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Showing 1 - 200 of 3048 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: 24, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 22, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 86, 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: 358, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, 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   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 225, 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: 1)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 24, 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: 4)
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: 21)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 134, 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: 26, 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: 25, 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: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 27, 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: 11)
Advances in Digestive Medicine     Open Access   (Followers: 6)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 43, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 25, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 42, 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: 50, 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: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 8, 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: 17)
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: 2, 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: 362, 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: 7, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 30, 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: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 43, 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: 327, 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: 8, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 413, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 16, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 30, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 40, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 54, 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: 8, 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: 46, 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: 47, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 40, 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: 32, 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: 200, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 59, 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: 25, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 26, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 24, 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: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 58, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 12)
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: 37, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 166, 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: 23, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 170, SJR: 1.907, h-index: 126)

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Journal Cover American Journal of Pathology
  [SJR: 2.653]   [H-I: 228]   [26 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0002-9440
   Published by Elsevier Homepage  [3051 journals]
  • Magnetic Resonance Imaging and Molecular Characterization of a
           Hormone-Mediated Murine Model of Prostate Enlargement and Bladder Outlet
    • Authors: Erin M. McAuley; Devkumar Mustafi; Brian W. Simons; Rebecca Valek; Marta Zamora; Erica Markiewicz; Sophia Lamperis; Anthony Williams; Brian B. Roman; Chad Vezina; Greg Karczmar; Aytekin Oto; Donald J. Vander Griend
      Pages: 2378 - 2387
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Erin M. McAuley, Devkumar Mustafi, Brian W. Simons, Rebecca Valek, Marta Zamora, Erica Markiewicz, Sophia Lamperis, Anthony Williams, Brian B. Roman, Chad Vezina, Greg Karczmar, Aytekin Oto, Donald J. Vander Griend
      Urinary complications resulting from benign prostatic hyperplasia and bladder outlet obstruction continue to be a serious health problem. Novel animal model systems and imaging approaches are needed to understand the mechanisms of disease initiation, and to develop novel therapies for benign prostatic hyperplasia. Long-term administration of both estradiol and testosterone in mice can result in prostatic enlargement and recapitulate several clinical components of lower urinary tract symptoms. Herein, we use longitudinal magnetic resonance imaging and histological analyses to quantify changes in prostatic volume, urethral volume, and genitourinary vascularization over time in response to estradiol-induced prostatic enlargement. Our data demonstrate significant prostatic enlargement by 12 weeks after treatment, with no detectable immune infiltration by macrophages or T- or B-cell populations. Importantly, the percentage of cell death, as measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling, was significantly decreased in the prostatic epithelium of treated animals as compared to controls. We found no significant change in prostate cell proliferation in treated mice when compared to controls. These studies highlight the utility of magnetic resonance imaging to quantify changes in prostatic and urethral volumes over time. In conjunction with histological analyses, this approach has the high potential to enable mechanistic studies of initiation and progression of clinically relevant lower urinary tract symptoms. In addition, this model is tractable for investigation and testing of therapeutic interventions to ameliorate or potentially reverse prostatic enlargement.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.014
  • The LIM-Only Protein Four and a Half LIM Domain Protein 2 Attenuates
           Development of Psoriatic Arthritis by Blocking Adam17-Mediated Tumor
           Necrosis Factor Release
    • Authors: Rafael L. Dantas; Bent Brachvogel; Tanja Schied; Vera Bergmeier; Boris Skryabin; Thomas Vogl; Stephan Ludwig; Viktor Wixler
      Pages: 2388 - 2398
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Rafael Leite Dantas, Bent Brachvogel, Tanja Schied, Vera Bergmeier, Boris Skryabin, Thomas Vogl, Stephan Ludwig, Viktor Wixler
      Four and a half LIM domain protein 2 (Fhl2) is an intracellular adaptor molecule with a high protein-protein interaction capacity. It acts as a modulator of several signaling molecules in the cytosol and as a cofactor of transcription in the nucleus. Recent studies suggest the role of Fhl2 in tissue repair and the anti-inflammatory response. Herein, we show that Fhl2-deficient mice develop a more severe psoriatic arthritis disease under induction of the inducible human tumor necrosis factor (hTNF) transgene than wild-type mice. The disease was accompanied by increased infiltration of activated macrophages and T regulatory cells in skin and digit joints as well as by increased expression of matrix metalloproteases and bone-specific proteases. The more severe pathogenesis of psoriatic arthritis in Fhl2 knockout mice coincided with enhanced levels of soluble hTNF cytokine, but surprisingly not with transcription of the hTNF transgene. Studying the shedding of cell membrane–bound hTNF by Adam17, a known Fhl2 interacting protein, revealed an enhanced release of TNF in the absence of Fhl2. In summary, our results show that Fhl2 anticipates the emerging inflammation and specifically the development of psoriatic arthritis by impeding the Adam17-mediated release of TNF.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.015
  • Reduced Glutathione Level Promotes Epithelial-Mesenchymal Transition in
           Lens Epithelial Cells via a Wnt/β-Catenin–Mediated Pathway
    • Authors: Zongbo Wei; Jane Caty; Jeremy Whitson; Amy D. Zhang; Ramkumar Srinivasagan; Terrance J. Kavanagh; Hong Yan; Xingjun Fan
      Pages: 2399 - 2412
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Zongbo Wei, Jane Caty, Jeremy Whitson, Amy D. Zhang, Ramkumar Srinivasagan, Terrance J. Kavanagh, Hong Yan, Xingjun Fan
      The epithelial-mesenchymal transition (EMT) process plays a pivotal role in the pathogenesis of posterior capsular opacification because of remnant lens epithelial cell proliferation, migration, and transformation after cataract surgery. The latter, we hypothesize, may result in posterior capsule wrinkling and opacification because of a profound change in the lens growth environment via a 1000-fold reduction of extracellular glutathione (GSH) levels. To test this hypothesis, we investigated the EMT process in cell culture and GSH biosynthesis deficiency mouse models. Our data indicate a dramatic increase of pro-EMT markers, such as type I collagen, α-smooth muscle actin, vimentin, and fibronectin, under conditions of lens GSH depletion. Further study suggests that decreased GSH triggers the Wnt/β-catenin signal transduction pathway, independent of transforming growth factor-β. Equally important, the antioxidants N-acetyl cysteine and GSH ethyl ester could significantly attenuate the EMT signaling stimulated by decreased GSH levels. These findings were further confirmed by mock cataract surgery in both gamma glutamyl-cysteine ligase, catalytic subunit, and gamma glutamyl-cysteine ligase, modifier subunit, knockout mouse models. Remarkably, increased EMT marker expression, β-catenin activation, and translocation into the nucleus were found in both knockout mice compared with the wild type, and such increased expression could be significantly attenuated by N-acetyl cysteine or GSH ethyl ester treatment. This study, for the first time we believe, links oxidative stress to lens fibrosis and posterior capsular opacification formation via EMT-mediated mechanisms.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.018
  • Sphingosine Kinase-2 Deficiency Ameliorates Kidney Fibrosis by
           Up-Regulating Smad7 in a Mouse Model of Unilateral Ureteral Obstruction
    • Authors: Stephanie Schwalm; Sandra Beyer; Helena Frey; Riad Haceni; Georgios Grammatikos; Dominique Thomas; Gerd Geisslinger; Liliana Schaefer; Andrea Huwiler; Josef Pfeilschifter
      Pages: 2413 - 2429
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Stephanie Schwalm, Sandra Beyer, Helena Frey, Riad Haceni, Georgios Grammatikos, Dominique Thomas, Gerd Geisslinger, Liliana Schaefer, Andrea Huwiler, Josef Pfeilschifter
      Kidney fibrosis is a hallmark of chronic kidney disease and leads to extracellular matrix accumulation, organ scarring, and loss of kidney function. In this study, we investigated the role of sphingosine kinase-2 (SPHK2) on the progression of tubular fibrosis by using a mouse unilateral ureteral obstruction (UUO) model. We found that SPHK2 protein and activity are up-regulated in fibrotic renal tissue. Functionally, Sphk2-deficient (Sphk2 −/− ) mice showed an attenuated fibrotic response to UUO compared with wild-type mice, as demonstrated by reduced collagen abundance and decreased expression of fibronectin-1, collagen I, α-smooth muscle actin, connective tissue growth factor (CTGF), and plasminogen activator inhibitor (PAI-1). More important, these changes were associated with increased expression of the antifibrotic protein Smad7 and higher levels of sphingosine in Sphk2 −/− UUO kidneys. Mechanistically, sphingosine ameliorates transforming growth factor-β–induced collagen accumulation, CTGF, and PAI-1 expression, but enhances Smad7 protein expression in primary kidney fibroblasts. In a complementary approach, in human Sphk2-overexpressing mice, UUO resulted in exacerbated signs of fibrosis with increased collagen accumulation, higher expression levels of fibronectin-1, collagen I, α-smooth muscle actin, CTGF, and PAI-1, but decreased Smad7 expression. SPHK2 plays an important role in kidney fibrogenesis by modulating transforming growth factor-β signaling. Thus, SPHK2 might be an attractive new target for the treatment of fibrosis in chronic kidney disease.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.06.017
  • Systemic Monocyte Chemotactic Protein-1 Inhibition Modifies Renal
           Macrophages and Restores Glomerular Endothelial Glycocalyx and Barrier
           Function in Diabetic Nephropathy
    • Authors: Margien G.S. Boels; Angela Koudijs; M. Cristina Avramut; Wendy M.P.J. Sol; Gangqi Wang; Annemarie M. van Oeveren-Rietdijk; Anton Jan van Zonneveld; Hetty C. de Boer; Johan van der Vlag; Cees van Kooten; Dirk Eulberg; Bernard M. van den Berg; Daphne H.T. IJpelaar; Ton J. Rabelink
      Pages: 2430 - 2440
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Margien G.S. Boels, Angela Koudijs, M. Cristina Avramut, Wendy M.P.J. Sol, Gangqi Wang, Annemarie M. van Oeveren-Rietdijk, Anton Jan van Zonneveld, Hetty C. de Boer, Johan van der Vlag, Cees van Kooten, Dirk Eulberg, Bernard M. van den Berg, Daphne H.T. IJpelaar, Ton J. Rabelink
      Inhibition of monocyte chemotactic protein-1 (MCP-1) with the Spiegelmer emapticap pegol (NOX-E36) shows long-lasting albuminuria-reducing effects in diabetic nephropathy. MCP-1 regulates inflammatory cell recruitment and differentiation of macrophages. Because the endothelial glycocalyx is also reduced in diabetic nephropathy, we hypothesized that MCP-1 inhibition restores glomerular barrier function through influencing macrophage cathepsin L secretion, thus reducing activation of the glycocalyx-degrading enzyme heparanase. Four weeks of treatment of diabetic Apoe knockout mice with the mouse-specific NOX-E36 attenuated albuminuria without any change in systemic hemodynamics, despite persistent loss of podocyte function. MCP-1 inhibition, however, increased glomerular endothelial glycocalyx coverage, with preservation of heparan sulfate. Mechanistically, both glomerular cathepsin L and heparanase expression were reduced. MCP-1 inhibition resulted in reduced CCR2-expressing Ly6Chi monocytes in the peripheral blood, without affecting overall number of kidney macrophages at the tissue level. However, the CD206+/Mac3+ cell ratio, as an index of presence of anti-inflammatory macrophages, increased in diabetic mice after treatment. Functional analysis of isolated renal macrophages showed increased release of IL-10, whereas tumor necrosis factor and cathepsin L release was reduced, further confirming polarization of tissue macrophages toward an anti-inflammatory phenotype during mouse-specific NOX-E36 treatment. We show that MCP-1 inhibition restores glomerular endothelial glycocalyx and barrier function and reduces tissue inflammation in the presence of ongoing diabetic injury, suggesting a therapeutic potential for NOX-E36 in diabetic nephropathy.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.020
  • The Role of Angiotensin II in Parietal Epithelial Cell Proliferation and
           Crescent Formation in Glomerular Diseases
    • Authors: Paola Rizzo; Rubina Novelli; Cinzia Rota; Elena Gagliardini; Barbara Ruggiero; Daniela Rottoli; Ariela Benigni; Giuseppe Remuzzi
      Pages: 2441 - 2450
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Paola Rizzo, Rubina Novelli, Cinzia Rota, Elena Gagliardini, Barbara Ruggiero, Daniela Rottoli, Ariela Benigni, Giuseppe Remuzzi
      Crescentic glomerulonephritis (GN) is a devastating disease with rapidly progressive deterioration in kidney function, which, histologically, manifests as crescent formation in most glomeruli. We previously found that crescents derive from the aberrant proliferation and migration of parietal epithelial cells (PECs)/progenitor cells, and that the angiotensin (ang) II/ang II type-1 (AT1) receptor pathway may participate, together with the stromal cell–derived factor-1 (SDF-1)/C-X-C chemokine receptor 4 axis, in the development of those lesions. Herein, we elucidated sequential events and cellular and molecular interactions occurring during crescentic lesion onset and evolution. By analyzing kidney biopsy specimens of patients with extracapillary GN, divided according to the grade of glomerular lesions, we found that the accumulation of macrophages expressing matrix metalloproteinase-12 started manifesting in glomeruli affected by early-stage lesions, whereas AT1 receptor expression could not be detected. In glomeruli with advanced lesions, AT1 receptor expression increased markedly, and the up-regulation of SDF-1, and its receptor C-X-C chemokine receptor 7, was documented on podocytes and PECs, respectively. In vitro studies were instrumental to demonstrating the role of ang II in inducing podocyte SDF-1 production, which ultimately activates PECs. The present findings support the possibility that angiotensin-converting enzyme inhibitor treatment might limit PEC activation and reduce the frequency and extension of crescents in extracapillary GN.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.004
  • Imaging of Wound Closure of Small Epithelial Lesions in the Mouse Trachea
    • Authors: Sarah Kretschmer; Mario Pieper; Antje Klinger; Gereon Hüttmann; Peter König
      Pages: 2451 - 2460
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Sarah Kretschmer, Mario Pieper, Antje Klinger, Gereon Hüttmann, Peter König
      Integrity of the airway epithelium is essential for normal lung function. However, studies analyzing the repair process of small epithelial lesions in pseudostratified airway epithelium are missing. To follow airway-epithelial wound closure over time, we lesioned small areas of the mouse tracheal epithelium (1 to 12 cells) using a femtosecond laser and followed wound closure up to 6 hours by autofluorescence multiphoton microscopy. Selected lesions were also examined by scanning and transmission electron microscopy and by staining of filamentous actin. Most lesions with a size up to six cells closed by elongation of the surrounding epithelial cells within 6 hours, and all damaged cells were extruded from the epithelium. Electron microscopy confirmed that the surrounding epithelial cells directly closed lesions up to six cells. Most lesions larger than six cells did not close in the observation period of 6 hours, but we observed that basal cells flattened to cover the basement membrane. Delayed wound closure was, in part, attributable to damage of the basement membrane. Cells facing the lesion exhibited increased filamentous actin staining, indicating active cell movement. Not all cells initially facing the lesion participated directly in wound closure, indicating that closure is driven by movement of individual cells rather than a transepithelial coordinated process. Small wounds in the pseudostratified airway epithelium close within hours to preserve epithelial integrity.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.006
  • Inhibition of Glycogen Synthase Kinase 3β Blocks Mesomesenchymal
           Transition and Attenuates Streptococcus pneumonia–Mediated Pleural
           Injury in Mice
    • Authors: Jake Boren; Grant Shryock; Alexis Fergis; Ann Jeffers; Shuzi Owens; Wenyi Qin; Kathleen B. Koenig; Yoshikazu Tsukasaki; Satoshi Komatsu; Mitsuo Ikebe; Steven Idell; Torry A. Tucker
      Pages: 2461 - 2472
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Jake Boren, Grant Shryock, Alexis Fergis, Ann Jeffers, Shuzi Owens, Wenyi Qin, Kathleen B. Koenig, Yoshikazu Tsukasaki, Satoshi Komatsu, Mitsuo Ikebe, Steven Idell, Torry A. Tucker
      Pleural loculation affects about 30,000 patients annually in the United States and in severe cases can resolve with restrictive lung disease and pleural fibrosis. Pleural mesothelial cells contribute to pleural rind formation by undergoing mesothelial mesenchymal transition (MesoMT), whereby they acquire a profibrotic phenotype characterized by increased expression of α-smooth muscle actin and collagen 1. Components of the fibrinolytic pathway (urokinase plasminogen activator and plasmin) are elaborated in pleural injury and strongly induce MesoMT in vitro. These same stimuli enhance glycogen synthase kinase (GSK)-3β activity through increased phosphorylation of Tyr-216 in pleural mesothelial cells and GSK-3β mobilization from the cytoplasm to the nucleus. GSK-3β down-regulation blocked induction of MesoMT. Likewise, GSK-3β inhibitor 9ING41 blocked induction of MesoMT and reversed established MesoMT. Similar results were demonstrated in a mouse model of Streptococcus pneumoniae–induced empyema. Intraperitoneal administration of 9ING41, after the induction of pleural injury, attenuated injury progression and improved lung function (lung volume and compliance; P < 0.05 compared with untreated and vehicle controls). MesoMT marker α-smooth muscle actin was reduced in 9ING41-treated mice. Pleural thickening was also notably reduced in 9ING41-treated mice (P < 0.05). Collectively, these studies identify GSK-3β as a newly identified target for amelioration of empyema-related pleural fibrosis and provide a strong rationale for further investigation of GSK-3β signaling in the control of MesoMT and pleural injury.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.007
  • Thyroid Hormone Receptor-β Agonist GC-1 Inhibits Met-β-Catenin–Driven
           Hepatocellular Cancer
    • Authors: Elisabetta Puliga; Qian Min; Junyan Tao; Rong Zhang; Tirthadipa Pradhan-Sundd; Minakshi Poddar; Sucha Singh; Amedeo Columbano; Jinming Yu; Satdarshan P. Monga
      Pages: 2473 - 2485
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Elisabetta Puliga, Qian Min, Junyan Tao, Rong Zhang, Tirthadipa Pradhan-Sundd, Minakshi Poddar, Sucha Singh, Amedeo Columbano, Jinming Yu, Satdarshan P. Monga
      The thyromimetic agent GC-1 induces hepatocyte proliferation via Wnt/β-catenin signaling and may promote regeneration in both acute and chronic liver insufficiencies. However, β-catenin activation due to mutations in CTNNB1 is seen in a subset of hepatocellular carcinomas (HCC). Thus, it is critical to address any effect of GC-1 on HCC growth and development before its use can be advocated to stimulate regeneration in chronic liver diseases. In this study, we first examined the effect of GC-1 on β-catenin–T cell factor 4 activity in HCC cell lines harboring wild-type or mutated-CTNNB1. Next, we assessed the effect of GC-1 on HCC in FVB mice generated by hydrodynamic tail vein injection of hMet-S45Y-β-catenin, using the sleeping beauty transposon-transposase. Four weeks following injection, mice were fed 5 mg/kg GC-1 or basal diet for 10 or 21 days. GC-1 treatment showed no effect on β-catenin–T cell factor 4 activity in HCC cells, irrespective of CTNNB1 mutations. Treatment with GC-1 for 10 or 21 days led to a significant reduction in tumor burden, associated with decreased tumor cell proliferation and dramatic decreases in phospho-(p-)Met (Y1234/1235), p–extracellular signal-related kinase, and p-STAT3 without affecting β-catenin and its downstream targets. GC-1 exerts a notable antitumoral effect on hMet-S45Y-β-catenin HCC by inactivating Met signaling. GC-1 does not promote β-catenin activation in HCC. Thus, GC-1 may be safe for use in inducing regeneration during chronic hepatic insufficiency.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.005
  • Cysteine Protease–Dependent Mucous Disruptions and Differential Mucin
           Gene Expression in Giardia duodenalis Infection
    • Authors: Christina B. Amat; Jean-Paul Motta; Elena Fekete; France Moreau; Kris Chadee; Andre G. Buret
      Pages: 2486 - 2498
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Christina B. Amat, Jean-Paul Motta, Elena Fekete, France Moreau, Kris Chadee, Andre G. Buret
      The intestinal mucous layer provides a critical host defense against pathogen exposure and epithelial injury, yet little is known about how enteropathogens may circumvent this physiologic barrier. Giardia duodenalis is a small intestinal parasite responsible for diarrheal disease and chronic postinfectious illness. This study reveals a complex interaction at the surface of epithelial cells, between G. duodenalis and the intestinal mucous layer. Here, we reveal mechanisms whereby G. duodenalis evades and disrupts the first line of host defense by degrading human mucin-2 (MUC2), depleting mucin stores and inducing differential gene expression in the mouse small and large intestines. Human colonic biopsy specimens exposed to G. duodenalis were depleted of mucus, and in vivo mice infected with G. duodenalis had a thinner mucous layer and demonstrated differential Muc2 and Muc5ac mucin gene expression. Infection in Muc2 −/− mice elevated trophozoite colonization in the small intestine and impaired weight gain. In vitro, human LS174T goblet-like cells were depleted of mucus and had elevated levels of MUC2 mRNA expression after G. duodenalis exposure. Importantly, the cysteine protease inhibitor E64 prevented mucous degradation, mucin depletion, and the increase in MUC2 expression. This article describes a novel role for Giardia's cysteine proteases in pathogenesis and how Giardia's disruptions of the mucous barrier facilitate bacterial translocation that may contribute to the onset and propagation of disease.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.009
  • Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the
           Vagina of Mice through Nuclear Estrogen Receptor α Activation
    • Authors: Thibaut Benoit; Marie-Cecile Valera; Coralie Fontaine; Melissa Buscato; Francoise Lenfant; Isabelle Raymond-Letron; Florence Tremollieres; Michel Soulie; Jean-Michel Foidart; Xavier Game; Jean-Francois Arnal
      Pages: 2499 - 2507
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Thibaut Benoit, Marie-Cecile Valera, Coralie Fontaine, Melissa Buscato, Francoise Lenfant, Isabelle Raymond-Letron, Florence Tremollieres, Michel Soulie, Jean-Michel Foidart, Xavier Game, Jean-Francois Arnal
      The genitourinary syndrome of menopause has a negative impact on quality of life of postmenopausal women. The treatment of vulvovaginal atrophy includes administration of estrogens. However, oral estrogen treatment is controversial because of its potential risks on venous thrombosis and breast cancer. Estetrol (E4) is a natural estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered as a weak estrogen. However, E4 was recently evaluated in phase 1 to 2 clinical studies and found to act as an oral contraceptive in combination with a progestin, without increasing the level of coagulation factors. We recently showed that E4 stimulates uterine epithelial proliferation through nuclear estrogen receptor (ER) α, but failed to elicit endothelial responses. Herein, we first evaluated the morphological and functional impacts of E4 on the vagina of ovariectomized mice, and we determined the molecular mechanism mediating these effects. Vaginal epithelial proliferation and lubrication after stimulation were found to increase after E4 chronic treatment. Using a combination of pharmacological and genetic approaches, we demonstrated that these E4 effects on the vagina are mediated by nuclear ERα activation. Altogether, we demonstrate that the selective activation of nuclear ERα is both necessary and sufficient to elicit functional and structural effects on the vagina, and therefore E4 appears promising as a therapeutic option to improve vulvovaginal atrophy.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.013
  • Ggnbp2-Null Mutation in Mice Leads to Male Infertility due to a Defect at
           the Spermiogenesis Stage
    • Authors: Lingyun Liu; Yan He; Kaimin Guo; Linying Zhou; Xian Li; Michael Tseng; Lu Cai; Zi-Jian Lan; Junmei Zhou; Hongliang Wang; Zhenmin Lei
      Pages: 2508 - 2519
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Lingyun Liu, Yan He, Kaimin Guo, Linying Zhou, Xian Li, Michael Tseng, Lu Cai, Zi-Jian Lan, Junmei Zhou, Hongliang Wang, Zhenmin Lei
      Gametogenetin binding protein 2 (GGNBP2) is an evolutionarily conserved zinc finger protein. Although Ggnbp2-null embryos in the B6 background died because of a defective placenta, 6.8% of Ggnbp2-null mice in the B6/129 mixed background were viable and continued to adulthood. Adult Ggnbp2-null males were sterile, with smaller testes and an azoospermic phenotype, whereas mutant females were fertile. Histopathological analysis of 2-month–old Ggnbp2-null testes revealed absence of mature spermatozoa in the seminiferous tubules and epididymides and reduction of the number of spermatids. Ultrastructural analysis indicated dramatic morphological defects of developing spermatids in the Ggnbp2-null testes, including irregularly shaped acrosomes, acrosome detachment, cytoplasmic remnant, ectopic manchette, and ill-formed head shape in both elongating and elongated spermatids. However, the numbers of spermatogonia, spermatocytes, Leydig cells, and Sertoli cells in Ggnbp2-null testes did not significantly differ from the wild-type siblings. Gonadotropins, testosterone, and the blood-testis barrier were essentially unaffected. Western blot analyses showed increases in α-E-catenin, β-catenin, and N-cadherin, decreases in E-cadherin, afadin, and nectin-3, and no changes in vinculin, nectin-2, focal adhesion kinase, and integrin-β1 protein levels in Ggnbp2-null testes compared to wild-type siblings. Together, this study demonstrates that GGNBP2 is critically required for maintenance of the adhesion integrity of the adlumenal germ epithelium and is indispensable for normal spermatid transformation into mature spermatozoa in mice.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.016
  • Intermittent Glucocorticoid Dosing Improves Muscle Repair and Function in
           Mice with Limb-Girdle Muscular Dystrophy
    • Authors: Mattia Quattrocelli; Isabella M. Salamone; Patrick G. Page; James L. Warner; Alexis R. Demonbreun; Elizabeth M. McNally
      Pages: 2520 - 2535
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Mattia Quattrocelli, Isabella M. Salamone, Patrick G. Page, James L. Warner, Alexis R. Demonbreun, Elizabeth M. McNally
      The muscular dystrophies are genetically diverse. Shared pathological features among muscular dystrophies include breakdown, or loss of muscle, and accompanying fibrotic replacement. Novel strategies are needed to enhance muscle repair and function and to slow this pathological remodeling. Glucocorticoid steroids, like prednisone, are known to delay loss of ambulation in patients with Duchenne muscular dystrophy but are accompanied by prominent adverse effects. However, less is known about the effects of steroid administration in other types of muscular dystrophies, including limb-girdle muscular dystrophies (LGMDs). LGMD 2B is caused by loss of dysferlin, a membrane repair protein, and LGMD 2C is caused by loss of the dystrophin-associated protein, γ-sarcoglycan. Herein, we assessed the efficacy of steroid dosing on sarcolemmal repair, muscle function, histopathology, and the regenerative capacity of primary muscle cells. We found that in murine models of LGMD 2B and 2C, daily prednisone dosing reduced muscle damage and fibroinflammatory infiltration. However, daily prednisone dosing also correlated with increased muscle adipogenesis and atrophic remodeling. Conversely, intermittent dosing of prednisone, provided once weekly, enhanced muscle repair and did not induce atrophy or adipogenesis, and was associated with improved muscle function. These data indicate that dosing frequency of glucocorticoid steroids affects muscle remodeling in non-Duchenne muscular dystrophies, suggesting a positive outcome associated with intermittent steroid dosing in LGMD 2B and 2C muscle.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.017
  • In Vivo Expression of miR-32 Induces Proliferation in Prostate
    • Authors: Leena Latonen; Mauro Scaravilli; Andrew Gillen; Samuli Hartikainen; Fu-Ping Zhang; Pekka Ruusuvuori; Paula Kujala; Matti Poutanen; Tapio Visakorpi
      Pages: 2546 - 2557
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Leena Latonen, Mauro Scaravilli, Andrew Gillen, Samuli Hartikainen, Fu-Ping Zhang, Pekka Ruusuvuori, Paula Kujala, Matti Poutanen, Tapio Visakorpi
      miRNAs are important regulators of gene expression and are often deregulated in cancer. We have previously shown that miR-32 is an androgen receptor–regulated miRNA overexpressed in castration-resistant prostate cancer and that miR-32 can improve prostate cancer cell growth in vitro. To assess the effects of miR-32 in vivo, we developed transgenic mice overexpressing miR-32 in the prostate. The study indicated that transgenic miR-32 expression increases replicative activity in the prostate epithelium. We further observed an aging-associated increase in the incidence of goblet cell metaplasia in the prostate epithelium. Furthermore, aged miR-32 transgenic mice exhibited metaplasia-associated prostatic intraepithelial neoplasia at a low frequency. When crossbred with mice lacking the other allele of tumor-suppressor Pten (miR-32xPten +/− mice), miR-32 expression increased both the incidence and the replicative activity of prostatic intraepithelial neoplasia lesions in the dorsal prostate. The miR-32xPten +/− mice also demonstrated increased goblet cell metaplasia compared with Pten +/− mice. By performing a microarray analysis of mouse prostate tissue to screen downstream targets and effectors of miR-32, we identified RAC2 as a potential, and clinically relevant, target of miR-32. We also demonstrate down-regulation of several interesting, potentially prostate cancer–relevant genes (Spink1, Spink5, and Casp1) by miR-32 in the prostate tissue. The results demonstrate that miR-32 increases proliferation and promotes metaplastic transformation in mouse prostate epithelium, which may promote neoplastic alterations in the prostate.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.012
  • Stromal Expression of Activated Leukocyte Cell Adhesion Molecule Promotes
           Lung Tumor Growth and Metastasis
    • Authors: Ann-Helen Willrodt; Michal Beffinger; Martina Vranova; Darya Protsyuk; Katja Schuler; Maria Jadhav; Mathias Heikenwalder; Maries van den Broek; Lubor Borsig; Cornelia Halin
      Pages: 2558 - 2569
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Ann-Helen Willrodt, Michal Beffinger, Martina Vranova, Darya Protsyuk, Katja Schuler, Maria Jadhav, Mathias Heikenwalder, Maries van den Broek, Lubor Borsig, Cornelia Halin
      Activated leukocyte cell adhesion molecule (ALCAM) is expressed on various cell types, including leukocytes, endothelial cells, and certain tumor cells. Although ALCAM expression on tumor cells has been linked to tumor invasion and metastatic spread, the contribution of ALCAM expressed in cells forming the tumor stroma to cancer progression has not been investigated. In this study, ALCAM-deficient (ALCAM−/−) mice were used to evaluate the role of ALCAM in lung tumor growth and metastasis. ALCAM−/− mice displayed an altered blood vascular network in the lung and the diaphragm, indicative of an angiogenetic defect. The absence of ALCAM expression in cells forming the stromal tumor microenvironment profoundly affected lung tumor growth in three different i.v. metastasis models. In the case of Lewis lung carcinoma (LLC), an additional defect in tumor cell homing to the lungs and a resulting reduction in the number of lung tumor nodules were observed. Similarly, when LLC cells were implanted subcutaneously for the study of spontaneous tumor cell metastasis, the rate of LLC metastasis to the lungs was profoundly reduced in ALCAM−/− mice. Taken together, our work demonstrates for the first time the in vivo contribution of ALCAM to angiogenesis and reveals a novel role of stromally expressed ALCAM in supporting tumor growth and metastatic spread.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.008
  • Deletion of Endothelial Transforming Growth Factor–β Signaling Leads to
           Choroidal Neovascularization
    • Authors: Anja Schlecht; Sarah V. Leimbeck; Herbert Jägle; Annette Feuchtinger; Ernst R. Tamm; Barbara M. Braunger
      Pages: 2570 - 2589
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Anja Schlecht, Sarah V. Leimbeck, Herbert Jägle, Annette Feuchtinger, Ernst R. Tamm, Barbara M. Braunger
      The molecular pathogenesis of choroidal neovascularization (CNV), an angiogenic process that critically contributes to vision loss in age-related macular degeneration, is unclear. Herein, we analyzed the role of transforming growth factor (TGF)-β signaling for CNV formation by generating a series of mutant mouse models with induced conditional deletion of TGF-β signaling in the entire eye, the retinal pigment epithelium (RPE), or the vascular endothelium. Deletion of TGF-β signaling in the eye caused CNV, irrespectively if it was ablated in newborn or 3-week–old mice. Areas of CNV showed photoreceptor degeneration, multilayered RPE, basal lamina deposits, and accumulations of monocytes/macrophages. The changes progressed, leading to marked structural and functional alterations of the retina. Although the specific deletion of TGF-β signaling in the RPE caused no obvious changes, specific deletion in vascular endothelial cells caused CNV and a phenotype similar to that observed after the deletion in the entire eye. We conclude that impairment of TGF-β signaling in the vascular endothelium of the eye is sufficient to trigger CNV formation. Our findings highlight the importance of TGF-β signaling as a key player in the development of ocular neovascularization and indicate a fundamental role of TGF-β signaling in the pathogenesis of age-related macular degeneration.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.06.018
  • Essential Role of IL-12 in Angiogenesis in Type 2 Diabetes
    • Authors: Maha Ali; Vishal Mali; Samuel Haddox; Soad M. AbdelGhany; Sahar E.M. El-deek; Atif Abulfadl; Khalid Matrougui; Souad Belmadani
      Pages: 2590 - 2601
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Maha Ali, Vishal Mali, Samuel Haddox, Soad M. AbdelGhany, Sahar E.M. El-deek, Atif Abulfadl, Khalid Matrougui, Souad Belmadani
      Recently, IL-12 emerged as a critical player in type 2 diabetes complications. We previously reported that ischemia-induced angiogenesis is compromised in type 2 diabetic mice. In this study, we determined that IL-12 disruption rescued angiogenesis and arteriogenesis in type 2 diabetic mice. To induce type 2 diabetes, wild-type (WT), p40IL-12−/− (p40−/−), and p35IL-12−/− (p35−/−) mice were fed a high-fat diet (HFD) for 12 weeks. Body weight, glucose test tolerance, and insulin test tolerance were assessed. After 12 weeks of an HFD, the femoral artery was ligated and blood flow recovery was measured every week for 4 weeks. WT, p40−/−, and p35−/− mice fed an HFD become obese after 12 weeks and exhibit glucose intolerance and insulin resistance. Blood flow recovery was fully restored in 2 to 3 weeks after femoral artery ligation in all groups of mice fed a normal diet. However, after 12 weeks of an HFD, blood flow recovery was compromised in WT mice, whereas it was fully recovered in p40−/− and p35−/− mice. The mechanism of blood flow recovery involves an increase in capillary/arteriole density, endothelial nitric oxide synthase/Akt/vascular endothelial growth factor receptor 2 signaling, and a reduction in oxidative stress and inflammation. The disruption of IL-12 promotes angiogenesis and increases blood flow recovery in obese type 2 diabetic mice by an endothelial nitric oxide synthase/Akt/vascular endothelial growth factor receptor 2/oxidative stress–inflammation–dependent mechanism.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.021
  • Lymphotoxins Promote the Progression of Human Lymphatic Malformation by
           Enhancing Lymphatic Endothelial Cell Proliferation
    • Authors: Jie-Gang Yang; Yan-Fang Sun; Ke-Fei He; Jian-Gang Ren; Zhuo-Jue Liu; Bing Liu; Wei Zhang; Yi-Fang Zhao
      Pages: 2602 - 2615
      Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11
      Author(s): Jie-Gang Yang, Yan-Fang Sun, Ke-Fei He, Jian-Gang Ren, Zhuo-Jue Liu, Bing Liu, Wei Zhang, Yi-Fang Zhao
      Formation of inflammation-related tertiary lymphoid organs promotes human lymphatic malformation (LM) development. However, the role of lymphotoxins (LTs) and LT-related inducible ligand, the crucial mediators for tertiary lymphoid organ formation, is undetermined in LMs. Herein, we show that LTs and LT-related inducible ligand promote LM development by enhancing lymphatic endothelial cell (LEC) proliferation via activating NF-κB pathways. The expression of LTs and their receptors was increased in LMs, especially the infected ones, when compared with normal skins. Nuclear translocation of p65, p52, and RelB in the LECs of LMs indicated the activation of classic and alternative NF-κB pathways. Pearson's correlation and cluster analysis suggested the close relationship between LEC proliferation and NF-κB activation. Moreover, in vitro data demonstrated LTs accelerated the proliferation of human dermal LECs (HdLECs) through activation of NF-κB. In addition, lipopolysaccharide (LPS) up-regulated LT receptor expression in HdLECs, leading to increased sensitivity to LTs. Suppression of LT receptors hampered LPS-enhanced HdLEC proliferation, indicating the crucial role of LT pathways in inflammatory lymphangiogenesis. Besides, evidence from the LM rat models demonstrated LTα and LPS enhanced LEC proliferation, therefore promoting LM development. Blocking LT pathways by neutralizing antibodies against LTα and lymphotoxin β receptor may decelerate the growth of the disease. In summary, our present study demonstrated activation of LT signaling pathways in LECs contributed to the progression of LMs.

      PubDate: 2017-11-08T17:50:20Z
      DOI: 10.1016/j.ajpath.2017.07.019
  • Race in Cancer Health Disparities Theme Issue Colorectal Cancer Disparity
           in African Americans: Risk Factors and Carcinogenic Mechanisms
    • Authors: Rosa M. Xicola; Zarko Manojlovic; Gaius J. Augustus; Sonia S. Kupfer; John Carpten; Nathan A. Ellis; Xavier Llor
      Abstract: Publication date: Available online 9 November 2017
      Source:The American Journal of Pathology
      Author(s): Gaius J. Augustus, Nathan A. Ellis
      African Americans have the highest incidence and mortality rates of colorectal cancer (CRC) of any ethnic group in the United States. Although some of these disparities can be explained by differences in access to care, cancer screening, and other socioeconomic factors, disparities remain after adjustment for these factors. Consequently, an examination of recent advances in the understanding of ethnicity-specific factors, including genetic and environmental factors relating to risk of CRC, the biology of CRC progression, and the changes in screening and mortality, is important for evaluating our progress towards eliminating the disparities. An overarching limitation in this field is the number and sample size of studies performed to characterize the etiologic bases of CRC incidence and mortality in African Americans. Despite this limitation, significant differences in etiology are manifest in many studies. These differences need validation, and their impacts on disparities need more detailed investigation. Perhaps most heartening, improvements in CRC screening can be attributed to the smallest difference in CRC incidence between African Americans and whites since the late 1980s. Cancer mortality, however, remains a persistent difference.

      PubDate: 2017-11-16T06:08:34Z
      DOI: 10.1016/s0016-5085(17)30558-9
  • Extracellular lipids accumulate in human carotid arteries as distinct
           three-dimensional structures and have proinflammatory properties
    • Authors: Satu Lehti; Su D. Nguyen; Ilya Belevich; Helena Vihinen; Hanna M. Heikkilä; Rabah Soliymani; Reijo Käkelä; Jani Saksi; Matti Jauhiainen; Gregory A. Grabowski; Outi Kummu; Sohvi Hörkkö; Marc Baumann; Perttu J. Lindsberg; Eija Jokitalo; Petri T. Kovanen; Katariina Öörni
      Abstract: Publication date: Available online 14 November 2017
      Source:The American Journal of Pathology
      Author(s): Satu Lehti, Su D. Nguyen, Ilya Belevich, Helena Vihinen, Hanna M. Heikkilä, Rabah Soliymani, Reijo Käkelä, Jani Saksi, Matti Jauhiainen, Gregory A. Grabowski, Outi Kummu, Sohvi Hörkkö, Marc Baumann, Perttu J. Lindsberg, Eija Jokitalo, Petri T. Kovanen, Katariina Öörni
      Lipid accumulation is a key characteristic of advancing atherosclerotic lesions. Here we analyzed the ultrastructure of the accumulated lipids in endarterectomized human carotid atherosclerotic plaques using three-dimensional (3D) electron microscopy, a method never used in this context before. 3D-electron microscopy revealed intracellular lipid droplets and extracellular lipoprotein particles. The majority of the particles were aggregated and some connected to needle-shaped or sheet-like cholesterol crystals. Proteomic analysis of isolated extracellular lipoprotein particles revealed that apolipoprotein B is their main protein component indicating their origin from low density lipoprotein, intermediate density lipoprotein, very low density lipoprotein, lipoprotein (a), or chylomicron remnants. The particles also contained small exchangeable apolipoproteins, complement components, and immunoglobulins. Lipidomic analysis revealed differences between plasma lipoproteins and the particles thereby indicating involvement of lipolytic enzymes in their generation. Incubation of human monocyte-derived macrophages with the isolated extracellular lipoprotein particles or with plasma lipoproteins that had been lipolytically modified in vitro induced intracellular lipid accumulation and triggered inflammasome activation in them. Taken together, extracellular lipids accumulate in human carotid plaques as distinct 3D-structures that include aggregated and fused lipoprotein particles and cholesterol crystals. The particles originate from plasma lipoproteins, show signs of lipolytic modifications and associate with cholesterol crystals. By inducing intracellular cholesterol accumulation (ie, foam cell formation) and inflammasome activation, the extracellular lipoprotein particles may actively enhance atherogenesis.

      PubDate: 2017-11-16T06:08:34Z
      DOI: 10.1016/j.ajpath.2017.09.019
  • Distinct effects of interleukin-6 classic and trans-signaling in bone
           fracture healing
    • Authors: Katja Prystaz; Kathrin Kaiser; Anna Kovtun; Melanie Haffner-Luntzer; Verena Fischer; Anna E. Rapp; Astrid Liedert; Gudrun Strauss; Georg H. Waetzig; Stefan Rose-John; Anita Ignatius
      Abstract: Publication date: Available online 13 November 2017
      Source:The American Journal of Pathology
      Author(s): Katja Prystaz, Kathrin Kaiser, Anna Kovtun, Melanie Haffner-Luntzer, Verena Fischer, Anna E. Rapp, Astrid Liedert, Gudrun Strauss, Georg H. Waetzig, Stefan Rose-John, Anita Ignatius
      Bone healing is a complex process with closely linked phases of inflammation, regeneration, and remodeling. Interleukin-6 (IL-6) may crucially regulate this process; however, the underlying mechanisms are presently unclear. IL-6 signals are transmitted via the transmembrane glycoprotein 130 by two distinct mechanisms: classic signaling employing the membrane-anchored IL-6 receptor, and trans-signaling using its soluble form. Here, we investigated the hypothesis that IL-6 classic and trans-signaling have different functions during bone healing. To investigate fracture healing, 12-week–old C57BL/6J mice received a femur osteotomy. To study the function of IL-6 during the inflammatory phase, either an anti–IL-6 antibody, which inhibits IL-6 classic and trans-signaling, or sgp130Fc, which selectively blocks trans-signaling, was injected after 30 minutes and 48 hours. To analyze IL-6 effects in the repair phase, compounds were injected from day 7 onwards. Global IL-6 inhibition in the early phase post-fracture reduced systemic inflammation, the recruitment of immune cells, and bone regeneration, resulting in delayed fracture healing. Global IL-6 inhibition during the repair phase disturbed bone formation and remodeling. In contrast, inhibition of IL-6 trans-signaling exerted minor effects on the immune response and did not influence bone repair, suggesting that the classic pathway accounts for most of the effects observed after global IL-6 inhibition. Our results reveal that IL-6 classic signaling but not IL-6 trans-signaling is essential for bone repair.

      PubDate: 2017-11-16T06:08:34Z
      DOI: 10.1016/j.ajpath.2017.10.011
  • Neural EGFL like 1 regulates cartilage maturation through runt-related
           transcription factor 3–mediated Indian hedgehog signaling
    • Authors: Chenshuang Zhong; Zheng Jie Jiang Wenlu Jiang Kevin Lee Emily
      Abstract: Publication date: Available online 11 November 2017
      Source:The American Journal of Pathology
      Author(s): Chenshuang Li, Zhong Zheng, Jie Jiang, Wenlu Jiang, Kevin Lee, Emily A. Berthiaume, Eric C. Chen, Cymbeline T. Culiat, Yan-Heng Zhou, Xinli Zhang, Kang Ting, Chia Soo
      The pro-chondrogenic function of runt-related transcription factor 2 (Runx2) was previously considered to be dependent on direct binding with the promoter of Indian hedgehog (Ihh)—the major regulator of chondrocyte differentiation, proliferation, and maturation. Our previous studies identified neural EGFL like 1 (Nell-1) as a Runx2-responsive growth factor for chondrogenic differentiation and maturation. In this study, we further revealed that the pro-chondrogenic activities of Nell-1 also rely on Ihh signaling, by showing: [1] Nell-1 significantly elevated Ihh signal transduction, [2] Nell-1 deficiency markedly reduced Ihh activation in chondrocytes, and [3] Nell-1–stimulated chondrogenesis was significantly reduced by the specific hedgehog inhibitor, cyclopamine. Importantly, we demonstrated that Nell-1–responsive Ihh signaling and chondrogenic differentiation extended to Runx2 -/- models in vitro and in vivo. In Runx2 -/- chondrocytes, Nell-1 stimulated the expression and signal transduction of Runx3, another transcription factor required for complete chondrogenic differentiation and maturation. Furthermore, knocking down Runx3 in Runx2 -/- chondrocytes abolished Nell-1’s stimulation of Ihh-associated molecule expression, which validates Runx3 as a major mediator of Nell-1–stimulated Ihh activation. For the first time, we identify the Runx2→Nell-1→Runx3→Ihh signaling cascade during chondrogenic differentiation and maturation, as an alternative, but critical pathway for Runx2 to function as a pro-chondrogenic molecule via Nell-1.

      PubDate: 2017-11-16T06:08:34Z
  • Analysis of Tumor Biology to Advance Cancer Health Disparity Research
    • Authors: Cheryl Jacobs; Smith Tsion Zewdu Minas Stefan Ambs
      Abstract: Publication date: Available online 11 November 2017
      Source:The American Journal of Pathology
      Author(s): Cheryl Jacobs Smith, Tsion Zewdu Minas, Stefan Ambs
      Cancer mortality rates in the US continue to decline. Reductions in tobacco use, uptake of preventive measures, adoption of early detection methods, and better treatments have resulted in improved cancer outcomes for men and women. Despite this progress, some population groups continue to experience an excessive cancer burden when compared with other population groups. One of the most prominent cancer health disparities exists in prostate cancer. Prostate cancer mortality rates are highest among men of African ancestry when compared with other men, both in the US and globally. This disparity and other cancer health disparities are largely explained by differences in access to health care, diet, lifestyle, cultural barriers, and disparate exposures to carcinogens and pathogens. Dietary and lifestyle factors, pathogens, and ancestry-related factors can modify tumor biology and induce a more aggressive disease. There are now numerous examples of how environmental exposures like tobacco, chronic stress, or dietary factors induce an adverse tumor biology, leading to a more aggressive disease and decreased patient survival. Because of population differences in the exposure to these risk factors, they can be the cause of cancer disparities. In this review, we will summarize recent advances in our understanding of prostate and breast cancer disparities in the US and discuss how the analysis of tumor biology can advance health disparity research.

      PubDate: 2017-11-16T06:08:34Z
  • Linking Race, Cancer Outcomes and Tissue Repair
    • Authors: Jung Byun; Samson Park Ambar Caban Alana Jones Kevin Gardner
      Abstract: Publication date: Available online 11 November 2017
      Source:The American Journal of Pathology
      Author(s): Jung S. Byun, Samson Park, Ambar Caban, Alana Jones, Kevin Gardner
      The burden of cancer in the United States is unevenly spread across its different populations, with stark differences in both disease prevalence and outcome based on race and ethnicity. Although a large portion of these differences can be explained by a variety of socio-behavioral and socio-economic factors, even after these exposures are taken into consideration, significant disparities persist. In this review, we explore a conceptual framework of biological theories and unifying concepts, based on an evolutionary perspective, that may help better define common guiding principles for exploration of underlying etiologies of cancer health disparities. The ultimate goal of this conceptual perspective is to outline approaches that may aid in establishing integrated pathway and processes analyses to provide useful insights to guide the development of future interventions. These interventions will improve outcome, increase prevention, and ultimately eliminate all disparities.

      PubDate: 2017-11-16T06:08:34Z
  • The Science of Cancer Health Disparities
    • Authors: Kevin Gardner
      Abstract: Publication date: Available online 11 November 2017
      Source:The American Journal of Pathology
      Author(s): Kevin Gardner
      Teaser This Guest Editorial highlights the reviews in Race in Cancer Health Disparities Theme Issue that improve our understanding of the complex role of race in disparities in cancer frequency and outcome.

      PubDate: 2017-11-16T06:08:34Z
      DOI: 10.1016/j.ajpath.2017.08.037
  • Triple-Negative Breast Cancer, Stem Cells, and African Ancestry
    • Authors: Evelyn Jiagge; Dhananjay Chitale Lisa Newman
      Abstract: Publication date: Available online 11 November 2017
      Source:The American Journal of Pathology
      Author(s): Evelyn Jiagge, Dhananjay Chitale, Lisa A. Newman
      Triple-negative breast cancers (TNBC) are more common among African ancestry populations, such as African Americans and western, sub-Saharan Africans, compared to European ancestry populations. This phenotype prevalence contributes to breast cancer outcome disparities between African Americans and Caucasian Americans. Breast cancer stem cells represent the tumor subpopulation responsible for metastatic virulence and ongoing research seeks to characterize the extent to which TNBC versus non-TNBC stem cells may differ. This review summarizes the existing literature regarding TNBC and stem cells as they pertain to the breast cancer burden of African ancestry populations. Additional research related to variation in somatic tumor genomics between African American and Caucasian American is also summarized. This review furthermore explores the history of insights regarding breast cancer disparities related to racial-ethnic identity, socioeconomic status, and tumor biology.

      PubDate: 2017-11-16T06:08:34Z
  • 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
  • Obesity and Triple-Negative Breast Cancer: Disparities, Controversies, and
    • Authors: Eric Dietze; Tanya Chavez Victoria Seewaldt
      Abstract: Publication date: Available online 9 November 2017
      Source:The American Journal of Pathology
      Author(s): Eric C. Dietze, Tanya A. Chavez, Victoria L. Seewaldt
      Once considered a problem of Western nations, obesity (body mass index ≥30kg/m2) has rapidly increased since the 1970s to become a major threat to world health. Since 1970, the face of obesity has changed from a disease of affluence and abundance to a disease of poverty. Over the last 10 years, studies have mechanistically linked obesity and an obese tumor microenvironment with signaling pathways that predict aggressive breast cancer biology. For example, in the United States African-American women are more likely than non-Hispanic European-American women to be obese and to be diagnosed with triple-negative breast cancer (TNBC). In 2008, the Carolina Breast Study showed that obesity (increased waist-hip ratio) was linked to an increased incidence of TNBC in premenopausal and postmenopausal African-American women. Subsequently, several groups have investigated the potential link between obesity and TNBC in African-American women. To date, the data are complex and sometimes contradictory. Here we review epidemiologic studies investigating the potential association between obesity, metabolic syndrome, and TNBC in African-American women as well as mechanistic studies linking insulin-signaling to the obese breast microenvironment, tissue inflammation, and aggressive TNBC biology.

      PubDate: 2017-11-16T06:08:34Z
  • 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
  • Matrin 3 is a component of neuronal cytoplasmic inclusions of motor
           neurons in sporadic amyotrophic lateral sclerosis
    • Authors: Mikiko Tada; Hiroshi Doi Shigeru Koyano Shun Kubota Ryoko Fukai
      Abstract: Publication date: Available online 9 November 2017
      Source:The American Journal of Pathology
      Author(s): Mikiko Tada, Hiroshi Doi, Shigeru Koyano, Shun Kubota, Ryoko Fukai, Shunta Hashiguchi, Noriko Hayashi, Yuko Kawamoto, Misako Kunii, Kenichi Tanaka, Keita Takahashi, Yuki Ogawa, Ryo Iwata, Shoji Yamanaka, Hideyuki Takeuchi, Fumiaki Tanaka
      Mutations in the matrin 3 (MATR3) gene have been identified as a cause of familial amyotrophic lateral sclerosis, but the involvement of MATR3 protein in sporadic amyotrophic lateral sclerosis (SALS) pathology has not been fully assessed. Here, we immunohistochemically analyzed MATR3 pathology in the spinal cords of SALS and control autopsies. MATR3 immunostaining of the motor neuron nuclei revealed two distinct patterns, mild and strong staining. There were no differences in the ratio of mild versus strong nuclear staining between the SALS and control cases. MATR3-containing neuronal cytoplasmic inclusions (NCIs) were observed in 60% of SALS cases. Most motor neurons with MATR3-positive NCIs exhibited a mild nuclear staining pattern. Although 16.8% of NCIs positive for TDP-43 were estimated as double-labeled by MATR3, no MATR3-positive/TDP-43–negative NCIs were observed. Although a previous study showed that MATR3-positive NCIs are present only in cases with C9orf72 hexanucleotide repeat expansion, ubiquitin-positive granular NCIs were not observed in the cerebellum, which have been reported as specific to C9orf72-related ALS. Six of the ALS cases were confirmed to be negative for the GGGGCC hexanucleotide. Our results reveal that MATR3 is a component of TDP-43–positive NCIs in motor neurons, even in SALS, and indicate the broader involvement of MATR3 in ALS pathology and the heterogeneity of TDP-43–positive NCIs.

      PubDate: 2017-11-16T06:08:34Z
  • Epigenetic Mechanisms of ATM Activation after Helicobacter pylori
    • Authors: Juliana Carvalho; Santos Rafael Zuppardo Gambeloni Aline Tengan Roque Sebastian
      Abstract: Publication date: Available online 9 November 2017
      Source:The American Journal of Pathology
      Author(s): Juliana Carvalho Santos, Rafael Zuppardo Gambeloni, Aline Tengan Roque, Sebastian Oeck, Marcelo Lima Ribeiro
      Gastric cancer (GC) is the second leading cause of cancer-related mortality worldwide. The disease develops from the accumulation of several genetic and epigenetic changes. Among other risk factors, Helicobacter pylori infection is considered the main driving factor of GC development. H. pylori infection increases DNA damage levels and leads to epigenetic dysregulation, which may favor gastric carcinogenesis. An early step in double strand break repair is the recruitment of (ataxia-telangiectasia mutated serine/threonine kinase (ATM) to the damaged site, where it plays a key role in advancing the DNA damage checkpoint process. H. pylori infection has been associated with the introduction of double strand breaks in epithelial cells, triggering damage signaling and repair response involving ATM. Thus, the current study analyzed the effect of H. pylori infection on the DNA damage response sensor, ATM, in gastric epithelial cells and in biopsies from patients with GC. In this work, we identified that H. pylori infection stimulated DNA damage, and therefore induced ATM in a virulence factor-dependent manner. In addition, we found that H. pylori might activate ATM through histone H3 and H4 hyperacetylation and DNA promoter hypomethylation. Our findings reveal a mechanism associating ATM signaling induction with H. pylori infection.

      PubDate: 2017-11-16T06:08:34Z
  • Lysophosphatidic acid receptor 1 is important for intestinal epithelial
           barrier function and susceptibility to colitis
    • Authors: Songbai Lin; Yiran Han Kayte Jenkin Sei-Jung Lee Maiko Sasaki
      Abstract: Publication date: Available online 9 November 2017
      Source:The American Journal of Pathology
      Author(s): Songbai Lin, Yiran Han, Kayte Jenkin, Sei-Jung Lee, Maiko Sasaki, Jan-Michael Klapproth, Peijian He, C. Chris Yun
      Intestinal epithelial cells form a barrier that is critical in protecting the host from the hostile luminal environment. Previously, we showed that lysophosphatidic acid receptor 1 (LPAR1) regulates proliferation of intestinal epithelial cells such that the absence of LPA1 mitigates epithelial wound healing process. This study provides evidence that LPA1 is important for the maintenance of epithelial barrier integrity. The epithelial permeability, determined by fluorescently labeled dextran flux and transepithelial resistance, is increased in Lpar1 -/- (Lpa1-/-) mouse intestine. Serum liposaccharide level and bacteria loads in the intestinal mucosa and peripheral organs were elevated in Lpa1-/- mice. Decreased claudin-4, caudin-7, and E-cadherin expression in Lpa1-/- mice further suggested defective apical junction integrity in these mice. Regulation of LPA1 expression in Caco-2 cells modulated epithelial permeability and the expression levels of junctional proteins. The increased epithelial permeability in Lpa1-/- mice correlated with increased susceptibility to an experimental model of colitis that resulted in more severe inflammation and increased mortality compared to control mice. Treatment of Caco-2 cells with tumor necrosis factor-α and interferon-γ significantly increased paracellular permeability, which was blocked by co-treatment with LPA, but not in LPA1 knockdown cells. Similarly, orally given LPA blocked tumor necrosis factor–mediated intestinal barrier defect in mice. LPA1 plays a significant role in maintenance of epithelial barrier in the intestine via regulation of apical junction integrity.

      PubDate: 2017-11-16T06:08:34Z
  • Restoration of polr1c in early embryogenesis rescues the Type 3 Treacher
           Collins Syndrome facial malformation phenotype in zebrafish
    • Authors: Ernest Man; Lok Kwong Jeff Cheuk Hin Marco Chi Chung
      Abstract: Publication date: Available online 9 November 2017
      Source:The American Journal of Pathology
      Author(s): Ernest Man Lok Kwong, Jeff Cheuk Hin Ho, Marco Chi Chung Lau, May-Su You, Yun-Jin Jiang, William Ka Fai Tse
      Treacher Collins Syndrome (TCS) is a rare congenital birth disorder (1 in 50,000 live births) characterized by severe craniofacial defects. Recently, our group unfolded the pathogenesis of polr1c Type 3 TCS by using the zebrafish model. Facial development depends on the neural crest cells, in which polr1c plays a role in regulating its expression. In this report, we aim to identify the functional time window of polr1c in TCS by the use of photo-morpholino to restore the polr1c expression at different time points. Results suggested that the restoration of polr1c at 8 hours post fertilization could rescue the TCS facial malformation phenotype by correcting the neural crest cell expression, reducing the cell death, and normalizing the p53 mRNA expression level in the rescued morphants. However, such recovery could not be reproduced if the polr1c is restored after 30 hours post fertilization.

      PubDate: 2017-11-16T06:08:34Z
  • Regulation of Cellular Senescence by miR-34a in Alcoholic Liver Injury
    • Authors: Ying Wan; Kelly McDaniel Nan Sugeily Ramos-Lorenzo Trenton Glaser Julie
      Abstract: Publication date: Available online 8 November 2017
      Source:The American Journal of Pathology
      Author(s): Ying Wan, Kelly McDaniel, Nan Wu, Sugeily Ramos-Lorenzo, Trenton Glaser, Julie Venter, Heather Francis, Lindsey Kennedy, Keisaku Sato, Tianhao Zhou, Konstantina Kyritsi, Qiaobing Huang, Tami Annable, Chaodong Wu, Shannon Glaser, Gianfranco Alpini, Fanyin Meng
      Alcoholic liver disease remains a major cause of liver-related morbidity and mortality, which ranges from alcoholic steatohepatitis to fibrosis/cirrhosis and hepatocellular carcinoma, and the related mechanisms are understood poorly. In this study, we aimed to investigate the role of miR-34a in alcohol-induced cellular senescence and liver fibrosis. We found that hepatic miR-34a expression was upregulated in ethanol-fed mice and heavy drinkers with steatohepatitis compared with respective controls. Mice treated with miR-34a Vivo-Morpholino developed less severe liver fibrosis than wild-type mice after 5 weeks of ethanol feeding. Further mechanism exploration showed that inhibition of miR-34a increased cellular senescence of hepatic stellate cells (HSCs) in ethanol-fed mice, although it decreased senescence in total liver and hepatocytes, which was verified by the changes of senescence-associated β-galactosidase and gene expression. Furthermore, enhanced cellular senescence was observed in liver tissues from steatohepatitis patients compared with healthy controls. In addition, the expression of transforming growth factor-β1, drosophila mothers against decapentaplegic protein 2 (Smad2), and Smad3 was decreased after inhibition of miR-34a in ethanol-fed mice. Our in vitro experiments showed that silencing of miR-34a partially blocked activation of HSCs by lipopolysaccharide and enhanced senescence of HSCs. Furthermore, inhibition of miR-34a decreased lipopolysaccharide-induced fibrotic gene expression in cultured hepatocytes. In conclusion, our data suggest that miR-34a functions as a profibrotic factor that promotes alcohol-induced liver fibrosis by reducing HSC senescence and increasing the senescence of hepatocytes.

      PubDate: 2017-11-08T17:50:20Z
  • 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
  • This Month in AJP
    • Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11

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

      PubDate: 2017-11-08T17:50:20Z
  • Correction
    • Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11

      PubDate: 2017-11-08T17:50:20Z
  • Correction
    • Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11

      PubDate: 2017-11-08T17:50:20Z
  • Correction
    • Abstract: Publication date: November 2017
      Source:The American Journal of Pathology, Volume 187, Issue 11

      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
  • This Month in AJP
    • Abstract: Publication date: Available online 14 October 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: 2017-10-18T14:59:21Z
  • 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
      Abstract: Publication date: Available online 14 October 2017
      Source:The American Journal of Pathology
      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. Here we show that neointima formation after carotid artery wire injury reduces markedly in CD40−/−apoE−/− mice but only slightly in CD40L−/−apoE−/− mice, compared with apolipoprotein E-deficient (apoE−/−) mice. Wild-type and CD40-deficient platelets were isolated from blood of apoE−/− and CD40−/−apoE−/− mice, respectively. Intravenous injection of thrombin-activated platelets into CD40−/−apoE−/− mice was performed every five days starting at two 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 and further promoting the luminal deposition of platelet-derived RANTES/CCL5 and expression of monocyte chemoattractant protein-1 and vascular cell adhesion molecule1 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 following vascular interventions.

      PubDate: 2017-10-18T14:59:21Z
      DOI: 10.1016/j.ajpath.2017.09.007
  • 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
  • Inhibition of Mammalian Target of Rapamycin Signaling with Rapamycin
           Prevents Trauma-Induced Heterotopic Ossification
    • Authors: Ammar T. Qureshi; Devaveena Dey; Erin M. Sanders; Jonathan G. Seavey; Allison M. Tomasino; Kaitlyn Moss; Benjamin Wheatley; David Cholok; Shawn Loder; John Li; Benjamin Levi; Thomas A. Davis
      Abstract: Publication date: Available online 10 October 2017
      Source:The American Journal of Pathology
      Author(s): Ammar T. Qureshi, Devaveena Dey, Erin M. Sanders, Jonathan G. Seavey, Allison M. Tomasino, Kaitlyn Moss, Benjamin Wheatley, David Cholok, Shawn Loder, John Li, Benjamin Levi, Thomas A. Davis
      A pressing clinical need exists for 63% to 65% of combat-wounded service members and 11% to 20% of civilians who develop heterotopic ossification (HO) after blast-related extremity injury and traumatic injuries, respectively. The mammalian target of rapamycin pathway is a central cellular sensor of injury. We evaluated the prophylactic effects of rapamycin, a selective inhibitor of mammalian target of rapamycin signaling, on HO formation in a rat model of blast-related, polytraumatic extremity injury. Rapamycin was administered intraperitoneally daily for 14 days at 0.5 mg/kg or 2.5 mg/kg. Ectopic bone formation was monitored by micro-computed tomography and confirmed by histologic examination. Connective tissue progenitor cells, platelet-derived growth factor receptor-α–positive cells, and α-smooth muscle actin–positive blood vessels were assayed at postoperative day 7 by colony formation and immunofluorescence. Early gene expression changes were determined by low-density microarray. There was significant attenuation of 1) total new bone and soft tissue ectopic bone with 0.5 mg/kg (38.5% and 14.7%) and 2.5 mg/kg rapamycin (90.3% and 82.9%), respectively, 2) connective tissue progenitor cells, 3) platelet-derived growth factor receptor-α–positive cells, 4) α-smooth muscle actin–positive blood vessels, and 5) of key extracellular matrix remodeling (CD44, Col1a1, integrins), osteogenesis (Sp7, Runx2, Bmp2), inflammation (Cxcl5, 10, IL6, Ccl2), and angiogenesis (Angpt2) genes. No wound healing complications were noted. Our data demonstrate the efficacy of rapamycin in inhibiting blast trauma-induced HO by a multipronged mechanism.

      PubDate: 2017-10-12T17:47:40Z
      DOI: 10.1016/j.ajpath.2017.07.010
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Heriot-Watt University
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