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Publisher: Elsevier   (Total: 3118 journals)

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Showing 1 - 200 of 3118 Journals sorted alphabetically
A Practical Logic of Cognitive Systems     Full-text available via subscription   (Followers: 7)
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 25, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 22, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 89, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 25, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 30, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 4)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 5, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 374, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 27, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 1)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (Followers: 1, SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 234, SJR: 3.683, h-index: 202)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.615, h-index: 21)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.442, h-index: 21)
Acta Oecologica     Hybrid Journal   (Followers: 10, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 25, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 4, SJR: 0.383, h-index: 19)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 2)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 5, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 4, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 5)
Acute Pain     Full-text available via subscription   (Followers: 13)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 6)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 22)
Advanced Cement Based Materials     Full-text available via subscription   (Followers: 3)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 137, SJR: 5.2, h-index: 222)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.265, h-index: 53)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.299, h-index: 15)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 27, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 6, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 22, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 26, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 4)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 13)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 26, SJR: 0.183, h-index: 23)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.665, h-index: 29)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 9, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 29, SJR: 0.938, h-index: 33)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 16, SJR: 0.223, h-index: 22)
Advances in Dermatology     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 12)
Advances in Digestive Medicine     Open Access   (Followers: 7)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 6)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 46, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 26, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 44, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 3)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 52, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Genetics     Full-text available via subscription   (Followers: 15, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 22, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 26)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 3, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 2)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 5, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 23)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 9, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 24, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 13)
Advances in Pharmacology     Full-text available via subscription   (Followers: 15, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 62)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.1, h-index: 2)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 5)
Advances in Space Research     Full-text available via subscription   (Followers: 368, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Surgery     Full-text available via subscription   (Followers: 8, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 31, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 16)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 6, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 45, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 336, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 5, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 9, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 444, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 15, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 42, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 56, SJR: 1.879, h-index: 120)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.434, h-index: 14)
Air Medical J.     Hybrid Journal   (Followers: 5, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 11, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 8)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access   (Followers: 1)
Algal Research     Partially Free   (Followers: 9, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 4, SJR: 0.776, h-index: 35)
Alpha Omegan     Full-text available via subscription   (SJR: 0.121, h-index: 9)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 9, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 48, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 49, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 48, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 41, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 9, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 32, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 26, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 31, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 46, SJR: 2.023, h-index: 189)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 204, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 60, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 6)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.249, h-index: 88)
American J. of Otolaryngology     Hybrid Journal   (Followers: 24, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 27, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 26, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 35, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 6)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 59, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 13)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 4, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 36, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 164, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 8, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 12)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 1)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 22, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  

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Journal Cover American Journal of Pathology
  [SJR: 2.653]   [H-I: 228]   [27 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0002-9440
   Published by Elsevier Homepage  [3118 journals]
  • Patched 1 Expression Correlates with Biochemical Relapse in High-Risk
           Prostate Cancer Patients
    • Authors: Annelies Gonnissen; Sofie Isebaert; Christiaan Perneel; Chad M. McKee; Filip Van Utterbeeck; Evelyne Lerut; Clare Verrill; Richard J. Bryant; Steven Joniau; Ruth J. Muschel; Karin Haustermans
      Abstract: Publication date: Available online 12 January 2018
      Source:The American Journal of Pathology
      Author(s): Annelies Gonnissen, Sofie Isebaert, Christiaan Perneel, Chad M. McKee, Filip Van Utterbeeck, Evelyne Lerut, Clare Verrill, Richard J. Bryant, Steven Joniau, Ruth J. Muschel, Karin Haustermans
      There is an unmet clinical need for adequate biomarkers to aid risk stratification and management of prostate cancer (PCa) patients. Even within the high-risk PCa category not all patients will invariably have a poor prognosis, and improved stratification of this heterogeneous group is needed. In this context, components of the hedgehog (Hh) pathway may have promise as biomarkers, as the available evidence suggests increased Hh pathway activity may confer a poorer outcome in advanced and castrate-resistant PCa. In this study potential associations between Hh pathway protein expression and clinico-pathological factors, including time to biochemical recurrence (BCR), were investigated using a tissue microarray constructed from benign and malignant prostate samples from 75 predominantly high-risk PCa patients who underwent radical prostatectomy. Hh signaling activity was found to differ between benign and malignant prostate tissue, with a greater amount of active Hh signaling present in malignant than benign prostate epithelium. High expression of PTCH1 in malignant prostate epithelium was found to be an independent predictor of BCR in high-risk PCa patients. GLI1 may potentially represent a clinically useful biomarker of an aggressive tumor phenotype. Evaluation of Hh signaling activity in PCa patients may be useful for risk-stratification, and epithelial PTCH1 expression in particular may be a prognostic marker for BCR in high-risk PCa patients.

      PubDate: 2018-01-14T02:06:42Z
      DOI: 10.1016/j.ajpath.2017.11.019
  • This Month in AJP
    • Abstract: Publication date: Available online 11 January 2018
      Source:The American Journal of Pathology

      Teaser The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.

      PubDate: 2018-01-14T02:06:42Z
  • Prognostic Value of the Expression of DNA Repair–Related Biomarkers
           Mediated by Alcohol in Gastric Cancer Patients
    • Authors: Yiyin Zhang; Hongyang Wu; Feng Yang; Jie Ning; Min Li; Chenchen Zhao; Shuping Zhong; Kangsheng Gu; Hua Wang
      Abstract: Publication date: Available online 10 January 2018
      Source:The American Journal of Pathology
      Author(s): Yiyin Zhang, Hongyang Wu, Feng Yang, Jie Ning, Min Li, Chenchen Zhao, Shuping Zhong, Kangsheng Gu, Hua Wang
      Alcohol consumption likely induces gastric carcinogenesis through deregulation of RNA polymerase (Pol) III genes and oxidative damage. Transcription factor IIB-related factor 1 (BRF1) overexpression alleviates RNA Pol III transcription inhibition through breast cancer susceptibility gene 1 (BRCA1). Myeloperoxidase (MPO) involvement in cancer is induced by alcohol-mediated oxidative damage. BRCA1/2 and MPO play key roles in DNA repair. BRCA1 and BRCA2 exert different roles in homologous recombination repair. By using human gastric cancer (GC) biopsies, we investigated the prognostic value of these proteins upon alcohol induction. In total, high expression of BRF1 (P = 0.010) and positive cell infiltration of MPO (P = 0.004) in tumor tissues as well as positive expression of BRCA1 (P < 0.001) in para-tumor tissues were more frequent in GC patients with hazardous or harmful alcohol consumption habits. BRF1 (P = 0.021), BRCA2 (P < 0.001), and MPO (P = 0.039) were independent prognostic factors for disease-free survival. BRCA1 (P = 0.005) and BRCA2 (P < 0.001) also were identified as independent prognostic factors for overall survival. Furthermore, BRCA2 was an independent unfavorable prognostic factor for disease-free survival and overall survival (P < 0.001) in GC patients who underwent platinum-based adjuvant chemotherapy. BRF1, BRCA1/2, and MPO are DNA repair–related biomarkers, induced by alcohol with prognostic value in GC patients.

      PubDate: 2018-01-14T02:06:42Z
      DOI: 10.1016/j.ajpath.2017.10.010
  • Alterations of Ocular Hemodynamics Impair Ophthalmic Vascular and
           Neuroretinal Function
    • Authors: Shu-Huai Tsai; Wankun Xie; Min Zhao; Robert H. Rosa; Travis W. Hein; Lih Kuo
      Abstract: Publication date: Available online 5 January 2018
      Source:The American Journal of Pathology
      Author(s): Shu-Huai Tsai, Wankun Xie, Min Zhao, Robert H. Rosa, Travis W. Hein, Lih Kuo
      Hypertension is associated with numerous diseases, but its direct impact on the ocular circulation and neuroretinal function remains unclear. Herein, mouse eyes were challenged with different levels of hemodynamic insult via transverse aortic coarctation, which increased blood pressure and flow velocity by 50% and 40%, respectively, in the right common carotid artery, and reduced those parameters by 30% and 40%, respectively, in the left common carotid artery. Blood velocity in the right central retinal artery gradually increased up to 40% at 4 weeks of transverse aortic coarctation, and the velocity in the left central retinal artery gradually decreased by 20%. The fundus and retinal architecture were unaltered by hemodynamic changes. Endothelium-dependent vasodilations to acetylcholine and adenosine were reduced only in right (hypertensive) ophthalmic arteries. Increased cellularity in the nerve fiber/ganglion cell layers, enhanced glial fibrillary acidic protein expression, and elevated superoxide level were found only in hypertensive retinas. The electroretinogram showed decreased scotopic b-waves in the hypertensive eyes and decreased scotopic oscillatory potentials in both hypertensive and hypotensive eyes. In conclusion, hypertension sustained for 4 weeks causes ophthalmic vascular dysfunction, retinal glial cell activation, oxidative stress, and neuroretinal impairment. Although ophthalmic vasoregulation is insensitive to hypotensive insult, the ocular hypoperfusion causes neuroretinal dysfunction.

      PubDate: 2018-01-14T02:06:42Z
      DOI: 10.1016/j.ajpath.2017.11.015
  • Role of A-Kinase Anchoring Protein Phosphorylation in Alcohol-Induced
           Liver Injury and Hepatic Stellate Cell Activation
    • Authors: Komal Ramani; Maria Lauda Tomasi; Joshua Berlind; Nirmala Mavila; Zhaoli Sun
      Abstract: Publication date: Available online 2 January 2018
      Source:The American Journal of Pathology
      Author(s): Komal Ramani, Maria Lauda Tomasi, Joshua Berlind, Nirmala Mavila, Zhaoli Sun
      Alcoholic liver injury is associated with hepatic stellate cell (HSC) activation. A-kinase anchoring protein 12 (AKAP12) scaffolds protein kinase C (PKC-α) and cyclin-D1, which is regulated by its phosphorylation, and spatiotemporally controls cell proliferation, invasiveness, and chemotaxis. HSC activation induces AKAP12 expression but the role of AKAP12's scaffolding activity in liver function is unknown. Since AKAP12 phosphorylation is enhanced in ethanol-treated HSCs, we examined AKAP12's scaffolding functions in alcohol-mediated HSC activation and liver injury. AKAP12 expression, interaction, and phosphorylation was assayed in in vitro and in vivo ethanol models and human subjects by real-time PCR, co-immunoprecipitation, immunoblotting, and phospho-proteomics/phosTag. Ethanol induced AKAP12 phosphorylation in the liver and in primary HSCs, but not in hepatocytes. AKAP12's scaffolding activity for PKC-α/cyclin-D1 decreased in ethanol-treated HSCs but not hepatocytes. AKAP12 negatively regulated HSC activation, which was reversed by ethanol-mediated AKAP12 phosphorylation. AKAP12 interacted with heat shock protein 47 (HSP47) that chaperones collagen and induces its secretion. Ethanol inhibited AKAP12-HSP47 and induced HSP47–collagen interaction. Ethanol-induced phospho-AKAP12 was unable to bind to HSP47 compared to its unphosphorylated counterpart; thereby proving that ethanol-mediated phosphorylation of AKAP12 inhibited the HSP47–AKAP12 scaffold. Silencing AKAP12 facilitated the chaperoning of collagen by HSP47. Hence, AKAP12 scaffolds HSP47 and regulates collagen-HSP47 interaction. Ethanol quenches AKAP12's scaffolding activity through phosphorylation and facilitates HSC activation.

      PubDate: 2018-01-02T18:37:04Z
      DOI: 10.1016/j.ajpath.2017.11.017
  • The Effects of Systemic Therapy of PEGylated NELL-1 on Fracture Healing in
    • Authors: Justine Tanjaya; Elizabeth L. Lord; Chenchao Wang; Yulong Zhang; Jong Kil Kim; Alan Nguyen; Llyod Baik; Hsin Chuan Pan; Eric Chen; Jin Hee Kwak; Xinli Zhang; Benjamin Wu; Chia Soo; Kang Ting
      Abstract: Publication date: Available online 30 December 2017
      Source:The American Journal of Pathology
      Author(s): Justine Tanjaya, Elizabeth L. Lord, Chenchao Wang, Yulong Zhang, Jong Kil Kim, Alan Nguyen, Llyod Baik, Hsin Chuan Pan, Eric Chen, Jin Hee Kwak, Xinli Zhang, Benjamin Wu, Chia Soo, Kang Ting
      Fractures are common with an incidence of 13.7 per 1000 adults annually. Systemic agents have been widely used for enhancing bone regeneration; however, the efficacy of these therapeutics for the management and prevention of fracture remains unclear. NELL-1 is a potent pro-osteogenic cytokine that has been modified with PEGylation (PEGylated NELL-1; NELL-PEG) to enhance its pharmacokinetics for systemic therapy. Our aim was to investigate the effects of systemic administration of NELL-PEG on fracture healing in mice and on overall bone properties in uninjured bones. Ten-week-old CD-1 mice were subjected to an open osteotomy of bilateral radii and treated with weekly injections of NELL-PEG or PEG phosphate buffered saline as control. Systemic injection of NELL-PEG resulted in improved bone mineral density of the fracture site and accelerated callus union. After four weeks of treatment, mice treated with NELL-PEG exhibited substantially enhanced callus volume, callus mineralization, and biomechanical properties. NELL-PEG injection significantly augmented bone regeneration, as confirmed by high expression of bone turnover rate, bone formation rate, and mineral apposition rate. Consistently, the immunohistochemistry results also confirmed a high bone remodeling activity in the NELL-PEG–treated group. Our findings suggest that weekly injection of NELL-PEG may have the clinical potential to accelerate fracture union and enhance overall bone properties, which may help prevent subsequent fractures.

      PubDate: 2018-01-02T18:37:04Z
      DOI: 10.1016/j.ajpath.2017.11.018
  • Enhancing Scientific Foundations to Ensure Reproducibility
    • Authors: Terry Hsieh; Max H. Vaickus; Daniel G. Remick
      Pages: 6 - 10
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Terry Hsieh, Max H. Vaickus, Daniel G. Remick
      Progress in science is dependent on a strong foundation of reliable results. The publish or perish paradigm in research, coupled with an increase in retracted articles from the peer-reviewed literature, is beginning to erode the trust of both the scientific community and the public. The NIH is combating errors by requiring investigators to follow new guidelines addressing scientific premise, experimental design, biological variables, and authentication of reagents. Herein, we discuss how implementation of NIH guidelines will help investigators proactively address pitfalls of experimental design and methods. Careful consideration of the variables contributing to reproducibility helps ensure robust results. The NIH, investigators, and journals must collaborate to ensure that quality science is funded, explored, and published.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.08.028
  • Primary Cilia in Brain Development and Diseases
    • Authors: Yong Ha Youn; Young-Goo Han
      Pages: 11 - 22
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Yong Ha Youn, Young-Goo Han
      The primary cilium, a sensory appendage that is present in most mammalian cells, plays critical roles in signaling pathways and cell cycle progression. Mutations that affect the structure or function of primary cilia result in ciliopathies, a group of developmental and degenerative diseases that affect almost all organs and tissues. Our understanding of the constituents, development, and function of primary cilia has advanced considerably in recent years, revealing pathogenic mechanisms that potentially underlie ciliopathies. In the brain, the primary cilia are crucial for early patterning, neurogenesis, neuronal maturation and survival, and tumorigenesis, mostly through regulating cell cycle progression, Hedgehog signaling, and WNT signaling. We review these advances in our knowledge of primary cilia, focusing on brain development, and discuss the mechanisms that may underlie brain abnormalities in ciliopathies.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.08.031
  • Function and Dysfunction of Adult Hippocampal Neurogenesis in Regeneration
           and Disease
    • Authors: Lei Peng; Michael A. Bonaguidi
      Pages: 23 - 28
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Lei Peng, Michael A. Bonaguidi
      The hippocampus is the only known brain region where physiological neurogenesis continues into adulthood across mammalian species and in humans. However, disease and injury can change the level of adult hippocampal neurogenesis, which plays an important role in regulating cognitive and emotional abilities. Alterations in hippocampal neurogenesis can mediate treatment of mental illness or affect the brain's capacity for repair and regeneration. In the present review, we evaluate how adult neurogenesis contributes to the repair and regeneration of hippocampal circuitry in the face of diseases and injuries. We also discuss possible future directions for harnessing adult neurogenesis for therapeutic use.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.09.004
  • Space Invaders
    • Authors: Justine Sinnaeve; Bret C. Mobley; Rebecca A. Ihrie
      Pages: 29 - 38
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Justine Sinnaeve, Bret C. Mobley, Rebecca A. Ihrie
      Increasing evidence indicates that the adult neurogenic niche of the ventricular-subventricular zone (V-SVZ), beyond serving as a potential site of origin, affects the outcome of malignant brain cancers. Glioma contact with this niche predicts worse prognosis, suggesting a supportive role for the V-SVZ environment in tumor initiation or progression. In this review, we describe unique components of the V-SVZ that may permit or promote tumor growth within the region. Cell-cell interactions, soluble factors, and extracellular matrix composition are discussed, and the role of the niche in future therapies is explored. The purpose of this review is to highlight niche intrinsic factors that may promote or support malignant cell growth and maintenance, and point out how we might leverage these features to improve patient outcome.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.08.029
  • The Healthy and Diseased Microenvironments Regulate Oligodendrocyte
    • Authors: Prisca S. Leferink; Vivi M. Heine
      Pages: 39 - 52
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Prisca S. Leferink, Vivi M. Heine
      White matter disorders are characterized by deficient myelin or myelin loss, lead to a range of neurologic dysfunctions, and can result in early death. Oligodendrocytes, which are responsible for white matter formation, are the first targets for treatment. However, many studies indicate that failure of white matter repair goes beyond the intrinsic incapacity of oligodendrocytes to (re)generate myelin and that failed interactions with neighboring cells or factors in the diseased microenvironment can underlie white matter defects. Moreover, most of the white matter disorders show specific white matter pathology caused by different disease mechanisms. Herein, we review the factors within the cellular and the extracellular microenvironment regulating oligodendrocyte properties and discuss stem cell tools to identify microenvironmental factors of importance to the development of improved regenerative medicine for patients with white matter disorders.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.08.030
  • Determinants of Axon Growth, Plasticity, and Regeneration in the Context
           of Spinal Cord Injury
    • Authors: Angela R. Filous; Jan M. Schwab
      Pages: 53 - 62
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Angela R. Filous, Jan M. Schwab
      The mechanisms that underlie recovery after injury of the central nervous system have rarely been definitively established. Axon regrowth remains the major prerequisite for plasticity, regeneration, circuit formation, and eventually functional recovery. The attributed functional relevance of axon regrowth, however, will depend on several subsequent conditional neurobiological modifications, including myelination and synapse formation, but also pruning of aberrant connectivity. Despite the ability to revamp axon outgrowth by altering an increasing number of extracellular and intracellular targets, disentangling which axons are responsible for the recovery of function from those that are functionally silent, or even contributing to aberrant functions, represents a pertinent void in our understanding, challenging the intuitive translational link between anatomical and functional regeneration. Anatomic hallmarks of regeneration are not static and are largely activity dependent. Herein, we survey mechanisms leading to the formation of dystrophic growth cone at the injured axonal tip, the subsequent axonal dieback, and the molecular determinants of axon growth, plasticity, and regeneration in the context of spinal cord injury.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.09.005
  • Reduced Expression of Hydrogen Sulfide–Generating Enzymes Down-Regulates
           15-Hydroxyprostaglandin Dehydrogenase in Chorion during Term and Preterm
    • Authors: Qianqian Sun; Zixi Chen; Ping He; Yuan Li; Xiaoying Ding; Ying Huang; Hang Gu; Xin Ni
      Pages: 63 - 71
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Qianqian Sun, Zixi Chen, Ping He, Yuan Li, Xiaoying Ding, Ying Huang, Hang Gu, Xin Ni
      Chorionic NAD-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) plays a pivotal role in controlling the amount of prostaglandins in the uterus and has been implicated in the process of labor. Prior studies identified hydrogen sulfide–generating enzymes cystathionine-β-synthetase (CBS) and cystathionine-γ-lyase (CSE) in fetal membranes. We investigated whether hydrogen sulfide is involved in the regulation of PGDH expression in the chorion during labor. The chorionic tissues were obtained from pregnant women at preterm in labor and at term in labor or not in labor at term. Levels of CSE and CBS and hydrogen sulfide production rate were down-regulated in term in labor and preterm in labor groups compared with not in labor at term group. The CBS level correlated to PGDH expression in the chorion. Hydrogen sulfide donor NaHS and precursor l-cysteine dose-dependently stimulated PGDH expression and activity in cultured chorionic trophoblasts. The effect of l-cysteine was blocked by CBS inhibitor and CBS siRNA but not by CSE inhibitor and CSE siRNA. Hydrogen sulfide treatment suppressed miR-26b and miR-199a expression in chorionic trophoblasts. miR-26b and miR-199a mimics blocked hydrogen sulfide upregulation of PGDH expression. Our results indicate that hydrogen sulfide plays pivotal roles in maintenance of PGDH expression in the chorion during human pregnancy. Reduced expression of hydrogen sulfide–generating enzymes contributes to an increased amount of prostaglandins in the uterus during labor.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.09.006
  • Co-Localization of Insulin-Like Growth Factor Binding Protein-1, Casein
           Kinase-2β, and Mechanistic Target of Rapamycin in Human Hepatocellular
           Carcinoma Cells as Demonstrated by Dual Immunofluorescence and in Situ
           Proximity Ligation Assay
    • Authors: Sahil S. Singal; Karen Nygard; Manthan R. Dhruv; Kyle Biggar; Majida A. Shehab; Shawn S.-C. Li; Thomas Jansson; Madhulika B. Gupta
      Pages: 111 - 124
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Sahil S. Singal, Karen Nygard, Manthan R. Dhruv, Kyle Biggar, Majida A. Shehab, Shawn S.-C. Li, Thomas Jansson, Madhulika B. Gupta
      Insulin-like growth factor binding protein (IGFBP)–1 influences fetal growth by modifying insulin-like growth factor–I (IGF-I) bioavailability. IGFBP-1 phosphorylation, which markedly increases its affinity for IGF-I, is regulated by mechanistic target of rapamycin (mTOR) and casein kinase (CSNK)–2. However, the underlying molecular mechanisms remain unknown. We examined the cellular localization and potential interactions of IGFBP-1, CSNK-2β, and mTOR as a prerequisite for protein–protein interaction. Analysis of dual immunofluorescence images indicated a potential perinuclear co-localization between IGFBP-1 and CSNK-2β and a nuclear co-localization between CSNK-2β and mTOR. Proximity ligation assay (PLA) indicated proximity between IGFBP-1 and CSNK-2β as well as mTOR and CSNK-2β but not between mTOR and IGFBP-1. Three-dimensional rendering of the PLA images validated that IGFBP-1 and CSNK-2β interactions were in the perinuclear region and mTOR and CSNK-2β interactions were also predominantly perinuclear rather than nuclear as indicated by mTOR and CSNK-2β co-localization. Compared with control, hypoxia and rapamycin treatment showed markedly amplified PLA signals for IGFBP-1 and CSNK-2β (approximately 18-fold, P = 0.0002). Stable isotope labeling with multiple reaction monitoring–mass spectrometry demonstrated that hypoxia and rapamycin treatment increased IGFBP-1 phosphorylation at Ser98/Ser101/Ser119/Ser174 but most considerably (106-fold) at Ser169. We report interactions between CSNK-2β and IGFBP-1 as well as mTOR and CSNK-2β, providing strong evidence of a mechanistic link between mTOR and IGF-I signaling, two critical regulators of cell growth via CSNK-2.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.09.009
  • Lymphocyte-Dominant Encephalitis and Meningitis in Simian Immunodeficiency
           Virus–Infected Macaques Receiving Antiretroviral Therapy
    • Authors: Lisa M. Mangus; Sarah E. Beck; Suzanne E. Queen; Samuel A. Brill; Erin N. Shirk; Kelly A. Metcalf Pate; Dillon C. Muth; Robert J. Adams; Lucio Gama; Janice E. Clements; Joseph L. Mankowski
      Pages: 125 - 134
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Lisa M. Mangus, Sarah E. Beck, Suzanne E. Queen, Samuel A. Brill, Erin N. Shirk, Kelly A. Metcalf Pate, Dillon C. Muth, Robert J. Adams, Lucio Gama, Janice E. Clements, Joseph L. Mankowski
      A retrospective neuropathologic review of 30 SIV-infected pigtailed macaques receiving combination antiretroviral therapy (cART) was conducted. Seventeen animals with lymphocyte-dominant inflammation in the brain and/or meninges that clearly was morphologically distinct from prototypic SIV encephalitis and human immunodeficiency virus encephalitis were identified. Central nervous system (CNS) infiltrates in cART-treated macaques primarily comprised CD20+ B cells and CD3+ T cells with fewer CD68+ macrophages. Inflammation was associated with low levels of SIV RNA in the brain as shown by in situ hybridization, and generally was observed in animals with episodes of cerebrospinal fluid (CSF) viral rebound or sustained plasma and CSF viremia during treatment. Although the lymphocytic CNS inflammation in these macaques shared morphologic characteristics with uncommon immune-mediated neurologic disorders reported in treated HIV patients, including CNS immune reconstitution inflammatory syndrome and neurosymptomatic CSF escape, the high prevalence of CNS lesions in macaques suggests that persistent adaptive immune responses in the CNS also may develop in neuroasymptomatic or mildly impaired HIV patients yet remain unrecognized given the lack of access to CNS tissue for histopathologic evaluation. Continued investigation into the mechanisms and outcomes of CNS inflammation in cART-treated, SIV-infected macaques will advance our understanding of the consequences of residual CNS HIV replication in patients on cART, including the possible contribution of adaptive immune responses to HIV-associated neurocognitive disorders.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.08.035
  • The Hajdu Cheney Mutation Is a Determinant of B-Cell Allocation of the
           Splenic Marginal Zone
    • Authors: Jungeun Yu; Stefano Zanotti; Bhavita Walia; Evan Jellison; Archana Sanjay; Ernesto Canalis
      Pages: 149 - 159
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Jungeun Yu, Stefano Zanotti, Bhavita Walia, Evan Jellison, Archana Sanjay, Ernesto Canalis
      The neurogenic locus notch homolog protein (Notch)-2 receptor is a determinant of B-cell allocation, and gain-of-NOTCH2–function mutations are associated with Hajdu–Cheney syndrome (HCS), a disease presenting with osteoporosis and acro-osteolysis. We generated a mouse model reproducing the HCS mutation (Notch2HCS), and heterozygous global mutant mice displayed gain-of-Notch2 function. In the mutant spleen, the characteristic perifollicular rim marking the marginal zone (MZ), which is the interface between the nonlymphoid red pulp and the lymphoid white pulp, merged with components of the white pulp. As a consequence, the MZ of Notch2HCS mice occupied most of the splenic structure. To explore the mechanisms involved, lymphocyte populations from the bone marrow and spleen were harvested from heterozygous Notch2HCS mice and sex-matched control littermates and analyzed by flow cytometry. Notch2HCS mice had an increase in CD21/35highCD23− splenic MZ B cells of approximately fivefold and a proportional decrease in splenic follicular B cells (CD21/35intCD23+) at 1, 2, and 12 months of age. Western blot analysis revealed that Notch2HCS mutant splenocytes had increased phospho-Akt and phospho–Jun N-terminal kinase, and gene expression analysis of splenic CD19+ B cells demonstrated induction of Hes1 and Hes5 in Notch2HCS mutants. Anti-Notch2 antibodies decreased MZ B cells in control and Notch2HCS mice. In conclusion, Notch2HCS mutant mice have increased mature B cells in the MZ of the spleen.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.09.010
  • Cobalamin-Associated Superoxide Scavenging in Neuronal Cells Is a
           Potential Mechanism for Vitamin B12–Deprivation Optic Neuropathy
    • Authors: Wesley Chan; Mohammadali Almasieh; Maria-Magdalena Catrinescu; Leonard A. Levin
      Pages: 160 - 172
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Wesley Chan, Mohammadali Almasieh, Maria-Magdalena Catrinescu, Leonard A. Levin
      Chronic deficiency of vitamin B12 is the only nutritional deficiency definitively proved to cause optic neuropathy and loss of vision. The mechanism by which this occurs is unknown. Optic neuropathies are associated with death of retinal ganglion cells (RGCs), neurons that project their axons along the optic nerve to the brain. Injury to RGC axons causes a burst of intracellular superoxide, which then signals RGC apoptosis. Vitamin B12 (cobalamin) was recently shown to be a superoxide scavenger, with a rate constant similar to superoxide dismutase. Given that vitamin B12 deficiency causes an optic neuropathy through unknown mechanisms and that it is a potent superoxide scavenger, we tested whether cobalamin, a vitamin B12 vitamer, would be neuroprotective in vitro and in vivo. We found that cobalamin scavenged superoxide in neuronal cells in vitro treated with the reduction-oxidation cycling agent menadione. In vivo confocal scanning laser ophthalmoscopy demonstrated that optic nerve transection in Long-Evans rats increased superoxide levels in RGCs. The RGC superoxide burst was significantly reduced by intravitreal cobalamin and resulted in increased RGC survival. These data demonstrate that cobalamin may function as an endogenous neuroprotectant for RGCs through a superoxide-associated mechanism.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.08.032
  • Nephrosphere-Derived Cells Are Induced to Multilineage Differentiation
           when Cultured on Human Decellularized Kidney Scaffolds
    • Authors: Silvia Bombelli; Chiara Meregalli; Carla Scalia; Giorgio Bovo; Barbara Torsello; Sofia De Marco; Massimiliano Cadamuro; Paolo Viganò; Guido Strada; Giorgio Cattoretti; Cristina Bianchi; Roberto A. Perego
      Pages: 184 - 195
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Silvia Bombelli, Chiara Meregalli, Carla Scalia, Giorgio Bovo, Barbara Torsello, Sofia De Marco, Massimiliano Cadamuro, Paolo Viganò, Guido Strada, Giorgio Cattoretti, Cristina Bianchi, Roberto A. Perego
      In end-stage chronic kidney disease, the option of organ transplantation is limited because of the scarce availability of kidneys. The combination of stem cell research, regenerative medicine, and tissue engineering seems a promising approach to produce new transplantable kidneys. Currently, the possibility to repopulate naturally obtained scaffolds with cells of different sources is advancing. Our aim was to test, for the first time, whether the nephrosphere (NS) cells, composed by renal stem/progenitor-like cells, were able to repopulate different nephron portions of renal extracellular matrix scaffolds obtained after decellularization of human renal tissue slices. Our decellularization protocol enabled us to obtain a completely acellular renal scaffold while maintaining the extracellular matrix structure and composition in terms of collagen IV, laminin, and fibronectin. NS cells, cultured on decellularized renal scaffolds with basal medium, differentiated into proximal and distal tubules as well as endothelium, as highlighted by histology and by the specific expression of epithelial cytokeratin 8.18, proximal tubular CD10, distal tubular cytokeratin 7, and endothelial von Willebrand factor markers. Endothelial medium promoted the differentiation toward the endothelium, whereas epithelial medium promoted the differentiation toward the epithelium. NS cells seem to be a good tool for scaffold repopulation, paving the way for experimental investigations focused on whole-kidney reconstruction.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.09.012
  • Chorionic Gonadotropin-β Modulates Epithelial-Mesenchymal Transition in
           Colorectal Carcinoma Metastasis
    • Authors: Futoshi Kawamata; Hiroshi Nishihara; Shigenori Homma; Yasutaka Kato; Masumi Tsuda; Yuji Konishi; Lei Wang; Shinji Kohsaka; Cheng Liu; Tadashi Yoshida; Mishie Tanino; Shinya Tanaka; Hideki Kawamura; Toshiya Kamiyama; Akinobu Taketomi
      Pages: 204 - 215
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Futoshi Kawamata, Hiroshi Nishihara, Shigenori Homma, Yasutaka Kato, Masumi Tsuda, Yuji Konishi, Lei Wang, Shinji Kohsaka, Cheng Liu, Tadashi Yoshida, Mishie Tanino, Shinya Tanaka, Hideki Kawamura, Toshiya Kamiyama, Akinobu Taketomi
      Ectopic production of free β human chorionic gonadotropin (hCGβ) has been associated with aggressive behavior in non-trophoblastic tumors. hCGβ shares common evolutionary sequences with transforming growth factor-β (TGF-β), which represents a major driving force of epithelial-to-mesenchymal transition (EMT). In this study, we examined the biological roles of hCGβ during EMT and its clinical significance in colorectal cancer (CRC) progression. Eighty CRC specimens and 54 preoperative serum samples were analyzed. hCGβ-overexpressing human CRC cell lines were examined for invasiveness and tumorigenicity, and the expression of EMT-associated genes was investigated. In human CRC, histologic hCGβ positivity [13/80 (16.3%)] was lower than serologic hCGβ positivity [13/54 (24.1%)]. However, it was significantly correlated with several clinicopathological features and unfavorable outcome (P < 0.05). hCGβ-overexpressing cell lines had increased invasiveness, migratory ability, and metastatic potential in mice (P < 0.01). Western blot, PCR, and microarray analyses showed hCGβ altered expression of EMT-related genes, including E-cadherin, phosphorylated SMAD2, SNAIL, and TWIST. hCGβ-induced SNAIL and TWIST overexpression levels were reversible by type I and type II TGF-β receptor inhibitors (P < 0.05). hCGβ thus induces EMT via the TGF-β signaling pathway, and it may represent a molecular target in CRC treatment.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.08.034
  • Neurotrophin Receptors TrkA, p75NTR, and Sortilin Are Increased and
           Targetable in Thyroid Cancer
    • Authors: Sam Faulkner; Philip Jobling; Christopher W. Rowe; S.M. Rodrigues Oliveira; Severine Roselli; Rick F. Thorne; Christopher Oldmeadow; John Attia; Chen Chen Jiang; Xu Dong Zhang; Marjorie M. Walker; Hubert Hondermarck
      Pages: 229 - 241
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Sam Faulkner, Philip Jobling, Christopher W. Rowe, S.M. Rodrigues Oliveira, Severine Roselli, Rick F. Thorne, Christopher Oldmeadow, John Attia, Chen Chen Jiang, Xu Dong Zhang, Marjorie M. Walker, Hubert Hondermarck
      Neurotrophin receptors are emerging targets in oncology, but their clinicopathologic significance in thyroid cancer is unclear. In this study, the neurotrophin tyrosine receptor kinase TrkA (also called NTRK1), the common neurotrophin receptor p75NTR, and the proneurotrophin receptor sortilin were analyzed with immunohistochemistry in a cohort of thyroid cancers (n = 128) and compared with adenomas and normal thyroid tissues (n = 62). TrkA was detected in 20% of thyroid cancers, compared with none of the benign samples (P = 0.0007). TrkA expression was independent of histologic subtypes but associated with lymph node metastasis (P = 0.0148), suggesting the involvement of TrkA in tumor invasiveness. Nerves in the tumor microenvironment were positive for TrkA. p75NTR was overexpressed in anaplastic thyroid cancers compared with papillary and follicular subtypes (P < 0.0001). Sortilin was overexpressed in thyroid cancers compared with benign thyroid tissues (P < 0.0001). Neurotrophin receptor expression was confirmed in a panel of thyroid cancer cell lines at the mRNA and protein levels. Functional investigations using the anaplastic thyroid cancer cell line CAL-62 found that siRNA against TrkA, p75NTR, and sortilin decreased cell survival and cell migration through decreased SRC and ERK activation. Together, these data reveal TrkA, p75NTR, and sortilin as potential therapeutic targets in thyroid cancer.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.09.008
  • Overexpression of Flap Endonuclease 1 Correlates with Enhanced
           Proliferation and Poor Prognosis of Non–Small-Cell Lung Cancer
    • Authors: Keqiang Zhang; Sawa Keymeulen; Rebecca Nelson; Tommy R. Tong; Yate-Ching Yuan; Xinwei Yun; Zheng Liu; Joshua Lopez; Dan J. Raz; Jae Y. Kim
      Pages: 242 - 251
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Keqiang Zhang, Sawa Keymeulen, Rebecca Nelson, Tommy R. Tong, Yate-Ching Yuan, Xinwei Yun, Zheng Liu, Joshua Lopez, Dan J. Raz, Jae Y. Kim
      Flap endonuclease 1 (FEN1) plays a crucial role in both DNA replication and damage repair. In this study, FEN1 expression and its clinical-pathologic significance in non–small-cell lung cancer (NSCLC) was investigated. Quantitative RT-PCR and immunohistochemistry analysis identified that both FEN1 mRNA and protein were highly overexpressed in about 36% of 136 cancer tissues compared to adjacent tissues, in which FEN1 was generally undetectable. Notably, patients with FEN1-overexpressed cancers were prone to have poor differentiation and poor prognosis. A strong positive correlation between the levels of FEN1 and Ki-67 staining was identified in these NSCLC tissues (r = 0.485), suggesting overexpressed FEN1 conferred a proliferative advantage to NSCLC. Furthermore, knockdown of FEN1 resulted in G1/S or G2/M phase cell cycle arrest and suppressed in vitro cellular proliferation in NSCLC cancer cells. Consistently, a selective FEN1 inhibitor was shown to effectively inhibit cellular proliferation of NSCLC cells in a dose-dependent manner. Additionally, knockdown of FEN1 significantly attenuated homologous DNA repair efficiency and enhanced cytotoxic effects of cisplatin in NSCLC cells. Taken together, these findings have indicated that overexpressed FEN1 represents a prognostic biomarker and potential therapeutic target for NSCLC treatment, which warrants further study.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.09.011
  • Platelet CD40 Mediates Leukocyte Recruitment and Neointima Formation after
           Arterial Denudation Injury in Atherosclerosis-Prone Mice
    • Authors: Rong Jin; Adam Y. Xiao; Zifang Song; Shiyong Yu; Jarvis Li; Mei-Zhen Cui; Guohong Li
      Pages: 252 - 263
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): Rong Jin, Adam Y. Xiao, Zifang Song, Shiyong Yu, Jarvis Li, Mei-Zhen Cui, Guohong Li
      The role of platelets in the development of thrombosis and abrupt closure after angioplasty is well recognized. However, the direct impact of platelets on neointima formation after arterial injury remains undetermined. Herein, we show that neointima formation after carotid artery wire injury reduces markedly in CD40−/− apolipoprotein E–deficient (apoE−/−) mice but only slightly in CD40 ligand−/−apoE−/− mice, compared with apoE−/− mice. Wild-type and CD40-deficient platelets were isolated from blood of apoE−/− and CD40−/−apoE−/− mice, respectively. The i.v. injection of thrombin-activated platelets into CD40−/−apoE−/− mice was performed every 5 days, starting at 2 days before wire injury. Injection of wild-type platelets promoted neointima formation, which was associated with increased inflammation by stimulating leukocyte recruitment via up-regulation of circulating platelet surface P-selectin expression and the formation of platelet-leukocyte aggregates. It was also associated with further promoting the luminal deposition of platelet-derived regulated on activation normal T cell expressed and secreted/chemokine (C-C motif) ligand 5 and expression of monocyte chemoattractant protein-1 and vascular cell adhesion molecule 1 in wire-injured carotid arteries. Remarkably, all these inflammatory actions by activated platelets were abrogated by lack of CD40 on injected platelets. Moreover, injection of wild-type platelets inhibited endothelial recovery in wire-injured carotid arteries, but this effect was also abrogated by lack of CD40 on injected platelets. Results suggest that platelet CD40 plays a pivotal role in neointima formation after arterial injury and might represent an attractive target to prevent restenosis after vascular interventions.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.09.007
  • Neural Regeneration a Century after Ramón y Cajal's Decree
    • Authors: Otero
      Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1
      Author(s): José J. Otero
      Teaser This Guest Editorial introduces this month's special Neural Regeneration and Development Theme Issue, a series of reviews intended to highlight the advances in modern neuroscience and to depict the chasms in our understanding of the brain.

      PubDate: 2017-12-26T18:12:14Z
  • Correction
    • Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1

      PubDate: 2017-12-26T18:12:14Z
  • Note of Concern
    • Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1

      PubDate: 2017-12-26T18:12:14Z
  • Instructions to Authors
    • Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1

      PubDate: 2017-12-26T18:12:14Z
  • Scientific Integrity Policy
    • Abstract: Publication date: January 2018
      Source:The American Journal of Pathology, Volume 188, Issue 1

      PubDate: 2017-12-26T18:12:14Z
  • Mouse Metanephric Mesenchymal Cell–Derived Angioblasts Undergo
           Vasculogenesis in Three-Dimensional Culture
    • Authors: Mandakini Patel; Chakradhar Velagapudi; Hannah Burns; Robert Doss; Myung-Ja Lee; Meenalakshmi M. Mariappan; Brent Wagner; Mazen Arar; Veronique L. Barnes; Hanna E. Abboud; Jeffrey L. Barnes
      Abstract: Publication date: Available online 19 December 2017
      Source:The American Journal of Pathology
      Author(s): Mandakini Patel, Chakradhar Velagapudi, Hannah Burns, Robert Doss, Myung-Ja Lee, Meenalakshmi M. Mariappan, Brent Wagner, Mazen Arar, Veronique L. Barnes, Hanna E. Abboud, Jeffrey L. Barnes
      In vitro models for the investigation of renal vascular development are limited. We previously showed that isolated metanephric mesenchymal (MM) and ureteric bud (UB) cells grown in three-dimensional (3D) matrices formed organoids consisting of primitive vascular structures surrounding a polarized epithelium. Here, we examined the potential of two principal effectors of vasculogenesis, vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor B chain (PDGF-BB), to stimulate MM cell differentiation. The results showed that MM cells possess angioblast characteristics by expressing phenotypic markers for endothelial and mesenchymal cells. UB cells synthesize VEGF-A and PDGF-BB proteins and RNA; whereas, the MM cells express the respective cognate receptors, supporting their role in directional induction of vasculogenesis. VEGF-A stimulated proliferation of MM cells in monolayer and in 3D sponges, but did not affect MM cell migration, organization, or vasculogenesis. On the other hand, PDGF-BB stimulated MM cell proliferation, migration, and vasculogenesis in monolayer and organization of the cells into primitive capillary-like assemblies in 3D sea sponge scaffolds in vitro. A role for PDGF-BB in vasculogenesis in the 3D MM/UB co-culture system was validated by direct interference with PDGF-BB or PDGFR-β cell interactions implicating PDGF-BB as a primary effector of MM cell vasculogenesis. Thus, MM cells resemble early renal angioblasts that may provide an ideal platform for the investigation of renal vasculogenesis in vitro.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.10.022
  • MicroRNA-31-3p Is Involved in Substance P (SP)-Associated Inflammation in
           Human Colonic Epithelial Cells and Experimental Colitis
    • Authors: Kai Fang; Ivy Ka Man Law; David Padua; Aristea Sideri; Vanessa Huang; Christopher G. Kevil; Dimitrios Iliopoulos; Charalabos Pothoulakis
      Abstract: Publication date: Available online 16 December 2017
      Source:The American Journal of Pathology
      Author(s): Kai Fang, Ivy Ka Man Law, David Padua, Aristea Sideri, Vanessa Huang, Christopher G. Kevil, Dimitrios Iliopoulos, Charalabos Pothoulakis
      Substance P (SP) mediates colitis. SP signaling regulates the expression of several microRNAs (miRNAs), including miR-31-3p, in human colonocytes. However, the role of miR-31-3p in colitis and the underlying mechanisms has not been elucidated. We performed real time PCR analysis of miR-31-3p expression in human colonic epithelial cells overexpressing neurokinin-1 receptor (NCM460 NK-1R) in response to SP stimulation and in NCM460 cells following interleukin (IL)-6, IL8, tumor necrosis factor (TNF)-α, and interferon-γ exposure. Functions of miR-31-3p were tested in NCM460-NK-1R cells and the TNBS and DSS models of colitis. Targets of miRNA-31-3p were confirmed by Western blot and luciferase reporter assays. JNK inhibition decreased SP-induced miR-31-3p expression. MiR-31-3p expression was increased in both TNBS- and DSS-induced colitis and human colonic biopsies from ulcerative colitis, compared to controls. Intracolonic administration of a miR-31-3p chemical inhibitor exacerbated TNBS and DSS-induced colitis and increased colonic TNF-α, CXCL10, and CCL2 mRNA expression. Conversely, overexpression of miR-31-3p ameliorated the severity of DSS-induced colitis. Bioinformatic, luciferase reporter assay, and Western-blot analyses identified RhoA as a target of miR-31-3p in NCM460 cells. Constitutive activation of RhoA led to increased expression of CCL2, IL6, TNF-α, and CXCL10 in NCM460-NK-1R cells upon SP stimulation. Our results reveal a novel SP-miR-31-3p-RhoA pathway that protects from colitis. The use of miR-31-3p mimics may be a promising approach for colitis treatment.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.10.023
  • Fibrosis in Preeclamptic Placentas Is Associated with Stromal Fibroblasts
           Activated by the Transforming Growth Factor Beta 1 (TGFB1) Signaling
    • Authors: Takako Ohmaru-Nakanishi; Kazuo Asanoma; Mai Fujikawa; Yasuyuki Fujita; Hiroshi Yagi; Ichiro Onoyama; Nobuhiro Hidaka; Kenzo Sonoda; Kiyoko Kato
      Abstract: Publication date: Available online 16 December 2017
      Source:The American Journal of Pathology
      Author(s): Takako Ohmaru-Nakanishi, Kazuo Asanoma, Mai Fujikawa, Yasuyuki Fujita, Hiroshi Yagi, Ichiro Onoyama, Nobuhiro Hidaka, Kenzo Sonoda, Kiyoko Kato
      Although fibrosis is one of the most prominent pathological features of preeclamptic (PE) placentas, its mechanism remains largely unknown. Consistent with previous reports, we observed overexpression of collagen; actin, alpha 2, smooth muscle, aorta; connective tissue growth factor; and fibronectin in PE placentas compared with control ones. To investigate the mechanism of fibrosis in PE placentas, placental fibroblasts were isolated from PE placentas or normal pregnancies at delivery. The expression of fibrosis-related factors in fibroblasts was evaluated by real-time reverse transcription PCR, western blotting, ELISA, and gene microarrays. An in vitro collagen gel contraction assay was also performed. Fibroblasts isolated from PE placentas showed higher expression levels of fibrosis-related factors compared with those from control ones. Global gene expression profiling of PE fibroblasts was contrasted with that of control ones, and indicated intimate association with transforming growth factor beta 1 (TGFB1) signaling. Furthermore, the PE fibroblasts expressed abundant phosphorylated SMAD family member 2 and showed higher expression levels of target genes of TGFB1 signaling compared with the control ones. The PE fibroblasts also had a greater ability to contract compared with the control ones. Contractility also depended on TGFB1 signaling. Our results suggest that TGFB1 signaling is activated in the fibroblasts in PE placentas and that these active fibroblasts contribute to fibrosis.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.11.008
  • A large set of miRNAs is dysregulated since the earliest steps of human
           hepatocellular carcinoma development
    • Authors: Pia Sulas; Luca Di Tommaso; Chiara Novello; Francesca Rizzo; Antonio Rinaldi; Alessandro Weisz; Amedeo Columbano; Massimo Roncalli
      Abstract: Publication date: Available online 15 December 2017
      Source:The American Journal of Pathology
      Author(s): Pia Sulas, Luca Di Tommaso, Chiara Novello, Francesca Rizzo, Antonio Rinaldi, Alessandro Weisz, Amedeo Columbano, Massimo Roncalli
      Hepatocellular carcinoma (HCC) mostly results from a stepwise process characterized by the development of premalignant lesions, such as low- or high-grade dysplastic nodules (LGDN and HGDN, respectively) in a cirrhotic setting. MicroRNAs (miRNAs) are small noncoding RNAs involved in post-transcriptional regulation of gene expression that can act as oncogenes or tumor suppressors. Whether and which miRNAs are involved in the early stages of HCC development remains elusive. Here, small RNA sequencing was applied to profile miRNA expression in 55 samples (cirrhotic nodules, CNs), LGDNs, HGDNs, early HCCs, and small progressed HCCs, obtained from 17 patients bearing HCCs of different etiology. A miRNA expression signature of 62 miRNAs distinguishing small progressed HCCs from matched CNs was identified. Interestingly, 52 of these miRNAs discriminated CNs from LGDNs/HGDNs, regardless of the etiology, and remained modified along the tumorigenic process. Functional analysis of the predicted mRNA targets of deregulated miRNAs identified common modifications between early and late stages of HCC development likely involved in the stepwise process of HCC development. Our results demonstrate that miRNA deregulation happens very early in human liver carcinogenesis, implying their critical role in the tumorigenic process. The identification of miRNAs discriminating cirrhotic from neoplastic nodules may have relevant translational implications for early diagnosis.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.10.024
  • Endothelin-2 injures the blood-retinal barrier and macroglial Müller
    • Authors: Saeed Fadal Alrashdi; Devy Deliyanti; Dean Michael Talia; Jennifer Louise Wilkinson-Berka
      Abstract: Publication date: Available online 15 December 2017
      Source:The American Journal of Pathology
      Author(s): Saeed Fadal Alrashdi, Devy Deliyanti, Dean Michael Talia, Jennifer Louise Wilkinson-Berka
      Although increasing evidence indicates that endothelin-2 (Edn2) has distinct roles in tissue pathology including inflammation, glial cell dysfunction, and angiogenesis, its role in the retina and the factors that regulate its actions are not fully understood. We hypothesized that Edn2 damages the blood-retinal barrier (BRB) and this is mediated by interactions with the renin-angiotensin aldosterone system and reactive oxygen species derived from NADPH oxidase (Nox). C57BL/6J mice received an intravitreal injection of Edn2 or control vehicle to examine the blood pressure–independent effects of Edn2. Mice administered Edn2 were randomized to receive by intraperitoneal injection treatments that inhibited the Edn type a receptor, Edn type b receptor, angiotensin type 1 receptor, mineralocorticoid receptor, or Nox isoforms 1/4. One month later, mice administered Edn2 exhibited breakdown of the BRB with increased vascular leakage, vascular endothelial growth factor expression, and infiltrating macrophages (Ly6C+CD45highCD11b+). Further, macroglial Müller cells, which influence the integrity of the BRB and prevent retinal oedema, became gliotic and expressed increased levels of water (aquaporin-4) and ion (Kir4.1) channels. This Edn2-mediated retinopathy was reduced by all treatments. Complementary in vitro studies in cultured Müller cells supported these findings and demonstrated the importance of ROS in mediating these events. In conclusion, Edn2 has detrimental effects on the BRB and Müller cells that involve interactions with the renin-angiotensin aldosterone system and Nox1/4.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.11.009
  • γδ T cells contribute to injury in the developing brain
    • Authors: Anna-Maj Albertsson; Xiaoli Zhang; Regina Vontell; Dan Bi; Roderick T. Bronson; Veena Supramaniam; Ana A. Baburamani; Sha Hua; Arshed Nazmi; Susanna Cardell; Changlian Zhu; Harvey Cantor; Carina Mallard; Henrik Hagberg; Jianmei W. Leavenworth; Xiaoyang Wang
      Abstract: Publication date: Available online 15 December 2017
      Source:The American Journal of Pathology
      Author(s): Anna-Maj Albertsson, Xiaoli Zhang, Regina Vontell, Dan Bi, Roderick T. Bronson, Veena Supramaniam, Ana A. Baburamani, Sha Hua, Arshed Nazmi, Susanna Cardell, Changlian Zhu, Harvey Cantor, Carina Mallard, Henrik Hagberg, Jianmei W. Leavenworth, Xiaoyang Wang
      Brain injury in premature infants, especially periventricular leukomalacia, is an important cause of neurological disabilities. Inflammation contributes to the development of perinatal brain injury, but the essential mediators leading to brain injury in early life remain largely unknown. Neonates have reduced capacity for mounting conventional αβT-cell responses. However γδT-cells are already functionally competent during early development and are important in early life immunity. We investigated the potential contribution of γδT-cells to preterm brain injury by using postmortem brains from human preterm infants with periventricular leukomalacia and two animal models of preterm brain injury—the hypoxic-ischemic mouse model and a fetal sheep asphyxia model. Large numbers of γδT-cells were observed in the brains of mice, sheep, and postmortem preterm infants after injury, and depletion of γδT-cells provided protection in the mouse model. The common γδT-cell associated cytokines interferon-γ and interleukin (IL)-17A were not detectable in the brain. Although there were increased mRNA levels of Il17f and Il22 in the mouse brains after injury, neither IL-17F nor IL-22 cytokines contributed to preterm brain injury. These findings highlight unique features of injury in the developing brain where, unlike injury in the mature brain, γδT-cells function as important initiators of injury independently of common γδT-cell associated cytokines. This new finding will help to identify therapeutic targets for preventing or treating preterm infants with brain injury.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.11.012
  • Knockout of l-Histidine Decarboxylase (HDC-/-) Prevents Cholangiocyte
           Damage and Hepatic Fibrosis in Mice Subjected to High-Fat Diet Feeding via
           Disrupted Histamine/Leptin Signaling
    • Authors: Lindsey Kennedy; Laura Hargrove; Jennifer Demieville; Jennifer Bailey; Wasim Dar; Kishore Polireddy; Qingzheng Chen; Moises I. Nevah Rubin; Amelia Sybenga; Sharon DeMorrow; Fanyin Meng; Lindsey Stockton; Gianfranco Alpini; Heather Francis
      Abstract: Publication date: Available online 15 December 2017
      Source:The American Journal of Pathology
      Author(s): Lindsey Kennedy, Laura Hargrove, Jennifer Demieville, Jennifer Bailey, Wasim Dar, Kishore Polireddy, Qingzheng Chen, Moises I. Nevah Rubin, Amelia Sybenga, Sharon DeMorrow, Fanyin Meng, Lindsey Stockton, Gianfranco Alpini, Heather Francis
      Administration of a high-fat diet (HFD) coupled with sugar, mimicking a Western diet, causes fatty liver disease in mice. Histamine induces biliary proliferation and fibrosis, and regulates leptin signaling. Wild-type (WT) and l-histidine decarboxylase (Hdc -/- ) mice were fed a control diet or a HFD coupled with a high fructose corn syrup equivalent. H&E and Oil Red O staining were performed to determine steatosis. Intrahepatic biliary mass and cholangiocyte proliferation were evaluated by immunohistochemistry. Senescence and fibrosis were measured by qPCR and immunohistochemistry. Hepatic stellate cell activation was detected by immunofluorescence. Histamine and leptin levels were measured by EIA. The leptin receptor, Ob-R, was evaluated by qPCR in cholangiocytes lacking HDC. The HDC/histamine/histamine receptor axis, ductular reaction, and biliary senescence were evaluated in patients with non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, or end-stage liver disease. Hdc -/- HFD mice had increased steatosis compared to WT HFD mice. WT HFD mice had increased intrahepatic biliary mass, biliary proliferation and senescence, fibrosis, and hepatic stellate cell activation, which were reduced in Hdc -/- HFD mice. In Hdc -/- HFD mice, serum leptin levels increased, whereas biliary Ob-R expression decreased. NASH patients had increased HDC/histamine/histamine receptor signaling. Hdc -/- HFD mice are susceptible to obesity via dysregulated leptin/Ob-R signaling, whereas the lack of HDC protects from HFD-induced fibrosis and cholangiocyte damage. HDC/histamine/leptin signaling may be important in managing obesity-induced biliary damage.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.11.016
  • Fibroblasts Promote Inflammation and Pain via Interleukin-1α–Induction
           of the Monocyte Chemoattractant CCL2
    • Authors: Hannah Louise Paish; Nicolas Stewart Kalson; Graham Robert Smith; Alicia del Carpio Pons; Thomas Edward Baldock; Nicholas Smith; Katarzyna Swist-Szulik; David John Weir; Michelle Bardgett; David John Deehan; Derek Austin Mann; Lee Anthony Borthwick
      Abstract: Publication date: Available online 15 December 2017
      Source:The American Journal of Pathology
      Author(s): Hannah Louise Paish, Nicolas Stewart Kalson, Graham Robert Smith, Alicia del Carpio Pons, Thomas Edward Baldock, Nicholas Smith, Katarzyna Swist-Szulik, David John Weir, Michelle Bardgett, David John Deehan, Derek Austin Mann, Lee Anthony Borthwick
      Fibroblasts persist within fibrotic scar tissue and exhibit considerable phenotypic and functional plasticity. Here, we hypothesized that scar-associated fibroblasts may be a source of stress-induced inflammatory exacerbations and pain. To test this idea we used a human model of surgery-induced fibrosis, total knee arthroplasty (TKA). Using a combination of tissue protein expression profiling and bioinformatics we discovered that many months following TKA the fibrotic joint exists in a state of unresolved chronic inflammation. Moreover, the infrapatellar fat pad, a soft tissue that becomes highly fibrotic in the post-TKA joint, expresses multiple inflammatory mediators including the monocyte chemoattractant CCL2 and the innate immune trigger interleukin-1α (IL-1α). Fibroblasts isolated from the post-TKA fibrotic infrapatellar fat pad express the interleukin-1 receptor and upon exposure to IL-1α polarize to a highly inflammatory state that enables them to stimulate the recruitment of monocytes. Blockade of fibroblast CCL2 or its transcriptional regulator NF-kB prevented IL-1α–induced monocyte recruitment. Clinical investigations discovered that levels of patient reported pain in the post-TKA joint correlated with concentrations of CCL2 in the joint tissue such that the chemokine is effectively a pain biomarker in the TKA patient. We propose that an IL-1α–NF-kB–CCL2 signaling pathway operating within scar-associated fibroblasts may be therapeutically manipulated for alleviating inflammation and pain in fibrotic joints and other tissues.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.11.007
  • Discrete pools of oligomeric amyloid-β track with spatial learning
           deficits in a mouse model of Alzheimer amyloidosis
    • Authors: Angie C.A. Chiang; Stephanie W. Fowler; Rohit Reddy; Olga Pletnikova; Juan C. Troncoso; Mathew A. Sherman; Sylvain E. Lesne; Joanna L. Jankowsky
      Abstract: Publication date: Available online 15 December 2017
      Source:The American Journal of Pathology
      Author(s): Angie C.A. Chiang, Stephanie W. Fowler, Rohit Reddy, Olga Pletnikova, Juan C. Troncoso, Mathew A. Sherman, Sylvain E. Lesne, Joanna L. Jankowsky
      Despite increasing appreciation that oligomeric amyeloid beta (Aβ) may contribute to cognitive decline of Alzheimer disease, defining the most critical forms has been thwarted by the changeable nature of these aggregates and the varying methods used for detection. Here, using a broad approach, we quantified Aβ oligomers during the evolution of cognitive deficits in an aggressive model of Aβ amyloidosis. Amyloid precursor protein/tetracycline transactivator mice underwent behavioral testing at 3, 6, 9, and 12 months of age to evaluate spatial learning and memory, followed by histological assessment of amyloid burden and biochemical characterization of oligomeric Aβ species. Transgenic mice displayed progressive impairments in acquisition and immediate recall of the trained platform location. Biochemical analysis of cortical extracts from behaviorally tested mice revealed distinct age-dependent patterns of accumulation in mulitple oligomeric species. Dot blot analysis demonstrated that non-fibrillar Aβ oligomers (A11) were highly soluble and extracted into a fraction enriched for extracellular proteins, whereas pre-fibrillar (OC) species required high-detegerent conditions to retrieve, consistent with membrane localization. Low-detergent extracts tested by 82E1 ELISA confirmed the presence of bona fide Aβ oligomers, whereas immunoprecipitation-Western using high-detergent extracts revealed a variety of SDS-stable low-n species. These findings show that different Aβ oligomers vary in solubility consistent with distinct localization, and identify A11-positive non-fibrillar aggregates as tracking most closely with cognitive decline in this model.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.11.011
  • Acquisition of Cholangiocarcinoma Traits during Advanced Hepatocellular
           Carcinoma Development in Mice
    • Authors: Liyuan Li; Maoxiang Qian; I-Hsuan Chen; David Finkelstein; Arzu Onar-Thomas; Melissa Johnson; Christopher Calabrese; Armita Bahrami; Dolores H. López-Terrada; Jun J. Yang; W. Andy Tao; Liqin Zhu
      Abstract: Publication date: Available online 15 December 2017
      Source:The American Journal of Pathology
      Author(s): Liyuan Li, Maoxiang Qian, I-Hsuan Chen, David Finkelstein, Arzu Onar-Thomas, Melissa Johnson, Christopher Calabrese, Armita Bahrami, Dolores H. López-Terrada, Jun J. Yang, W. Andy Tao, Liqin Zhu
      Past studies have identified hepatic tumors with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) characteristics which have a more aggressive behavior and a poorer prognosis than classic HCC. Whether this pathological heterogeneity is due to a cell of origin of bipotent liver progenitors or the plasticity of cellular constituents comprising these tumors remains debated. In this study, we investigated the potential acquisition of CC-like traits during advanced development of HCC in mice. Primary and rare high-grade HCC developed in a genetic mouse model. A mouse model of highly efficient HCC invasion and metastasis via orthotopic transplantation of liver cancer organoids propagated from primary tumors in the genetic model was further developed. Invasive/metastatic tumors developed in both models closely recapitulated advanced human HCC, and displayed a striking acquisition of CC-related pathological and molecular features, which was absent in the primary HCC tumors. Our study directly demonstrates the pathological evolution of HCC during advanced tumor development, providing the first evidence that tumors with mixed HCC and CC features, or at least a subset of these tumors, represent a more advanced developmental stage of HCC. Lastly, liver cancer organoid–generated high-grade tumors exhibited significantly in creased extracellular vesicle (EV) secretion, suggesting that identifying tumor-specific EV proteins in plasma may be a promising tool for liver cancer detection.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.11.013
  • Malnutrition in pancreatic ductal adenocarcinoma (PDA): dietary pancreatic
           enzymes improve short-term health but stimulate tumor growth
    • Authors: Yalda Zolghadri; Shreoshi Pal Choudhuri; Ozhan Ocal; Somayeh Layeghi- Ghalehsoukhteh; Feaven Berhe; Michael A. Hale; Thomas M. Wilkie
      Abstract: Publication date: Available online 15 December 2017
      Source:The American Journal of Pathology
      Author(s): Yalda Zolghadri, Shreoshi Pal Choudhuri, Ozhan Ocal, Somayeh Layeghi- Ghalehsoukhteh, Feaven Berhe, Michael A. Hale, Thomas M. Wilkie
      Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer that resists efforts to identify better chemotherapeutics. PDA is associated with chronic pancreatitis and acinar cell dedifferentiation. This reduces enzyme production by the exocrine pancreas, resulting in digestive insufficiencies. Malabsorption of partially digested food can cause bloating, overfilled intestines, abdominal pain, excessive feces, steatorrhea, and malnutrition. These maladies affect quality of life and restrict treatment options for pancreatitis and PDA. Here, we characterize the health benefits and risks of dietary pancreatic enzymes in three mouse models of PDA—KC, KCR8-16, and KIC. KC expresses oncogenic Kras G12D in pancreatic tissue whereas KCR8-16 also has deletions of the Rgs8 and Rgs16 genes. Rgs proteins inhibit the release of digestive enzymes evoked by G-protein coupled receptor agonists. KC and KCR8-16 mice developed dedifferentiated exocrine pancreata within two months of age, and became malnourished, underweight, hypoglycemic, and hypothermic. KC mice adapted but KCR8-16 rapidly transitioned to starvation after mild metabolic challenges. Dietary pancreatic enzyme supplements reversed these symptoms in KC and KCR8-16 animals, and extended survival. Therefore, we tested benefits of pancreatic enzymes in an aggressive mouse model of PDA (KIC). Median survival improved with dietary pancreatic enzyme supplements and was further extended when combined with warfarin and gemcitabine chemotherapy. However, dietary pancreatic enzymes stimulated tumor growth in the terminal stages of disease progression in KIC mice.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.11.014
  • Hepatic stem/progenitor cell activation differs between primary sclerosing
           and primary biliary cholangitis
    • Authors: Guido Carpino; Vincenzo Cardinale; Trine Folseraas; Diletta Overi; Annarosa Floreani; Antonio Franchitto; Paolo Onori; Nora Cazzagon; Pasquale Bartolomeo Berloco; Tom Hemming Karlsen; Domenico Alvaro; Eugenio Gaudio
      Abstract: Publication date: Available online 15 December 2017
      Source:The American Journal of Pathology
      Author(s): Guido Carpino, Vincenzo Cardinale, Trine Folseraas, Diletta Overi, Annarosa Floreani, Antonio Franchitto, Paolo Onori, Nora Cazzagon, Pasquale Bartolomeo Berloco, Tom Hemming Karlsen, Domenico Alvaro, Eugenio Gaudio
      Primary sclerosing cholangitis and primary biliary cholangitis are human primary cholangiopathies; these diseases are characterized by the damage of mature cholangiocytes and by the appearance of ductular reaction as the results of hepatic progenitor cell activation. The aims of this study were to evaluate differences in progenitor cell niche activation between these two human cholangiopathies. Human liver tissue was obtained from normal liver donors (n=5), primary sclerosing (n=20), and primary biliary cholangitis (n=20). Ductular reaction, progenitor cell phenotype, and signaling pathways were investigated by immunohistochemistry and immunofluorescence. Our results indicated that ductular reaction is more extended, appears earlier, and has a higher proliferation index in primary biliary cholangitis compared to primary sclerosing cholangitis. In primary biliary cholangitis, ductular reaction strongly correlates with clinical prognostic scores. A higher percentage of Sox9+ and Keratin-19+ cells but lower features of hepatocyte fate characterize progenitor cell activation in primary biliary cholangitis versus primary sclerosing cholangitis. Lower levels of laminin and NOTCH1 but higher expression of WNT pathway components characterize progenitor cell niche in primary sclerosing cholangitis compared to primary biliary cholangitis. In conclusion, progenitor cell activation differs between primary sclerosing cholangitis and primary biliary cholangitis and is characterized by a divergent fate commitment and different signaling pathway predominance. In primary biliary cholangitis, ductular reaction represents a relevant histologic prognostic marker.

      PubDate: 2017-12-26T18:12:14Z
      DOI: 10.1016/j.ajpath.2017.11.010
  • This Month in AJP
    • Abstract: Publication date: Available online 11 November 2017
      Source:The American Journal of Pathology

      Teaser The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.

      PubDate: 2017-11-16T06:08:34Z
  • A New Scope and a New Editorial Team for The American Journal of Pathology
    • Authors: Martha B. Furie
      Abstract: Publication date: Available online 10 November 2017
      Source:The American Journal of Pathology
      Author(s): Martha B. Furie
      Teaser This Editorial describes new enhanced scope of The American Journal of Pathology and introduces its new editorial team.

      PubDate: 2017-11-16T06:08:34Z
      DOI: 10.1016/j.ajpath.2017.10.008
  • Haploinsufficiency of hnRNP U changes activity pattern and metabolic
    • Authors: Beibei Lai; Jianghuan Zou Zhaoyu Lin Zhipeng Anying Song Ying
      Abstract: Publication date: Available online 9 November 2017
      Source:The American Journal of Pathology
      Author(s): Beibei Lai, Jianghuan Zou, Zhaoyu Lin, Zhipeng Qu, Anying Song, Ying Xu, Xiang Gao
      The neuropeptides arginine vasopressin (Avp) and vasoactive intestinal polypeptide (Vip) are critical for the communication and coupling of suprachiasmatic nucleus neurons, which organize daily rhythms of physiology and behavior in mammals. However, how these peptides are regulated remains uncharacterized. Here, we demonstrate that heterogeneous nuclear ribonucleoprotein U (hnRNP U) is essential for the expression of Avp and Vip. Loss of one copy of the Hnrnpu gene resulted in fragmented locomotor activities and disrupted metabolic rhythms. Hnrnpu +/- mice were more active than wild-type mice in the day time but more inactive at night. These phenotypes were partially rescued by micro-infusion of Avp and Vip into free-moving animals. In addition, hnRNP U modulated Avp and Vip via directly binding to their promoters together with Bmal1: Clock heterodimers. Our work identifies hnRNP U as a novel regulator of the circadian pacemaker and provides new insights into the mechanism of rhythm output.

      PubDate: 2017-11-16T06:08:34Z
  • Antiandrogens Reduce Intratumoral Androgen Concentrations and Induce
           Androgen Receptor Expression in Castration-Resistant Prostate Cancer
    • Authors: Matias Knuuttila; Arfa Mehmood Riikka Huhtaniemi Emrah Yatkin Merja Riikka
      Abstract: Publication date: Available online 7 November 2017
      Source:The American Journal of Pathology
      Author(s): Matias Knuuttila, Arfa Mehmood, Riikka Huhtaniemi, Emrah Yatkin, Merja R. Häkkinen, Riikka Oksala, Teemu D. Laajala, Henrik Ryberg, David J. Handelsman, Tero Aittokallio, Seppo Auriola, Claes Ohlsson, Asta Laiho, Laura L. Elo, Petra Sipilä, Sari I. Mäkelä, Matti Poutanen
      The development of castration-resistant prostate cancer (CRPC) is associated with the activation of intratumoral androgen biosynthesis and an increase in androgen receptor (AR) expression. We recently demonstrated that similarly to the clinical CRPC, orthotopically grown castration-resistant VCaP (CR-VCaP) xenografts express high levels of AR and retain intratumoral androgen concentrations similar to tumors grown in intact mice. Here, we show that antiandrogen treatment (enzalutamide or ARN-509) significantly reduced (10-fold, P < 0.01) intratumoral testosterone and dihydrotestosterone concentrations in the CR-VCaP tumors, indicating that the reduction in intratumoral androgens is a novel mechanism by which antiandrogens mediate their effects in CRPC. Antiandrogen treatment also altered the expression of multiple enzymes potentially involved in steroid metabolism. Identical to clinical CRPC, the expression levels of the full-length AR (2-fold, P < 0.05) and the AR splice variants AR-V1 (3-fold, P < 0.05) and AR-V7 (3-fold, P < 0.01) were further increased in the antiandrogen-treated tumors. Non-significant effects were observed in the expression of certain classical androgen-regulated genes, such as TMPRSS2 and KLK3, despite the low levels of testosterone and dihydrotestosterone. However, other genes recently identified to be highly sensitive to androgen-regulated AR action, such as NOV and ST6GalNAc1, were markedly altered, which indicated reduced androgen action. Taken together, the data indicate that besides blocking AR, antiandrogens modify androgen signaling in CR-VCaP xenografts at multiple levels.

      PubDate: 2017-11-08T17:50:20Z
  • Immuno-metabolic determinants of chemoradiotherapy response and survival
           in head and neck squamous cell carcinoma
    • Authors: Rosemarie Krupar; Matthias G. Hautmann; Ravi R. Pathak; Indu Varier; Cassandra McLaren; Doris Gaag; Claus Hellerbrand; Matthias Evert; Simon Laban; Christian Idel; Vlad Sandulache; Sven Perner; Anja K. Bosserhoff; Andrew G. Sikora
      Abstract: Publication date: Available online 27 October 2017
      Source:The American Journal of Pathology
      Author(s): Rosemarie Krupar, Matthias G. Hautmann, Ravi R. Pathak, Indu Varier, Cassandra McLaren, Doris Gaag, Claus Hellerbrand, Matthias Evert, Simon Laban, Christian Idel, Vlad Sandulache, Sven Perner, Anja K. Bosserhoff, Andrew G. Sikora
      Tumor immune microenvironment and tumor metabolism are major determinants of chemoradiotherapy response. We assessed the interdependency and prognostic significance of specific immune and metabolic phenotypes in head and neck squamous cell carcinoma (HNSCC) and evaluated changes in reactive oxygen species as a mechanism of treatment response in tumor spheroid/immunocyte co-cultures. Pretreatment tumor biopsies were immunohistochemically characterized in a cohort of 73 HNSCC patients treated by definitive chemoradiotherapy and correlated with survival. The prognostic significance of CD8A, GLUT1, and COX5B gene expression were analyzed within The Cancer Genome Atlas database. HNSCC spheroids were co-cultured in vitro with peripheral blood mononuclear cells (PBMC) in the presence of the glycolysis inhibitor 2-deoxyglucose and radiation treatment followed by PBMC chemotaxis determination via fluorescence microscopy. In the chemoradiotherapy-treated HNSCC cohort mitochondrial-rich (COX5B) metabolism correlated with increased and glucose-dependent (GLUT1) metabolism with decreased intratumoral CD8/CD4 ratios. High CD8/CD4 together with mitochondrial-rich or glucose-independent metabolism was associated with improved short-term survival. The Cancer Genome Atlas analysis confirmed that patients with a favorable immune and metabolic gene signature (high CD8A, high COX5B, low GLUT1) had improved short- and long-term survival. In vitro, 2-deoxyglucose and radiation synergistically up-regulated reactive oxygen species–dependent PBMC chemotaxis to HNSCC spheroids. Our results suggest that glucose-independent tumor metabolism is associated with CD8-dominant anti-tumor immune infiltrate, and together these contribute to improved chemoradiotherapy response in HNSCC.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.09.013
  • Ectopic phosphorylated Creb marks dedifferentiated proximal tubules in
           cystic kidney disease
    • Authors: Pawan Puri; Caitlin M. Schaefer; Daniel Bushnell; Mary E. Taglienti; Jordan A. Kreidberg; Bradley K. Yoder; Carlton M. Bates
      Abstract: Publication date: Available online 26 October 2017
      Source:The American Journal of Pathology
      Author(s): Pawan Puri, Caitlin M. Schaefer, Daniel Bushnell, Mary E. Taglienti, Jordan A. Kreidberg, Bradley K. Yoder, Carlton M. Bates
      Ectopic cAMP signaling is pathological in polycystic kidney disease; however, its spatio-temporal actions are unclear. We characterized expression of phosphorylated Creb (p-Creb), a target and mediator of cAMP signaling, in developing and cystic kidney models. We also examined tubule-specific effects of cAMP analogs in cystogenesis in embryonic kidney explants. In wild-type mice, p-Creb marked nephron progenitors (NP), early epithelial NP derivatives, ureteric bud, and cortical stroma; p-Creb was present in differentiated thick ascending limb of Henle, collecting duct, and stroma; however, it disappeared in mature NP-derived proximal tubules. In Six2cre;Frs2α Fl/Fl mice, a renal cystic model, ectopic p-Creb stained proximal tubule–derived cystic segments that lost the differentiation marker LTL. Furthermore, LTL-negative/p-Creb-positive cyst segments (re)-expressed Ncam1, Pax2, and Sox9 markers of immature nephron structures and dedifferentiated proximal tubules following acute kidney injury. These de-differentiation markers were co-expressed with p-Creb in renal cysts in Itf88 knockout mice subjected to ischemia and Six2cre;Pkd1 Fl/Fl mice, other renal cystogenesis models. 8-Br-cAMP addition to wild-type embryonic kidney explants induced proximal tubular cystogenesis and p-Creb expression; these effects were blocked by co-addition of PKA inhibitor. Thus p-Creb/ cAMP signaling is appropriate in NP and early nephron derivatives, but disappears in mature proximal tubules. Moreover, ectopic p-Creb expression/cAMP signaling marks dedifferentiated proximal tubular cystic segments. Furthermore, proximal tubules are predisposed to become cystic after cAMP stimulation.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.09.015
  • Loss of β Epithelial Sodium Channel Function in Meibomian Glands Produces
           Pseudohypoaldosteronism 1–Like Ocular Disease in Mice
    • Authors: Dongfang Yu; Yogesh Saini; Gang Chen; Andrew J. Ghio; Hong Dang; Kimberlie A. Burns; Yang Wang; Richard M. Davis; Scott H. Randell; Charles R. Esther; Friedrich Paulsen; Richard C. Boucher
      Abstract: Publication date: Available online 26 October 2017
      Source:The American Journal of Pathology
      Author(s): Dongfang Yu, Yogesh Saini, Gang Chen, Andrew J. Ghio, Hong Dang, Kimberlie A. Burns, Yang Wang, Richard M. Davis, Scott H. Randell, Charles R. Esther, Friedrich Paulsen, Richard C. Boucher
      Human subjects with pseudohypoaldosteronism-1 due to loss of function mutations in epithelial Na+ channel (ENaC) subunits exhibit meibomian gland (MG) dysfunction. A conditional βENaC MG knockout mouse model was generated to elucidate the pathogenesis of absent ENaC function in the MG and associated ocular surface disease. βENaC MG KO mice exhibited a striking age dependent, female predominant MG dysfunction phenotype, with white toothpaste–like secretions observed obstructing MG orifices at seven weeks of age. There were compensatory increases in tear production but higher tear Na+ and indices of mucin concentration in βENaC MG KO mice. Histologically, MG acinar atrophy was observed with ductal enlargement and ductal epithelial hyperstratification. Inflammatory cell infiltration was observed in both MG and conjunctiva of βENaC MG KO mice. In older βENaC MG KO mice (five to 11 months), significant ocular surface pathologies were noted, including corneal opacification, ulceration, neovascularization, and ectasia. Inflammation in MG and conjunctiva was confirmed by increased cytokine gene and protein expression and positive Ly-6B.2 immunostaining. Cell proliferation assays revealed lower proliferation rates of MG cells derived from βENaC MG KO than control mice, suggesting that βENaC plays a role in cell renewal of mouse MG. Loss of βENaC function resulted in MG disease and severe ocular surface damage that phenocopied aspects of human pseudohypoaldosteronism-1 MG disease and was sex dependent.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.09.016
  • The role of extracellular histones in influenza virus pathogenesis
    • Authors: Harshini K. Ashar; Nathan C. Mueller; Jennifer M. Rudd; Timothy A. Snider; Mallika Achanta; Maram Prasanthi; Sivasami Pulavendran; Paul G. Thomas; Ramachandran Akhilesh; Jerry R. Malayer; Jerry W. Ritchey; Rachakatla Rajasekhar; Vincent TK. Chow; Charles T. Esmon; Narasaraju Teluguakula
      Abstract: Publication date: Available online 26 October 2017
      Source:The American Journal of Pathology
      Author(s): Harshini K. Ashar, Nathan C. Mueller, Jennifer M. Rudd, Timothy A. Snider, Mallika Achanta, Maram Prasanthi, Sivasami Pulavendran, Paul G. Thomas, Ramachandran Akhilesh, Jerry R. Malayer, Jerry W. Ritchey, Rachakatla Rajasekhar, Vincent TK. Chow, Charles T. Esmon, Narasaraju Teluguakula
      Although exaggerated host immune responses have been implicated in influenza-induced lung pathogenesis, the etiological factors that contribute to these events are not completely understood. We have previously demonstrated that neutrophil extracellular traps exacerbate pulmonary injury during influenza pneumonia. Histones are the major protein components of neutrophil extracellular traps and are known to have cytotoxic effects. Here, we examined the role of extracellular histones in lung pathogenesis during influenza. Mice infected with influenza virus displayed high accumulation of extracellular histones, with widespread pulmonary microvascular thrombosis. Occluded pulmonary blood vessels with vascular thrombi often exhibited endothelial necrosis surrounded by hemorrhagic effusions and pulmonary edema. Histones released during influenza induced cytotoxicity and showed strong binding to platelets within thrombi in infected mouse lungs. Nasal wash samples of influenza-infected patients also showed increased accumulation of extracellular histones, suggesting a possible clinical relevance of elevated histones in pulmonary injury. Although histones inhibited influenza growth in vitro, in vivo treatment with histones did not yield antiviral effects and instead exacerbated lung pathology. Blocking with anti-histone antibodies causes marked decrease in lung pathology in lethal influenza-challenged mice and improved protection when administered in combination with the antiviral agent oseltamivir. These findings support the pathogenic effects of extracellular histones by exacerbating pulmonary injury during influenza, and targeting histones provides a novel therapeutic approach to alleviate influenza pneumonia.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.09.014
  • Exploring the Role of IL-32 in human immunodeficiency virus–related
           Kaposi sarcoma
    • Authors: George Semango; Bas Heinhuis; Theo S. Plantinga; Willeke A.M. Blokx; Gibson Kibiki; Tolbert Sonda; Daudi Mavura; Elisante John Masenga; Mramba Nyindo; Andre J.A.M. van der Ven; Leo A.B. Joosten
      Abstract: Publication date: Available online 14 October 2017
      Source:The American Journal of Pathology
      Author(s): George Semango, Bas Heinhuis, Theo S. Plantinga, Willeke A.M. Blokx, Gibson Kibiki, Tolbert Sonda, Daudi Mavura, Elisante John Masenga, Mramba Nyindo, Andre J.A.M. van der Ven, Leo A.B. Joosten
      The intracellular pro-inflammatory mediator interleukin (IL)-32 is associated with tumor progression; however, the mechanisms remain unknown. We studied the IL-32 mRNA expression as well as other pro-inflammatory cytokines and mediators including IL-1α, IL-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, the pro-angiogenic and anti-apoptotic enzyme COX-2, the IL-8 receptor CXCR1, and the intracellular kinase FAK-1. The interaction of IL-32 expression with expression of IL-6, TNFα, IL-8, and COX-2 was also investigated. Biopsies of 11 human immunodeficiency (HIV)-related, seven non HIV–related Kaposi sarcoma (KS), and seven normal skin tissues of Dutch origin were analyzed. RNA was isolated from the paraffin material and gene expression levels of IL-32α, β, and γ isoforms, IL1a, IL1b, IL6, IL8, TNFA, PTGS2, CXCR1, and PTK2 were determined using quantitative real-time PCR. Significantly higher expression of IL-32β and IL-32γ isoforms was observed in HIV-related KS biopsies compared to non HIV–related KS and normal skin tissue. The splicing ratio of the IL-32 isoforms showed IL-32γ as the highest expressed isoform, followed by IL-32β in HIV-related KS cases compared to non HIV–related KS and normal skin tissue. Our data suggest a possible survival mechanism by the splicing of IL-32γ to IL-32β and also IL-6, IL-8, and CXCR1 signalling pathways to reverse the pro-apoptotic effect of IL-32γ isoform leading to tumor cell survival and thus favoring tumor progression.

      PubDate: 2017-10-18T14:59:21Z
      DOI: 10.1016/j.ajpath.2017.08.033
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Heriot-Watt University
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