nourbakhsh, Adnan Mansoor, Konstantin Koro, Qingrun Zhang, Parham MinooApproximately 15% to 20% of colorectal cancers are developed through the serrated pathway of tumorigenesis which is associated with BRAF mutation, CpG island methylation phenotype, and MLH1 methylation. However, the detailed process of progression from sessile serrated adenoma (SSA) to dysplasia and carcinoma has not been elucidated. To further characterize mechanisms involved in the dysplastic progression of SSA, we investigated differential expressions of mRNAs between areas with and without dysplasia within same SSA polyps. Significantly dysregulated genes in paired samples were applied for functional annotation and biological significance using Ingenuity Pathway Analysis software and Database for Annotation, Visualization and Integrity Discovery (DAVID). The same lysates from a subset of matched samples were subjected for miRNA expression profiling. Differentially expressed miRNAs were determined, and their targeted mRNAs were compared in parallel to the list of differentially expressed mRNAs from RNA sequencing study. Fourteen common mRNA targets were identified, which include AXIN2, a known indicator of WNT/B-catenin pathway activation. Together, in this study, different genes/pathways/biological processes involved in the initiation and progression of dysplasia in the serrated pathway are documented. One of the most significant findings is the involvement of WNT/B-catenin pathway in the dysplastic progression of SSAs with different genes being targeted in early versus advanced dysplasia.
  • The Clinical Autopsy and Genetic Testing
    • Abstract: Publication date: Available online 11 June 2019Source: The American Journal of PathologyAuthor(s): Jeffrey Sklar
  • Heparanase level in the microcirculation as possible modulator of the
           metastatic process
    • Abstract: Publication date: Available online 23 May 2019Source: The American Journal of PathologyAuthor(s): Neta Nevo, Shourouk Ghanem, Yonatan Crispel, Mifleh Tatour, Haim Cohen, Inna Kogan, Myriam Ben-Arush, Yona NadirMetastasis most commonly occurs in the liver, lungs, bones and brain, implying its preference for specific organs. We hypothesized that organ microcirculation coagulation environment predisposes to tumor cell retention. Analysis of coagulation factors was performed using immunostaining, ELISA and heparanase procoagulant activity assay. In normal mice, expressions of heparanase, tissue factor (TF), TF pathway inhibitor (TFPI) and TFPI-2 were low in the microcirculation of the liver, lungs, brain cortex, bones, and high in the microcirculation of sub-cutis, skeletal muscles, brain sub-cortex and bone marrow. C57BL/6 mice subcutaneously injected with B16 (F10) melanoma cells demonstrated lower levels of heparanase, TF, TFPI and TFPI-2 in metastasis blood vessels compared to those of the primary tumor. In these metastatic mice, liver and lung microcirculation turned to express high levels of coagulation proteins. Additionally, heparanase over-expression mice, although developed a larger primary tumor, did not demonstrate a metastasis tendency, as opposed to controls (p
  • Perilipin 1 Expression Differentiates Liposarcoma from Other Types of Soft
           Tissue Sarcoma
    • Abstract: Publication date: Available online 22 May 2019Source: The American Journal of PathologyAuthor(s): Beate Katharina Straub, Hagen Roland Witzel, Lena Maria Pawella, Marcus Renner, Eva Eiteneuer, Merita Hashani, Peter Schirmacher, Wilfried Roth, Gunhild MechtersheimerLipid droplets, a morphological feature of adipocytic tumors, are strongly regulated by associated proteins of the perilipin/PAT-family. So far, the use of perilipins as markers for differential diagnosis of soft tissue tumors has only been studied in a few cases. The aim of the study was to investigate the expression of perilipins in 478 human soft tissue tumors as well as 60 respective normal tissues. All cases of well differentiated liposarcoma, over 90% of myxoid round cell liposarcoma and over 70% of pleomorphic liposarcoma, yet only in the well differentiated components of dedifferentiated liposarcoma were immunohistochemically positive for perilipin 1. All other types of soft tissue sarcoma were negative for perilipin 1. Perilipin 2 was more prominent in dedifferentiated and pleomorphic liposarcoma and nearly all other especially high-grade sarcoma. In well differentiated liposarcoma, lipoma or normal adipose tissue, perilipin 2 was virtually absent. In addition, long-term stimulation of adipogenesis in the liposarcoma cell line LiSa-2 restored perilipin 1 expression as exhibited in the source tumor. Furthermore, knock-down of perilipin 2 or 3 in LiSa-2 cells influenced lipid droplet number and size as well as cell vitality. In summary, perilipin 1 is a promising marker for the differential diagnosis of liposarcomas from other soft tissue sarcoma whereas perilipin 2 correlates negatively with tumor grade and may offer a potential therapeutic use.
  • Sildenafil Prevents Marfan-Associated Emphysema and Early Pulmonary Artery
           Dilation in Mice
    • Abstract: Publication date: Available online 22 May 2019Source: The American Journal of PathologyAuthor(s): Zoe White, Nadia Milad, Arash Y. Tehrani, Jennifer Lamothe, James C. Hogg, Mitra Esfandiarei, Michael Seidman, Steven Booth, Tillie-Louise Hackett, Mathieu C. Morissette, Pascal BernatchezMarfan syndrome (MFS) is a connective tissue disorder caused by fibrillin-1 (fbn1) gene mutations. While aortic rupture is the major cause of mortality in MFS, patients also suffer from poorly understood pulmonary complications. Loss of basal nitric oxide (NO) production and vascular integrity are proposed to take part in MFS aortic root disease, yet their contribution to lung complications has yet to be determined. Due to its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 (PDE5) inhibitor, sildenafil (SIL) could attenuate aortic root remodeling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation and exacerbated elastic fiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and the severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent micro-array analyses showed changes to gene signatures involved in the inflammatory response in the MFS lung treated with SIL, without significant downregulation of connective tissue or TGF-β signalling genes. Since PDE5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodeling.
  • X-ray micro-computed tomography for non-destructive 3D X-ray histology
    • Abstract: Publication date: Available online 22 May 2019Source: The American Journal of PathologyAuthor(s): Orestis L. Katsamenis, Michael Olding, Jane A. Warner, David S. Chatelet, Mark G. Jones, Giacomo Sgalla, Bennie Smit, Oliver J. Larkin, Ian Haig, Luca Richeldi, Ian Sinclair, Peter M. Lackie, Philipp Schneider Historically, micro-computed tomography has been considered unsuitable for histological analysis of unstained formalin-fixed and paraffin-embedded (FFPE) soft tissue biopsies due to a lack of image contrast between the tissue and the paraffin. However, we recently demonstrated that μCT can successfully resolve microstructural detail in routinely prepared tissue specimens. Here, we illustrate how μCT imaging of standard FFPE biopsies can be seamlessly integrated into conventional histology workflows, enabling non-destructive three-dimensional (3D) X-ray histology, the use and benefits of which we showcase for the exemplar of human lung biopsy specimens. This technology advancement was achieved through manufacturing a first-of-kind μCT scanner for X-ray histology and developing optimised imaging protocols, which do not require any additional sample preparation. 3D X-ray histology allows for non-destructive 3D imaging of tissue microstructure, resolving structural connectivity and heterogeneity of complex tissue networks, such as the vascular or the respiratory tract. We also demonstrate that 3D X-ray histology can yield consistent and reproducible image quality, enabling quantitative assessment of tissue’s 3D microstructures, which is inaccessible to conventional two-dimensional histology. Being non-destructive the technique does not interfere with histology workflows, permitting subsequent tissue characterisation by means of conventional light microscopy-based histology, immunohistochemistry, and immunofluorescence. 3D X-ray histology can be readily applied to a plethora of archival materials, yielding unprecedented opportunities in diagnosis and research of disease.
  • Transient Receptor Potential Vanilloid 4 (TRPV4) is required for foreign
           body response and giant cell formation
    • Abstract: Publication date: Available online 21 May 2019Source: The American Journal of PathologyAuthor(s): Rishov Goswami, Rakesh Arya, Debabrata Biswas, Xiaoping Zhu, Shaik O. Rahaman The presence of biomaterials and devices implanted into soft tissue is associated with development of a foreign body response (FBR), a chronic inflammatory condition that can ultimately lead to implant failure, which may cause harm to or death of the patient. Development of FBR includes activation of macrophages at the tissue-implant interface, generation of destructive foreign body giant cells (FBGCs), and generation of fibrous tissue that encapsulates the implant. However, the mechanisms underlying the FBR remain poorly understood, as neither the materials comprising the implants nor their chemical properties can explain triggering of the FBR. Here, we report that genetic ablation of TRPV4, a Ca2+-permeable mechanosensitive cation channel in the transient receptor potential vanilloid family, protects TRPV4 KO mice from FBR-related events. The mice showed diminished collagen deposition along with reduced macrophage accumulation and FBGC formation compared to WT mice in a subcutaneous implantation model. Analysis of macrophage markers in spleen tissues and peritoneal cavity showed that the TRPV4 deficiency did not impair basal macrophage maturation. Furthermore, genetic deficiency or pharmacologic antagonism of TRPV4 blocked cytokine-induced FBGC formation, which was restored by lentivirus-mediated TRPV4 reintroduction. Taken together, these results suggest an important, previously unknown role for TRPV4 in FBR.
  • E-cadherin is important for Meibomian gland function as revealed by a new
           human ex vivo slice culture model
    • Abstract: Publication date: Available online 20 May 2019Source: The American Journal of PathologyAuthor(s): Vera Rötzer, Francesca Melega, Fabian Garreis, Friedrich Paulsen, Jens WaschkeABSTRACTMeibomian glands within the eyelid are important for the maintenance of the integrity and health of the ocular surface. Patients with the blistering skin disease pemphigus vulgaris (PV), which is caused by autoantibodies against desmosomal cadherins, often suffer from Dry Eye Disease (DED). Therefore, we studied regulation of cell cohesion in human Meibomian gland epithelial cells (HMGEC). During serum-induced differentiation for 1d up to 6d, HMGEC drastically enhanced intercellular cohesion whereas lipid production did not change. The expression profiles of the desmosomal PV-antigens desmoglein (Dsg) 3 and 1 but not of the adherens junction component E-cadherin (Ecad) was dependent on the presence of serum. Surprisingly, after 1d but not after 6d of serum-induced differentiation, an inhibitory antibody against Ecad drastically reduced intercellular cohesion and blocked lipid production of HMGEC. In contrast, antibodies against desmosomal cadherins including human and mouse pemphigus autoantibodies had no effect on monolayer integrity and lipid production. Because in Meibomian glands from Dsg3-deficient mice lipid production was unaltered, we established an ex vivo slice culture model of human eyelids to allow studies in a more physiological environment. Here, the inhibitory antibody against Ecad but not a Dsg3-specific PV-antibody interfered with stimulated lipid production. Together, these data demonstrate that cell cohesion is maintained differently in Meibomian gland cells and indicate that E-cadherin is important for Meibomian gland function.
  • Endothelial HIF-1α Is Required for Vascular Repair and Resolution of
           Inflammatory Lung Injury through FoxM1
    • Abstract: Publication date: Available online 20 May 2019Source: The American Journal of PathologyAuthor(s): Xiaojia Huang, Xianming Zhang, David X. Zhao, Jun Yin, Guochang Hu, Colin E. Evans, You-Yang Zhao Endothelial barrier dysfunction is a central factor in the pathogenesis of persistent lung inflammation and protein-rich edema formation, the hallmarks of acute respiratory distress syndrome. However, little is known about the molecular mechanisms that are responsible for vascular repair and resolution of inflammatory injury after sepsis challenge. Here we show that hypoxia inducible factor-1α (HIF-1α) expressed in endothelial cells (ECs) is the critical transcriptional factor mediating vascular repair and resolution of inflammatory lung injury. Following sepsis challenge, HIF-1α but not HIF-2α expression was rapidly induced in lung vascular ECs, and mice with EC-restricted disruption of Hif1α (Hif1af/f/Tie2Cre+) exhibited defective vascular repair, persistent inflammation, and increased mortality in contrast to the WT littermates following polymicrobial sepsis or endotoxemia challenge. Hif1af/f/Tie2Cre+ lungs exhibited marked decrease of EC proliferation during recovery following sepsis challenge, which was associated with inhibited expression of FoxM1, a reparative transcription factor. Therapeutic restoration of endothelial FoxM1 expression via liposomal delivery of FoxM1 plasmid DNA to Hif1af/f/Tie2Cre+ mice resulted in re-activation of the vascular repair program, and improved survival. Together, our studies for the first time delineate the essential role of endothelial HIF-1α in driving the vascular repair program. Thus, therapeutic activation of HIF-1α-dependent vascular repair may represent a novel and effective therapy to treat inflammatory vascular diseases such as sepsis and acute respiratory distress syndrome.
  • Heart inflammation: immune cells roles and roads to the heart.
    • Abstract: Publication date: Available online 18 May 2019Source: The American Journal of PathologyAuthor(s): Francisco J. Carrillo-Salinas, Njabulo Ngwenyama, Marina Anastasiou, Kuljeet Kaur, Pilar AlcaideHeart failure (HF) has been traditionally viewed as a disease of the cardiac muscle associated with systemic inflammation. Burgeoning evidence implicates immune effector mechanisms that include immune cell activation and trafficking to the heart. Immune cell infiltration in the myocardium can have adverse effects in the heart and contribute to the pathogenesis of HF. Both innate and adaptive immunity operate sequentially, and the specificity of these responses depends on the initial trigger sensed by the heart. While the role of the immune system in the initial inflammatory response to infection and injury is well studied, what sets the trajectory to HF from different etiologies, and the role of immunity once HF has been established is less understood. Here, we review experimental and clinical knowledge of cardiac inflammation induced by different triggers that often result in HF from different etiologies. We focus on the mechanisms of immune cell activation systemically, and in the pathways immune cells use to traffic to the heart.
  • Invasive Ductular Reaction Operates Hepatobiliary Junctions upon
           Hepatocellular Injury in Rodents and Humans
    • Abstract: Publication date: Available online 18 May 2019Source: The American Journal of PathologyAuthor(s): Laure-Alix Clerbaux, Rita Manco, Noémi Van Hul, Caroline Bouzin, Amedeo Sciarra, Christine Sempoux, Neil D. Theise, Isabelle A. LeclercqDuctular reaction (DR) is observed in virtually all liver diseases both in humans and rodents. Depending on the injury, DR is confined within the periportal area or invades the parenchyma. Upon severe hepatocellular injury, invasive DR has been proposed to arise for supplying the liver with new hepatocytes. However, experimental data evidenced that DR contribution to hepatocyte repopulation is at the most modest, unless replicative capacity of hepatocytes is abrogated. Here, we proposed that invasive DR could contribute to operating hepatobiliary junctions upon hepatocellular injury. We used the choline-deficient ethionine-supplemented (CDE) mouse model of hepatocellular injury and human liver samples to evaluate the hepatobiliary junctional role of the invasive form of DR. We showed that CDE-induced DR expanded as biliary epithelium into the lobule and established new junctions with the canaliculi. By contrast, no new ductular-canalicular junctions were observed in mouse models of biliary obstructive injury exhibiting non-invasive DR. Similarly, in humans, an increased number of hepatobiliary junctions were observed in hepatocellular diseases (viral, drug-induced or metabolic) in which DR invaded the lobule but not in biliary diseases (obstruction or cholangitis) in which DR was contained within the portal mesenchyme. In conclusion, our data in rodents and humans support that invasive DR plays a hepatobiliary junctional role to maintain structural continuity between hepatocytes and ducts in disorders affecting hepatocytes.
  • Progranulin Promotes Bleomycin-Induced Skin Sclerosis by Enhancing
           TGF-β/Smad3 Signaling through Up-Regulation of TGF-β Type I Receptor
    • Abstract: Publication date: Available online 18 May 2019Source: The American Journal of PathologyAuthor(s): Ting Yang, Xuemei Zhang, Aijun Chen, Yunju Xiao, Si Sun, Jurong Yan, Yuwei Cao, Jin Chen, Fengzeng Li, Kun HuangProgranulin (PGRN) is an autocrine growth factor with numerous physiological and pathological roles. Previous reports demonstrated PGRN could increase dermal fibroblasts in wound healing and activate cancer associated fibroblasts in some cancers. Because systemic sclerosis (SSc) is a prototypical fibrosis-related disorder, here, our aim was to clarify the role and mechanism of PGRN in bleomycin (BLM)-induced model of SSc for the first time. We observed that the serum PGRN levels were increased in SSc patients compared with healthy controls. Immunohistology and RT-qPCR demonstrated that PGRN was also elevated in the lesion from mice model of BLM-induced dermal fibrosis. Additionally, in BLM-treated mice, PGRN deficiency not only attenuated dermal fibrosis but also decreased the differentiation of myofibroblasts. The reduced progression of skin sclerosis in PGRN-deficient mice was associated with downregulation of TGF-β receptor I (TβR I) and decreased level of p-Smad3, with correspondingly impaired the expression of its downstream target gene connective tissue growth factor(CTGF) in skin lesion. In contrast, exogenous PGRN significantly increased the level of TβR I and p-Smad3 in cultured mouse fibroblasts.This study demonstrates that PGRN plays a promoting role in the development of dermal fibrosis through the activation of the TGF-β/Smad3 signaling via upregulation of TβR I. PGRN may be a new therapeutic target in SSc.
  • Neutrophil Elastase Damages the Pulmonary Endothelial Glycocalyx in
           Lipopolysaccharide-Induced Experimental Endotoxemia
    • Abstract: Publication date: Available online 18 May 2019Source: The American Journal of PathologyAuthor(s): Kodai Suzuki, Hideshi Okada, Genzou Takemura, Chihiro Takada, Ayumi Kuroda, Hirohisa Yano, Ryogen Zaikokuji, Kentaro Morishita, Hiroyuki Tomita, Kazumasa Oda, Saori Matsuo, Akihiro Uchida, Tetsuya Fukuta, So Sampei, Nagisa Miyazaki, Tomonori Kawaguchi, Takatomo Watanabe, Takahiro Yoshida, Hiroaki Ushikoshi, Shozo YoshidaNeutrophil elastase (NE) is necessary for effective sterilization of phagocytosed bacterial and fungal pathogens; however, NE itself increases alveolocapillary permeability, and induces proinflammatory cytokine production in sepsis-induced acute respiratory distress syndrome. Under septic conditions, the pulmonary endothelial glycocalyx covering on the healthy endothelium surface is injured, but the contribution of NE to this injury remains unknown. Our aim was to examine whether NE-induced pulmonary endothelial injury is associated with endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 9–12-week-old granulocyte colony-stimulating factor knockout (G-CSFKO) mice, which harbor few neutrophils, and littermate control mice; in a second assay, mice were injected with the NE-inhibitor sivelestat (0.2 mg/kg) at 3, 6, 9, and 12 hours after LPS administration. Subsequently, vascular endothelial injury was evaluated through ultrastructural analysis. At 48 hours post-LPS injection, survival rate was>3-fold higher among G-CSFKO than control mice, and degradation of both thrombomodulin and syndecan-1 was markedly attenuated in G-CSFKO compared to control mice. Ultrastructural analysis revealed attenuated vascular endothelial injury and clear preservation of the endothelial glycocalyx in G-CSFKO mice. Moreover, after LPS exposure, survival rate was ∼9-fold higher among sivelestat-injected mice than control mice, and sivelestat treatment potently preserved vascular endothelial structures and the endothelial glycocalyx. In conclusion, NE is associated with pulmonary endothelial injury under LPS-induced endotoxemic conditions.
  • Environmental Cadmium Enhances Lung Injury by Respiratory Syncytial Virus
    • Abstract: Publication date: Available online 18 May 2019Source: The American Journal of PathologyAuthor(s): Xin Hu, Ki-hye Kim, Youri Lee, Jolyn Fernandes, M. Ryan Smith, Yujin Jung, Michael Orr, Sang-Moo Kang, Dean P. Jones, Young-Mi Go Cadmium (Cd) is a naturally occurring environmental toxicant that disrupts mitochondrial function at occupational exposure levels. The impacts of Cd exposure at low levels through dietary intake remain largely uncharacterized. Human respiratory syncytial virus (RSV) causes severe morbidity which can require hospitalization and result in death in young children and elderly populations. The impacts of environmental Cd exposure on the severity of RSV disease are unknown. Herein, we used a mouse model to examine whether Cd pre-exposure at a level of dietary intake potentiates pulmonary inflammation upon subsequent infection with RSV. Mice were given Cd or saline in drinking water for 28 days. Subsets of these mice were infected with RSV at 5 days before the end of the study. Cd pre-exposure caused relatively subtle changes in lung; however, it elevated IL-4 level and altered metabolites associated with fatty acid metabolism. After RSV infection, mice pre-exposed to Cd had elevated lung RSV titer and increased inflammation as measured by histopathology, immune cell infiltration, cytokines and chemokines. RSV infection following Cd pre-exposure also caused widespread perturbation in metabolism of glycerophospholipids and amino acids (Trp, Met, Cys, branched chain amino acids), as well as carnitine shuttle associated with mitochondrial energy metabolism. The results show that Cd burden by dietary intake potentiates RSV infection and severe disease with associated mitochondrial metabolic disruption.
  • Apolipoprotein E/Aβ Complex Accumulates in AD Cortical Synapses via apoE
           Receptors and Is Enhanced by APOE4
    • Abstract: Publication date: Available online 17 May 2019Source: The American Journal of PathologyAuthor(s): Tina Bilousova, Mikhail Melnik, Emily Miyoshi, Bianca L. Gonzalez, Wayne W. Poon, Harry V. Vinters, Carol A. Miller, Maria M. Corrada, Claudia Kawas, Asa Hatami, Ricardo Albay, Charles Glabe, Karen Hoppens GylysApolipoprotein E (apoE) co-localizes with amyloid-beta (Aβ) in Alzheimer’s disease (AD) plaques and in synapses, and evidence suggests that direct interactions between apoE and Aβ are important for apoE’s effects in AD. The present work examines the hypothesis that apoE receptors mediate uptake of apoE/Aβ complex into synaptic terminals. Western analysis shows multiple SDS-stable assemblies in synaptosomes from human AD cortex; apoE/Aβ complex was markedly increased in AD compared to aged control samples. Complex formation between apoE and Aβ was confirmed by co-immunoprecipitation experiments. The apoE receptors low density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1) were quantified in synaptosomes using flow cytometry, revealing up-regulation of LRP1 in early- and late-stage AD. Dual labeling flow cytometry analysis of LRP1- and LDLR-positives indicate a majority (∼65%) of LDLR and LRP1 is associated with PSD-95-positive synaptosomes, indicating that remaining LRP1 and LDLR receptors are exclusively presynaptic. Flow cytometry analysis of Nile Red labeling revealed a reduction in cholesterol esters in AD synaptosomes. Dual labeling experiments showed apoE and Aβ concentration into LDLR and LRP1-positive synaptosomes, along with free and esterified cholesterol. Synaptic Aβ was increased by apoE4 in control and AD samples. These results are consistent with uptake of apoE/Aβ complex and associated lipids into synaptic terminals, with subsequent Aβ clearance in control synapses and accumulation in AD synapses.
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Heriot-Watt University
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