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Publisher: Elsevier   (Total: 3168 journals)

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Showing 1 - 200 of 3168 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 39, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 26, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 105, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 28, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 42, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 7)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 6)
Acta Astronautica     Hybrid Journal   (Followers: 454, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 30, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 3)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 11, SJR: 0.18, CiteScore: 1)
Acta Histochemica     Hybrid Journal   (Followers: 5, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 330, 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: 2, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 26, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 7, 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: 18, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 13, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 23)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 200, 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: 30, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 12, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 12, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 24, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 15, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 1, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 35, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 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: 11, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 11, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 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: 16)
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: 52, 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: 67, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Genetics     Full-text available via subscription   (Followers: 21, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 7, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 26, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 26)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 3, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 37, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 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: 21, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 15, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 9, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 5, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 25)
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: 27, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 19)
Advances in Pharmacology     Full-text available via subscription   (Followers: 17, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 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: 11)
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: 68)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 3, SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Space Research     Full-text available via subscription   (Followers: 437, 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: 6, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 55, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 396, 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: 492, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 18, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 32, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 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: 8, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 12)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 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: 11, 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: 67, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 47, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 13)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 37, 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: 37, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 50)
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: 279, 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: 67, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 25, 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: 221, 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: 237, SJR: 1.58, CiteScore: 3)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 7, 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  [3168 journals]
  • Angiocrine Hgf signaling controls physiologic organ and body size and
           dynamic hepatocyte proliferation to prevent liver damage during
    • Abstract: Publication date: Available online 27 November 2019Source: The American Journal of PathologyAuthor(s): Xue-jun Zhang, Victor Olsavszky, Yuhan Yin, Baocai Wang, Thomas Engleitner, Rupert Öllinger, Kai Schledzewski, Philipp-Sebastian Koch, Roland Rad, Roland M. Schmid, Helmut Friess, Sergij Goerdt, Norbert Hüser, Cyrill Géraud, Guido von Figura, Daniel HartmannAbstractLiver sinusoidal endothelial cells (LSEC) control organ functions, metabolism, and development through the secretion of angiokines. LSEC express hepatocyte growth factor (Hgf), which is involved in prenatal development, metabolic homeostasis, and liver regeneration. This study aimed to elucidate the precise contribution of LSEC-derived Hgf in physiologic homeostasis and liver regeneration. Stab2-iCretg/wt;Hgffl/fl (HgfΔLSEC) mice were generated to abrogate Hgf expression selectively in LSEC from early fetal development onwards, to study global development, metabolic and endothelial zonation, and organ functions as well as liver regeneration in response to 70% partial hepatectomy (PH). Although zonation and liver-to-body weight ratios were not altered, total body weight, and total liver weight were reduced in HgfΔLSEC. Necrotic organ damage was more marked in HgfΔLSEC mice and regeneration was delayed 72h after PH. This was associated with decreased hepatocyte proliferation at 48h after PH. Molecularly, HgfΔLSEC mice showed down-regulation of Hgf/c-MET signaling and decreased expression of Deptor in hepatocytes. In vitro knock-down of Deptor was associated with decreased proliferation. Therefore, angiocrine Hgf controls hepatocyte proliferation and susceptibility to necrosis following partial hepatectomy via the Hgf/c-Met axis involving Deptor to prevent excessive organ damage.
  • Necroptosis in the Pathophysiology of Disease
    • Abstract: Publication date: Available online 26 November 2019Source: The American Journal of PathologyAuthor(s): Mitri K. Khoury, Kartik Gupta, Sarah R. Franco, Bo LiuOver the past 15 years, elegant studies have demonstrated that under certain conditions, programmed cell death resembles necrosis and depends on a unique molecular pathway with no overlap with apoptosis. This form of regulated necrosis is represented by necroptosis, in which the receptor interacting protein kinase 3 (RIPK3) and its substrate MLKL play a crucial role. With the development of knockout mouse models and molecular inhibitors unique to necroptotic proteins, this cell-death has been found to occur virtually in all tissues and diseases evaluated. There are different immunologic consequences depending on whether cells die through apoptosis or necroptosis. Therefore, distinguishing between these two forms of cell death may be critical during pathological evaluations. In this review, we provide an understanding of necroptotic cell-death and highlight diseases in which necroptosis has been found to play a role. We also discuss the inhibitors of necroptosis and the ways these inhibitors have been used in pre-clinical models of diseases. These two discussions offer an understanding of the role of necroptosis in diseases and will foster efforts to pharmacologically target this unique yet pervasive form of programmed cell-death in the clinic.
  • miRNA-149* suppresses liver cancer progression by down-regulating TRADD
           protein expression
    • Abstract: Publication date: Available online 26 November 2019Source: The American Journal of PathologyAuthor(s): Qingqing Feng, Hongli Zhang, Xiaobo Nie, Yuanqiang Li, Wei-Dong Chen, Yan-Dong WangAbstractLiver cancer is the third leading cause of cancer-related death worldwide. Here we show that microRNA-149* (miR-149*) serves as a novel tumor suppressor for liver tumorigenesis. Mice with genetic deletion of miR-149* (miR-149*-/- mice), which caused loss of both miR-149 and miR-149*, were considerably more susceptible to acute liver injury and hepatic carcinogenesis induced by diethylnitrosamine than wild-type mice, accompanied by increased compensatory proliferation and up-regulated gene expression of certain inflammatory cytokines. miR-149* mimics dramatically impaired liver cancer cell proliferation and migration in vitro, and blocked liver cancer progression in a xenograft model. Furthermore, miR-149* strongly suppressed NF-κB signaling and repressed tumor necrosis factor receptor type 1–associated DEATH domain protein expression in NF-κB signaling pathway. These results reveal that miR-149*, as a novel liver tumor suppressor, may serve as a potential therapeutic target for liver cancer treatment.
  • Effect of Inhibition of Colony Stimulating Factor 1 Receptor on Choroidal
           Neovascularization in Mice
    • Abstract: Publication date: Available online 26 November 2019Source: The American Journal of PathologyAuthor(s): Petra Schwarzer, Despina Kokona, Andreas Ebneter, Martin S. ZinkernagelAbstractNeovascular age-related macular degeneration is one of the leading causes of blindness. Microglia and macrophages play critical role in choroidal neovascularization (CNV) and may therefore be potential targets to modulate the disease course. This study evaluated the effect of the colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX5622 on experimental laser-induced CNV. A 98% reduction of retinal microglia cells was observed in the retina one week after initiation of PLX5622 treatment, preventing accumulation of macrophages within the laser site and leading to a reduction of leukocytes within the choroid after CNV induction. Mice treated with PLX5622 had a significantly faster decrease of the CNV lesion size as revealed by in vivo imaging and immunohistochemistry from day 3 to day 14 compared to untreated mice. Several inflammatory modulators, such as CCL9, granulocyte-macrophage colony-stimulating factor, ssoluble tumor necrosis factor receptor-I, interleukin-1α, and matrix metallopeptidase-2 were elevated in the acute phase of the disease when microglia were ablated with PLX5622, whereas other cytokines (eg, interferon-γ, interleukin-4, and interleukin-10) were reduced. Our results suggest that CSF-1R inhibition may be a novel therapeutic target in patients with neovascular age-related macular degeneration.
  • Identification of Prognostic Biomarkers in the Urinary Peptidome of the
           Small Renal Mass
    • Abstract: Publication date: December 2019Source: The American Journal of Pathology, Volume 189, Issue 12Author(s): Ashley Di Meo, Ihor Batruch, Marshall D. Brown, Chuance Yang, Antonio Finelli, Michael A.S. Jewett, Eleftherios P. Diamandis, George M. YousefRenal cell carcinoma (RCC) is often diagnosed incidentally as a small renal mass (SRM; pT1a, ≤4 cm). Increasing concerns surrounding the overtreatment of patients with benign or clinically silent SRMs has resulted in a recent shift in treatment recommendations, especially in elderly and infirm patients. There are currently no biomarkers that can predict progression. We used a quantitative label-free liquid chromatography–tandem mass spectrometry peptidomics approach and targeted parallel-reaction monitoring to identify early, noninvasive diagnostic and prognostic biomarkers for early-stage RCC-SRMs. In total, 115 urine samples, including 33 renal oncocytoma (≤4 cm) cases, 30 progressive and 26 nonprogressive clear cell RCC-SRM cases, and 26 healthy controls were evaluated. Nine endogenous peptides that displayed significantly elevated expression in clear cell RCC-SRMs relative to healthy controls were identified. Peptides NVINGGSHAGNKLAMQEF, VNVDEVGGEALGRL, and VVAGVANALAHKYH showed significantly elevated expression in clear cell RCC-SRMs relative to renal oncocytoma. Additionally, peptides SHTSDSDVPSGVTEVVVKL and IVDNNILFLGKVNRP displayed significantly elevated expression in progressive relative to nonprogressive clear cell RCC-SRMs. Peptide SHTSDSDVPSGVTEVVVKL showed the most significant discriminatory utility (area under the curve, 0.76; 95% CI, 0.62–0.90; P = 0.0027). Patients with elevated SHTSDSDVPSGVTEVVVKL expression had significantly shorter overall survival (hazard ratio, 4.13; 95% CI, 1.09–15.65; P = 0.024) compared to patients with low expression. Pretreatment characterization of urinary peptides can provide insight into early RCC progression and may aid clinical decision-making and improve disease management.
  • Correction
    • Abstract: Publication date: December 2019Source: The American Journal of Pathology, Volume 189, Issue 12Author(s):
  • Avian Reticuloendotheliosis Viral Oncogene Related B Regulates Lymphatic
           Endothelial Cells during Vessel Maturation and Is Required for Lymphatic
           Vessel Function in Adult Mice
    • Abstract: Publication date: December 2019Source: The American Journal of Pathology, Volume 189, Issue 12Author(s): Qianqian Liang, Li Zhang, Ronald W. Wood, Rui-Cheng Ji, Brendan F. Boyce, Edward.M. Schwarz, Yongjun Wang, Lianping XingNF-κB signals through canonical transcription factor p65 (RelA)/p50 and noncanonical avian reticuloendotheliosis viral oncogene related B (RelB)/p52 pathways. The RelA/p50 is involved in basal and inflammatory lymphangiogenesis. However, the role of RelB/p52 in lymphatic vessel biology is unknown. Herein, we investigated changes in lymphatic vessels (LVs) in mice deficient in noncanonical NF-κB signaling and the function of RelB in lymphatic endothelial cells (LECs). LVs were examined in Relb−/−, p52−/−, or control mice, and the gene expression profiles in LECs with RelB knockdown. Relb−/−, but not p52−/−, mice exhibited multiple LV abnormalities. They include the following: i) increased capillary vessel diameter, ii) reduced smooth muscle cell (SMC) coverage of mature vessels, iii) leakage, and iv) loss of active and passive lymphatic flow. Relb−/− mature LVs had thinner vessel walls, more apoptotic LECs and SMCs, and fewer LEC junctions. RelB knockdown LECs had decreased growth, survival, and adhesion, and dysregulated signaling pathways involving these cellular events. These results suggest that Relb−/− mice have abnormal LVs, mainly in mature vessels with reduced SMC coverage, leakage, and loss of contractions. RelB knockdown in LECs leads to reduced growth, survival, and adhesion. RelB plays a vital role in LEC-mediated LV maturation and function.
  • Klotho Deficiency Induces Arteriolar Hyalinosis in a Trade-Off with
           Vascular Calcification
    • Abstract: Publication date: December 2019Source: The American Journal of Pathology, Volume 189, Issue 12Author(s): Rik Mencke, Anja T. Umbach, Lucas M. Wiggenhauser, Jakob Voelkl, Hannes Olauson, Geert Harms, Marian Bulthuis, Guido Krenning, Leticia Quintanilla-Martinez, Harry van Goor, Florian Lang, Jan-Luuk HillebrandsHyalinosis is a vascular lesion affecting the renal vasculature and contributing to aging-related renal function decline. We assessed whether arteriolar hyalinosis is caused by Klotho deficiency, a state known to induce both renal and vascular phenotypes associated with aging. Histochemistry was used to assess hyalinosis in Klotho−/− kidneys, compared with Klotho+/− and wild-type littermates. Immunohistochemistry was used to investigate vascular lesion composition and the different layers of the vascular wall. Finally, spironolactone was used to inhibit calcification in kl/kl mice, and vascular lesions were characterized in the kidney. Arteriolar hyalinosis was detected in Klotho−/− mice, which was present up to the afferent arterioles. Hyalinosis was accompanied by loss of α-smooth muscle actin expression, whereas the endothelial lining was mostly intact. Hyalinous lesions were positive for IgM and iC3b/c/d, indicating subendothelial leakage of plasma proteins. The presence of extracellular matrix proteins suggested increased production by smooth muscle cells (SMCs). Finally, in Klotho−/− mice with marked vascular calcification, treatment with spironolactone allowed for replacement of calcification by hyalinosis. Klotho deficiency potentiates both endothelial hyperpermeability and SMC dedifferentiation. In the absence of a calcification-inducing stimulus, SMCs assume a synthetic phenotype in response to subendothelial leakage of plasma proteins. In the kidney, this results in arteriolar hyalinosis, which contributes to the decline in renal function. Klotho may play a role in preventing aging-related arteriolar hyalinosis.
  • Endogenous Calcitonin Gene–Related Peptide Deficiency Exacerbates
           Postoperative Lymphedema by Suppressing Lymphatic Capillary Formation and
           M2 Macrophage Accumulation
    • Abstract: Publication date: December 2019Source: The American Journal of Pathology, Volume 189, Issue 12Author(s): Shuhei Matsui, Megumu Tanaka, Akiko Kamiyoshi, Takayuki Sakurai, Yuka Ichikawa-Shindo, Hisaka Kawate, Kun Dai, Nanqi Cui, Yangxuan Wei, Masaaki Tanaka, Shinji Kakihara, Keisei Nakamura, Akihiro Yamauchi, Kumiko Ishida, Satoshi Tanaka, Mikito Kawamata, Takayuki ShindoLymphedema is a chronic condition caused by disruption of lymphatic vessels, which often occurs after invasive surgery. Calcitonin gene–related peptide (CGRP) is a 37-amino acid peptide produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene (Calca). CGRP was initially identified as a neuropeptide released primarily from sensory nerves and involved in regulating pathophysiological nociceptive pain. However, recent studies have shown CGRP is also released from a variety of other cells and possesses multiple functions. In this study, CGRP knockout (−/−) mice were used to show the actions of endogenous CGRP in postoperative lymphedema. After generating a mouse postoperative tail lymphedema model, the edema was observed to be more severe in CGRP−/− mice than in wild-type mice. Numbers of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1)–positive lymphatic capillaries were decreased and lymphatic capillary formation–related factors were down-regulated in CGRP−/− mice. In addition, accumulation of M2 but not M1 macrophages was selectively reduced in the edematous tissue of CGRP−/− mice. Selective depletion of M2 macrophages decreased lymphatic capillary formation and worsened lymphedema in wild-type mice but not CGRP−/− mice, where numbers of M2 macrophages were already diminished. These findings suggest that endogenous CGRP acts to ameliorate postoperative lymphedema by enhancing lymphatic capillary formation and that M2 macrophages play critical roles. CGRP may be a useful therapeutic target for the treatment of postoperative lymphedema.
  • Down-Regulation of Circular RNA_000926 Attenuates Renal Cell Carcinoma
           Progression through miRNA-411–Dependent CDH2 Inhibition
    • Abstract: Publication date: December 2019Source: The American Journal of Pathology, Volume 189, Issue 12Author(s): Dong Zhang, Xiao-Jie Yang, Qi-Dong Luo, De-Lai Fu, Zhao-Lun Li, Peng Zhang, Tie ChongMany studies have recognized that circular RNAs (circRNAs) can be promising targets for renal cell carcinoma (RCC) by acting as competing endogenous RNAs for miRNAs. This study intends to uncover the implication of a novel circRNA, circ_000926 in RCC, and how it affects tumorigenesis. Microarray-based circRNA/gene expression profiling of RCC was used to identify differentially expressed circRNAs/genes in RCC and normal tissues. miRNAs targeting the screened circRNAs/genes were predicted online, followed by analyzing circ_000926 expression in RCC. The crosstalk among circ_000926, miRNA-411 (miR-411), and CDH2 was then validated. The expression of circ_000926, miR-411, and cadherin 2 (CDH2) was up-regulated or down-regulated in RCC cells to unearth their effects on the biological behaviors of RCC cells. circ_000926 was highly expressed in RCC tissues and cell lines, whereas CDH2 was verified to be a target of miR-411. As a competing endogenous RNA, circ_000926 could directly bind to miR-411 to up-regulate CDH2. Down-regulation of circ_000926 resulted in inhibited growth, migration, and invasion abilities of RCC cells, as well as suppressed epithelial-mesenchymal transition and tumor growth. However, the inhibition of miR-411 or elevation of CDH2 reversed the antitumor effects induced by silencing circ_000926. Down-regulation of circ_000926 exerts an inhibitory effect on RCC progression through miR-411–dependent CDH2 inhibition, highlighting a potential target for RCC treatment.
  • Spatiotemporal Gradient of Cortical Neuron Death Contributes to
           Microcephaly in Knock-In Mouse Model of Ligase 4 Syndrome
    • Abstract: Publication date: December 2019Source: The American Journal of Pathology, Volume 189, Issue 12Author(s): Melody P. Lun, Morgan L. Shannon, Sevgi Keles, Ismail Reisli, Nicole Luche, Douglas Ryan, Kelly Capuder, Luigi D. Notarangelo, Maria K. LehtinenCells of the developing central nervous system are particularly susceptible to formation of double-stranded DNA breaks (DSBs) arising from physiological and/or environmental insults. Therefore, efficient repair of DSBs is especially vital for maintaining cellular health and proper functioning in the developing brain. Here, increased expression of DSB initiating and nonhomologous end joining repair machinery in newborn neurons in the developing brains of both mouse and human are demonstrated. In parallel, the first characterization is provided of the brain phenotype in the Lig4R278H/R278H (Lig4R/R) mouse model of DNA Ligase 4 (LIG4) syndrome, in which a hypomorphic Lig4 mutation, originally identified in patients, impedes nonhomologous end joining. It is shown that Lig4R/R mice develop nonprogressive microcephaly, resulting primarily from apoptotic death of newborn neurons that is both spatially and temporally specific during peak cortical neurogenesis. This apoptosis leads to a reduction in neurons throughout the postnatal cerebral cortex, but with a more prominent impact on those of the lower cortical layers. Together, these findings begin to uncover the pathogenesis of microcephaly in LIG4 syndrome and open avenues to more focused investigations on the critical roles of DSB formation and repair in vulnerable neuronal populations of the brain.
  • Achaete-Scute Homologue 2–Regulated Follicular Helper T Cells Promote
           Autoimmunity in a Murine Model for Sjögren Syndrome
    • Abstract: Publication date: December 2019Source: The American Journal of Pathology, Volume 189, Issue 12Author(s): Kunihiro Otsuka, Akiko Yamada, Masako Saito, Aya Ushio, Mami Sato, Satoru Kisoda, Wenhua Shao, Takaaki Tsunematsu, Yasusei Kudo, Rieko Arakaki, Naozumi IshimaruFollicular helper T (Tfh) cells contribute to various immune responses as well as to the pathogenesis of several immune diseases. However, the precise mechanism underlying the onset or development of autoimmunity via Tfh cells remains unclear. Herein, the detailed relationship between autoimmune disease and Tfh cells was analyzed using a murine model for Sjögren syndrome (SS) wherein the mice underwent neonatal thymectomy. Germinal center (GC) development was promoted in this SS model along with an increase of Tfh cells and GC B cells. The severity of the autoimmune lesions was correlated with the number of Tfh cells detected in the spleen of the SS model mice. In addition, treatment with an anti-CD20 monoclonal antibody effectively suppressed the autoimmune lesions with a reduction of Tfh cells and GC B cells. Comprehensive gene analysis revealed that several genes associated with Tfh cell differentiation, including achaete-scute homologue 2 (Ascl2), were up-regulated in peripheral CD25− CD4+ T cells in SS model mice compared with those in control mice. Moreover, an experiment using CD4Cre Bcl6fl/fl mice that received neonatal thymectomy treatment demonstrated that Ascl2 contributes to the Tfh cell differentiation associated with autoimmunity during the early stages, independent of Bcl6. In conclusion, our results indicate that abnormal Tfh cell differentiation via Ascl2 regulation might contribute to the pathogenesis of autoimmunity.
  • Serum Amyloid P and a Dendritic Cell–Specific Intercellular Adhesion
           Molecule-3–Grabbing Nonintegrin Ligand Inhibit High-Fat Diet–Induced
           Adipose Tissue and Liver Inflammation and Steatosis in Mice
    • Abstract: Publication date: December 2019Source: The American Journal of Pathology, Volume 189, Issue 12Author(s): Darrell Pilling, Nehemiah Cox, Megan A. Thomson, Tejas R. Karhadkar, Richard H. GomerHigh-fat diet (HFD)–induced inflammation is associated with a variety of health risks. The systemic pentraxin serum amyloid P (SAP) inhibits inflammation. SAP activates the high-affinity IgG receptor Fcγ receptor I (FcγRI; CD64) and the lectin receptor dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN; CD209). Herein, we show that for mice on an HFD, injections of SAP and a synthetic CD209 ligand (1866) reduced HFD-increased adipose and liver tissue inflammation, adipocyte differentiation, and lipid accumulation in adipose tissue. HFD worsened glucose tolerance test results and caused increased adipocyte size; for mice on an HFD, SAP improved glucose tolerance test results and reduced adipocyte size. Mice on an HFD had elevated serum levels of IL-1β, IL-23, interferon (IFN)-β, IFN-γ, monocyte chemoattractant protein 1 [MCP-1; chemokine (C-C motif) ligand 2 (CCL2)], and tumor necrosis factor-α. SAP reduced serum levels of IL-23, IFN-β, MCP-1, and tumor necrosis factor-α, whereas 1866 reduced IFN-γ. In vitro, SAP, but not 1866, treated cells isolated from white fat tissue (stromal vesicular fraction) produced the anti-inflammatory cytokine IL-10. HFD causes steatosis, and both SAP and 1866 reduced it. Conversely, compared with control mice, SAP knockout mice fed on a normal diet had increased white adipocyte cell sizes, increased numbers of inflammatory cells in adipose and liver tissue, and steatosis; and these effects were exacerbated on an HFD. SAP and 1866 may inhibit some, but not all, of the effects of a high-fat diet.
  • Elevated miR-615-3p Expression Predicts Adverse Clinical Outcome and
           Promotes Proliferation and Migration of Prostate Cancer Cells
    • Abstract: Publication date: December 2019Source: The American Journal of Pathology, Volume 189, Issue 12Author(s): Emma B. Laursen, Jacob Fredsøe, Linnéa Schmidt, Siri H. Strand, Helle Kristensen, Anne K.I. Rasmussen, Tina F. Daugaard, Peter Mouritzen, Søren Høyer, Gitte Kristensen, Hein V. Stroomberg, Klaus Brasso, Martin Andreas Røder, Michael Borre, Karina D. SørensenmiR-615-3p has previously been described as up-regulated in prostate cancer (PC) tissue samples compared with nonmalignant controls; however, its prognostic potential and functional role in PC remain largely unknown. In this study, we investigated the clinical and biological relevance of miR-615-3p in PC. The expression of miR-615-3p was measured in PC tissue specimens from 239 men who underwent radical prostatectomy (RP), and it was investigated if miR-615-3p could predict postoperative biochemical recurrence (BCR). These findings were subsequently validated in three independent RP cohorts (n = 222, n = 273, and n = 387) and functional overexpression studies conducted in PC cells (PC3M). High miR-615-3p expression was significantly associated with BCR in four independent PC patient cohorts (P 
  • Transforming Growth Factor-β Receptor Internalization via Caveolae Is
           Regulated by Tubulin-β2 and Tubulin-β3 during Endothelial-Mesenchymal
    • Abstract: Publication date: December 2019Source: The American Journal of Pathology, Volume 189, Issue 12Author(s): Katarzyna Sobierajska, Marta E. Wawro, Wojciech M. Ciszewski, Jolanta NiewiarowskaFibrotic disorders, which are caused by long-term inflammation, are observed in numerous organs. These disorders are regulated mainly through transforming growth factor (TGF)-β family proteins by a fundamental cellular mechanism, known as the endothelial-mesenchymal transition. Therefore, there is a pressing need to identify the mechanisms and potential therapeutic targets that enable the inhibition of endothelial transdifferentiation. This study is the first to demonstrate that glycosylation of tubulin-β2 and tubulin-β3 in microtubules enhances sensitivity to TGF-β1 stimulation in human microvascular endothelial cells. We observed that the microtubules enriched in glycosylated tubulin-β2 and tubulin-β3 were necessary for caveolae-dependent TGF-β receptor internalization. Post-translational modulation is critical for the generation of myofibroblasts through endothelial-mesenchymal transition during fibrosis development. We suggest that microtubule glycosylation may become the target of new effective therapies for patients with recognized fibrotic diseases.
  • Comparison of Normal and Metaplastic Epithelium in Patients with Stable
           versus Persistently Symptomatic Severe Asthma Using Laser-Capture
           Microdissection and Data-Independent Acquisition–Mass Spectrometry
    • Abstract: Publication date: December 2019Source: The American Journal of Pathology, Volume 189, Issue 12Author(s): Maria Weitoft, Catharina Müller, Emma Åhrman, Leif Bjermer, Hans Jürgen Hoffmann, Jonas Erjefält, Gunilla Westergren-ThorssonA proportion of patients with severe asthma (SA) show poor responses to traditional asthma medications; however, it remains unknown why some patients remain persistently symptomatic. Our objective was to explore the use of laser-capture microdissection of specific epithelial structures combined with quantitative data-independent acquisition mass spectrometry to elucidate differences in protein composition in patients with SA with varying symptom control. Unbiased label-free quantitative proteome analyses were performed on laser-capture–microdissected areas of specific epithelial structures from patients with SA with varying degrees of symptom control. A total of 1993 stable SA and 1652 symptomatic SA proteins in normal epithelium and 1458 stable SA and 1647 symptomatic SA proteins in metaplastic epithelium were quantified. When comparing proteome profiles based on symptom control, 33 proteins in patients with stable SA (≥twofold change; P ≤ 0.05) and 13 proteins in patients with persistently symptomatic SA (≥twofold change; P ≤ 0.05) were enriched significantly. When comparing proteome profiles based on epithelial status, 21 proteins in normal epithelium (≥twofold change; P ≤ 0.05) and 6 proteins in metaplastic epithelium (≥twofold change; P ≤ 0.05) were enriched significantly. New treatment strategies are needed for patients with severe asthma and exploratory studies of unbiased nature such as this may help when searching for new mechanisms and potential targets involved in the disease pathology.
  • Glucagon Like Peptide-1 Receptor Agonism Improves Nephrotoxic Serum
           Nephritis by Inhibiting T Cell Proliferation
    • Abstract: Publication date: Available online 22 November 2019Source: The American Journal of PathologyAuthor(s): Foteini Moschovaki Filippidou, Alexander H. Kirsch, Matthias Thelen, Máté Kétszeri, Katharina Artinger, Ida Aringer, Corinna Schabhüttl, Agnes A. Mooslechner, Bianca Frauscher, Marion Pollheimer, Tobias Niedrist, Andreas Meinitzer, Daniel J. Drucker, Thomas R. Pieber, Philipp Eller, Alexander R. Rosenkranz, Akos Heinemann, Kathrin EllerGlucagon like peptide (GLP)-1 analogs such as liraglutide improved albuminuria in patients with type 2 diabetes in large randomized controlled trials. One of the suspected mechanisms is the anti-inflammatory potential of GLP-1 receptor (Glp1r) agonism. Thus, we tested the anti-inflammatory action of Glp1r-agonism in a non-diabetic, T-cell–mediated murine model of nephrotoxic serum nephritis (NTS). The role of Glp1r in NTS was evaluated by using Glp1r −/− mice or C57BL/6 mice treated with liraglutide. In vitro, murine T cells were stimulated in the presence of liraglutide or vehicle. Glp1r −/− mice displayed increased renal infiltration of neutrophils and T cells after induction of NTS. Splenocyte proliferation and TH1 cytokine transcription were increased in spleen and lymph nodes of Glp1r −/−. Liraglutide treatment significantly improved the renal outcome of NTS in C57BL/6 mice by decreasing renal infiltration and proliferation of T cells, which resulted in decreased macrophage infiltration. In vitro, T cells stimulated in the presence of liraglutide showed decreased proliferation of TH1 and TH17 cells. Liraglutide blocked glycolysis in T cells and decreased their Glut1 mRNA expression. Together, Glp1r agonism protects mice from a T-cell–dependent glomerulonephritis model by inhibition of T cell proliferation possibly by interacting with their metabolic program. This mechanism may explain in part the reno-protective effects of Glp1r agonism in diabetic nephropathy.
  • This Month in AJP
    • Abstract: Publication date: Available online 22 November 2019Source: The American Journal of PathologyAuthor(s):
  • Next-generation sequencing reveals potential predictive biomarkers and
           targets of therapy for urothelial carcinoma in situ of the urinary bladder
    • Abstract: Publication date: Available online 15 November 2019Source: The American Journal of PathologyAuthor(s): Stefan Garczyk, Nadina Ortiz-Brüchle, Ursula Schneider, Isabella Lurje, Karolina Guricova, Nadine Therese Gaisa, Eva Lorsy, Katharina Lindemann-Docter, Axel Heidenreich, Ruth KnüchelAbstractBacillus Calmette-Guérin instillation following removal of the tumor is the first-line of treatment for urothelial carcinoma in situ (CIS), the precursor lesion of most muscle-invasive bladder cancers. Bacillus Calmette-Guérin therapy fails in>50% of cases and second-line radical cystectomy is associated with overtreatment and drastic lifestyle consequences. Given the need for alternative bladder-preserving therapies, we identified genomic alterations (GAs) in urothelial CIS having the potential to predict response to targeted therapies. Laser-capture microdissection was applied to isolate 30 samples (25 CIS and five muscle controls) from 26 fresh-frozen cystectomy specimens. Targeted next-generation sequencing of 31 genes was performed. The panel comprised genes frequently affected in muscle-invasive bladder cancer of non-papillary origin, focusing on potentially actionable GAs described to predict response to approved targeted therapies or drugs that are in registered clinical trials. Ninety-two percent of CIS patients harbored at least one potentially actionable GA, which were were identified in TP53/cell cycle pathway–related genes (eg, TP53, MDM2) in 72%, genes encoding chromatin-modifying proteins (eg, ARID1A, KDM6A) in 68%, DNA damage repair genes (eg, BRCA2, ATM) in 60%, and PI3K/MAPK pathway genes (eg, ERBB2, FGFR1) in 36% of the cases. These data might help guide the selection of targeted therapies to be investigated in future clinical CIS trials, and may provide a basis for future mechanistic studies of urothelial CIS pathogenesis.
  • Mycobacterial Trehalose 6,6’-Dimycolate Induced M1-Type Inflammation
    • Abstract: Publication date: Available online 14 November 2019Source: The American Journal of PathologyAuthor(s): Thao K.T. Nguyen, John d’Aigle, Luis Chinea, Zainab Niaz, Robert L. Hunter, Shen-An Hwang, Jeffrey K. ActorAbstractMurine models of Mycobacterium tuberculosis (Mtb) infection demonstrate progression of M1-like (pro-inflammatory) and M2-like (anti-inflammatory) macrophage morphology following primary granuloma formation. The Mtb cell wall cording factor, trehalose 6,6’-dimycolate (TDM), is a physiologically-relevant and useful molecule for modeling early macrophage-mediated events during establishment of the tuberculosis-induced granuloma pathogenesis. Here we show that TDM is a major driver of the early M1-like macrophage response as seen during initiation of the granulomas of primary pathology. Pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-12p40 are produced in lung tissue after administration of TDM to mice. Furthermore, CD11b+CD45+ macrophages with a high surface expression of the M1-like markers CD38 and CD86 were found present in regions of pathology in lungs of mice at 7 days post TDM introduction. Conversely, only low phenotypic marker expression of M2-like markers CD206 and EGR-2 were present on macrophages. These findings suggest that TDM plays a role in establishment of the M1-like shift in the microenvironment during primary tuberculosis.
  • Cecal tumorigenesis in AhR-deficient mice depends on cecum-specific MAPK
           pathway activation and inflammation
    • Abstract: Publication date: Available online 14 November 2019Source: The American Journal of PathologyAuthor(s): Hisanori Matoba, Masaya Takamoto, Chifumi Fujii, Masatomo Kawakubo, Eriko Kasuga, Tomio Matsumura, Tatsuya Natori, Ken Misawa, Shun’ichiro Taniguchi, Jun NakayamaAbstractThe aryl hydrocarbon receptor (AhR) is a transcription factor known as a dioxin receptor. Recently, Ahr-/- mice were revealed to develop cecal tumors with inflammation and Wnt/β-catenin pathway activation. However, whether β-catenin degradation is AhR-dependent remains unclear. To determine whether other signaling pathways function in Ahr-/- cecal tumorigenesis, we investigated histological characteristics of the tumors, cytokine/chemokine production in tumors and Ahr-/- peritoneal macrophages. AhR expression was also assessed in human colorectal carcinomas. Ten of the 28 Ahr-/- mice developed cecal lesions by 50 weeks of age, an incidence significantly lower than previously reported. Cecal lesions of Ahr-/- mice developed from serrated hyperplasia to adenoma/dysplasia-like neoplasia with enhanced proliferation. Macrophage and neutrophil infiltration into the lesions was also observed early in serrated hyperplasia, although adjacent mucosa was devoid of inflammation. Il1b, Il6, Ccl2, and Cxcl5 were up-regulated at lesion sites, while only IL-6 production increased in Ahr-/- peritoneal macrophages following LPS+ATP stimulation. Neither c-Myc up-regulation nor β-catenin nuclear translocation was observed unlike previously reported. Interestingly, enhanced phosphorylation of Erk, Src, and EGFR, and Amphiregulin up-regulation at Ahr-/- lesion sites were detected. In human serrated lesions, however, AhR expression in epithelial cells was up-regulated despite morphological similarity to Ahr-/- cecal lesions. Our results suggest novel mechanisms underlying Ahr-/- cecal tumorigenesis, depending primarily on cecum-specific MAPK pathway activation and inflammation.
  • Thrombospondin-1 exacerbates acute liver failure and hepatic
           encephalopathy pathology in mice by activating transforming growth factor
           beta 1
    • Abstract: Publication date: Available online 14 November 2019Source: The American Journal of PathologyAuthor(s): Brandi Jefferson, Malaika Ali, Stephanie Grant, Gabriel Frampton, Michaela Ploof, Sarah Andry, Sharon DeMorrow, Matthew McMillinAbstractSevere hepatic insults can lead to acute liver failure and the development of hepatic encephalopathy (HE). Transforming growth factor beta 1 (TGFβ1) has been demonstrated to contribute to HE from acute liver failure; however, TGFβ1 must be activated to bind its receptor and generate downstream effects. One protein that can activate TGFβ1 is thrombospondin-1 (TSP-1). Therefore, the aim of this study was to assess the role of TSP-1 in acute liver failure and HE pathogenesis. C57Bl/6 or TSP-1 knockout (TSP-1-/-) mice were injected with azoxymethane (AOM) to induce acute liver failure and HE. Liver damage, neurological decline, and molecular analyses of TSP-1 and TGFβ1 signaling were performed. AOM-treated mice had elevated TSP-1 and TGFβ1 mRNA and protein expression in the liver. TSP-1-/- mice administered AOM had reduced liver injury as assessed by histology and serum transaminases compared to C57Bl/6 AOM-treated mice. TSP-1-/- mice treated with AOM had reduced TGFβ1 signaling which was associated with less hepatic cell death as assessed by TUNEL staining and cleaved caspase 3 expression. TSP-1-/- AOM-treated mice had a reduced rate of neurological decline, less cerebral edema and a decrease in microglia activation in comparison to C57Bl/6 mice treated with AOM. Taken together, TSP-1 is an activator of TGFβ1 signaling during AOM-induced acute liver failure and contributes to both liver pathology and HE progression.
  • Role of Mechanistic Target of Rapamycin and Autophagy in Alcohol-Induced
           Adipose Atrophy and Liver Injury
    • Abstract: Publication date: Available online 13 November 2019Source: The American Journal of PathologyAuthor(s): Yuan Li, Xiaojuan Chao, Shaogui Wang, Jessica A. Williams, Hong-Min Ni, Wen-Xing DingAbstractChronic alcohol consumption induces adipose tissue atrophy. However, the mechanisms for how alcohol induces lipodystrophy and its impact on liver steatosis and injury are not fully elucidated. Autophagy is a highly conserved lysosomal degradation pathway, which regulates cellular homeostasis. Mice with autophagy-deficiency in adipose tissue have impaired adipogenesis. However, whether autophagy plays a role in alcohol-induced adipose atrophy and how altered adipocyte autophagy contributes to alcohol-induced liver remains unclear. To determine the role of adipose autophagy and mTOR in alcohol-induced adipose and liver pathogenesis, we generated adipocyte-specific Atg5 knockout (A-Atg5 KO), A- mTOR (mechanistic target of rapamycin) KO, A-Raptor KO, and A-TSC1 (tuberous sclerosis complex 1) KO mice by crossing floxed mice with Adipoq-Cre. The KO mice and their matched wild-type (WT) mice were challenged with chronic-plus-binge (Gao-binge) alcohol mouse model. Gao-binge alcohol induced adipose atrophy with increased autophagy and decreased Akt/mTOR signaling in epididymal adipose tissue in WT mice. A-Raptor KO mice experienced exacerbated alcohol-induced steatosis, but neither A-mTOR nor A-TSC1 KO mice exhibited similar detrimental effects. A-Atg5 KO mice had increased circulating levels of fibroblast growth factor 21 (FGF21) and adiponectin, which were resistant to alcohol-induced adipose atrophy and liver injury. In conclusion, autophagy deficiency in adipose tissue leads to reduced sensitivity to alcohol-induced adipose atrophy, which ameliorates alcohol-induced liver injury in mice.
  • Two distinct tumorigenic processes in endometrial endometrioid
    • Abstract: Publication date: Available online 13 November 2019Source: The American Journal of PathologyAuthor(s): Yuko Sugiyama, Osamu Gotoh, Nobuyuki Fukui, Norio Tanaka, Katsuhiko Hasumi, Yutaka Takazawa, Tetsuo Noda, Seiichi MoriAbstractEndometrial endometrioid adenocarcinoma (EEA) is conventionally considered to be a single pathological entity that develops through a hyperplasia–carcinoma sequence under the influence of estrogen. Previously, another EEA subtype was described and proposed to arise directly from normal endometrium. These conventional and de novo subtypes are designated groups 1 and 2, respectively. To identify the molecular mechanisms of these distinct tumorigenic processes, we conducted comprehensive integrated analyses of genomic data with hormonal status for group-1 paired carcinoma and hyperplasia and group-2 carcinoma samples. Whereas group-1 carcinomas mostly exhibited genomically stable characteristics and the activation of estrogen signaling, group-2 EEAs showed enriched hypermutator and CpG island methylator phenotypes. Pairwise comparisons of hyperplasia and carcinoma, along with time-course analyses of the hyperplasia–carcinoma sequence revealed the acquisition of driver mutations in the evolutionary process of hyperplasia but not in the transition from hyperplasia to carcinoma. The current study confirms the existence of two different histopathological programs during EEA development that harbor distinct molecular bases, and demonstrates the biological relevance of these differential tumorigenic processes.
  • Medroxyprogesterone Acetate Prevention of Cervical Cancer through
           Progesterone Receptor in a Human Papillomavirus Transgenic Mouse Model
    • Abstract: Publication date: Available online 12 November 2019Source: The American Journal of PathologyAuthor(s): Seunghan Baik, Fabiola F. Mehta, Sang-Hyuk ChungCervical dysplastic lesions called cervical intraepithelial neoplasias (CINs) need be treated to prevent cervical cancer. Currently available surgical procedures are effective, but the development of noninvasive treatment is warranted. In human papillomavirus transgenic mice engineered to express human papillomavirus type 16 E6 and E7, short-term treatment with 17β-estradiol induces CINs that progress to cervical cancer if the treatment is continued. In the present study, this mouse model was used to determine whether medroxyprogesterone acetate (MPA), a progestin drug, is chemopreventive. Human papillomavirus transgenic mice bearing CIN lesions were treated with MPA plus 17β-estradiol. Unlike control mice treated with 17β-estradiol alone, cervical cancer was absent in the MPA-treated mice. This observation suggests that MPA prevented CIN from progressing to invasive cancer. MPA was associated with inhibited cell proliferation and the promotion of apoptosis in CIN lesions. Confirming the role of the progesterone receptor, the preventive effect of MPA was absent in human papillomavirus transgenic mice in which the expression of progesterone receptor was genetically ablated. These results suggest that MPA is efficient in treating progesterone receptor–positive CIN lesions. These findings provide the basis for a biomarker-driven clinical trial of the secondary prevention of cervical cancer.
  • Total absence of dystrophin expression exacerbates ectopic myofiber
           calcification, fibrosis, and alters macrophage infiltration patterns
    • Abstract: Publication date: Available online 11 November 2019Source: The American Journal of PathologyAuthor(s): Christopher NJ. Young, Maxime RF. Gosselin, Robin Rumney, Aleksandra Oksiejuk, Natalia Chira, Lukasz Bozycki, Paweł Matryba, Kacper Łukasiewicz, Alex P. Kao, Joseph Dunlop, Samuel C. Robson, Krzysztof Zabłocki, Dariusz C. GóreckiAbstractDuchenne muscular dystrophy (DMD) causes severe disability and death of young men due to progressive muscle degeneration aggravated by sterile inflammation. DMD is also associated with cognitive and bone-function impairments. This complex phenotype results from the cumulative loss of a spectrum of dystrophin isoforms expressed from the largest human gene. Although there is evidence for the loss of shorter isoforms having impact in the central nervous system, their role in muscle is unclear. We found that at eight weeks, the active phase of pathology in dystrophic mice, dystrophin-null mice (mdxβgeo) presented with a mildly exacerbated phenotype but without an earlier onset, increased serum CK levels, or decreased muscle strength. However, at 12 months, mdxβgeo diaphragm strength was lower while fibrosis increased, compared to mdx. The most striking features of the dystrophin-null phenotype were increased ectopic myofiber calcification and altered macrophage infiltration patterns, particularly the close association of macrophages with calcified fibers. Ectopic calcification had the same temporal pattern of presentation and resolution in mdxβgeo and mdx muscles despite very significant intensity differences across muscle groups. Comparison of the rare dystrophin-null patients against those with mutations affecting full-length dystrophins may provide mechanistic insights for developing more effective treatments for DMD.
  • Innate immune signaling contributes to tubular-cell senescence in the
           Glis2 knockout mouse model of nephronophthisis
    • Abstract: Publication date: Available online 30 October 2019Source: The American Journal of PathologyAuthor(s): Heng Jin, Yan Zhang, Dingxiao Liu, Shan Shan Wang, Qiong Ding, Prerna Rastogi, Madison Purvis, Angela Wang, Sarah Elhadi, Chongyu Ren, Chao Cao, Yanfen Chai, Peter Igarashi, Anton M. Jetten, Dongmei Lu, Massimo AttanasioABSTRACTNephronophthisis (NPHP), the leading genetic cause of end-stage renal failure in children and young adults, is a group of autosomal recessive diseases characterized by kidney-cyst degeneration and fibrosis for which no therapy is currently available. To date, mutations in over 25 genes have been identified as causes of this disease that in several cases result in chronic DNA damage in kidney tubular cells. Among such mutations, those in the transcription factor-encoding GLIS2 cause NPHP type 7. Loss of function of mouse Glis2 causes senescence of kidney tubular cells. Senescent cells secrete pro-inflammatory molecules that induce progressive organ damage through several pathways, among which NF-kB signaling is prevalent. Here we show that the NF-kB signaling is active in Glis2 knockout kidney epithelial cells and that genetic inactivation of the toll-like receptor/interleukin 1 receptor (TLR/IL-1R) or pharmacological elimination of senescent cells (senolytic therapy) reduce tubule damage, fibrosis, and apoptosis in the Glis2 mouse model of NPHP. Notably, in Glis2, Tlr2 double knockouts, senescence was also reduced and proliferation was increased, suggesting that loss of TLR2 activity improves the regenerative potential of tubular cells in Glis2 knockout kidneys. Our results further suggest that a combination of TLR/IL-1R inhibition and senolytic therapy may delay the progression of kidney disease in NPHP type 7 and other forms of this disease.
  • The MHC II-CD4 Immunologic Synapse in Alcoholic Hepatitis and Autoimmune
           Liver Pathology: The Role of Aberrant MHC II in Hepatocytes
    • Abstract: Publication date: Available online 25 October 2019Source: The American Journal of PathologyAuthor(s): Jiajie G. Lu, Ping Ji, Samuel W. FrenchAbstractThe major histocompatibility complex class II (MHC II) - CD4 immunologic synapse is classically described between the T cell receptor of CD4 positive lymphocytes and MHC II on antigen presenting cells. This interaction and others between surrounding costimulatory and checkpoint molecules promotes differentiation of naïve CD4 T lymphocytes into helper T cells subtypes including Th1, Th2, and Th17 that have more tailored immunologic responses. Although MHC II is mainly produced by professional antigen presenting cells, it can be aberrantly produced by other cell types, including hepatocytes in various liver pathologies such as autoimmune hepatitis and alcoholic hepatitis. This can lead to direct targeting of hepatocytes by CD4 positive lymphocytes, which form an immunologic synapse with the hepatocyte. The lymphocytes internalize the MHC II – CD4 complexes in a phagocytosis-like mechanism and in the process eat the hepatocyte piece by piece. We review the evidence for this mechanism and the role of these autoimmune responses in various liver diseases, including alcoholic hepatitis, autoimmune hepatitis, and primary biliary cirrhosis. The role of aberrant MHC II in malignancy, including hepatocellular carcinoma, is also reviewed. Further understanding of this mechanism can lead to better understanding of the immune mechanisms involved in these liver pathologies, with potential diagnostic and therapeutic applications.
  • Single cell RNA sequencing identifies YAP1-dependent hepatic mesothelial
           progenitors in fibrolamellar carcinoma
    • Abstract: Publication date: Available online 24 October 2019Source: The American Journal of PathologyAuthor(s): Mark L. Jewell, Jason R. Gibson, Cynthia D. Guy, Jeongeun Hyun, Kuo Du, Seh-Hoon Oh, Richard T. Premont, David S. Hsu, Thomas Ribar, Simon G. Gregory, Anna Mae DiehlAbstractFibrolamellar carcinoma (FLC) is characterized by in-frame fusion of DNAJB1 with PRKACA and by dense desmoplasia. Surgery is the only effective treatment, since mechanisms supporting tumor survival are unknown. We used single cell RNA-sequencing to characterize a patient-derived FLC xenograft model and identify therapeutic targets. Human FLC cells segregated into four discrete clusters that all expressed the oncogene YAP1. The two communities most enriched with cells co-expressing FLC markers (CD68, AKAP12, KRT7, EPCAM, and CPS1) also had the most cells expressing YAP1 and its pro-proliferative target genes (AREG, CCND1), suggesting these were proliferative FLC cell clusters. The other two clusters were enriched with cells expressing profibrotic YAP1 target genes, ACTA2, ELN, and COL1A1, indicating these were fibrogenic FLC cells. All clusters expressed the YAP1 target gene and mesothelial progenitor marker MSLN, and many MSLN(+) cells co-expressed albumin. Trajectory analysis predicted that the four FLC communities were derived from a single cell type transitioning among phenotypic states. After establishing a novel FLC cell line that harbored the DNAJB1-PRKACA fusion, YAP1 was inhibited, which significantly reduced expression of known YAP1-target genes as well as cell growth and migration. Thus, both FLC epithelial and stromal cells appear to arise from DNAJB1-PRKACA fusion in a YAP1-dependent liver mesothelial progenitor, identifying YAP1 as a target for FLC therapy.
  • Neurokinin-1 Receptor Antagonism Ameliorates Dry Eye Disease by Inhibiting
           Antigen-Presenting Cell Maturation and Th17 Cell Activation
    • Abstract: Publication date: Available online 24 October 2019Source: The American Journal of PathologyAuthor(s): Man Yu, Sang-Mok Lee, Hyunsoo Lee, Afsaneh Amouzegar, Takeshi Nakao, Yihe Chen, Reza DanaABSTRACTNeuroinflammation plays an important role in the pathogenesis of ocular surface disease including dry eye disease (DED), but very little is known about the contribution of substance P (SP) to DED. In this study, we investigated the expression of SP at the ocular surface and evaluated its effect on maturation of antigen presenting cells (APCs), the key cell component involved in the induction of Th17 response in DED. The effect of topical blockade of SP signaling was further investigated using neurokinin-1 (NK1R) inhibitors on APC maturation, Th17 cell activation, and disease severity in a mouse model of DED. The results demonstrate that SP is constitutively expressed at the ocular surface, and trigeminal ganglion (TG) neurons are the major source of SP in DED. SP derived from TG enhanced the expression of MHC II maturation marker by BMDCs, an effect that is abrogated by blockade of SP signaling using NK1R antagonist Spantide. Finally, using a well-established murine model of DED, topical treatment of DED mice with NK1R antagonists CP-99,994 and L-733,060 suppressed APC acquisition of MHC II, reduced Th17 cell activity, and ameliorated DED severity. These findings are of translational value, as they suggest that antagonizing NK1R-mediated SP signaling may be an effective strategy in suppressing Th17-mediated ocular surface disease.
  • Correction
    • Abstract: Publication date: Available online 23 October 2019Source: The American Journal of PathologyAuthor(s):
  • A guide for the use of the ferret model for influenza virus infection
    • Abstract: Publication date: Available online 23 October 2019Source: The American Journal of PathologyAuthor(s): Jessica A. Belser, Alissa M. Eckert, Thanhthao Huynh, Joy M. Gary, Jana M. Ritter, Terrence M. Tumpey, Taronna R. MainesAbstractAs influenza viruses continue to jump species barriers to cause human infection, assessments of disease severity and viral replication kinetics in vivo provide crucial information for public health professionals. The ferret model is a valuable resource for evaluating influenza virus pathogenicity; thus, understanding the most effective sample collection and usage techniques, as well as the full spectrum of attainable data following experimental inoculation in this species, is paramount. This is especially true for scheduled necropsy of virus-infected ferrets, a standard component in evaluation of influenza virus pathogenicity, as necropsy findings can provide important information regarding disease severity and pathogenicity that is not otherwise available from the live animal. In this review, we describe the range of influenza viruses assessed in ferrets, the measures of experimental disease severity in this model, and optimal sample collection during necropsy of virus-infected ferrets. Collectively, this information is critical for assessing systemic involvement following influenza virus infection in mammals.
  • Interleukin17–CXCR2 axis facilitates breast cancer progression by
           up-regulating neutrophil recruitment
    • Abstract: Publication date: Available online 22 October 2019Source: The American Journal of PathologyAuthor(s): Lingyun Wu, Mohammad Awaji, Sugandha Saxena, Michelle L. Varney, Bhawna Sharma, Rakesh K. SinghAbstractRecent evidence suggests that interactions among pro-inflammatory cytokines, chemokines, and cancer cell–recruited neutrophils result in enhanced metastasis and chemotherapy resistance. Nonetheless, the detailed mechanism remains unclear. Our aim was to discover the role of interleukin 17 (IL-17), CXCR2 ligands, and cancer-associated neutrophils in chemotherapy resistance and metastasis in breast cancer. Mice were injected with Cl66 murine mammary tumor cells, Cl66 cells resistant to doxorubicin (Cl66-Dox), or paclitaxel (Cl66-Pac). Higher levels of IL17 receptor (IL17R), CXCR2 chemokines, and CXCR2 were observed in tumors generated from Cl66-Dox, and Cl66-Pac cells in comparison with tumors generated from Cl66 cells. Tumors generated from Cl66-Dox and Cl66-Pac cells had higher infiltration of neutrophils and T helper 17 cells. In comparison with primary tumor sites, there were increased levels of CXCR2, CXCR2-ligands, and IL17R within the metastatic lesions. Moreover, IL17 increased the expression of CXCR2 ligands and cell proliferation of Cl66 cells. The supernatant of Cl66-Dox and Cl66-Pac cells enhanced neutrophil chemotaxis. In addition, IL-17–induced neutrophil chemotaxis was dependent on CXCR2 signaling. Collectively, these data demonstrate that the IL-17–CXCR2 axis facilitates the recruitment of neutrophils to the tumor sites, thus allowing them to play a cancer-promoting role in cancer progression.
  • Keratinocyte growth factor reduces injury and leads to early recovery from
           cyclophosphamide bladder injury
    • Abstract: Publication date: Available online 22 October 2019Source: The American Journal of PathologyAuthor(s): Sridhar Tatarao Narla, Daniel Scott Bushnell, Caitlin Marie Schaefer, Mehdi Nouraie, Carlton Matthew BatesAbstractKeratinocyte growth factor (KGF) improves outcomes after cyclophosphamide-induced bladder injury. To understand the underlying mechanisms, we subcutaneously administered KGF to mice 24 hours prior to intraperitoneal cyclophosphamide administration, followed by histological assays and immunostaining. In vehicle (PBS)-pretreated mice, non-apoptotic superficial urothelial cell death from two to six hours and apoptosis in intermediate and basal cells from four to 24 hours was observed post cyclophosphamide treatment. Despite loss of superficial cells, KGF suppressed intermediate and basal cell apoptosis likely via pAKT signaling in pretreated mice. Six and 24 hours post-cyclophosphamide treatment, KGF-pretreated mice also had apparent pERK-driven proliferation of mostly keratin 5 (KRT5)+/KRT14- intermediate cells. One to 28 days post cyclophosphamide treatment, mostly KRT14+ basal progenitor cells proliferated in response to injury, peaking at three days in both treatment groups; however, proliferation rates were lower in the KGF-group at three days, consistent with less injury. Three days post injury, unlike the control, KGF-pretreated mice had regenerated superficial cells. Ten and 28 days post cyclophosphamide treatment, KGF-pretreated mice had little proliferation and marked restoration of urothelial layers, whereas the PBS-group had ongoing regeneration. Administration of KGF to uninjured mice reproduced ERK-driven KRT5+/KRT14- proliferation seen in injured mice; KRT14+ cells were unaffected. KGF-pretreatment blocks cyclophosphamide-induced intermediate and basal cell apoptosis likely by pAKT and drives pERK-mediated KRT5+/KRT14- cell proliferation, leading to early urothelial regeneration.
  • Prostate Cancer: The Role of Inflammation and Chemokines
    • Abstract: Publication date: November 2019Source: The American Journal of Pathology, Volume 189, Issue 11Author(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 leukocyte subsets with procancer and anticancer 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 after subsequent activation, they 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 that 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 Inability of the Choroid to Revascularize in Oxygen-Induced
           Retinopathy Results from Increased p53/miR-Let-7b Activity
    • Abstract: Publication date: November 2019Source: The American Journal of Pathology, Volume 189, Issue 11Author(s): Tianwei E. Zhou, Tang Zhu, José C. 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 avascularization, 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 proangiogenic 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 miR-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.
  • Long Intervening Noncoding 00467 RNA Contributes to Tumorigenesis by
           Acting as a Competing Endogenous RNA against miR-107 in Cervical Cancer
    • Abstract: Publication date: November 2019Source: The American Journal of Pathology, Volume 189, Issue 11Author(s): Guang-Cai Li, Li Xin, Yong-Sheng Wang, Ying ChenThe functional roles of individual large intervening noncoding RNAs in carcinogenesis and progression of cervical cancer have been uncovered in previous studies. In this study, we aimed to identify the role of long intervening noncoding 00467 (LINC00467) in epithelial-mesenchymal transition (EMT), invasion and migration of cervical cancer cells by regulating miR-107 and kinesin family member 23 (KIF23). Microarray analyses were used to detect cervical cancer–related differentially expressed genes, followed by determination of LINC00467, miR-107, and KIF23 levels and subcellular location of LINC00467. Cervical cancer cells were treated with a series of siRNA and mimics to measure the regulatory role of LINC00467, miR-107, and KIF23 in EMT, cell invasion, migration and proliferation, and tumorigenic ability in vivo and in vitro. LINC00467 and KIF23 were highly expressed, whereas miR-107 was poorly expressed, in cervical cancer. LINC00467 was found to be primarily located in the cytoplasm and function as a competing endogenous RNA against miR-107 to suppress KIF23. Cell proliferation, migration, invasion, and EMT in vitro were inhibited as a result of lentiviral-mediated LINC00467 knockdown and miR-107 overexpression in cervical cancer. In addition, LINC00467 silencing or miR-107 up-regulation repressed tumorigenic ability in xenograft tumor-bearing nude mice in cervical cancer in vivo. LINC00467 silencing or miR-107 up-regulation may serve as novel potential strategies for the treatment of cervical cancer.
  • Myeloid-Derived Lymphatic Endothelial Cell Progenitors Significantly
           Contribute to Lymphatic Metastasis in Clinical Breast Cancer
    • Abstract: Publication date: November 2019Source: The American Journal of Pathology, Volume 189, Issue 11Author(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 it 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-LECPs) derived from the bone marrow (BM). As BC recruits massive numbers of provascular myeloid cells, we hypothesized that M-LECPs, 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-LECPs were found in peripheral blood and tumor tissues of BC patients. Moreover, the density of M-LECPs and lymphatic vessels positive for myeloid marker proteins strongly correlated with patient node status. It was also established that tumor M-LECPs coexpress 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-LECPs are similarly recruited to tumors and integrate into preexisting lymphatics. Finally, we demonstrate that adoptive transfer of in vitro differentiated M-LECPs, but not naïve or nondifferentiated 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.
  • Proresolving Mediators LXB4 and RvE1 Regulate Inflammation in Stromal
           Cells from Patients with Shoulder Tendon Tears
    • Abstract: Publication date: November 2019Source: The American Journal of Pathology, Volume 189, Issue 11Author(s): Stephanie G. Dakin, Romain A. Colas, Kim Wheway, Bridget Watkins, Louise Appleton, Jonathan Rees, Stephen Gwilym, Christopher Little, Jesmond Dalli, Andrew J. CarrTendon stromal cells isolated from patients with chronic shoulder rotator cuff tendon tears have dysregulated resolution responses. Current therapies do not address the biological processes concerned with persistent tendon inflammation; therefore, new therapeutic approaches that target tendon stromal cells are required. We examined whether two specialized proresolving mediators (SPMs), lipoxin B4 (LXB4) and resolvin E1 (RvE1), modulate the bioactive lipid mediator profiles of IL-1β–stimulated tendon cells derived from patients with shoulder tendon tears and healthy volunteers. We also examined whether LXB4 or RvE1 treatments moderated the proinflammatory phenotype of tendon tear stromal cells. Incubation of IL-1β–treated patient-derived tendon cells in LXB4 or RvE1 up-regulated concentrations of SPMs. RvE1 treatment of diseased tendon stromal cells increased 15-epi-LXB4 and regulated postaglandin F2α. LXB4 or RvE1 also induced expression of the SPM biosynthetic enzymes 12-lipoxygenase and 15-lipoxygenase. RvE1 treatment up-regulated the proresolving receptor human resolvin E1 compared with 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, phosphorylated signal transducer and activator of transcription 1, and IL-6. LXB4 and RvE1 counterregulate inflammatory processes in tendon stromal cells, supporting the role of these molecules as potential therapeutics to resolve tendon inflammation.
  • N-Acetylcysteine Resolves Placental Inflammatory-Vasculopathic Changes in
           Mice Consuming a High-Fat Diet
    • Abstract: Publication date: November 2019Source: The American Journal of Pathology, Volume 189, Issue 11Author(s): Lyda Williams, Emmanuel S. Burgos, Patricia M. Vuguin, Clarence R. Manuel, Ryan Pekson, Swapna Munnangi, Sandra E. Reznik, Maureen J. CharronThe mechanism by which poor maternal nutrition can affect the long-term health of offspring is poorly understood. In mice, we previously found that maternal high-fat diet (HFD) exposure results in reduced fetal growth regardless of maternal genotype. We tested 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 morphologic features was investigated. Placentas from wild-type dams maintained on a HFD but not those heterozygous (+/−) for Glut4 (Slc2a4) on the same diet had 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 had decreased mRNA and immunostaining of IL-1β and monocyte chemoattractant protein-1, decreased mRNA of inflammatory genes, and increased mRNA of Vegfa. These results strongly suggest consumption of an 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 programed metabolic disease of HFD-exposed offspring.
  • A New Role for the Spleen: Aggravation of the Systemic Inflammatory
           Response in Rats with Severe Acute Pancreatitis
    • Abstract: Publication date: November 2019Source: The American Journal of Pathology, Volume 189, Issue 11Author(s): Rui Zhou, Jian Zhang, Wangjun Bu, Wei Zhang, Baojun Duan, Xianwei Wang, Libo Yao, Zongfang Li, Jun LiLittle is known about the role of the spleen in mediating systemic inflammatory responses in severe acute pancreatitis (SAP). 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 histologic, immunohistochemical, and immunologic analyses. After 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. In addition, pancreatic tissues of rats with splenectomy contained lower levels of serum amylase, tumor necrosis factor-α, and IL-6 and exhibited less acinar cell death, leukocyte infiltration, and interstitial edema 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 hours 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.
  • Repression of Death Receptor–Mediated Apoptosis of Hepatocytes by
           Hepatitis B Virus e Antigen
    • Abstract: Publication date: November 2019Source: The American Journal of Pathology, Volume 189, Issue 11Author(s): Wei Liu, Teng-Fei Guo, Zhen-Tang Jing, Qiao-Yun TongHepatitis B virus (HBV) e antigen (HBeAg) is associated with viral persistence and pathogenesis. Resistance of HBV-infected hepatocytes to apoptosis is seen as one of the primary promotors for HBV chronicity and malignancy. Fas receptor/ligand (Fas/FasL) and the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) system plays a key role in hepatic death during HBV infection. We found that HBeAg mediates resistance of hepatocytes to FasL or TRAIL-induced apoptosis. Introduction of HBeAg into human hepatocytes rendered resistance to FasL or TRAIL cytotoxicity in a p53-dependent manner. HBeAg further inhibited the expression of p53, total Fas, membrane-bound Fas, TNF receptor superfamily member 10a, and TNF receptor superfamily member 10b at both mRNA and protein levels. In contrast, HBeAg enhanced the expression of soluble forms of Fas through facilitation of Fas alternative mRNA splicing. In a mouse model, expression of HBeAg in mice injected with recombinant adenovirus–associated virus 8 inhibited agonistic anti-Fas antibody–induced hepatic apoptosis. Xenograft tumorigenicity assay also found that HBeAg-induced carcinogenesis was resistant to the proapoptotic effect of TRAIL and chemotherapeutic drugs. These results indicate that HBeAg may prevent hepatocytes from FasL and TRAIL-induced apoptosis by regulating the expression of the proapoptotic and antiapoptotic forms of death receptors, which may contribute to the survival and persistence of infected hepatocytes during HBV infection.
  • Vitamin D and Calcium Supplementation Accelerates Randall's Plaque
           Formation in a Murine Model
    • Abstract: Publication date: November 2019Source: The American Journal of Pathology, Volume 189, Issue 11Author(s): Elise Bouderlique, Ellie Tang, Joëlle Perez, Amélie Coudert, Dominique Bazin, Marie-Christine Verpont, Christophe Duranton, Isabelle Rubera, Jean-Philippe Haymann, Georges Leftheriotis, Ludovic Martin, Michel Daudon, Emmanuel LetavernierMost kidney stones are made of calcium oxalate crystals. Randall's plaque, an apatite deposit at the tip of the renal papilla, is considered to at the origin of these stones. Hypercalciuria may promote Randall's plaque formation and growth. We analyzed whether long-term exposure of Abcc6−/− mice (a murine model of Randall's plaque) to vitamin D supplementation, with or without a calcium-rich diet, would accelerate the formation of Randall's plaque. Eight groups of mice (including Abcc6−/− and wild type) received vitamin D alone (100,000 UI/kg every 2 weeks), a calcium-enriched diet alone (calcium gluconate 2 g/L in drinking water), both vitamin D supplementation and a calcium-rich diet, or a standard diet (controls) for 6 months. Kidney calcifications were assessed by 3-dimensional microcomputed tomography, μ-Fourier transform infrared spectroscopy, field emission-scanning electron microscopy, transmission electron microscopy, and Yasue staining. At 6 months, Abcc6−/− mice exposed to vitamin D and calcium supplementation developed massive Randall's plaque when compared with control Abcc6−/− mice (P 
  • Tumor-Promoting Activity of Long Noncoding RNA LINC00466 in Lung
           Adenocarcinoma via miR-144–Regulated HOXA10 Axis
    • Abstract: Publication date: November 2019Source: The American Journal of Pathology, Volume 189, Issue 11Author(s): Tiangang Ma, Yanbing Hu, Yingxue Guo, Bingdi YanPrevious investigations have implicated long noncoding RNAs in lung adenocarcinoma, which is an aggressive disease with poor prognosis and high mortality. Through the alteration of lung adenocarcinoma–related long noncoding RNA and miRNA based on microarray analysis, our aim was to understand 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 LINC00466, siRNA 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 it 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.
  • Jay McKay McDonald, M.D., 1943–2019
    • Abstract: Publication date: November 2019Source: The American Journal of Pathology, Volume 189, Issue 11Author(s): Gene P. Siegal, Kevin A. Roth, Robert W. Hardy
  • Long Noncoding RNA LINC01133 Confers Tumor-Suppressive Functions in
           Ovarian Cancer by Regulating Leucine-Rich Repeat Kinase 2 as an miR-205
    • Abstract: Publication date: November 2019Source: The American Journal of Pathology, Volume 189, Issue 11Author(s): Min Liu, Cuiping Shen, Changxiu WangOvarian cancer represents one of the most commonly occurring malignant tumors among females. Long noncoding RNAs act as biomarkers associated with the pathophysiology of multiple kinds of malignancies, including ovarian cancer. This study aimed to clarify the molecular mechanism of LINC01133 in the progression of ovarian cancer. Initially, microarray-based analysis was used to screen differentially expressed long noncoding RNAs and miRNAs, with LINC01133 and miR-205 obtained for this study. The biological functions of LINC01133, miR-205, and leucine-rich repeat kinase 2 (LRRK2) were validated on cell proliferation, migration, and invasion of ovarian cancer through gain-of-function and loss-of-function experiments. Finally, tumorigenesis was measured in vivo by inducing tumor xenograft in nude mice. The findings revealed a poor expression of LINC01133 in ovarian cancer tissue and cell, which was predominantly expressed in the cytoplasm. LINC01133 repressed cell proliferation, invasion, migration, and tumorigenic ability. miR-205 targeted and negatively regulated LRRK2. LINC01133 was also found to function as an miR-205 sponge to decrease ovarian cancer cell proliferation, migration, and invasion by elevating LRRK2. These in vitro findings were reproduced in vivo on tumor xenograft in nude mice. In conclusion, because of its role as an miR-205 sponge, LINC01133 repressed the development of ovarian cancer by up-regulating LRRK2.
  • Lymphotoxin-beta receptor signaling is crucial for the vascularization of
           transplanted metanephros
    • Abstract: Publication date: Available online 16 October 2019Source: The American Journal of PathologyAuthor(s): Valerio Brizi, Christodoulos Xinaris
  • This Month in AJP
    • Abstract: Publication date: Available online 16 October 2019Source: The American Journal of PathologyAuthor(s): Chhavi Chauhan
  • Non-SMC condensin I complex subunit D2 is a prognostic factor in
           triple-negative breast cancer for the ability to promote cell cycle and
           enhance invasion
    • Abstract: Publication date: Available online 12 October 2019Source: The American Journal of PathologyAuthor(s): Yajing Zhang, Fangfang Liu, Chengli Zhang, Meijing Ren, Manchao Kuang, Ting Xiao, Xuebing Di, Lin Feng, Li Fu, Shujun ChengTriple-negative breast cancer (TNBC) is a heterogeneous disease with an unfavorable prognosis and no specific targeted therapies. The role of non-SMC condensin I complex subunit D2 (NCAPD2), a regulatory subunit of the condensin I complex that mainly participates in chromosome condensation and segregation, has not been reported in cancer. We therefore evaluated the prognostic value and biological function of NCAPD2 in TNBC. The expression of NCAPD2 was studied in 179 TNBC tissues by immunohistochemistry and associations among NCAPD2 expression, clinicopathological features, and the prognosis information of TNBC patients were analyzed. The mRNA expression profiles of 99 TNBC tissues were also studied and cell biological behaviors were detected when NCAPD2 was altered in three TNBC cell lines. NCAPD2 expression was positively associated with lymph node metastasis (P = 3.84×10-06), poor overall survival (P = 0.0033), and worse disease-free survival (P = 0.0013) of TNBC patients. Moreover, knockdown of NCAPD2 might cause G2/M arrest through p53 signaling pathway, which led to proliferation inhibition, polyploid cell production and cell apoptosis, and also inhibited the invasiveness of TNBC cells. For the first time, we report the close relationship between NCAPD2 and cancer, and demonstrate that NCAPD2 plays an important role in TNBC progression and acts as an independent poor prognostic factor and a potential therapeutic target for TNBC.
  • Intestinal epithelial chemokine (C-C motif) ligand 7 overexpression
           enhances acetaminophen-induced hepatotoxicity in mice
    • Abstract: Publication date: Available online 11 October 2019Source: The American Journal of PathologyAuthor(s): Mengwei Niu, Zhihong Luo, Shenhai Gong, Sanda Win, Neil Kaplowitz, Yong Jiang, Peng ChenAbstractAcetaminophen (APAP) overdose–induced hepatotoxicity is the leading cause of drug-induced liver injury worldwide. The related injury pathogenesis is mainly focused on the liver. Here, we report that gut barrier disruption may also be involved in APAP hepatotoxicity. APAP administration led to gut leakiness and colonic epithelial chemokine (C-C motif) ligand 7 (CCL7) up-regulation. Intestinal epithelial cell (IEC)-specific CCL7 transgenic mice (CCL7tgIEC mice) showed markedly increased myosin light chain kinase (MLCK) phosphorylation and elevated gut permeability and bacterial translocation into the liver compared to wild-type mice. Global transcriptome analysis revealed that the expression of hepatic pro-inflammatory genes was enhanced in CCL7tgIEC mice compared to wild-type animals. Moreover, CCL7 overexpression in intestinal epithelial cells significantly augmented APAP-induced acute liver injury. Our data provides new evidence that dysfunction of CCL7-mediated gut barrier integrity may be an important contributor to APAP-induced hepatotoxicity.
  • Involvement of Transcription Factor 21 in the Pathogenesis of Fibrosis in
    • Abstract: Publication date: Available online 11 October 2019Source: The American Journal of PathologyAuthor(s): Umida Ganieva, Tomoko Nakamura, Satoko Osuka, Bayasula, Natsuki Nakanishi, Yukiyo Kasahara, Nobuyoshi Takasaki, Ayako Muraoka, Shotaro Hayashi, Takashi Nagai, Tomohiko Murase, Maki Goto, Akira Iwase, Fumitaka KikkawaAbstractRepeated tissue injury and repair, and fibrosis play a pivotal role in endometriosis. Fibrotic tissue consists of extracellular matrix proteins, regulated by transcriptional factors promoting cell proliferation and survival. Periostin is one of the putative key extracellular matrix proteins. This study aimed to determine whether transcription factor 21 (TCF21) is involved in the development of endometriosis as an upstream regulatory gene of periostin. Formalin-fixed, paraffin-embedded tissue samples (normal endometrium of women without endometriosis, NE; eutopic endometrium of women with endometriosis, EE; ovarian endometriosis, OE; deep infiltrating endometriosis, DIE) and respective cells were analyzed. Basal, transiently stimulated, and knocked down periostin and TCF21 concentrations in stromal cells of women with or without endometriosis were examined. Periostin and TCF21 expressions were undetected in NE, weakly positive in EE, moderately positive in OE, and strongly positive in DIE. Th2 type cytokines (interleukin-4, interleukin-13, and transforming growth factor-β1) increased the mRNA expression of periostin and TCF21. These cytokines, periostin, and TCF21 co-localized in the stroma of OE and DIE. siTCF21 suppressed periostin expression. Transfection of TCF21 plasmid vector into stromal cells of women without endometriosis, which originally expressed neither periostin nor TCF21, resulted in TCF21 and periostin expression. TCF21 and periostin are involved in the regulation of fibrosis in endometriosis. TCF21 may be a promising therapeutic target and biomarker in endometriosis.
  • RNA Expression Profiling of Lymphoepithelioma-Like Carcinoma of the
           Bladder Reveals a Basal-like Molecular Subtype
    • Abstract: Publication date: Available online 11 October 2019Source: The American Journal of PathologyAuthor(s): Ujjawal Manocha, Jordan Kardos, Sara Selitsky, Mi Zhou, Steven M. Johnson, Cori Breslauer, Jonathan I. Epstein, William Y. Kim, Sara E. WobkerLymphoepithelioma-like carcinoma of the bladder (LELC-B) is a rare subtype of urothelial carcinoma consisting of undifferentiated epithelial cells within a dense inflammatory cell infiltrate. We set out to molecularly characterize LELC-B through RNA expression profiling as well as immunohistochemistry to understand its underlying biology. Sixteen cases of LELC-B were identified at Johns Hopkins University. RNAseq was performed on 14 cases. Immunohistochemical staining for PD-L1 and mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 was performed. Transcriptomic profiling of LELC-B showed that they are enriched in a basal-like phenotype, with 12 of 14 LELC-B cases correlating to the basal centroid of the BASE47 PAM classifier. Gene signature analysis confirmed the lymphocyte infiltration profile consistent with the histomorphology. LELC-B lacked features to explain the robust lymphocytic infiltrate, such as loss of mismatch repair protein expression or expression of Epstein-Barr virus transcripts. Nonetheless, PD-L1 immunohistochemistry was positive in 93% of LELC cases. Our study demonstrates that LELC-B tumors are enriched in a basal-like molecular subtype, share a high level of immune infiltration and PD-L1 expression similar to basal tumors. The basal-like phenotype is consistent with the known sensitivity of LELC-B to chemotherapy and suggests that immune checkpoint therapy should be explored in this rare disease.
  • Ferroptosis affects the progression of non-alcoholic steatohepatitis via
           the modulation of lipid peroxidation–mediated cell death in mice
    • Abstract: Publication date: Available online 11 October 2019Source: The American Journal of PathologyAuthor(s): Jing Qi, Jong-Won Kim, Zixiong Zhou, Chae Woong Lim, Bumseok KimAbstractOxidative stress and its-associated lipid peroxidation play a key role in non-alcoholic steatohepatitis (NASH). Ferroptosis is a recently recognized type of cell death characterized by an iron dependent and lipid peroxidation–mediated non-apoptotic cell death. We demonstrate the impact of ferroptosis on the progression of NASH induced by methionine/choline-deficient diet (MCD) feeding for 10 days. RSL-3 (a ferroptosis inducer) treatment showed decreased hepatic expression of GPX4, and conversely increased 12/15-lipoxygenase, and apoptosis inducing factor, indicating that ferroptosis plays a key role in NASH-related lipid peroxidation and its-associated cell death. Consistently, levels of serum biochemical, hepatic steatosis, inflammation, and apoptosis in MCD-fed mice were exacerbated with RSL-3 treatment. However, MCD-fed mice treated with sodium selenite (a GPX4 activator) showed increase of hepatic GPX4, accompanied by reduced NASH severity. To chelate iron, deferoxamine mesylate salt was used. Administration of deferoxamine mesylate salt significantly reduced NASH severity and abolished the harmful effects of RSL-3 in MCD-fed mice. Finally, treatment with Liproxstatin-1 (a ferroptosis inhibitor) repressed hepatic lipid peroxidation, and its associated cell death, resulting in decreased NASH severity. Consistent with the in vivo findings, modulation of ferroptosis /GPX4 affected hepatocellular death in palmitic acid–induced in vitro NASH milieu. We conclude that GPX4 and its-related ferroptosis might play a major role in the development of NASH.
  • Insights into Fibroblast Plasticity: CCN2 Is Required for Activation of
           Cancer-Associated Fibroblasts in a Murine Model of Melanoma
    • Abstract: Publication date: Available online 11 October 2019Source: The American Journal of PathologyAuthor(s): Matthew Tsang, Katherine Quesnel, Krista Vincent, James Hutchenreuther, Lynne-Marie Postovit, Andrew LeaskTumor stroma resembles a fibrotic microenvironment, being characterized by the presence of myofibroblast-like cancer-associated fibroblasts (CAFs). In wild-type mice injected with melanoma cells, we show that the stem cell transcription factor Sox2 is expressed by tumor cells and induced in CAFs derived from synthetic fibroblasts. These fibroblasts were labeled postnatally with green fluorescent protein using mice expressing a tamoxifen-dependent Cre recombinase under the control of a fibroblast-specific promoter/enhancer. Conversely, fibroblast activation was impaired in mice with a fibroblast-specific deletion of Ccn2, associated with reduced expression of alpha-smooth muscle actin and Sox2. Multipotent Sox2-expressing skin-derived precursor (SKP) spheroids were cultured from murine back skin. Using lineage tracing and flow cytometry, approximately 40% of SKPs were found to be derived from a Col1a2 origin and acquired multipotency in culture. Inhibition of mechanotransduction pathways prevented myofibroblast differentiation of SKPs and expression of Ccn2. In SKPs deleted for Ccn2, differentiation into a myofibroblast, but not an adipocyte or neuronal phenotype, was also impaired. In human melanoma, CCN2 expression was associated with a profibrotic ITGA11-expressing subset of cancer-associated fibroblasts that negatively associated with survival. Collectively, these results suggest that synthetic dermal fibroblasts possess a previously unheralded in vivo and in vitro plasticity, and that CCN2 is required for the differentiation of dermal progenitor cells into a myofibroblast/CAF phenotype and is therefore a therapeutic target in melanoma.
  • Cell of Origin and Immunological Events in the Pathogenesis of Breast
           Implant–Associated Anaplastic Large Cell Lymphoma
    • Abstract: Publication date: Available online 11 October 2019Source: The American Journal of PathologyAuthor(s): Suzanne D. Turner, Giorgio Inghirami, Roberto N. Miranda, Marshall E. KadinBreast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is a CD30-positive, anaplastic lymphoma kinase–negative T-cell lymphoma. Nearly all cases have been associated with textured implants. Most cases are of effusion-limited, indolent disease, with an excellent prognosis following implant and capsule removal. However, capsular invasion and tumor mass has a more aggressive course, and a fatal outcome risk. This review summarizes the current knowledge on BIA-ALCL cell of origin and immunological factors underlying its pathogenesis. Cytokine expression profiling of BIA-ALCL cell lines and clinical specimens reveal a predominantly Th17/Th1 signature, implicating this as its cell of origin. However, a Th2 allergic inflammatory response is suggested by the presence of interleukin-13, with infiltration of eosinophils and IgE-coated mast cells in clinical specimens of BIA-ALCL. The microenvironment-induced T-cell plasticity, a factor increasingly appreciated, may partially explain these divergent results. Mutations resulting in constitutive JAK-STAT activation have been detected and associated with BIA-ALCL pathogenesis in a small number of cases. One possible scenario is that an inflammatory microenvironment stimulates an immune response followed by polyclonal expansion of Th17/Th1 cell subsets with release of inflammatory cytokines and chemokines and accumulation of seroma. JAK-STAT3 gain-of-function mutations within this pathway and others may subsequently lead to monoclonal T-cell proliferation and clinical BIA-ALCL. Current research suggests that therapies targeting JAK proteins warrant investigation in BIA-ALCL.
  • Intestinal SIRT1 Deficiency Protects Mice from Ethanol-Induced Liver
           Injury by Mitigating Ferroptosis
    • Abstract: Publication date: Available online 11 October 2019Source: The American Journal of PathologyAuthor(s): Zhou Zhou, Ting Jie Ye, Elizabeth DeCaro, Brian Buehler, Zachary Stahl, Gregory Bonavita, Michael Daniels, Min YouABSTRACTAberrant liver sirtuin 1 (SIRT1), a mammalian NAD+-dependent protein deacetylase, is implicated in the pathogenesis of alcoholic liver disease. However, the role of intestinal SIRT1 in alcoholic liver disease is presently unknown. This study investigated the involvement of intestine-specific SIRT1 in ethanol-induced liver dysfunction in mice. Ethanol feeding studies were performed on knockout mice with intestinal specific SIRT1 deletion (SIRT1iKO) and flox control (WT) mice with a chronic-plus-binge ethanol feeding protocol. Following ethanol administration, hepatic inflammation and liver injury were substantially attenuated in the SIRT1iKO mice compared to WT mice, suggesting that intestinal SIRT1 played a detrimental role in the ethanol-induced liver injury. Mechanistically, the hepatic protective effect of intestinal SIRT1 deficiency was attributable to ameliorated dysfunctional iron metabolism, increased hepatic glutathione contents, and attenuated lipid peroxidation, along with normalization of a panel of genes implicated in the ferroptosis process in the livers of ethanol-fed mice. This study demonstrates that ablation of intestinal SIRT1 protected mice from the ethanol-induced inflammation and liver damage. The protective effects of intestinal SIRT1 deficiency are mediated, at least partially, by mitigating hepatic ferroptosis. Targeting intestinal SIRT1 or dampening hepatic ferroptosis signaling may have therapeutic potential for alcoholic liver disease in humans.
  • Age-related pathology associated with H1N1 A/California/07/2009 influenza
           virus infection
    • Abstract: Publication date: Available online 1 October 2019Source: The American Journal of PathologyAuthor(s): Stephanie J. Bissel, Chalise E. Carter, Guoji Wang, Scott K. Johnson, Lauren P. Lashua, Alyson Kelvin, Clayton A. Wiley, Elodie Ghedin, Ted M. RossAbstractInfluenza virus infection causes a spectrum of diseases ranging from mild upper respiratory tract infection to severe lower respiratory tract infection that can lead to diffuse alveolar damage, interstitial and airspace inflammation, or acute respiratory failure. Mechanisms instructing disease severity are not completely understood but host, viral, and bacterial factors influence disease outcome. With age being one host factor associated with higher risk of severe influenza, we investigated regional pulmonary distribution and severity of pneumonia following 2009 H1N1 influenza virus infection in newly weaned, adult, and aged ferrets to better understand age-dependent susceptibility and pathology. Aged ferrets exhibited greater weight loss and higher rates of mortality than adult ferrets, whereas the majority of newly weaned ferrets did not lose weight but had a lack of weight gain. Newly weaned ferrets exhibited minimal pneumonia, whereas adult and aged ferrets showed a spectrum of pneumonia severity. Influenza virus–induced pneumonia peaked earliest in adult ferrets, whereas aged ferrets had delayed presentation. Bronchial severity differed between groups, but bronchial pathology was comparable among all cohorts. Alveolar infection was strikingly different between groups. Newly weaned ferrets showed little alveolar cell infection. Adult and aged ferrets demonstrated alveolar infection, but aged ferrets were unable to clear infection. These different age-related pneumonia and infection patterns suggest therapeutic strategies to treat influenza should be tailored contingent on age.
  • Host Lymphotoxin-Beta Receptor Signaling is Crucial for Angiogenesis of
           Metanephric Tissue Transplanted into Lymphoid Sites
    • Abstract: Publication date: Available online 1 October 2019Source: The American Journal of PathologyAuthor(s): Maria Giovanna Francipane, Bing Han, Eric LagasseAbstractThe mouse lymph node (LN) can provide a niche to grow metanephric kidney to maturity. Here, we show that signaling through the lymphotoxin-beta receptor (LTβR) is critical for kidney organogenesis both in the LN and the omentum. By transplanting kidney rudiments either in the LNs of mice undergoing LTβR antagonist treatment or in the omenta of LTβR knockout (LTβR-/-) mice, the host LTβR signals were found to be crucial for obtaining a well-vascularized kidney graft. Indeed, defective LTβR signaling correlated with decreased expression of endothelial and angiogenic markers in kidney grafts as well as structural alterations. As the number of glomerular endothelial cells expressing the LTβR target nuclear factor κB–inducing kinase (NIK) decreased in the absence of a functional LTβR, it was speculated that an LTβR/NIK axis mediated the angiogenetic signals required for successful ectopic kidney organogenesis, given the established role of NIK in neovascularization. However, the transplantation of kidney rudiments in omenta of NIK-/- mice revealed that NIK is dispensable for ectopic kidney vascular integration and maturation. Finally, defective LTβR signaling impaired compensatory glomerular adaptation to renal mass reduction, indicating that kidney regeneration approaches, besides whole kidney reconstruction, might benefit from the presence of LTβR signals.
  • Wasf3 deficiency reveals involvement in metastasis in a mouse model of
           breast cancer
    • Abstract: Publication date: Available online 19 September 2019Source: The American Journal of PathologyAuthor(s): Haiyan Qin, Sumin Lu, Muthusamy Thangaraju, John K. CowellAbstractThe WASF3 gene has been implicated in cancer cell movement, invasion, and metastasis by regulating genetic pathways important in these processes. Invasion and metastasis assays, however, are largely centered on xenograft models in immune compromised mice. To facilitate analysis of the role of WASF3 in spontaneous development of cancer cell metastasis, we generated a Wasf3 null strain by deleting exons 4 and 5, which encode essential motifs for Wasf3 function. On exposure to cre-recombinase a stop codon is generated immediately downstream in exon 6. Using a CMV-cre strain, Wasf3 was constitutively inactivated, which led to viable mice with no visible morphological or behavioral abnormalities. There was no abnormal development or function of the mouse mammary gland in the Wasf3 null mice and brain development was normal. In the MMTV-PyMT strain, which shows early onset breast cancer development and metastasis, Wasf3 is up-regulated in metastatic lesions. When this oncogene was introduced onto the Wasf3-null background, although metastasis was observed in these mice, there was a reduction in the number and size of metastatic lesions in the lungs. These data provide evidence for a role in WASF3 in development of metastasis in a spontaneous model of breast cancer.
  • Detection of lung cancer lymph node metastases from whole-slide
           histopathological images using a two-step deep learning approach
    • Abstract: Publication date: Available online 18 September 2019Source: The American Journal of PathologyAuthor(s): Hoa Hoang Ngoc Pham, Mitsuru Futakuchi, Andrey Bychkov, Tomoi Furukawa, Kishio Kuroda, Junya FukuokaAbstractThe application of deep learning for the detection of lymph node metastases on histological slides has attracted worldwide attention due to its potentially important role in patient treatment and prognosis. Despite this attention, false positive predictions remain problematic, particularly in the case of reactive lymphoid follicles. In this study, a novel two-step deep learning algorithm was developed to address the issue of false-positive prediction while maintaining accurate cancer detection. Three-hundred and forty-nine whole-slide lung cancer lymph node images, including 233 slides for algorithm training, 10 slides for validation, and 106 slides for evaluation, were collected. In the first step, a deep learning algorithm was used to eliminate frequently misclassified noncancerous regions (lymphoid follicles). In the second step, a deep learning classifier was developed to detect cancer cells. Using this two-step approach, errors were reduced by 36.4% on average and up to 89% in slides with reactive lymphoid follicles. Furthermore, 100% sensitivity was reached in cases of macro-metastases, micro-metastases, and isolated tumor cells. To reduce the small number of remaining false-positives, an ROC curve was created using foci size thresholds of 0.6 mm and 0.7 mm, achieving sensitivity and specificity of 79.6% and 96.5%, and 75.5% and 98.2%, respectively. A two-step approach can be used to detect lung cancer metastases in lymph node tissue effectively and with few false-positives.
  • Bioactive lipids in shoulder tendon tears
    • Abstract: Publication date: Available online 14 September 2019Source: The American Journal of PathologyAuthor(s): Undurti N. Das
  • This Month in AJP
    • Abstract: Publication date: Available online 13 September 2019Source: The American Journal of PathologyAuthor(s): Chhavi Chauhan
  • Lactoferrin CpG Island Hypermethylation and Decoupling of mRNA and Protein
           Expression in the Early Stages of Prostate Carcinogenesis
    • Abstract: Publication date: Available online 6 September 2019Source: The American Journal of PathologyAuthor(s): Corey M. Porter, Michael C. Haffner, Ibrahim Kulac, Janielle P. Maynard, Javier A. Baena-Del Valle, William B. Isaacs, Srinivasan Yegnasubramanian, Angelo M. De Marzo, Karen S. SfanosAbstractLactoferrin (LTF) is an iron binding protein canonically known for its innate and adaptive immune functions. LTF may also act as a tumor suppressor with anti-proliferative action. LTF is inactivated genetically or epigenetically in various cancers, and a CpG island spanning the transcriptional start site of LTF is hypermethylated in prostate cancer cell lines. We therefore hypothesized that LTF expression is silenced via CpG island hypermethylation in the early stages of prostate tumorigenesis. Targeted methylation analysis was performed using a combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes and laser capture microdissection followed by bisulfite sequencing on DNA isolated from prostate tissue samples including both primary and metastatic disease. LTF mRNA in situ hybridization and LTF protein immunohistochemistry was also performed. We report that the LTF CpG island is frequently and densely methylated in high grade prostatic intraepithelial neoplasia, primary prostate carcinoma, and metastases. We further report a decoupling of lactoferrin mRNA and protein expression, including in lesions where LTF mRNA has presumably been silenced via CpG island methylation. We conclude that LTF mRNA expression is silenced in prostate tumorigenesis via hypermethylation, supporting a role for LTF as a prostate cancer tumor suppressor gene. Likewise, the frequency at which the LTF CpG island is methylated across samples suggests it is an important and conserved step in prostate cancer initiation.
  • The role of MET in melanoma and melanocytic lesions
    • Abstract: Publication date: Available online 30 August 2019Source: The American Journal of PathologyAuthor(s): Yan Zhou, Kyu Young Song, Alessio GiubellinoAbstractMelanoma is the leading cause of death due to cutaneous malignancy and its incidence is on the rise. Several signaling pathways have been recognized to have an etiopathogenetic role in precursor melanocytic lesions and malignant melanoma development and progression, including receptor tyrosine kinases. Among those, MET/HGF axis is emerging as a critical player not only in the tumor itself but also in the immune microenvironment in which the tumor grows and advance in its development. Moreover, this pathway’s activation has emerged as a paradigm of tumor resistance to modern targeted therapies and assessment of its expression in patients’ sample may be a valuable biomarker of tumor progression and response to targeted therapy.Here we summarize our current understanding of this important receptor tyrosine kinase in normal melanocyte proliferation/motility, tumor progression and metastasis, its genetic alterations in certain subtype of melanocytic lesions and how its pathway has been explored for the development of selective inhibitors.
  • Smooth Muscle α-actin Deficiency Leads to Decreased Liver Fibrosis via
           Impaired Cytoskeletal Signaling in Hepatic Stellate Cells
    • Abstract: Publication date: Available online 30 August 2019Source: The American Journal of PathologyAuthor(s): Don C. Rockey, Qinghong Du, Zengdun ShiIn the liver, smooth muscle α-actin (SM α-actin) is up-regulated in hepatic stellate cells (HSCs) as they transition to myofibroblasts during liver injury and the wound healing response. Whether SM α-actin has specific functional effects on cellular effectors of fibrosis such as HSC is controversial. Here, we focused on the relationship between SM α-actin and type 1 collagen expression (COL1A1), a major extracellular matrix protein important in liver fibrosis and demonstrate that knockout of SM α-actin leads to reduced liver fibrosis and COL1 expression. The mechanism for the reduction in fibrogenesis in vivo is multifactorial, including not only a reduction in the number of HSCs, but also HSC specific reduction in COL1 expression in Acta2 deficient HSCs. Despite a compensatory increase in expression of cytoplasmic β-actin and γ-actin isoforms in Acta2-/- HSCs, defects were identified in each transforming growth factor beta/Smad2/3 and ET-1/Erk1/2 signaling in Acta2-/- HSCs. These data not only suggest a molecular link between the SM α-actin cytoskeleton and classic fibrogenic signaling cascades, but also emphasize the relationship between SM α-actin and fibrogenesis in hepatic myofibroblasts in vivo.
  • Neutrophil-derived reactive oxygen orchestrates epithelial cell signaling
           events during intestinal repair
    • Abstract: Publication date: Available online 28 August 2019Source: The American Journal of PathologyAuthor(s): Jason D. Matthews, Joshua A. Owens, Crystal R. Naudin, Bejan J. Saeedi, Ashfaqul Alam, April R. Reedy, Benjamin H. Hinrichs, Ronen Sumagin, Andrew S. Neish, Rheinallt M. JonesAbstractRecent evidence has demonstrated that reactive oxygen, eg, hydrogen peroxide, can activate host cell signaling pathways that function in repair. We show that mice deficient in their capacity to generate reactive oxygen by the Nox2 holoenzyme, an enzyme complex highly expressed in neutrophils and macrophages, have disrupted capacity to orchestrate signaling events that function in mucosal repair. Similar observations were made for mice after neutrophil depletion, pinpointing this cell type as the source of the reactive oxygen driving redox protein signaling in the epithelium. To simulate epithelial exposure to high levels of reactive oxygen produced by neutrophils and gain new insight into this redox signaling, epithelial cells were treated with H2O2 and biochemical experiments conducted and a proteome-wide screen performed using isotope-coded affinity tags to detect proteins oxidized following exposure. This analysis implicated signaling pathways regulating focal adhesions, cell junctions, and maintenance of the cytoskeleton. These pathways are also known to act via coordinated phosphorylation events within proteins that constitute the focal adhesion complex, including focal adhesion kinase and Crk-associated substrate. We identified the Rho family small GTP–binding protein Rac1 and p21 activated kinases 2 as operational in these signaling and localization pathways. These data support the hypothesis that reactive oxygen species from neutrophils can orchestrate epithelial cell–signaling events functioning in intestinal repair.
  • Tissue iron promotes wound repair via M2 macrophage polarisation and the
           chemokines CCL17 and CCL22
    • Abstract: Publication date: Available online 27 August 2019Source: The American Journal of PathologyAuthor(s): Holly Nicola Wilkinson, Elizabeth Rose Roberts, Amber Rose Stafford, Kayleigh Louise Banyard, Paolo Matteucci, Kimberly Ann Mace, Matthew James HardmanAbstractMacrophages are important for effective iron recycling and erythropoiesis, but also play a crucial role in wound healing, orchestrating tissue repair. Recently, we demonstrated a significant accumulation of iron in healing wounds, and a requirement of iron for effective repair. Here, we sought to determine the influence of iron on macrophage function in the context of wound healing. Interestingly, wound macrophages extensively sequestered iron throughout healing, associated with a pro-healing M2 phenotype. In delayed healing diabetic mouse wounds, both macrophage polarisation and iron sequestration were impaired. In vitro studies revealed that iron promotes differentiation, while skewing macrophages towards a hypersecretory M2-like polarisation state. These macrophages produced high levels of CCL17 and CCL22, promoting wound re-epithelialization and extracellular matrix deposition in a human ex vivo wound healing model. Together, these findings reveal a novel, unappreciated role for iron in modulating macrophage behavior to promote subsequent wound repair. These findings support therapeutic evaluation of iron use to promote wound healing in the clinic.
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