Publisher: Elsevier   (Total: 3161 journals)

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Showing 1 - 200 of 3161 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: 106, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 28, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 44, 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: 446, 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: 324, 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 Psychologica     Hybrid Journal   (Followers: 26, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access   (Followers: 1)
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 7, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 8)
Acute Pain     Full-text available via subscription   (Followers: 15, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 18, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 13, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 22)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 188, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 13, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 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: 21, 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: 14)
Advances in Digestive Medicine     Open Access   (Followers: 13)
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: 45, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 30, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 9)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 52, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 2)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 68, 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: 12, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 8, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 26, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 26)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 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: 17, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 9, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 5, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 26)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular 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: 6, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 27, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 19)
Advances in Pharmacology     Full-text available via subscription   (Followers: 17, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 10, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 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: 69)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 7, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 3, SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 7)
Advances in Space Research     Full-text available via subscription   (Followers: 429, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 6)
Advances in Surgery     Full-text available via subscription   (Followers: 13, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 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: 56, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 395, 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: 487, 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: 46, 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: 55, 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: 48, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 13)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 15, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 39, 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: 263, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 67, 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: 30, 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: 6, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 44, SJR: 1.512, CiteScore: 5)
Analytica Chimica Acta : X     Open Access  
Analytical Biochemistry     Hybrid Journal   (Followers: 214, 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: 238, 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)
Annales d'Endocrinologie     Full-text available via subscription   (Followers: 3, SJR: 0.451, CiteScore: 1)

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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  [3161 journals]
  • Thrombin-Induced Decidual Colony-Stimulating Factor-2 Promotes
           Abruption-Related Preterm Birth by Weakening Fetal Membranes
    • Abstract: Publication date: February 2020Source: The American Journal of Pathology, Volume 190, Issue 2Author(s): Rachel G. Sinkey, Ozlem Guzeloglu-Kayisli, Sefa Arlier, Xiaofang Guo, Nihan Semerci, Robert Moore, Asli Ozmen, Kellie Larsen, Chinedu Nwabuobi, Deepak Kumar, John J. Moore, Lynn F. Buckwalder, Frederick Schatz, Umit A. Kayisli, Charles J. LockwoodPreterm premature rupture of membranes (PPROM) and thrombin generation by decidual cell–expressed tissue factor often accompany abruptions. Underlying mechanisms remain unclear. We hypothesized that thrombin-induced colony-stimulating factor-2 (CSF-2) in decidual cells triggers paracrine signaling via its receptor (CSF2R) in trophoblasts, promoting fetal membrane weakening and abruption-associated PPROM. Decidua basalis sections from term (n = 10), idiopathic preterm birth (PTB; n = 8), and abruption-complicated pregnancies (n = 8) were immunostained for CSF-2. Real-time quantitative PCR measured CSF2 and CSF2R mRNA levels. Term decidual cell (TDC) monolayers were treated with 10−8 mol/L estradiol ± 10−7 mol/L medroxyprogesterone acetate (MPA) ± 1 IU/mL thrombin pretreatment for 4 hours, washed, and then incubated in control medium with estradiol ± MPA. TDC-derived conditioned media supernatant effects on fetal membrane weakening were analyzed. Immunostaining localized CSF-2 primarily to decidual cell cytoplasm and cytotrophoblast cell membranes. CSF-2 immunoreactivity was higher in abruption-complicated or idiopathic PTB specimens versus normal term specimens (P 
  • Quantitative Proteomics of the Endothelial Secretome Identifies RC0497 as
           Diagnostic of Acute Rickettsial Spotted Fever Infections
    • Abstract: Publication date: February 2020Source: The American Journal of Pathology, Volume 190, Issue 2Author(s): Yingxin Zhao, Rong Fang, Jing Zhang, Yueqing Zhang, Jeremy Bechelli, Claire Smalley, Gustavo Valbuena, David H. Walker, José A. Oteo, Allan R. BrasierMediterranean spotted fever is a reemerging acute tick-borne infection produced by the α-proteobacterium, Rickettsia conorii. Rickettsia conorii infects vascular endothelial cells producing disseminated plasma leakage, manifesting as nonspecific fever, headache, and maculopapular rash. Because there are no available tests of early infection, Mediterranean spotted fever is often undiagnosed and untreated, resulting in significant mortality. To address this critical need, we have applied a quantitative proteomics pipeline for analyzing the secretome of primary human umbilical vein endothelial cells. Of the 104 proteins whose abundance changed significantly in the R. conorii–infected human umbilical vein endothelial cells’ secretome, 46 proteins were up-regulated: 45 were host secreted proteins (including cytokines), and 1 was a rickettsial protein, the putative N-acetylmuramoyl-l-alanine amidase RC0497. Proteins with sequence highly homologous to RC0497 were found to be shared by many species of the spotted fever group rickettsiae, but not typhus group rickettsiae. Quantitative targeted proteomics studies of plasma from a mouse model of sublethal and lethal R. conorii identified RC0497 in the blood, and its circulating levels were proportionally associated with infection outcome. Finally, the presence of RC0497 in the serum samples from a cohort of humans presenting with acute rickettsioses was confirmed. The detection of RC0497 has the potential to be a sensitive and specific marker for acute rickettsial spotted rickettsioses.
  • LINC00152 promotes hepatocellular carcinoma progression by regulating
           PI3k/Akt/mTOR signaling pathway through miR-139/PIK3CA
    • Abstract: Publication date: Available online 16 January 2020Source: The American Journal of PathologyAuthor(s): Shu-Qun Li, Qian Chen, Hui-Xia Qin, Ya-Qun Yu, Jun Weng, Qing-Rong Mo, Xiu-Fen Yin, Yan Lin, Wei-Jia LiaoAbstractHepatocellular carcinoma (HCC) ranks as the fifth most common cancer worldwide, and is the primary histological subtype of liver cancer with high incidence and poor prognosis. Recently, numerous long non-coding RNAs (lncRNAs) have been reported to be associated with the tumorigenesis of HCC, however, the underlying mechanisms of LINC00152 action in HCC are poorly understood. Herein, we identified a significant up-regulation of LINC00152 both in HCC tissues and cell lines. Functional studies showed that knockdown of LINC00152 inhibited cell proliferation, migration, and invasion, but promoted cell apoptosis, indicating its oncogenic functions in HCC tumorigenesis. Mechanistically, LINC00152 functioned as an efficient miR-139 sponge, thereby released the suppression of PIK3CA (a target gene of miR-139). Anti-miR-139 rescued the inhibition of cell proliferation, migration, and invasion induced by LINC00152 knockdown. Similarly, PIK3CA overexpressing plasmid also reversed miR-139–mediated biological functions in HCC cells. Taken together, our study revealed a crucial regulatory network of LINC00152/miR-139/PIK3CA axis in the tumorigenesis of HCC, implying that LINC00152 may be a biomarker and novel therapeutic target for further clinical therapy of HCC.
  • Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates epidermal
           keratinization under psoriatic skin inflammation
    • Abstract: Publication date: Available online 14 January 2020Source: The American Journal of PathologyAuthor(s): Tatsuya Ogawa, Yosuke Ishitsuka, Sae Inoue, Yoshiyuki Nakamura, Akimasa Saito, Naoko Okiyama, Yasuhiro Fujisawa, Jun-ichi Furuta, Rei Watanabe, Manabu FujimotoAbstractPsoriasis is an autoinflammatory/autoimmune skin disease and the epitome of exaggerated primary inflammatory response in the surface barrier tissue. Despite the efficacy of dimethyl fumarate, an electrophilic drug for psoriasis management, there is a paucity of mechanistic evidence in vivo. In response to electrophiles, the Kelch-like ECH-associated protein 1 (KEAP1)/ nuclear factor erythroid 2-related factor 2 (NRF2) system mediates a myriad of cytoprotective mechanisms, including the regulation of excessive inflammatory response and epidermal differentiation. Since the psoriasiform tissue reaction comprises neutrophil infiltration and parakeratotic scaling, it is hypothesized that Nrf2 not only regulates inflammatory responses but also maintains epidermal differentiation, a hallmark of epidermal homeostasis. By utilizing the imiquimod-induced cutaneous inflammation model, an exaggerated inflammatory response and impaired epidermal differentiation in Nrf2−/− mice was detected. Dimethyl fumarate treatment in Nrf2+/+ mice attenuated psoriasiform tissue reaction and rescued epidermal differentiation, which was not observed in Nrf2−/− mice. In accordance with the fact that psoriasis plaques form well-demarcated parakeratotic lesions in association with the psoriasiform tissue reaction, the lesional skin exhibited reduced expression levels of NRF2 and its downstream target genes compared with non-lesional skin. In conclusion, Nrf2 attenuates psoriasiform tissue reaction and underscore the mechanistic legitimacy of the electrophile-based approach for the management of psoriasis.
  • An animal model further uncovers the role of mutant Braf V600E during
           papillary thyroid cancer development
    • Abstract: Publication date: Available online 14 January 2020Source: The American Journal of PathologyAuthor(s): Bernd Koelsch, Sarah Theurer, Magdalena Staniszewska, Jacqueline Heupel, Amelie Koch, Svenja Mergener, Franziska Walk, Christine Fischer, Andrea Kutritz, Kurt W. Schmid, Andrea Kindler-RöhrbornAbstractPapillary thyroid carcinomas (PTC) account for 90% of human thyroid cancer cases which represent 1% of all cancer cases. They are likely to develop from papillary thyroid microcarcinomas (PTMC) found in up to 36% of healthy individuals due to rare progression events (0.01%). Although the prognosis of PTCs is excellent, 5% to 10% of tumors display an unfavorable outcome. About 45% of PTCs exhibit activating BRAFV600E mutations. Rats of the inbred BD strains postnatally exposed to the carcinogen N-ethyl-N-nitrosourea developed PTMCs which closely resembled their human counterparts judging from their histology, size, and marginal tendency to progress. DNA sequencing revealed mutations in exon 15 of the Braf gene identical to the human BRAFV600E mutation in 82% of the cases. Predominantly a 50:50 ratio of wild-type to mutant Braf alleles was seen regardless of tumor size or animal age indicating that the Braf mutation is an early if not the initial event in rat PTMC development. Surprisingly, most PTMC carrying a confirmed BrafV600E mutation did not display BrafV600E protein expression. As the BrafV600Egene is supposed to be the driver in PTC development down-regulation of expression should contribute to the low progression risk of PTMC. This model system will enable further insights into molecular mechanisms of PTMC initiation and progression to PTC, further translating into targeted tumor prevention strategies/ therapies.
  • microRNA-431 promotes metastasis of pancreatic neuroendocrine tumors by
           targeting DAB2IP, a RasGAP tumor suppressor
    • Abstract: Publication date: Available online 14 January 2020Source: The American Journal of PathologyAuthor(s): Tiantian Zhang, Soyoung Choi, Tuo Zhang, Zhengming Chen, Yudan Chi, Shixia Huang, Jenny Z. Xiang, Yi-Chieh Nancy DuAbstractThe incidence of pancreatic neuroendocrine tumor (PNET) is increasing, and it presents with various clinical manifestations, and unfavorable survival rate. A better understanding of the drivers of PNET tumorigenesis is urgently needed. Distinct miRNA signatures have been identified for different stages of tumorigenesis in both human and mouse PNETs. The functions of these miRNAs are poorly understood. miR431 is the most up-regulated miRNA in the metastatic signature. However, it is unknown whether miR431 contributes to metastasis of PNETs. Here, we show that miR431 overexpression activates Ras/Erk signaling and promotes epithelial-mesenchymal transition, migration/invasion in vitro, and metastasis in both xenograft and spontaneous mouse models of PNET. Treatment of PNET cells with Erk inhibitor or locked nucleic acids sequestering miR431 inhibits invasion. Four target prediction modules and dual-luciferase reporter assays were used to identify potential mRNA targets of miR431. A Ras GTPase activating protein (RasGAP) tumor suppressor, DAB2IP, was discovered as a miR431 target. Overexpression of DAB2IP’s rat homolog DIP, but not its mutant defective in RasGAP activity, reverses miR431’s effect on promoting invasion, Erk phosphorylation, and epithelial-mesenchymal transition of PNETs. Taken together, miR431 silences DAB2IP to active Ras/Erk and promote metastasis of PNETs. miR431 may be targeted to manage metastatic PNETs.
  • BAG3P215L/KO mice as a model of BAG3P209L
           myofibrillar myopathy
    • Abstract: Publication date: Available online 14 January 2020Source: The American Journal of PathologyAuthor(s): Rebecca Robertson, Talita C. Conte, Marie-Josée Dicaire, Vladimir V. Rymar, Abbas F. Sadikot, Robert J. Bryson-Richardson, Josée N. Lavoie, Erin O’Ferrall, Jason C. Young, Bernard BraisAbstractBCL-2–Associated Athanogene-3 (BAG3) is a co-chaperone to heat-shock proteins important in degrading misfolded proteins through chaperone-assisted selective autophagy. The recurrent dominant BAG3-P209L mutation results in a severe childhood-onset myofibrillar myopathy (MFM) associated with progressive muscle weakness, cardiomyopathy, and respiratory failure. Since a homozygous knock-in (KI) strain for the mP215L mutation homologous to the human P209L mutation did not have a gross phenotype, compound heterozygote knock-out (KO) and KI mP215L mice were generated to establish if further reduction in BAG3 expression would lead to a phenotype. The KI/KO mice show a significant decrease in voluntary movement compared to wild-type and KI/KI mice in the open field starting at seven months. The KI/KI and KI/KO mice both show significantly smaller muscle fiber cross-sectional area. However, only the KI/KO mice show clear skeletal muscle histological changes in MFM. As in patient muscle, there are increased levels of BAG3 interacting proteins such as p62, HSPB8, and alpha B-crystallin. The KI/KO mP215L strain is the first murine model of BAG3 myopathy that resembles the human skeletal muscle pathology. The results support the hypothesis that the pathological development of MFM requires a significant decrease in BAG3 protein level, and not only a gain of function caused by the dominant missense mutation.
  • Co-ordinated targeting of galanin receptors on cholangiocytes and hepatic
           stellate cells ameliorates liver fibrosis in Mdr2-knockout mice
    • Abstract: Publication date: Available online 14 January 2020Source: The American Journal of PathologyAuthor(s): Anca D. Petrescu, Stephanie Grant, Elaina Williams, Gabriel Frampton, Natalie Parks, Hanna Blaney, Marcus Davies, Rebekah John, Evan H. Reinhart, Matthew McMillin, Sharon DeMorrowAbstractGalanin (Gal) is a peptide with a role in neuroendocrine regulation of the liver. In this study we assessed the role of Gal and its receptors GalR1 and GalR2 in cholangiocyte proliferation and liver fibrosis in Mdr2-knockout (KO) mice as a model of chronic hepatic cholestasis. The distribution of Gal, GalR1, and GalR2 in specific liver cell types was assessed by laser-capture microdissection and confocal microscopy. Galanin immunoreactivity was detected in cholangiocytes, hepatic stellate cells (HSC), and hepatocytes. Cholangiocytes expressed GalR1, whereas HSC and hepatocytes expressed GalR2. Strategies were used to either stimulate or block GalR1 and GalR2 in FVB/N (wild type) and Mdr2KO mice, and measure biliary hyperplasia and hepatic fibrosis by qPCR and immuno-staining of specific markers. Galanin treatment increased cholangiocyte proliferation and fibrogenesis in both FVB/N and Mdr2KO mice. Suppression of GalR1, GalR2, or both receptors in Mdr2KO mice resulted in reduced bile duct mass and hepatic fibrosis. In vitro knockdown of GalR1 in cholangiocytes reduced αSMA expression in LX-2 cells treated with cholangiocyte-conditioned media. A GalR2 antagonist inhibited HSC activation when Gal was administered directly to LX-2 cells, but not via cholangiocyte-conditioned media. These data demonstrate that Gal contributes not only to cholangiocyte proliferation but also to liver fibrogenesis via the coordinate activation of GalR1 in cholangiocytes, and GalR2 in HSC.
  • Hyperlipidemia affects tight junctions and pump function in the corneal
    • Abstract: Publication date: Available online 13 January 2020Source: The American Journal of PathologyAuthor(s): Jinghua Bu, Jingwen Yu, Yang Wu, Xiaoxin Cai, Kechun Li, Liying Tang, Nan Jiang, M. Vimalin Jeyalatha, Minjie Zhang, Huimin Sun, Hui He, Andrew J. Quantock, Yongxiong Chen, Zuguo Liu, Wei LiAbstractHyperlipidemia impacts upon various diseases such as atherosclerosis, hypertension, and diabetes mellitus. However, its influence, if any, on ocular tissues is largely unknown. Here, we developed hyperlipidemic murine models by feeding 4-week–old male wild-type mice with a high fat diet and apolipoprotein E knockout (ApoE-/-) mice with a high fat diet or standard diet to investigate the corneal endothelial change under hyperlipidemic conditions. Oil Red O staining showed an accumulation of lipid droplets in corneal endothelial cells (CECs) of hyperlipidemic mice. Other manifestations included a reduced cell density and distorted cell morphology, a disruption of the endothelial cell tight junctions and adhesion junctions, a reduced number of surface microvilli, down-regulation of Na+-K+-ATPase expression and function, activation of oxidative stress, changes in mitochondrial ultrastructure, and increased apoptosis. CEC recovery after injury, moreover, was diminished in hyperlipidemic mice and high palmitate levels were found in the aqueous humor. In vitro hyperlipemia model, moreover, was found to be associated with dose-dependent CEC cytoxicitiy, altered cell morphology, reduced pump function, and an induction of oxidative stress leading to functional and pathological changes in the corneal endothelium.
  • Scientific Integrity Policy
    • Abstract: Publication date: January 2020Source: The American Journal of Pathology, Volume 190, Issue 1Author(s):
  • Increased Smooth Muscle Kv11.1 Channel Expression in Pulmonary
           Hypertension and Protective Role of Kv11.1 Channel Blocker Dofetilide
    • Abstract: Publication date: January 2020Source: The American Journal of Pathology, Volume 190, Issue 1Author(s): Nataliia V. Shults, Vladyslava Rybka, Yuichiro J. Suzuki, Tinatin I. BrelidzeKv11.1 potassium channels are essential for heart repolarization. Prescription medication that blocks Kv11.1 channels lengthens the ventricular action potential and causes cardiac arrhythmias. Surprisingly little is known about the Kv11.1 channel expression and function in the lung tissue. Here we report that Kv11.1 channels were abundantly expressed in the large pulmonary arteries (PAs) of healthy lung tissues from humans and rats. Kv11.1 channel expression was increased in the lungs of humans affected by chronic obstructive pulmonary disease–associated pulmonary hypertension and in the lungs of rats with pulmonary arterial hypertension (PAH). In healthy lung tissues from humans and rats, Kv11.1 channels were confined to the large PAs. In humans with chronic obstructive pulmonary disease–associated pulmonary hypertension and in rats with PAH, Kv11.1 channels were expressed in both the large and small PAs. The increase in Kv11.1 channel expression closely followed the time-course of the development of pulmonary vascular remodeling in PAH rats. Treatment of PAH rats with dofetilide, an Kv11.1 channel blocker approved by the US Food and Drug Administration for use in the treatment of arrythmia, inhibited PAH-associated pulmonary vascular remodeling. Taken together, the findings from this study uncovered a novel role of Kv11.1 channels in lung function and their potential as new drug targets in the treatment of pulmonary hypertension. The protective effect of dofetilide raises the possibility of repurposing this antiarrhythmic drug for the treatment of patients with pulmonary hypertension.
  • Instructions to Authors
    • Abstract: Publication date: January 2020Source: The American Journal of Pathology, Volume 190, Issue 1Author(s):
  • Endothelial Cell Calcium Signaling During Barrier Function and
    • Abstract: Publication date: Available online 19 December 2019Source: The American Journal of PathologyAuthor(s): Prarthana J. Dalal, William A. Muller, David P. SullivanAbstractCalcium is an essential second messenger in endothelial cells and plays a pivotal role in regulating a number of physiological processes including cell migration, angiogenesis, barrier function, and inflammation. An increase in intracellular Ca2+ concentration can trigger a number of diverse signaling pathways under both physiologic and pathologic conditions. In this review we will specifically discuss how calcium signaling pathways in endothelial cells play an essential role in affecting barrier function and facilitating inflammation. Inflammatory mediators such as thrombin and histamine increase intracellular calcium levels. This calcium influx causes adherens junctions disassembly and cytoskeletal rearrangements to facilitate endothelial cell retraction and increased permeability. During inflammation endothelial cell calcium entry and the calcium-related signaling events also help facilitate several leukocyte-endothelial cell interactions such as leukocyte rolling, adhesion, and ultimately transendothelial migration.
  • Distinct chronic post-viral lung diseases upon infection with influenza or
           parainfluenza viruses differentially impact superinfection outcome
    • Abstract: Publication date: Available online 19 December 2019Source: The American Journal of PathologyAuthor(s): Geyon L. Garcia, Alex Valenzuela, Tomaz Manzoni, Andrew Vaughan, Carolina B. LópezABSTRACTChronic obstructive pulmonary disease (COPD) and asthma remain prevalent human lung diseases. Variability in both epithelial and inflammatory components resulting in pathology heterogeneity complicate the development of treatments for these diseases. Early childhood infection with parainfluenza virus or respiratory syncytial virus strongly associates with the development of asthma and COPD later in life and exacerbations of these diseases correlate with the presence of viral RNA in the lung. Well-characterized animal models of post-viral chronic lung diseases are necessary to study the underlying mechanisms of viral-related COPD and asthma and to develop appropriate therapies. In this study, we cross-analyzed chronic lung disease caused by infection with Sendai virus (SeV) or influenza A virus in mice. Differences wee observed in both lesion composition and inflammatory profiles between SeV- and influenza A virus–induced long-term lung disease. In addition, a primary SeV infection led to worsened pathology upon secondary heterologous viral challenge while the reversed infection scheme protected from disease in response to a secondary viral challenge more than a month after the primary infection. These data demonstrate the differential impact of primary viral infections in the susceptibility to disease exacerbation in response to a different secondary viral infection and highlight the usefulness of these viral models as tools to understand the underlying mechanisms mediating distinct chronic post-viral lung diseases.
  • Recent Developments in Vascular Adventitial Pathobiology
    • Abstract: Publication date: Available online 19 December 2019Source: The American Journal of PathologyAuthor(s): Maria G. Tinajero, Avrum I. GotliebAbstractThe adventitia, the outer layer of the blood vessel wall, may be the most complex layer of the wall and may be the master regulator of wall physiology and pathobiology. This review proposes a major shift in thinking to apply a functional lens to the adventitia rather than only a structural lens. Human and experimental in vivo and in vitro studies show that the adventitia is a dynamic micro-environment in which adventitial and perivascular adipose tissue cells initiate and regulate important vascular functions in disease, especially intimal hyperplasia and atherosclerosis. Although well away from the blood-wall interface where much pathology has been identified, the adventitia has a profound influence on the population of intimal and medial endothelial, macrophage, and smooth muscle cell function. Vascular injury and dysfunction of the perivascular adipose tissue promotes expansion of the vasa vasorum, activation of fibroblasts, and differentiation of myofibroblasts. This regulates further biologic processes including fibroblast and myofibroblast migration and proliferation, inflammation, immunity, stem cell activation and regulation, extracellular matrix remodeling, and angiogenesis. A debate exists as to whether the adventitia initiates disease or is just an important participant. We describe a mechanistic model of adventitial function that brings together current knowledge and guides the design of future investigations to test specific hypotheses on adventitial pathobiology.
  • The immune response in non-metastatic axillary lymph nodes is associated
           with the presence of axillary metastasis and breast cancer patient outcome
    • Abstract: Publication date: Available online 19 December 2019Source: The American Journal of PathologyAuthor(s): Carlos López, Ramon Bosch, Guifre Orero, Anna Korzynska, Marcial García-Rojo, Gloria Bueno, María del Milagro Fernández-Carrobles, Albert Gibert-Ramos, Lukasz Roszkowiak, Cristina Callau, Laia Fontoura, Maria-Teresa Salvadó, Tomás Álvaro, Joaquín Jaén, Albert Roso-Llorach, Montserrat Llobera, Julia Gil, Montserrat Onyos, Benoît Plancoulaine, Jordi BaucellsAbstractTumor cells can modify the immune response in primary tumors and in the axillary lymph nodes with metastasis (ALN+) in breast cancer (BC), influencing patient outcome. We investigated whether patterns of immune cells in the primary tumor and in the axillary lymph nodes without metastasis (ALN-) differed between patients diagnosed without ALN+ (diagnosed-ALN-) and with ALN+ (diagnosed-ALN+), and the implications for clinical outcome. Eleven immune markers were studied using immunohistochemistry, tissue microarray and digital image analysis in 141 BC patients samples (75 diagnosed-ALN+ and 66 diagnosed-ALN-). Two logistic regression models were derived to identify the clinical, pathological, and immunological variables associated with the presence of ALN+ at diagnosis. There are immune patterns in the ALN- associated with the presence of ALN+ at diagnosis. The regression models revealed a small subgroup of diagnosed-ALN+ with ALN- immune patterns that were more similar to those of the ALN- of the diagnosed-ALN-. This small subgroup also showed similar clinical behavior to that of the diagnosed-ALN-. Another small subgroup of diagnosed-ALN- with ALN- immune patterns was found whose members were more similar to those of the ALN- of the diagnosed-ALN+. This small subgroup had similar clinical behavior to the diagnosed-ALN+. These data suggest that the immune response present in ALN- at diagnosis could influence the clinical outcome of BC patients.
  • This Month in AJP
    • Abstract: Publication date: Available online 16 December 2019Source: The American Journal of PathologyAuthor(s):
  • Partitioning-Defectiveness-6–Ephrin-B1 Interaction Is Regulated by
           Nephrin-Mediated Signal and Is Crucial in Maintaining Slit Diaphragm of
    • Abstract: Publication date: Available online 16 December 2019Source: The American Journal of PathologyAuthor(s): Sayuri Takamura, Yoshiyasu Fukusumi, Ying Zhang, Ichiei Narita, Hiroshi KawachiEphrin-B1 plays a critical role at slit diaphragm. Partitioning-defectiveness (Par)-6 is down-regulated in podocyte of ephrin-B1 knockout mouse, suggesting that Par-6 is associated with ephrin-B1. Par polarity complex, consisting of Par-6, Par-3, and atypical protein kinase C, is essential for tight junction formation. In this study, the expression of Par-6 was analyzed in the normal and nephrotic syndrome model rats, and the molecular association of Par-6, Par-3, ephrin-B1, and nephrin was assessed with the human embryonic kidney 293 cell expression system. Par-6 was concentrated at slit diaphragm. Par 6 interacted with ephrin-B1 but not with nephrin, and Par-3 interacted with nephrin but not with ephrin-B1. The complexes of Par-6–ephrin-B1 and Par-3–nephrin were linked via extracellular sites of ephrin-B1 and nephrin. The Par-6–ephrin-B1 complex was delinked from the Par-3–nephrin complex, and Par-6 and ephrin-B1 were clearly down-regulated already at early phase of nephrotic model. The alteration of Par-6/ephrin-B1 advanced that of Par-3/nephrin. Stimulation to nephrin phosphorylated not only nephrin but also ephrin-B1, and consequently inhibited the interaction between ephrin-B1 and Par-6. Par-6 appeared at presumptive podocyte of early developmental stage and moved to basal area at capillary loop stage to participate in slit diaphragm formation at the final stage. Par-6–ephrin-B1 interaction is crucial for formation and maintenance of slit diaphragm of podocyte.
  • Characterization of an Adapted Murine Model of Intrauterine
           Inflammation–Induced Preterm Birth
    • Abstract: Publication date: Available online 16 December 2019Source: The American Journal of PathologyAuthor(s): Hannah C. Zierden, Jairo I. Ortiz Ortiz, Peter Dimitrion, Victoria Laney, Sabrine Bensouda, Nicole M. Anders, Morgan Scardina, Thuy Hoang, Brigitte M. Ronnett, Justin Hanes, Irina Burd, Mala Mahendroo, Laura M. EnsignPreterm birth (PTB) affects nearly 15 million infants each year. Of these PTBs,>25% are a result of inflammation or infection. Animal models have improved our understanding of the mechanisms leading to PTB. Prior work has described induction of intrauterine inflammation in mice with a single injection of lipopolysaccharide (LPS). Herein, we have improved the reproducibility and potency of LPS in the model using two injections distal to the cervix. IVIS imaging revealed more uniform distribution of Evans Blue Dye using a double distal injection (DDI) approach compared with a single proximal injection (SPI). Endotoxin concentrations in vaginal lavage fluid from SPI dams were significantly higher than from DDI dams. At equivalent LPS doses, DDI consistently induced more PTB than SPI, and DDI showed a linear dose-response, whereas SPI did not. Gene expression in myometrial tissue revealed increased levels of inflammatory markers in dams that received LPS DDI compared with LPS SPI. The SPI group showed more significant overexpression in cervical remodeling genes, likely due to the leakage of LPS from the uterine horns through the cervix. The more reliable PTB induction and uniform uterine exposure provided by this new model will be useful for further studying fetal outcomes and potential therapeutics for the prevention of inflammation-induced PTB.
  • Collagen VI Deficiency Results in Structural Abnormalities in the Mouse
    • Abstract: Publication date: Available online 13 December 2019Source: The American Journal of PathologyAuthor(s): Jared A. Mereness, Soumyaroop Bhattacharya, Yue Ren, Qian Wang, Christopher S. Anderson, Kathy Donlon, Andrew M. Dylag, Jeannie Haak, Alessia Angelin, Paolo Bonaldo, Thomas J. MarianiCollagen VI (COL6) is known for its role in a spectrum of congenital muscular dystrophies, which are often accompanied by respiratory dysfunction. However, little is known regarding the function of COL6 in the lung. We confirmed the presence of COL6 throughout the basement membrane region of mouse lung tissue. Lung structure and organization were studied in a previously described Col6a1−/− mouse, which does not produce detectable COL6 in the lung. The Col6a1−/− mouse displayed multiple histopathologic alveolar and airway abnormalities. The airspaces of Col6a1−/− lungs appeared simplified, with larger (29%; P 
  • Src Kinase Is Biphosphorylated at Y416/Y527 and Activates the CUB-Domain
           Containing Protein 1/Protein Kinase C δ Pathway in a Subset of
           Triple-Negative Breast Cancers
    • Abstract: Publication date: Available online 13 December 2019Source: The American Journal of PathologyAuthor(s): Luke J. Nelson, Heather J. Wright, Nguyen B. Dinh, Kevin D. Nguyen, Olga V. Razorenova, F. Scott HeinemannTargeted therapeutics are needed for triple-negative breast cancer (TNBC). In this study, we investigated the activation of Src family of cytoplasmic tyrosine kinases (SFKs) and two SFK substrates—CUB-domain containing protein 1 (CDCP1) and protein kinase C δ (PKCδ)—in 56 formalin-fixed, paraffin-embedded (FFPE) TNBCs. Expression of SFK phosphorylated at Y416 (SFK_pY416+) in tumor cells was strongly associated with phosphorylation of CDCP1 and PKCδ (CDCP1_ pY743+ and PKCδ_pY311+), as assessed by immunohistochemistry, indicating increased SFK activity in situ. To enable biochemical analysis, protein extraction from FFPE tissue was optimized. Cleaved CDCP1 isoform (70 kDa) was expressed to a varying degree in all samples but only phosphorylated in TNBC tumor cells that expressed SFK_pY416. Interestingly, active SFK was found to be biphosphorylated (SFK_pY416+/pY527+). Biphosphorylated active SFK was observed more frequently in FOXA1− TNBCs. In addition, in SFK_pY416− samples, FOXA1+ TNBC tended to be SFK_pY527+ (classic inactive SFK), and FOXA1− TNBC tended to be SFK_pY527− (SFK poised for activation). Strong SFK_pY416 staining was also observed in tumor-infiltrating lymphocytes in a subset of TNBCs with high tumor-infiltrating lymphocyte content. This report will facilitate protein biochemical analysis of FFPE tumor samples and justifies the development of therapies targeting the SFK/CDCP1/PKCδ pathway for TNBC treatment.
  • Amplification of 7p12 Is Associated with Pathologic Nonresponse to
           Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer
    • Abstract: Publication date: Available online 13 December 2019Source: The American Journal of PathologyAuthor(s): Renate Pichler, Andrea K. Lindner, Eva Compérat, Peter Obrist, Georg Schäfer, Tilman Todenhöfer, Wolfgang Horninger, Zoran Culig, Gerold UntergasserPathologic downstaging (pDS) to neoadjuvant chemotherapy (NAC) is one of the most important predictors of survival in muscle-invasive bladder cancer (MIBC). The use of NAC is limited as pDS is only achieved in 30% to 40% of cases and predictive biomarkers are still lacking. We performed a comprehensive immunomolecular biomarker analysis to characterize the role of immune cells and inhibitory checkpoints, genome-wide frequencies of copy number alterations, mutational signatures in whole exome, and tumor mutational burden in predicting NAC response. Our retrospective study included 23 primary MIBC patients who underwent NAC, followed by radical cystectomy. pDS to NAC was a significant prognostic factor for better recurrence-free survival (P 
  • Inflammation and Ectopic Fat Deposition in the Aging Murine Liver Is
           Influenced by CCR2
    • Abstract: Publication date: Available online 13 December 2019Source: The American Journal of PathologyAuthor(s): Elizabeth C. Stahl, Evan R. Delgado, Frances Alencastro, Samuel T. LoPresti, Patrick D. Wilkinson, Nairita Roy, Martin J. Haschak, Clint D. Skillen, Satdarshan P. Monga, Andrew W. Duncan, Bryan N. BrownAging is associated with inflammation and metabolic syndrome, which manifests in the liver as nonalcoholic fatty liver disease (NAFLD). NAFLD can range in severity from steatosis to fibrotic steatohepatitis and is a major cause of hepatic morbidity. However, the pathogenesis of NAFLD in naturally aged animals is unclear. Herein, we performed a comprehensive study of lipid content and inflammatory signature of livers in 19-month–old aged female mice. These animals exhibited increased body and liver weight, hepatic triglycerides, and inflammatory gene expression compared with 3-month–old young controls. The aged mice also had a significant increase in F4/80+ hepatic macrophages, which coexpressed CD11b, suggesting a circulating monocyte origin. A global knockout of the receptor for monocyte chemoattractant protein (CCR2) prevented excess steatosis and inflammation in aging livers but did not reduce the number of CD11b+ macrophages, suggesting changes in macrophage accumulation precede or are independent from chemokine (C-C motif) ligand–CCR2 signaling in the development of age-related NAFLD. RNA sequencing further elucidated complex changes in inflammatory and metabolic gene expression in the aging liver. In conclusion, we report a previously unknown accumulation of CD11b+ macrophages in aged livers with robust inflammatory and metabolic transcriptomic changes. A better understanding of the hallmarks of aging in the liver will be crucial in the development of preventive measures and treatments for end-stage liver disease in elderly patients.
  • p53-Regulated Long Noncoding RNA PRECSIT Promotes Progression of Cutaneous
           Squamous Cell Carcinoma via STAT3 Signaling
    • Abstract: Publication date: Available online 12 December 2019Source: The American Journal of PathologyAuthor(s): Minna Piipponen, Liisa Nissinen, Pilvi Riihilä, Mehdi Farshchian, Markku Kallajoki, Juha Peltonen, Sirkku Peltonen, Veli-Matti KähäriLong noncoding RNAs (lncRNAs) have emerged as putative biomarkers and therapeutic targets in cancer. The role of lncRNA LINC00346 in cutaneous squamous carcinoma (cSCC) was examined. The expression of LINC00346 was up-regulated in cSCC cells compared with normal human epidermal keratinocytes. Elevated expression of LINC00346 was noted in tumor cells in cSCC tissue sections in vivo, as compared with cSCC in situ, and actinic keratosis by RNA in situ hybridization; and the expression in seborrheic keratosis and normal skin was very low. Immunohistochemical analysis of cSCC tissue sections and functional assays of cSCC cells in culture showed that LINC00346 expression is down-regulated by p53. Knockdown of LINC00346 inhibited invasion of cSCC cells in culture and suppressed growth of human cSCC xenografts in vivo. Knockdown of LINC00346 inhibited expression of activated STAT3 and resulted in down-regulation of the expression of matrix metalloproteinase (MMP)-1, MMP-3, MMP-10, and MMP-13. Based on these observations LINC00346 was named p53 regulated carcinoma-associated STAT3-activating long intergenic non-protein coding transcript (PRECSIT). These results identify PRECSIT as a new p53-regulated lncRNA, which promotes progression of cSCC via STAT3 signaling.
  • Angiocrine Hgf signaling controls physiologic organ and body size and
           dynamic hepatocyte proliferation to prevent liver damage during
    • Abstract: Publication date: Available online 27 November 2019Source: The American Journal of PathologyAuthor(s): Xue-jun Zhang, Victor Olsavszky, Yuhan Yin, Baocai Wang, Thomas Engleitner, Rupert Öllinger, Kai Schledzewski, Philipp-Sebastian Koch, Roland Rad, Roland M. Schmid, Helmut Friess, Sergij Goerdt, Norbert Hüser, Cyrill Géraud, Guido von Figura, Daniel HartmannAbstractLiver sinusoidal endothelial cells (LSEC) control organ functions, metabolism, and development through the secretion of angiokines. LSEC express hepatocyte growth factor (Hgf), which is involved in prenatal development, metabolic homeostasis, and liver regeneration. This study aimed to elucidate the precise contribution of LSEC-derived Hgf in physiologic homeostasis and liver regeneration. Stab2-iCretg/wt;Hgffl/fl (HgfΔLSEC) mice were generated to abrogate Hgf expression selectively in LSEC from early fetal development onwards, to study global development, metabolic and endothelial zonation, and organ functions as well as liver regeneration in response to 70% partial hepatectomy (PH). Although zonation and liver-to-body weight ratios were not altered, total body weight, and total liver weight were reduced in HgfΔLSEC. Necrotic organ damage was more marked in HgfΔLSEC mice and regeneration was delayed 72h after PH. This was associated with decreased hepatocyte proliferation at 48h after PH. Molecularly, HgfΔLSEC mice showed down-regulation of Hgf/c-MET signaling and decreased expression of Deptor in hepatocytes. In vitro knock-down of Deptor was associated with decreased proliferation. Therefore, angiocrine Hgf controls hepatocyte proliferation and susceptibility to necrosis following partial hepatectomy via the Hgf/c-Met axis involving Deptor to prevent excessive organ damage.
  • Necroptosis in the Pathophysiology of Disease
    • Abstract: Publication date: Available online 26 November 2019Source: The American Journal of PathologyAuthor(s): Mitri K. Khoury, Kartik Gupta, Sarah R. Franco, Bo LiuOver the past 15 years, elegant studies have demonstrated that under certain conditions, programmed cell death resembles necrosis and depends on a unique molecular pathway with no overlap with apoptosis. This form of regulated necrosis is represented by necroptosis, in which the receptor interacting protein kinase 3 (RIPK3) and its substrate MLKL play a crucial role. With the development of knockout mouse models and molecular inhibitors unique to necroptotic proteins, this cell-death has been found to occur virtually in all tissues and diseases evaluated. There are different immunologic consequences depending on whether cells die through apoptosis or necroptosis. Therefore, distinguishing between these two forms of cell death may be critical during pathological evaluations. In this review, we provide an understanding of necroptotic cell-death and highlight diseases in which necroptosis has been found to play a role. We also discuss the inhibitors of necroptosis and the ways these inhibitors have been used in pre-clinical models of diseases. These two discussions offer an understanding of the role of necroptosis in diseases and will foster efforts to pharmacologically target this unique yet pervasive form of programmed cell-death in the clinic.
  • miRNA-149* suppresses liver cancer progression by down-regulating TRADD
           protein expression
    • Abstract: Publication date: Available online 26 November 2019Source: The American Journal of PathologyAuthor(s): Qingqing Feng, Hongli Zhang, Xiaobo Nie, Yuanqiang Li, Wei-Dong Chen, Yan-Dong WangAbstractLiver cancer is the third leading cause of cancer-related death worldwide. Here we show that microRNA-149* (miR-149*) serves as a novel tumor suppressor for liver tumorigenesis. Mice with genetic deletion of miR-149* (miR-149*-/- mice), which caused loss of both miR-149 and miR-149*, were considerably more susceptible to acute liver injury and hepatic carcinogenesis induced by diethylnitrosamine than wild-type mice, accompanied by increased compensatory proliferation and up-regulated gene expression of certain inflammatory cytokines. miR-149* mimics dramatically impaired liver cancer cell proliferation and migration in vitro, and blocked liver cancer progression in a xenograft model. Furthermore, miR-149* strongly suppressed NF-κB signaling and repressed tumor necrosis factor receptor type 1–associated DEATH domain protein expression in NF-κB signaling pathway. These results reveal that miR-149*, as a novel liver tumor suppressor, may serve as a potential therapeutic target for liver cancer treatment.
  • Effect of Inhibition of Colony Stimulating Factor 1 Receptor on Choroidal
           Neovascularization in Mice
    • Abstract: Publication date: Available online 26 November 2019Source: The American Journal of PathologyAuthor(s): Petra Schwarzer, Despina Kokona, Andreas Ebneter, Martin S. ZinkernagelAbstractNeovascular age-related macular degeneration is one of the leading causes of blindness. Microglia and macrophages play critical role in choroidal neovascularization (CNV) and may therefore be potential targets to modulate the disease course. This study evaluated the effect of the colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX5622 on experimental laser-induced CNV. A 98% reduction of retinal microglia cells was observed in the retina one week after initiation of PLX5622 treatment, preventing accumulation of macrophages within the laser site and leading to a reduction of leukocytes within the choroid after CNV induction. Mice treated with PLX5622 had a significantly faster decrease of the CNV lesion size as revealed by in vivo imaging and immunohistochemistry from day 3 to day 14 compared to untreated mice. Several inflammatory modulators, such as CCL9, granulocyte-macrophage colony-stimulating factor, ssoluble tumor necrosis factor receptor-I, interleukin-1α, and matrix metallopeptidase-2 were elevated in the acute phase of the disease when microglia were ablated with PLX5622, whereas other cytokines (eg, interferon-γ, interleukin-4, and interleukin-10) were reduced. Our results suggest that CSF-1R inhibition may be a novel therapeutic target in patients with neovascular age-related macular degeneration.
  • Glucagon Like Peptide-1 Receptor Agonism Improves Nephrotoxic Serum
           Nephritis by Inhibiting T Cell Proliferation
    • Abstract: Publication date: Available online 22 November 2019Source: The American Journal of PathologyAuthor(s): Foteini Moschovaki Filippidou, Alexander H. Kirsch, Matthias Thelen, Máté Kétszeri, Katharina Artinger, Ida Aringer, Corinna Schabhüttl, Agnes A. Mooslechner, Bianca Frauscher, Marion Pollheimer, Tobias Niedrist, Andreas Meinitzer, Daniel J. Drucker, Thomas R. Pieber, Philipp Eller, Alexander R. Rosenkranz, Akos Heinemann, Kathrin EllerGlucagon like peptide (GLP)-1 analogs such as liraglutide improved albuminuria in patients with type 2 diabetes in large randomized controlled trials. One of the suspected mechanisms is the anti-inflammatory potential of GLP-1 receptor (Glp1r) agonism. Thus, we tested the anti-inflammatory action of Glp1r-agonism in a non-diabetic, T-cell–mediated murine model of nephrotoxic serum nephritis (NTS). The role of Glp1r in NTS was evaluated by using Glp1r −/− mice or C57BL/6 mice treated with liraglutide. In vitro, murine T cells were stimulated in the presence of liraglutide or vehicle. Glp1r −/− mice displayed increased renal infiltration of neutrophils and T cells after induction of NTS. Splenocyte proliferation and TH1 cytokine transcription were increased in spleen and lymph nodes of Glp1r −/−. Liraglutide treatment significantly improved the renal outcome of NTS in C57BL/6 mice by decreasing renal infiltration and proliferation of T cells, which resulted in decreased macrophage infiltration. In vitro, T cells stimulated in the presence of liraglutide showed decreased proliferation of TH1 and TH17 cells. Liraglutide blocked glycolysis in T cells and decreased their Glut1 mRNA expression. Together, Glp1r agonism protects mice from a T-cell–dependent glomerulonephritis model by inhibition of T cell proliferation possibly by interacting with their metabolic program. This mechanism may explain in part the reno-protective effects of Glp1r agonism in diabetic nephropathy.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
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