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Showing 1 - 200 of 3030 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 20, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 16, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 79, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 22, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 27, 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: 303, 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  
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: 196, 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: 9, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 21, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 5, 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: 3, 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)
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: 5)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 20)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 120, 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: 16, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 8, 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: 24, 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: 10, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 21, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 26, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in 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: 24, 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: 8, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 28, 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 Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 4)
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: 39, 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: 38, 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: 41, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
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: 18, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 22)
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: 33, 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: 4)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
Advances in Life Course Research     Hybrid Journal   (Followers: 7, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 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: 5, 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: 21)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 6, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 3)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
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: 20, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 14)
Advances in Pharmacology     Full-text available via subscription   (Followers: 13, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 7, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 17, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 56)
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: 1, SJR: 0.1, h-index: 2)
Advances in Space Research     Full-text available via subscription   (Followers: 332, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 7)
Advances in Surgery     Full-text available via subscription   (Followers: 6, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 28, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 14)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 12)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 42, 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: 304, 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: 4, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 7, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 390, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 15, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 29, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 36, 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: 48, 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: 3, 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: 9, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 5)
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  
Algal Research     Partially Free   (Followers: 7, 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: 5, SJR: 0.776, h-index: 35)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 6, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 45, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 5)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 3)
American Heart J.     Hybrid Journal   (Followers: 45, 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: 34, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 6, 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: 25, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 31, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 48, 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: 174, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 51, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 2)
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: 22, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 23, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 21, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 32, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 13, 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: 52, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 3)
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: 2, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 38, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 154, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 7, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 10)
Anesthésie & Réanimation     Full-text available via subscription  
Anesthesiology Clinics     Full-text available via subscription   (Followers: 21, 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: 143, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
Annales d'Endocrinologie     Full-text available via subscription   (SJR: 0.394, h-index: 30)
Annales d'Urologie     Full-text available via subscription  
Annales de Cardiologie et d'Angéiologie     Full-text available via subscription   (SJR: 0.177, h-index: 13)
Annales de Chirurgie de la Main et du Membre Supérieur     Full-text available via subscription  
Annales de Chirurgie Plastique Esthétique     Full-text available via subscription   (Followers: 2, SJR: 0.354, h-index: 22)
Annales de Chirurgie Vasculaire     Full-text available via subscription   (Followers: 1)

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Journal Cover American Journal of Pathology
  [SJR: 2.653]   [H-I: 228]   [23 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0002-9440
   Published by Elsevier Homepage  [3030 journals]
  • Peter C. Nowell, M.D., 1928–2016
    • Authors: David B. Roth
      First page: 696
      Abstract: Publication date: April 2017
      Source:The American Journal of Pathology, Volume 187, Issue 4
      Author(s): David B. Roth
      Teaser This In Memoriam highlights the life of Dr. Peter C. Nowell, M.D., former president of the American Society for Experimental Pathology (1970–1971).

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2017.01.001
  • Cathepsin H–Mediated Degradation of HDAC4 for Matrix Metalloproteinase
           Expression in Hepatic Stellate Cells
    • Authors: Zemin Yang; Yu Liu; Lan Qin; Pengfei Wu; Zanxian Xia; Mei Luo; Yilan Zeng; Hidekazu Tsukamoto; Zongyun Ju; Danmei Su; Han Kang; Zhixiong Xiao; Sujun Zheng; Zhongping Duan; Richard Hu; Qiang Wang; Stephen J. Pandol; Yuan-Ping Han
      Pages: 781 - 797
      Abstract: Publication date: April 2017
      Source:The American Journal of Pathology, Volume 187, Issue 4
      Author(s): Zemin Yang, Yu Liu, Lan Qin, Pengfei Wu, Zanxian Xia, Mei Luo, Yilan Zeng, Hidekazu Tsukamoto, Zongyun Ju, Danmei Su, Han Kang, Zhixiong Xiao, Sujun Zheng, Zhongping Duan, Richard Hu, Qiang Wang, Stephen J. Pandol, Yuan-Ping Han
      In three-dimensional extracellular matrix, mesenchymal cells including hepatic stellate cells (HSCs) gain the ability to express matrix metalloproteinases (MMPs) on injury signals. In contrast, in myofibroblastic HSCs in fibrotic liver, many MMP genes are silenced into an epigenetically nonpermissive state. The mechanism by which the three-dimensional extracellular matrix confers the MMP genes into an epigenetically permissive state has not been well characterized. In continuation of previous work, we show here that the up-regulation of MMP genes is mediated through degradation of class IIa histone deacetylases (HDACs) by certain cysteine cathepsins (Cts). In three-dimensional extracellular matrix culture, CtsH, among other cysteine cathepsins, was up-regulated and localized as puncta in the nuclear and cytoplasmic compartments in a complex with HDAC4 for its degradation. Conversely, along with HSC trans-differentiation, CtsH and CtsL were progressively down-regulated, whereas HDAC4 was concurrently stabilized. The inhibition of cysteine cathepsins by specific proteinase inhibitors or chloroquine, which raises cellular pH, restored HDAC4. Recombinant CtsH could break down HDAC4 in the transfected cells and in vitro at acidic pH. In human cirrhotic liver, activated HSCs express high levels of class IIa HDACs but little CtsH. We propose that cysteine cathepsin–mediated degradation of class IIa HDACs plays a key role in the modulation of MMP expression/suppression and HSC functions in tissue injury and fibrosis.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2016.12.001
  • Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central
           Nervous System Abnormalities
    • Authors: Jakub Sikora; Shaalee Dworski; E. Ellen Jones; Mustafa A. Kamani; Matthew C. Micsenyi; Tomo Sawada; Pauline Le Faouder; Justine Bertrand-Michel; Aude Dupuy; Christopher K. Dunn; Ingrid Cong Yang Xuan; Josefina Casas; Gemma Fabrias; David R. Hampson; Thierry Levade; Richard R. Drake; Jeffrey A. Medin; Steven U. Walkley
      Pages: 864 - 883
      Abstract: Publication date: April 2017
      Source:The American Journal of Pathology, Volume 187, Issue 4
      Author(s): Jakub Sikora, Shaalee Dworski, E. Ellen Jones, Mustafa A. Kamani, Matthew C. Micsenyi, Tomo Sawada, Pauline Le Faouder, Justine Bertrand-Michel, Aude Dupuy, Christopher K. Dunn, Ingrid Cong Yang Xuan, Josefina Casas, Gemma Fabrias, David R. Hampson, Thierry Levade, Richard R. Drake, Jeffrey A. Medin, Steven U. Walkley
      Farber disease is a rare autosomal recessive disorder caused by acid ceramidase deficiency that usually presents as early-onset progressive visceral and neurologic disease. To understand the neurologic abnormality, we investigated behavioral, biochemical, and cellular abnormalities in the central nervous system of Asah1 P361R/P361R mice, which serve as a model of Farber disease. Behaviorally, the mutant mice had reduced voluntary locomotion and exploration, increased thigmotaxis, abnormal spectra of basic behavioral activities, impaired muscle grip strength, and defects in motor coordination. A few mutant mice developed hydrocephalus. Mass spectrometry revealed elevations of ceramides, hydroxy-ceramides, dihydroceramides, sphingosine, dihexosylceramides, and monosialodihexosylganglioside in the brain. The highest accumulation was in hydroxy-ceramides. Storage compound distribution was analyzed by mass spectrometry imaging and morphologic analyses and revealed involvement of a wide range of central nervous system cell types (eg, neurons, endothelial cells, and choroid plexus cells), most notably microglia and/or macrophages. Coalescing and mostly perivascular granuloma–like accumulations of storage-laden CD68+ microglia and/or macrophages were seen as early as 3 weeks of age and located preferentially in white matter, periventricular zones, and meninges. Neurodegeneration was also evident in specific cerebral areas in late disease. Overall, our central nervous system studies in Asah1 P361R/P361R mice substantially extend the understanding of human Farber disease and suggest that this model can be used to advance therapeutic approaches for this currently untreatable disorder.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2016.12.005
  • Caveolin 1 and G-Protein–Coupled Receptor Kinase-2 Coregulate
           Endothelial Nitric Oxide Synthase Activity in Sinusoidal Endothelial Cells
    • Authors: Songling Liu; Richard T. Premont; Shweta Singh; Don C. Rockey
      Pages: 896 - 907
      Abstract: Publication date: April 2017
      Source:The American Journal of Pathology, Volume 187, Issue 4
      Author(s): Songling Liu, Richard T. Premont, Shweta Singh, Don C. Rockey
      Liver injury leads to a vasculopathy in which post-translational modifications of endothelial nitric oxide synthase (eNOS) lead to impaired nitric oxide synthesis. We hypothesized that caveolin 1 (CAV1), a well-known eNOS interactor, regulates eNOS activity in sinusoidal endothelial cells (SECs) via its interaction with G-protein–coupled receptor kinase-2 (GRK2) that also post-translationally modifies eNOS. Liver injury with portal hypertension was established using bile duct ligation in rats. CAV1 function was modified using a CAV1 scaffolding domain construct and cDNAs encoding wild-type CAV1, and CAV1 phosphorylation was increased in injured SECs, resulting in increased GRK2-CAV1 interaction and decreased eNOS activity. In injured SECs, endothelin-1 blocked CAV1 phosphorylation induced by CAV1 scaffolding domain, indicating that CAV1 interaction with GRK2 is inversely regulated by endothelin-1 and CAV1 scaffolding domain after liver injury. In addition, after transduction with DNA encoding wild-type CAV1 into SECs isolated from Cav1-deficient mice, GRK2 association with CAV1 was evident, whereas transduction with a dominant negative CAV1 mutated at tyrosine 14 reduced the interaction. Finally, isoproterenol-induced GRK2 phosphorylation enhanced CAV1-GRK2 interaction and reduced eNOS activity. Our data suggest a novel mechanism and model in which CAV1 phosphorylation facilitates CAV1 scaffolding and GRK2-CAV1 interaction, thus clustering eNOS within a complex that inhibits eNOS activity. This process takes place in injured, but not in normal, SECs.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2016.11.017
  • Placental Stem Villus Arterial Remodeling Associated with Reduced Hydrogen
           Sulfide Synthesis Contributes to Human Fetal Growth Restriction
    • Authors: Liangjian Lu; John Kingdom; Graham J. Burton; Tereza Cindrova-Davies
      Pages: 908 - 920
      Abstract: Publication date: April 2017
      Source:The American Journal of Pathology, Volume 187, Issue 4
      Author(s): Liangjian Lu, John Kingdom, Graham J. Burton, Tereza Cindrova-Davies
      Intrauterine fetal growth restriction (IUGR) is often associated with compromised umbilical arterial flow, indicating increased placental vascular resistance. Oxidative stress is causatively implicated. Hydrogen sulfide maintains differentiated smooth muscle in vascular beds, and its synthetic enzyme cystathionine-γ-lyase (CSE) is down-regulated in growth-restricted placentas. We hypothesized that remodeling of resistance arteries in stem villi contributes to IUGR by compromising umbilical blood flow via oxidative stress, reducing hydrogen sulfide signaling. Stem villus arteries in human IUGR placentas displaying absent or reversed end-diastolic flow contained reduced myosin heavy chain, smooth muscle actin, and desmin, and increased markers of dedifferentiation, cellular retinol-binding protein 1, and matrix metalloproteinase 2, compared to term and preterm controls. Wall thickness/lumen ratio was increased, lumen diameter decreased, but wall thickness remained unchanged in IUGR placentas. CSE correlated positively with myosin heavy chain, smooth muscle actin, and desmin. Birth weight correlated positively with CSE, myosin heavy chain, smooth muscle actin, and desmin, and negatively with cellular retinol-binding protein 1 and matrix metalloproteinase 2. These findings could be recapitulated in vitro by subjecting stem villus artery explants to hypoxia-reoxygenation, or inhibiting CSE. Treatment with a hydrogen sulfide donor, diallyl trisulfide, prevented these changes. IUGR is associated with vascular remodeling of the stem villus arteries. Oxidative stress results in reduction of placental CSE activity, decreased hydrogen sulfide production, and smooth muscle cell dedifferentiation in vitro. This vascular remodeling is reversible, and hydrogen sulfide donors are likely to improve pregnancy outcomes.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2016.12.002
  • Matrix Metalloproteinase-28 Is a Key Contributor to Emphysema Pathogenesis
    • Authors: Anne M. Manicone; Sina A. Gharib; Ke-Qin Gong; William E. Eddy; Matthew E. Long; Charles W. Frevert; William A. Altemeier; William C. Parks; A. McGarry Houghton
      Abstract: Publication date: Available online 8 April 2017
      Source:The American Journal of Pathology
      Author(s): Anne M. Manicone, Sina A. Gharib, Ke-Qin Gong, William E. Eddy, Matthew E. Long, Charles W. Frevert, William A. Altemeier, William C. Parks, A. McGarry Houghton
      Chronic obstructive pulmonary disease (COPD) comprises chronic bronchitis and emphysema, and is a leading cause of morbidity and mortality. Because tissue destruction is the prominent characteristic of emphysema, extracellular proteinases, particularly those with elastolytic ability, are often considered to be key drivers in this disease. Several human and mouse studies have implicated roles for matrix metalloproteinases (MMPs), particularly macrophage-derived proteinases, in COPD pathogenesis. MMP-28 is expressed by the pulmonary epithelium and macrophage, and we have found that it regulates macrophage recruitment and polarization. We hypothesized that MMP-28 has contributory roles in emphysema via alteration of macrophage numbers and activation. Because of the established association of emphysema pathogenesis to macrophage influx, we evaluated the inflammatory changes and lung histology of Mmp28 −/− mice exposed to 3 and 6 months of cigarette smoke. At earlier time points, we found altered macrophage polarization in the smoke-exposed Mmp28 −/− lung consistent with other published findings that MMP-28 regulates macrophage activation. At both 3 and 6 months, Mmp28 −/− mice had blunted inflammatory responses more closely resembling nonsmoked mice, with a reduction in neutrophil recruitment and CXCL1 chemokine expression. By 6 months, Mmp28 −/− mice were protected from emphysema. These results highlight a previously unrecognized role for MMP-28 in promoting chronic lung inflammation and tissue remodeling induced by cigarette smoke and highlight another potential target to modulate COPD.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2017.02.008
  • In Vivo Effects of Long-Term Cigarette Smoke Exposure on Mammary
           Tissue in Mice
    • Authors: Shannon Kispert; Susan Crawford; Grant Kolar; Jane McHowat
      Abstract: Publication date: Available online 4 April 2017
      Source:The American Journal of Pathology
      Author(s): Shannon Kispert, Susan Crawford, Grant Kolar, Jane McHowat
      Cigarette smoking is the leading cause of preventable death worldwide and has been linked to the development and progression of cancer. Many cohort studies have described the link between patients with breast cancer and those with long-term smoking history. Despite the claim of correlation, the mechanism by which cigarette smoke alters normal breast epithelial cells and stroma and contributes to tumor cell growth remains undefined. To investigate whether cigarette smoke promotes ductal epithelial cell hyperplasia by stimulating stromal endothelial cell proliferation, we exposed mice to cigarette smoke for 6 months. We observed epithelial proliferation, increased fibrosis, increased vascularity, and mast cell infiltration. This is the first study to look at the in vivo changes in the breast after long-term cigarette smoke exposure and provides a novel insight to understanding how cigarette smoke contributes to early changes that may contribute to tumor formation and progression. In conclusion, this study suggests that cigarette smoke modulates key stromal-epithelial interactions to support increased angiogenesis, desmoplasia, and abnormal ductal epithelial cell growth.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2017.02.004
  • Corrections
    • Abstract: Publication date: April 2017
      Source:The American Journal of Pathology, Volume 187, Issue 4

      PubDate: 2017-04-08T19:07:10Z
  • Corrections
    • Abstract: Publication date: April 2017
      Source:The American Journal of Pathology, Volume 187, Issue 4

      PubDate: 2017-04-08T19:07:10Z
  • Corrections
    • Abstract: Publication date: April 2017
      Source:The American Journal of Pathology, Volume 187, Issue 4

      PubDate: 2017-04-08T19:07:10Z
  • This Month in AJP
    • Abstract: Publication date: Available online 23 March 2017
      Source:The American Journal of Pathology

      PubDate: 2017-04-08T19:07:10Z
  • Low-Intensity Training and the C5a Complement Antagonist NOX-D21 Rescue
           the mdx Phenotype through Modulation of Inflammation
    • Authors: Janek Hyzewicz; Jun Tanihata; Mutsuki Kuraoka; Yuko Nitahara-Kasahara; Teiva Beylier; Urs T. Ruegg; Axel Vater; Shin'ichi Takeda
      Abstract: Publication date: Available online 18 March 2017
      Source:The American Journal of Pathology
      Author(s): Janek Hyzewicz, Jun Tanihata, Mutsuki Kuraoka, Yuko Nitahara-Kasahara, Teiva Beylier, Urs T. Ruegg, Axel Vater, Shin'ichi Takeda
      Inflammatory events occurring in dystrophic muscles contribute to the progression of Duchenne muscular dystrophy (DMD). Low-intensity training (LIT) attenuates the phenotype of mdx mice, an animal model for DMD. Therefore, we postulated that LIT could have anti-inflammatory properties. We assessed levels of inflammatory cytokines and infiltrated immune cells in gastrocnemius muscle of mdx mice after LIT. We detected high levels of complement component C5a, chemokine ligand (CCL) 2, CD68+ monocytes/macrophages, and proinflammatory M1 macrophages in muscles of mdx mice. LIT decreased CCL2 levels, increased CD68+ cell numbers, and shifted the macrophage population to the regenerative M2 type. We investigated whether inhibition of C5a or CCL2 with L-aptamers could mimic the effects of LIT. Although no effect of CCL2 inhibition was detected, treatment with the C5a inhibitor, NOX-D21, rescued the phenotype of nonexercised mdx mice, but not of exercised ones. In both cases, the level of CD68+ cells increased and macrophage populations leaned toward the inflammatory M1 type. In muscles of nonexercised treated mice, the level of IL-1 receptor antagonist increased, damage decreased, and fibers were switched toward the glycolytic fast type; in muscles of exercised mice, fibers were switched to the oxidative slow type. These results reveal the effects of LIT on the inflammatory status of mdx mice and suggest that NOX-D21 could be an anti-inflammatory drug for DMD.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2016.12.019
  • The Major Histocompatibility Complex Class III Haplotype Ltab-Ncr3
           Regulates Adjuvant-Induced but Not Antigen-Induced Autoimmunity
    • Authors: Anthony C.Y. Yau; Jonatan Tuncel; Rikard Holmdahl
      Abstract: Publication date: Available online 18 March 2017
      Source:The American Journal of Pathology
      Author(s): Anthony C.Y. Yau, Jonatan Tuncel, Rikard Holmdahl
      Rheumatoid arthritis is a complex disease associated with >100 risk loci, with the strongest association from the major histocompatibility complex (MHC) region. Here, we analyzed a new genetic association in the MHC class-III region (MHC-III) using adjuvant- and antigen-induced arthritis models. In addition, we used models for multiple sclerosis for comparison and dissected the MHC-III–mediated mechanisms of importance for antibody and T-cell responses to antigens. With the use of a panel of MHC-III recombinant inbred strains, we found that the 33-kb Ltab-Ncr3 haplotype in MHC-III was linked to the induction of arthritis with incomplete Freund's adjuvant, with similar effects in arthritis induced by several oil adjuvants (hexadecane, heptadecane, squalene, arlacel). Adoptive T-cell transfer experiment showed that this arthritis-protective effect operated during the priming of T cells by controlling their arthritogenicity. Interestingly, Ltab-Ncr3 did not regulate autoimmune diseases induced with tissue-specific antigens emulsified in adjuvant oils, such as collagen-induced arthritis or experimental autoimmune encephalomyelitis. No effect on antibody or T-cell response to tissue antigens in the Ltab-Ncr3 could be demonstrated. The finding that Ltab-Ncr3 is specific in regulating adjuvant-induced arthritis but not antigen-induced autoimmunity, and with unique effects on priming of autoreactive and arthritogenic T cells, provides new insight for understanding the regulation of autoimmune diseases.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2016.12.022
  • Dichotomy between Receptor-Interacting Protein 1– and
           Receptor-Interacting Protein 3–Mediated Necroptosis in Experimental
    • Authors: Jianghong Wu; Tunike Mulatibieke; Jianbo Ni; Xiao Han; Bin Li; Yue Zeng; Rong Wan; Xingpeng Wang; Guoyong Hu
      Abstract: Publication date: Available online 18 March 2017
      Source:The American Journal of Pathology
      Author(s): Jianghong Wu, Tunike Mulatibieke, Jianbo Ni, Xiao Han, Bin Li, Yue Zeng, Rong Wan, Xingpeng Wang, Guoyong Hu
      Pancreatic acinar cell necrosis and inflammatory responses are two key pathologic processes in acute pancreatitis (AP), which determines the severity and outcome of the disease. Recent studies suggest that necroptosis, a programed form of necrosis, is involved in the pathogenesis of AP, but the underlying mechanisms remain unknown. We investigated the expression of necrosome components, including receptor-interacting protein (RIP) 1, RIP3, and mixed lineage kinase domain-like (MLKL), and the molecular mechanisms in pancreatitis-associated necroptosis. We found that RIP3 and phosphorylated MLKL expression was positively related to the degree of necrosis, whereas RIP1 expression was negatively related to the degree of necrosis. Pharmacologic inhibition of RIP1 kinase activity exerted no protection against caerulein/cholecystokinin-8–induced AP, but knockdown of RIP1 with siRNA increased acinar cell necrosis and inhibition of NF-κB activation. RIP1 inhibition led to enhanced RIP3 expression. RIP3 and MLKL inhibition decreased acinar cell necrosis, in which the inhibition of RIP3 reduced the phosphorylation level of MLKL. RIP3 inhibition had no effect on trypsinogen activation but partly inhibited inflammasome activation. Our study strongly suggests that the imbalance between RIP1 and RIP3 shifts the cell death to necrosis, which unravels a new molecular pathogenesis of mechanism of AP and may provide insight into the development of novel therapeutic agent for other necrosis-related diseases.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2016.12.021
  • Complement Component C3 and Complement Factor B Promote Growth of
           Cutaneous Squamous Cell Carcinoma
    • Authors: Pilvi Riihilä; Liisa Nissinen; Mehdi Farshchian; Markku Kallajoki; Atte Kivisaari; Seppo Meri; Reidar Grénman; Sirkku Peltonen; Juha Peltonen; Taina Pihlajaniemi; Ritva Heljasvaara; Veli-Matti Kähäri
      Abstract: Publication date: Available online 17 March 2017
      Source:The American Journal of Pathology
      Author(s): Pilvi Riihilä, Liisa Nissinen, Mehdi Farshchian, Markku Kallajoki, Atte Kivisaari, Seppo Meri, Reidar Grénman, Sirkku Peltonen, Juha Peltonen, Taina Pihlajaniemi, Ritva Heljasvaara, Veli-Matti Kähäri
      Cutaneous squamous cell carcinoma (cSCC) is one of the most common metastatic skin cancers with increasing incidence. We examined the roles of complement component C3 and complement factor B (CFB) in the growth of cSCC. Analysis of cSCC cell lines (n = 8) and normal human epidermal keratinocytes (n = 11) with real-time quantitative PCR and Western blotting revealed up-regulation of C3 and CFB expression in cSCC cells. Immunohistochemical staining revealed stronger tumor cell–specific labeling for C3 and CFB in invasive cSCCs (n = 71) and recessive dystrophic epidermolysis bullosa–associated cSCCs (n = 11) than in cSCC in situ (n = 69), actinic keratoses (n = 63), and normal skin (n = 5). Significant up-regulation of C3 and CFB mRNA expression was noted in chemically induced mouse skin cSCCs, compared to benign papillomas, hyperplastic skin, and normal skin. The expression of C3 and CFB was higher in aggressive Ha-ras–transformed cell line (RT3) than in less tumorigenic HaCaT cell lines (HaCaT, A5, II-4). Knockdown of C3 and CFB expression inhibited migration and proliferation of cSCC cells and resulted in potent inhibition of extracellular signal–regulated kinase 1/2 activation. Knockdown of C3 and CFB markedly inhibited growth of human cSCC xenograft tumors in vivo. These results provide evidence for the roles of C3 and CFB in the development of cSCC and identify them as biomarkers and potential therapeutic targets in this metastatic skin cancer.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2017.01.006
  • Carbon Monoxide–Releasing Molecule-401 Suppresses Polymorphonuclear
           Leukocyte Migratory Potential by Modulating F-Actin Dynamics
    • Authors: Ken Inoue; Eric K. Patterson; Alfredo Capretta; Abdel R. Lawendy; Douglas D. Fraser; Gediminas Cepinskas
      Abstract: Publication date: Available online 17 March 2017
      Source:The American Journal of Pathology
      Author(s): Ken Inoue, Eric K. Patterson, Alfredo Capretta, Abdel R. Lawendy, Douglas D. Fraser, Gediminas Cepinskas
      Carbon monoxide–releasing molecules (CORMs) suppress inflammation by reducing polymorphonuclear leukocyte (PMN) recruitment to the affected organs. We investigated modulation of PMN–endothelial cell adhesive interactions by water-soluble CORM-401 using an experimental model of endotoxemia in vitro. Human umbilical vein endothelial cells grown on laminar-flow perfusion channels were stimulated with 1 μg/mL lipopolysaccharide for 6 hours and perfused with 100 μmol/L CORM-401 (or inactive compound iCORM-401)–pretreated PMN for 5 minutes in the presence of 1.0 dyn/cm2 shear stress. Human umbilical vein endothelial cell:PMN co-cultures were perfused for additional 15 minutes with PMN-free medium containing CORM-401/inactive CORM-401. The experiments were videorecorded (phase-contrast microscopy), and PMN adhesion/migration were assessed off-line. In parallel, CORM-401–dependent modulation of PMN chemotaxis, F-actin expression/distribution, and actin-regulating pathways [eg, p21-activated protein kinases (PAK1/2) and mitogen-activated protein kinase (MAPK) activation] were assessed in response to N-formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation. Pretreating PMN with CORM-401 did not suppress PMN adhesion, but significantly reduced PMN transendothelial migration (P < 0.0001) and fMLP-induced PMN chemotaxis (ie, migration directionality and velocity). These changes were associated with CORM-401–dependent suppression of F-actin levels/cellular distribution and fMLP-induced phosphorylation of PAK1/2 and extracellular signal–regulated kinase/C-Jun N-terminal kinase MAPK (P < 0.05). CORM-401 had no effect on p38 MAPK activation. In summary, this study demonstrates, for the first time, CORM-401–dependent suppression of neutrophil migratory potential associated with modulation of PAK1/2 and extracellular signal–regulated kinase/C-Jun N-terminal kinase MAPK signaling and intracellular F-actin dynamics.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2016.12.025
  • Association of Cardiac Galectin-3 Expression, Myocarditis, and Fibrosis in
           Chronic Chagas Disease Cardiomyopathy
    • Authors: Bruno Solano de Freitas Souza; Daniela Nascimento Silva; Rejane Hughes Carvalho; Gabriela Louise de Almeida Sampaio; Bruno Diaz Paredes; Luciana Aragão França; Carine Machado Azevedo; Juliana Fraga Vasconcelos; Cassio Santana Meira; Paulo Chenaud Neto; Simone Garcia Macambira; Kátia Nunes da Silva; Kyan James Allahdadi; Fabio Tavora; João David de Souza Neto; Ricardo Ribeiro dos Santos; Milena Botelho Pereira Soares
      Abstract: Publication date: Available online 17 March 2017
      Source:The American Journal of Pathology
      Author(s): Bruno Solano de Freitas Souza, Daniela Nascimento Silva, Rejane Hughes Carvalho, Gabriela Louise de Almeida Sampaio, Bruno Diaz Paredes, Luciana Aragão França, Carine Machado Azevedo, Juliana Fraga Vasconcelos, Cassio Santana Meira, Paulo Chenaud Neto, Simone Garcia Macambira, Kátia Nunes da Silva, Kyan James Allahdadi, Fabio Tavora, João David de Souza Neto, Ricardo Ribeiro dos Santos, Milena Botelho Pereira Soares
      Chronic Chagas disease cardiomyopathy, caused by Trypanosoma cruzi infection, is a major cause of heart failure in Latin America. Galectin-3 (Gal-3) has been linked to cardiac remodeling and poor prognosis in heart failure of different etiologies. Herein, we investigated the involvement of Gal-3 in the disease pathogenesis and its role as a target for disease intervention. Gal-3 expression in mouse hearts was evaluated during T. cruzi infection by confocal microscopy and flow cytometry analysis, showing a high expression in macrophages, T cells, and fibroblasts. In vitro studies using Gal-3 knockdown in cardiac fibroblasts demonstrated that Gal-3 regulates cell survival, proliferation, and type I collagen synthesis. In vivo blockade of Gal-3 with N-acetyl-d-lactosamine in T. cruzi–infected mice led to a significant reduction of cardiac fibrosis and inflammation in the heart. Moreover, a modulation in the expression of proinflammatory genes in the heart was observed. Finally, histological analysis in human heart samples obtained from subjects with Chagas disease who underwent heart transplantation showed the expression of Gal-3 in areas of inflammation, similar to the mouse model. Our results indicate that Gal-3 plays a role in the pathogenesis of experimental chronic Chagas disease, favoring inflammation and fibrogenesis. Moreover, by demonstrating Gal-3 expression in human hearts, our finding reinforces that this protein could be a novel target for drug development for Chagas cardiomyopathy.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2017.01.016
  • Adrenomedullin Suppresses Vascular Endothelial Growth Factor–Induced
           Vascular Hyperpermeability and Inflammation in Retinopathy
    • Authors: Akira Imai; Yuichi Toriyama; Yasuhiro Iesato; Kazutaka Hirabayashi; Takayuki Sakurai; Akiko Kamiyoshi; Yuka Ichikawa-Shindo; Hisaka Kawate; Megumu Tanaka; Tian Liu; Xian Xian; Liuyu Zhai; Kun Dai; Keiya Tanimura; Teng Liu; Nanqi Cui; Akihiro Yamauchi; Toshinori Murata; Takayuki Shindo
      Abstract: Publication date: Available online 17 March 2017
      Source:The American Journal of Pathology
      Author(s): Akira Imai, Yuichi Toriyama, Yasuhiro Iesato, Kazutaka Hirabayashi, Takayuki Sakurai, Akiko Kamiyoshi, Yuka Ichikawa-Shindo, Hisaka Kawate, Megumu Tanaka, Tian Liu, Xian Xian, Liuyu Zhai, Kun Dai, Keiya Tanimura, Teng Liu, Nanqi Cui, Akihiro Yamauchi, Toshinori Murata, Takayuki Shindo
      Diabetic macular edema (DME) is caused by blood-retinal barrier breakdown associated with retinal vascular hyperpermeability and inflammation, and it is the major cause of visual dysfunction in diabetic retinopathy. Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilator. ADM is expressed in the eyes and is up-regulated in various eye diseases, although the pathophysiological significance is largely unknown. We investigated the effect of ADM on DME. In Kimba mice, which overexpress human vascular endothelial growth factor in their retinas, the capillary dropout, vascular leakage, and vascular fragility characteristic of diabetic retinopathy were observed, and these changes were accompanied by retinal inflammation. Intravitreal or systemic administration of ADM to Kimba mice ameliorated both the capillary dropout and vascular leakage. Evaluation of the transendothelial electrical resistance and fluorescein isothiocyanate-dextran permeability of an endothelial cell monolayer using TR-iBRB retinal capillary endothelial cells revealed that vascular endothelial growth factor enhanced vascular permeability but that co-administration of ADM suppressed the effect, in part by enhancing tight junction formation between endothelial cells. In addition, a comprehensive PCR array analysis showed that ADM administration suppressed various molecules related to inflammation and NF-κB signaling within retinas. From these results, we suggest that by exerting inhibitory effects on retinal inflammation, vascular permeability, and blood-retinal barrier breakdown, ADM could serve as a novel therapeutic agent for the treatment of DME.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2017.01.014
  • Transforming Growth Factors α and β Are Essential for Modeling
           Cholangiocarcinoma Desmoplasia and Progression in a Three-Dimensional
           Organotypic Culture Model
    • Authors: Miguel A. Manzanares; Akihiro Usui; Deanna J. Campbell; Catherine I. Dumur; Gabrielle T. Maldonado; Michel Fausther; Jonathan A. Dranoff; Alphonse E. Sirica
      Abstract: Publication date: Available online 15 March 2017
      Source:The American Journal of Pathology
      Author(s): Miguel A. Manzanares, Akihiro Usui, Deanna J. Campbell, Catherine I. Dumur, Gabrielle T. Maldonado, Michel Fausther, Jonathan A. Dranoff, Alphonse E. Sirica
      To gain insight into the cellular and molecular interactions mediating the desmoplastic reaction and aggressive malignancy of mass-forming intrahepatic cholangiocarcinoma (ICC), we modeled ICC desmoplasia and progression in vitro. A unique three-dimensional (3D) organotypic culture model was established; within a dilute collagen–type I hydrogel, a novel clonal strain of rat cancer-associated myofibroblasts (TDFSM) was co-cultured with a pure rat cholangiocarcinoma cell strain (TDECC) derived from the same ICC type as TDFSM. This 3D organotypic culture model reproduced key features of desmoplastic reaction that closely mimicked those of the in situ tumor, as well as promoted cholangiocarcinoma cell growth and progression. Our results supported a resident liver mesenchymal cell origin of the TDFSM cells, which were not neoplastically transformed. Notably, 3D co-culturing of TDECC cells with TDFSM cells provoked the formation of a dense fibrocollagenous stroma in vitro that was associated with significant increases in both proliferative TDFSM myofibroblastic cells and TDECC cholangiocarcinoma cells accumulating within the gel matrix. This dramatic desmoplastic ICC-like phenotype, which was not observed in the TDECC or TDFSM controls, was highly dependent on transforming growth factor (TGF)-β, but not promoted by TGF-α. However, TGF-α was determined to be a key factor for promoting cholangiocarcinoma cell anaplasia, hyperproliferation, and higher malignant grading in this 3D culture model of desmoplastic ICC.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2017.01.013
  • Neural EGFL-Like 1 Is a Downstream Regulator of Runt-Related Transcription
           Factor 2 in Chondrogenic Differentiation and Maturation
    • Authors: Chenshuang Li; Jie Jiang; Zhong Zheng; Kevin S. Lee; Yanheng Zhou; Eric Chen; Cymbeline T. Culiat; Yiqiang Qiao; Xuepeng Chen; Kang Ting; Xinli Zhang; Chia Soo
      Abstract: Publication date: Available online 14 March 2017
      Source:The American Journal of Pathology
      Author(s): Chenshuang Li, Jie Jiang, Zhong Zheng, Kevin S. Lee, Yanheng Zhou, Eric Chen, Cymbeline T. Culiat, Yiqiang Qiao, Xuepeng Chen, Kang Ting, Xinli Zhang, Chia Soo
      Recent studies indicate that neural EGFL-like 1 (Nell-1), a secretive extracellular matrix molecule, is involved in chondrogenic differentiation. Herein, we demonstrated that Nell-1 serves as a key downstream target of runt-related transcription factor 2 (Runx2), a central regulator of chondrogenesis. Unlike in osteoblast lineage cells where Nell-1 and Runx2 demonstrate mutual regulation, further studies in chondrocytes revealed that Runx2 tightly regulates the expression of Nell-1; however, Nell-1 does not alter the expression of Runx2. More important, Nell-1 administration partially restored Runx2 deficiency–induced impairment of chondrocyte differentiation and maturation in vitro, ex vivo, and in vivo. Mechanistically, although the expression of Nell-1 is highly reliant on Runx2, the prochondrogenic function of Nell-1 persisted in Runx2 −/− scenarios. The biopotency of Nell-1 is independent of the nuclear import and DNA binding functions of Runx2 during chondrogenesis. Nell-1 is a key functional mediator of chondrogenesis, thus opening up new possibilities for the application of Nell-1 in cartilage regeneration.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2016.12.026
  • Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice
    • Authors: Allyson K. Martínez; Kendal Jensen; Chad Hall; April O'Brien; Laurent Ehrlich; Tori White; Fanyin Meng; Tianhao Zhou; John Greene; Francesca Bernuzzi; Pietro Invernizzi; David E. Dostal; Terry Lairmore; Gianfranco Alpini; Shannon Glaser
      Abstract: Publication date: Available online 14 March 2017
      Source:The American Journal of Pathology
      Author(s): Allyson K. Martínez, Kendal Jensen, Chad Hall, April O'Brien, Laurent Ehrlich, Tori White, Fanyin Meng, Tianhao Zhou, John Greene, Francesca Bernuzzi, Pietro Invernizzi, David E. Dostal, Terry Lairmore, Gianfranco Alpini, Shannon Glaser
      Nicotine, the main addictive substance in tobacco, is known to play a role in the development and/or progression of a number of malignant tumors. However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the growth of cholangiocarcinoma cells in vitro and the progression of cholangiocarcinoma in a mouse xenograft model. The predominant subunit responsible for nicotine-mediated proliferation in normal and cancer cells, the α7 nicotinic acetylcholine receptor (α7-nAChR), was more highly expressed in human cholangiocarcinoma cell lines compared with normal human cholangiocytes. Nicotine also stimulated the proliferation of cholangiocarcinoma cell lines and promoted α7-nAChR–dependent activation of proliferation and phosphorylation of extracellular-regulated kinase in Mz-ChA-1 cells. In addition, nicotine and PNU282987 (α7-nAChR agonist) accelerated the growth of the cholangiocarcinoma tumors in our xenograft mouse model and increased fibrosis, proliferation of the tumor cells, and phosphorylation of extracellular-regulated kinase activation. Finally, α7-nAChR was expressed at significantly higher levels in human cholangiocarcinoma compared with normal human control liver samples. Taken together, results of this study suggest that nicotine acts through α7-nAChR and plays a novel role in the pathogenesis of cholangiocarcinoma. Furthermore, nicotine may act as a mitogen in cholestatic liver disease processes, thereby facilitating malignant transformation.

      PubDate: 2017-04-08T19:07:10Z
      DOI: 10.1016/j.ajpath.2017.01.011
  • Hypoxia-Mediated Mechanisms Associated with Antiangiogenic Treatment
           Resistance in Glioblastomas
    • Authors: Sean Mahase; Rachel N. Rattenni; Pieter Wesseling; William Leenders; Clarissa Baldotto; Rajan Jain; David Zagzag
      Abstract: Publication date: Available online 9 March 2017
      Source:The American Journal of Pathology
      Author(s): Sean Mahase, Rachel N. Rattenni, Pieter Wesseling, William Leenders, Clarissa Baldotto, Rajan Jain, David Zagzag
      Glioblastomas (GBMs) are malignant tumors characterized by their vascularity and invasive capabilities. Antiangiogenic therapy (AAT) is a treatment option that targets GBM-associated vasculature to mitigate the growth of GBMs. However, AAT demonstrates transient effects, because many patients eventually develop resistance to this treatment. Several recent studies attempt to explain the molecular and biochemical basis of resistance to AAT in GBM patients. Experimental investigations suggest that the induction of extensive intratumoral hypoxia plays a key role in GBM escape from AAT. In this review, we examine AAT resistance in GBMs, with an emphasis on six potential hypoxia-mediated mechanisms: enhanced invasion and migration, including increased expression of matrix metalloproteinases and activation of the c-MET tyrosine kinase pathway; shifts in cellular metabolism, including up-regulation of hypoxia inducible factor-1α's downstream processes and the Warburg effect; induction of autophagy; augmentation of GBM stem cell self-renewal; possible implications of GBM-endothelial cell transdifferentiation; and vasoformative responses, including vasculogenesis, alternative angiogenic pathways, and vascular mimicry. Juxtaposing recent studies on well-established resistance pathways with that of emerging mechanisms highlights the overall complexity of GBM treatment resistance while also providing direction for further investigation.

      PubDate: 2017-03-12T17:02:49Z
      DOI: 10.1016/j.ajpath.2017.01.010
  • Evidence, Mechanism, and Clinical Relevance of the Transdifferentiation
           from Lung Adenocarcinoma to Squamous Cell Carcinoma
    • Authors: Shenda Hou; Shiyu Zhou; Zhen Qin; Liu Yang; Xiangkun Han; Shun Yao; Hongbin Ji
      Abstract: Publication date: Available online 9 March 2017
      Source:The American Journal of Pathology
      Author(s): Shenda Hou, Shiyu Zhou, Zhen Qin, Liu Yang, Xiangkun Han, Shun Yao, Hongbin Ji
      Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct subtypes of non–small-cell lung carcinoma. Interestingly, approximately 4% to 9% of human non–small-cell lung carcinoma tumors contain mixed adenomatous and squamous pathologies in a single lesion, clinically termed adenosquamous cell carcinoma. More important, these two different pathological components frequently share identical oncogenic mutations, indicative of a potential transition. Indeed, recent data have provided convincing evidence in supporting the ADC to SCC transdifferentiation in lungs. In the liver kinase B1 (official name STK11)–deficient mouse model, lung ADC can progressively transdifferentiate to SCC through pathologically mixed adenosquamous cell carcinoma as the intermediate status. Mechanistic studies further identify essential roles of extracellular matrix remodeling and metabolic reprogramming during this phenotypic transition. Small molecular compounds, including lysyl oxidase inhibitors and reactive oxygen species–inducing reagents such as phenformin, significantly accelerate the transition from lung ADC to SCC and thus confer lung tumors with drug resistance. Consistent with these findings, recent clinical studies have shown that epidermal growth factor receptor–mutant lung ADC can transdifferentiate to SCC in relapsed cancer patients. Together, these data support that this phenotypic transition from lung ADC to SCC might represent a novel mechanism for drug resistance. This review will summarize our current understanding of the transdifferentiation from lung ADC to SCC.

      PubDate: 2017-03-12T17:02:49Z
      DOI: 10.1016/j.ajpath.2017.01.009
  • Novel JAK3-Activating Mutations in Extranodal NK/T-cell Lymphoma, Nasal
    • Authors: Sung H. Sim; Soyeon Kim; Tae M. Kim; Yoon K. Jeon; Soo J. Nam; Yong-Oon Ahn; Bhumsuk Keam; Hyun H. Park; Dong-Wan Kim; Chul W. Kim; Dae S. Heo
      Abstract: Publication date: Available online 9 March 2017
      Source:The American Journal of Pathology
      Author(s): Sung H. Sim, Soyeon Kim, Tae M. Kim, Yoon K. Jeon, Soo J. Nam, Yong-Oon Ahn, Bhumsuk Keam, Hyun H. Park, Dong-Wan Kim, Chul W. Kim, Dae S. Heo
      Inhibition of the Janus kinase (JAK)–STAT pathway has been implicated as a treatment option for extranodal natural killer/T-cell lymphoma, nasal type (NTCL). However, JAK-STAT pathway alterations in NTCL are variable, and the efficacy of JAK-STAT pathway inhibition has been poorly evaluated. JAK3 mutation and STAT3 genetic alterations were investigated by direct sequencing and immunohistochemistry in 84 patients with newly diagnosed NTCL. Five of 71 patients with NTCL (7.0%) had JAK3 mutations in the pseudokinase domain: two JAK3 A573V, two JAK3 H583Y, and one JAK3 G589D mutation. Proliferation of Ba/F3 cells transduced with novel JAK3 mutations (JAK3 H583Y and JAK3 G589D) was independent of IL-3 and was inhibited by the JAK3 inhibitor tofacitinib (means ± SD drug concentration causing a 50% inhibition of the desired activity, 85 ± 10 nmol/L and 54 ± 9 nmol/L). Ribbon diagrams revealed that these JAK3 pseudokinase domain mutations were located at the pseudokinase-kinase domain interface. Although phosphorylated STAT3 was overexpressed in 35 of 68 patients with NTCL (51.4%), a STAT3 mutation (p.Tyr640Phe; STAT3 Y640F) at the SRC homology 2 domain was detected in 1 of the 63 patients (1.5%). A STAT3 inhibitor was active against STAT3-mutant SNK-6 and YT cells. Novel JAK3 mutations are oncogenic and druggable in NTCL. The JAK3 or STAT3 signal was altered in NTCL, and pathway inhibition might be a therapeutic option for patients with JAK3- or STAT3-mutant NTCL.

      PubDate: 2017-03-12T17:02:49Z
      DOI: 10.1016/j.ajpath.2017.01.004
  • Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization
           Controls Endochondral Ossification through Hyaluronan Metabolism
    • Authors: Masayuki Shimoda; Hiroyuki Yoshida; Sakiko Mizuno; Toru Hirozane; Keisuke Horiuchi; Yuta Yoshino; Hideaki Hara; Yae Kanai; Shintaro Inoue; Muneaki Ishijima; Yasunori Okada
      Abstract: Publication date: Available online 8 March 2017
      Source:The American Journal of Pathology
      Author(s): Masayuki Shimoda, Hiroyuki Yoshida, Sakiko Mizuno, Toru Hirozane, Keisuke Horiuchi, Yuta Yoshino, Hideaki Hara, Yae Kanai, Shintaro Inoue, Muneaki Ishijima, Yasunori Okada
      Hyaluronan (HA) plays an important role in the development and maintenance of tissues, and its degradation is implicated in many pathologic conditions. We recently reported that HA-binding protein involved in HA depolymerization (HYBID/KIAA1199; encoded by CEMIP) is a key molecule in HA depolymerization, but its developmental and pathologic functions remain elusive. We generated Hybid-deficient mice using the Cre/locus of crossover in P1 (loxP) system and analyzed their phenotypes. Hybid-deficient mice were viable and fertile, but their adult long bones were shorter than those of wild-type animals. Hybid-deficient mice showed lengthening of hypertrophic zone in the growth plate until 4 weeks after birth. There were fewer capillaries and osteoclasts at the chondroosseous junction in the Hybid-deficient mice compared with the wild-type mice. In situ hybridization demonstrated that Hybid was expressed by hypertrophic chondrocytes at the chondroosseous junction. Cultured primary chondrocytes expressed higher levels of Hybid than did osteoblasts or osteoclasts, and the Hybid expression in the chondrocytes was up-regulated after maturation to hypertrophic chondrocytes. High-molecular-weight HA was accumulated in the lengthened hypertrophic zone in Hybid-deficient mice. In addition, high-molecular-weight HA significantly reduced cell growth and tube formation in vascular endothelial growth factor–stimulated or –nonstimulated endothelial cells. HA metabolism by HYBID is involved in endochondral ossification during postnatal development by modulation of angiogenesis and osteoclast recruitment at the chondroosseous junction.

      PubDate: 2017-03-12T17:02:49Z
      DOI: 10.1016/j.ajpath.2017.01.005
  • Th17/IL-17 Cause Acceleration of Inflammation and Fat Loss by Inducing
           α2-Glycoprotein 1 (AZGP1) in Rheumatoid Arthritis with High-Fat Diet
    • Authors: Hyun Sik Na; Jeong-Eun Kwon; Seung Hoon Lee; JooYeon Jhun; Sung-Min Kim; Se-Young Kim; Eun-Kyung Kim; KyungAh Jung; Sung-Hwan Park; Mi-La Cho
      Abstract: Publication date: Available online 8 March 2017
      Source:The American Journal of Pathology
      Author(s): Hyun Sik Na, Jeong-Eun Kwon, Seung Hoon Lee, JooYeon Jhun, Sung-Min Kim, Se-Young Kim, Eun-Kyung Kim, KyungAh Jung, Sung-Hwan Park, Mi-La Cho
      Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects the joints. High-fat diet (HFD) is a risk factor for RA and is related to inflammation but responds minimally to medication. Given the association between HFD and inflammation, it is important to understand the function of inflammation-related T cells in RA with HFD. Collagen-induced arthritis (CIA), a model of RA, was induced in HFD mice by injection of collagen II, and metabolic markers and T cells were analyzed. The metabolic index and IgG assay results were higher in HFD-CIA mice than in nonfat diet–CIA mice. Numbers of inflammation-related T cells and macrophages, such as Th1 and Th17 cells and M1 macrophages, were higher in spleens of HFD-CIA mice. HFD-CIA mice had a high level of α2-glycoprotein 1 (Azgp1), a soluble protein that stimulates lipolysis. To examine the association between Azgp1 and Th17 cells, the reciprocal effects of Azgp1 and IL-17 on Th17 differentiation and lipid metabolism were measured. Interestingly, Azgp1 increased the Th17 population of splenocytes. Taken together, our data suggest that the acceleration of fat loss caused by Azgp1 in RA with metabolic syndrome is related to the increase of IL-17. Mice injected with the Azgp1-overexpression vector exhibited more severe CIA compared with the mock vector–injected mice.

      PubDate: 2017-03-12T17:02:49Z
      DOI: 10.1016/j.ajpath.2016.12.023
  • Activation of Constitutive Androstane Receptor Prevents Cholesterol
           Gallstone Formation
    • Authors: Shihai Cheng; Min Zou; Qinhui Liu; Jiangying Kuang; Jing Shen; Shiyun Pu; Lei Chen; Hong Li; Tong Wu; Rui Li; Yanping Li; Wei Jiang; Zhiyong Zhang; Jinhan He
      Abstract: Publication date: Available online 7 March 2017
      Source:The American Journal of Pathology
      Author(s): Shihai Cheng, Min Zou, Qinhui Liu, Jiangying Kuang, Jing Shen, Shiyun Pu, Lei Chen, Hong Li, Tong Wu, Rui Li, Yanping Li, Wei Jiang, Zhiyong Zhang, Jinhan He
      Cholesterol gallstone disease (CGD) is one of the most common gastrointestinal diseases. Lithogenic hepatic bile secretion precedes the formation of cholesterol gallstones. Constitutive androstane receptor (CAR), a member of nuclear family, plays an important role in cholesterol and bile acid metabolism. To examine whether activation of CAR can prevent cholesterol gallstone formation, we treated C57BL6/J mice maintained on a lithogenic diet with CAR agonist 1,4-bis-[2-(3, 5-dichlorpyridyloxy)] benzene and performed bile duct cannulation to study the dynamics of biliary lipids. We report that activation of CAR decreases the biliary cholesterol concentration and prevents CGD formation. The lower biliary cholesterol level was largely attributed to suppressed Abcg5 and Abcg8 expression in CAR-activated mice. CAR activation also promoted cholesterol conversion into bile acids by increasing the expression of Cyp7a1, a rate-limiting enzyme in bile acid biosynthesis. Activation of CAR enhanced bile acid re-absorption via increasing the expression of bile acid transporters Asbt and Ostβ in the ileum. The hepatic steatosis was also improved in the liver of CAR-activated mice. Furthermore, activation of CAR protected the mice against the liver X receptor α–sensitized CGD through suppressing the expression of Abcg5/8. Collectively, CAR plays an important role in maintaining the homeostasis of cholesterol, bile acids, and triglycerides levels, and it might be a promising therapeutic target for preventing or treating CGD.

      PubDate: 2017-03-07T16:42:54Z
      DOI: 10.1016/j.ajpath.2016.12.013
  • Nontypeable Haemophilus influenzae–Promoted Proliferation of
           KRas-Induced Early Adenomatous Lesions Is Completely Dependent on
           Toll-Like Receptor Signaling
    • Authors: Christopher Jungnickel; Philipp A. Schnabel; Rainer Bohle; Rainer Wiewrodt; Christian Herr; Robert Bals; Christoph Beisswenger
      Abstract: Publication date: Available online 6 March 2017
      Source:The American Journal of Pathology
      Author(s): Christopher Jungnickel, Philipp A. Schnabel, Rainer Bohle, Rainer Wiewrodt, Christian Herr, Robert Bals, Christoph Beisswenger
      Chronic obstructive pulmonary disease is a risk factor for lung cancer. COPD is characterized by chronic airway inflammation and lung infections. The airways of patients with COPD are frequently colonized with bacteria [eg, nontypeable Haemophilus influenzae (NTHi)] that cause pulmonary inflammation and exacerbations. Pulmonary adenocarcinomas are frequently associated with an activating mutation in the KRAS gene. We determined the function of Toll-like receptor (TLR) signaling on the progression of KRas-induced early adenomatous lesions in the lung. Wild-type (WT) mice and mice doubly deficient in Tlr-2 and -4 (Tlr2/4 −/− ), both with an oncogenic Kras allele in lung epithelium, were exposed to NTHi for 4 weeks. Exposure to NTHi resulted in increased tumor proliferation and growth in WT mice, but not in Tlr2/4 −/− mice. Alveolar adenomatous hyperplasia and adenocarcinoma were significantly increased in WT mice compared with Tlr2/4 −/− mice. The mean size of tumors was significantly larger in WT mice, whereas there was no difference in the number of alveolar lesions between WT and Tlr2/4 −/− mice. NTHi-induced pulmonary neutrophilic inflammation and tumor-associated neutrophils were reduced in Tlr2/4 −/− mice. Thus, subsequent to a driver mutation, NTHi-induced inflammation promotes proliferation of early adenomatous lesions in a TLR-dependent manner.

      PubDate: 2017-03-07T16:42:54Z
      DOI: 10.1016/j.ajpath.2017.01.003
  • Hepatic Induction of Fatty Acid Binding Protein 4 Plays a Pathogenic Role
           in Sepsis in Mice
    • Authors: Bingfang Hu; Yujin Li; Li Gao; Yan Guo; Yiwen Zhang; Xiaojuan Chai; Meishu Xu; Jiong Yan; Peipei Lu; Songrong Ren; Su Zeng; Yulan Liu; Wen Xie; Min Huang
      Abstract: Publication date: Available online 6 March 2017
      Source:The American Journal of Pathology
      Author(s): Bingfang Hu, Yujin Li, Li Gao, Yan Guo, Yiwen Zhang, Xiaojuan Chai, Meishu Xu, Jiong Yan, Peipei Lu, Songrong Ren, Su Zeng, Yulan Liu, Wen Xie, Min Huang
      Sepsis is defined as the host's deleterious systemic inflammatory response to microbial infections. Herein, we report an essential role of the fatty acid binding protein 4 (FABP4; alias adipocyte protein 2 or aP2), a lipid-binding chaperone, in sepsis response. Bioinformatic analysis of the Gene Expression Omnibus data sets showed the level of FABP4 was higher in the nonsurvival sepsis patients' whole blood compared to the survival cohorts. The expression of Fabp4 was induced in a liver-specific manner in cecal ligation and puncture (CLP) and lipopolysaccharide treatment models of sepsis. The induction of Fabp4 may have played a pathogenic role, because ectopic expression of Fabp4 in the liver sensitized mice to CLP-induced inflammatory response and worsened the animal's survival. In contrast, pharmacological inhibition of Fabp4 markedly alleviated the CLP responsive inflammation and tissue damage and improved survival. We conclude that FABP4 is an important mediator of the sepsis response. Early intervention by pharmacological inhibition of FABP4 may help to manage sepsis in the clinic.

      PubDate: 2017-03-07T16:42:54Z
      DOI: 10.1016/j.ajpath.2017.01.002
  • p53 and miR-34a Feedback Promotes Lung Epithelial Injury and Pulmonary
    • Authors: Shwetha K. Shetty; Nivedita Tiwari; Amarnath S. Marudamuthu; Bijesh Puthusseri; Yashodhar P. Bhandary; Jian Fu; Jeffrey Levin; Steven Idell; Sreerama Shetty
      Abstract: Publication date: Available online 6 March 2017
      Source:The American Journal of Pathology
      Author(s): Shwetha K. Shetty, Nivedita Tiwari, Amarnath S. Marudamuthu, Bijesh Puthusseri, Yashodhar P. Bhandary, Jian Fu, Jeffrey Levin, Steven Idell, Sreerama Shetty
      Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. The pathogenesis of interstitial lung diseases, including its most common form, IPF, remains poorly understood. Alveolar epithelial cell (AEC) apoptosis, proliferation, and accumulation of myofibroblasts and extracellular matrix deposition results in progressive loss of lung function in IPF. We found induction of tumor suppressor protein, p53, and apoptosis with suppression of urokinase-type plasminogen activator (uPA) and the uPA receptor in AECs from the lungs of IPF patients, and in mice with bleomycin, cigarette smoke, silica, or sepsis-induced lung injury. Treatment with the caveolin-1 scaffolding domain peptide (CSP) reversed these effects. Consistent with induction of p53, AECs from IPF lungs or mice with diverse types of lung injuries showed increased p53 acetylation and miR-34a expression with reduction in Sirt1. This was significantly reduced after treatment of wild-type mice with CSP, and uPA-deficient mice were unresponsive. Bleomycin failed to induce miR-34a in p53- or plasminogen activator inhibitor-1 (PAI-1)-deficient mice. CSP-mediated inhibition of miR-34a restored Sirt1, suppressed p53 acetylation and apoptosis in injured AECs, and prevented pulmonary fibrosis (PF). AEC-specific suppression of miR-34a inhibited bleomycin-induced p53, PAI-1, and apoptosis and prevented PF, whereas overexpression of precursor-miR-34a increased p53, PAI-1, and apoptosis in AECs of mice unexposed to bleomycin. Our study validates p53–miR-34a feedback as a potential therapeutic target in PF.

      PubDate: 2017-03-07T16:42:54Z
      DOI: 10.1016/j.ajpath.2016.12.020
  • Influenza Casts a Lung Shadow
    • Authors: Xavier De Luna; Kevan L. Hartshorn
      Abstract: Publication date: Available online 21 February 2017
      Source:The American Journal of Pathology
      Author(s): Xavier De Luna, Kevan L. Hartshorn
      Teaser This commentary highlights the article by Pociask et al that provides new insights into the lingering effects of influenza infection.

      PubDate: 2017-03-07T16:42:54Z
      DOI: 10.1016/j.ajpath.2017.01.007
  • This Month in AJP
    • Abstract: Publication date: Available online 20 February 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: 2017-03-07T16:42:54Z
  • Human Striatal Dopaminergic and Regional Serotonergic Synaptic
           Degeneration with Lewy Body Disease and Inheritance of APOE ε4
    • Authors: Nadia Postupna; Caitlin S. Latimer; Eric B. Larson; Emily Sherfield; Julie Paladin; Carol A. Shively; Matthew J. Jorgensen; Rachel N. Andrews; Jay R. Kaplan; Paul K. Crane; Kathleen S. Montine; Suzanne Craft; C. Dirk Keene; Thomas J. Montine
      Abstract: Publication date: Available online 16 February 2017
      Source:The American Journal of Pathology
      Author(s): Nadia Postupna, Caitlin S. Latimer, Eric B. Larson, Emily Sherfield, Julie Paladin, Carol A. Shively, Matthew J. Jorgensen, Rachel N. Andrews, Jay R. Kaplan, Paul K. Crane, Kathleen S. Montine, Suzanne Craft, C. Dirk Keene, Thomas J. Montine
      Cognitive impairment in older individuals is a complex trait that in population-based studies most commonly derives from an individually varying mixture of Alzheimer disease, Lewy body disease, and vascular brain injury. We investigated the molecular composition of synaptic particles from three sources: consecutive rapid autopsy brains from the adult changes in thought study, a population-based cohort; four aged nonhuman primate brains optimally processed for molecular investigation; and targeted replacement transgenic mice homozygous for APOE ε4. Our major goal was to characterize the molecular composition of human synaptic particles in regions of striatum and prefrontal cortex. We performed flow cytometry to measure six markers of synaptic subtypes, as well as amyloid β 42 and paired helical filament tau. Our results showed selective degeneration of dopaminergic terminals throughout the striatum in individuals with Lewy body disease, and serotonergic degeneration in human ventromedial caudate nucleus from individuals with an APOE ε4 allele. Similar results were seen in mouse caudate nucleus homozygous for APOE ε4 via targeted replacement. Together, extension of these clinical, pathologic, and genetic associations from tissue to the synaptic compartment of cerebral cortex and striatum strongly support our approach for accurately observing the molecular composition of human synapses by flow cytometry.

      PubDate: 2017-03-07T16:42:54Z
      DOI: 10.1016/j.ajpath.2016.12.010
  • High Glucose–Induced Hypomethylation Promotes Binding of Sp-1 to
           Myo-Inositol Oxygenase
    • Authors: Isha Sharma; Rajesh K. Dutta; Neel K. Singh; Yashpal S. Kanwar
      Abstract: Publication date: Available online 14 February 2017
      Source:The American Journal of Pathology
      Author(s): Isha Sharma, Rajesh K. Dutta, Neel K. Singh, Yashpal S. Kanwar
      The catabolic enzyme myo-inositol oxygenase (MIOX) is expressed in proximal tubules and up-regulated in the diabetic state. Previously, we reported its transcriptional and translation regulation by high glucose (HG), osmolytes, and fatty acids. However, its epigenetic regulation is unknown. Bisulfite sequencing revealed that both human and mouse MIOX promoters, enriched with CpG sites, are hypomethylated and unmethylated under HG ambience and hyperglycemic states associated with increased MIOX expression. Eletrophoretic mobility shift assays revealed increased binding of unmethylated oligos with nucleoproteins of cells maintained under HG. In addition, a strong binding of specificity protein (Sp)-1 transcription factor with MIOX promoter was observed under HG, especially with unmethylated Sp-1 oligo. Specificity of binding was established by supershift assays and treatment with the Sp-1 inhibitor mithramycin. Promoter analysis revealed an increase in luciferase activity under HG, which was reduced after mutation of the Sp-1–binding site. Sp1 siRNA treatment reduced mRNA and protein expression of Sp-1 and MIOX and generation of reactive oxygen species derived from NADPH oxidase (NOX)-4 and mitochondrial sources. In addition, there was reduced expression of hypoxia-inducible factor-1α relevant in the pathogenesis of diabetic nephropathy. Sp1 siRNA treatment reduced fibronectin expression, an extracellular matrix protein that is increased in diabetic nephropathy and tubulopathy. HG-induced MIOX expression was also reduced with the treatment of apelin-13, which deacetylates histones. Overall, these findings highlight the epigenetic regulation of MIOX in the pathogenesis of diabetic tubulopathy.

      PubDate: 2017-03-07T16:42:54Z
      DOI: 10.1016/j.ajpath.2016.12.011
  • The Neuropeptide Galanin Is Up-Regulated during Cholestasis and
           Contributes to Cholangiocyte Proliferation
    • Authors: Matthew McMillin; Gabriel Frampton; Stephanie Grant; Sharon DeMorrow
      Abstract: Publication date: Available online 11 February 2017
      Source:The American Journal of Pathology
      Author(s): Matthew McMillin, Gabriel Frampton, Stephanie Grant, Sharon DeMorrow
      During the course of cholestatic liver diseases, mitotically dormant cholangiocytes proliferate and subsequently acquire a neuroendocrine phenotype. Galanin is a neuroendocrine factor responsible for regulation of physiological responses, such as feeding behavior and mood, and has been implicated in the development of fatty liver disease, although its role in biliary hyperplasia is unknown. Biliary hyperplasia was induced in rats via bile duct ligation (BDL) surgery, and galanin was increased in serum and liver homogenates from BDL rats. Treatment of sham and BDL rats with recombinant galanin increased cholangiocyte proliferation and intrahepatic biliary mass, liver damage, and inflammation, whereas blocking galanin expression with specific vivo-morpholino sequences inhibited hyperplastic cholangiocyte proliferation, liver damage, inflammation, and subsequent fibrosis. The proliferative effects of galanin were via activation of galanin receptor 1 expressed specifically on cholangiocytes and were associated with an activation of extracellular signal–regulated kinase 1/2, and ribosomal S6 kinase 1 signal transduction pathways and subsequent increase in cAMP responsive element binding protein DNA-binding activity and induction of Yes-associated protein expression. Strategies to inhibit extracellular signal–regulated kinase 1/2, ribosomal S6 kinase 1, or cAMP responsive element binding protein DNA-binding activity prevented the proliferative effects of galanin. Taken together, these data suggest that targeting galanin signaling may be effective for the maintenance of biliary mass during cholestatic liver diseases.

      PubDate: 2017-03-07T16:42:54Z
      DOI: 10.1016/j.ajpath.2016.12.015
  • Epigenetic and Transcriptomic Regulation of Lung Repair during Recovery
           from Influenza Infection
    • Authors: Derek A. Pociask; Keven M. Robinson; Kong Chen; Kevin J. McHugh; Michelle E. Clay; Grace T. Huang; Panayiotis V. Benos; Yvonne M.W. Janssen-Heininger; Jay K. Kolls; Vikas Anathy; John F. Alcorn
      Abstract: Publication date: Available online 10 February 2017
      Source:The American Journal of Pathology
      Author(s): Derek A. Pociask, Keven M. Robinson, Kong Chen, Kevin J. McHugh, Michelle E. Clay, Grace T. Huang, Panayiotis V. Benos, Yvonne M.W. Janssen-Heininger, Jay K. Kolls, Vikas Anathy, John F. Alcorn
      Seasonal and pandemic influenza is a cause of morbidity and mortality worldwide. Most people infected with influenza virus display mild-to-moderate disease phenotypes and recover within a few weeks. Influenza is known to cause persistent alveolitis in animal models; however, little is known about the molecular pathways involved in this phenotype. We challenged C57BL/6 mice with influenza A/PR/8/34 and examined lung pathologic processes and inflammation, as well as transcriptomic and epigenetic changes at 21 to 60 days after infection. Influenza induced persistent parenchymal lung inflammation, alveolar epithelial metaplasia, and epithelial endoplasmic reticulum stress that were evident after the clearance of virus and resolution of morbidity. Influenza infection induced robust changes in the lung transcriptome, including a significant impact on inflammatory and extracellular matrix protein expression. Despite the robust changes in lung gene expression, preceding influenza (21 days) did not exacerbate secondary Staphylococcus aureus infection. Finally, we examined the impact of influenza on miRNA expression in the lung and found an increase in miR-155. miR-155 knockout mice recovered from influenza infection faster than controls and had decreased lung inflammation and endoplasmic reticulum stress. These data illuminate the dynamic molecular changes in the lung in the weeks after influenza infection and characterize the repair process, identifying a novel role for miR-155.

      PubDate: 2017-03-07T16:42:54Z
      DOI: 10.1016/j.ajpath.2016.12.012
  • H7N9 Influenza A Virus Exhibits Importin-α7–Mediated Replication in the
           Mammalian Respiratory Tract
    • Authors: Stephanie Bertram; Swantje Thiele; Carola Dreier; Patricia Resa-Infante; Annette Preuß; Debby van Riel; Chris K.P. Mok; Folker Schwalm; Joseph S.M. Peiris; Hans-Dieter Klenk; Gülsah Gabriel
      Abstract: Publication date: Available online 9 February 2017
      Source:The American Journal of Pathology
      Author(s): Stephanie Bertram, Swantje Thiele, Carola Dreier, Patricia Resa-Infante, Annette Preuß, Debby van Riel, Chris K.P. Mok, Folker Schwalm, Joseph S.M. Peiris, Hans-Dieter Klenk, Gülsah Gabriel
      The acute respiratory distress syndrome (ARDS) is the leading cause of death in influenza A virus (IAV)–infected patients. Hereby, the cellular importin-α7 gene plays a major role. It promotes viral replication in the lung, thereby increasing the risk for the development of pneumonia complicated by ARDS. Herein, we analyzed whether the recently emerged H7N9 avian IAV has already adapted to human importin-α7 use, which is associated with high-level virus replication in the mammalian lung. Using a cell-based viral polymerase activity assay, we could detect a decreased H7N9 IAV polymerase activity when importin-α7 was silenced by siRNA. Moreover, virus replication was diminished in the murine cells lacking the importin-α7 gene. Consistently, importin-α7 knockout mice presented reduced pulmonary virus titers and lung lesions as well as enhanced survival rates compared to wild-type mice. In summary, our results show that H7N9 IAV have acquired distinct features of adaptation to human host factors that enable enhanced virulence in mammals. In particular, adaptation to human importin-α7 mediates elevated virus replication in the mammalian lung, which might have contributed to ARDS observed in H7N9-infected patients.

      PubDate: 2017-02-09T14:14:35Z
      DOI: 10.1016/j.ajpath.2016.12.017
  • Blockade of p38 Mitogen-Activated Protein Kinase Inhibits Murine
           Sclerodermatous Chronic Graft-versus-Host Disease
    • Authors: Takashi Matsushita; Mutsumi Date; Miyu Kano; Kie Mizumaki; Momoko Tennichi; Tadahiro Kobayashi; Yasuhito Hamaguchi; Minoru Hasegawa; Manabu Fujimoto; Kazuhiko Takehara
      Abstract: Publication date: Available online 9 February 2017
      Source:The American Journal of Pathology
      Author(s): Takashi Matsushita, Mutsumi Date, Miyu Kano, Kie Mizumaki, Momoko Tennichi, Tadahiro Kobayashi, Yasuhito Hamaguchi, Minoru Hasegawa, Manabu Fujimoto, Kazuhiko Takehara
      Bone marrow transplantation (BMT) of B10.D2 mice into sublethally irradiated BALB/c mice across minor histocompatibility loci is a well-established animal model for human sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) and systemic sclerosis (SSc). The p38 mitogen-activated protein kinase (MAPK) pathway is a key regulator of inflammation and cytokine production. Furthermore, the activation of p38 MAPK plays an important role in collagen production in SSc. We investigated the effects of p38 MAPK inhibitor, VX-702, on Scl-cGVHD mice. VX-702 was orally administered to Scl-cGVHD mice from day 7 to 35 after BMT. We compared skin fibrosis of Scl-cGVHD mice between the VX-702–treated group and control group. Allogeneic BMT increased the phosphorylation of p38 MAPK in the skin. The administration of VX-702 attenuated the skin fibrosis of Scl-cGVHD compared to the control mice. Immunohistochemical staining showed that VX-702 suppressed the infiltration of CD4+ T cells, CD8+ T cells, and CD11b+ cells into the dermis of Scl-cGVHD mice compared to the control mice. VX-702 attenuated the mRNA expression of extracellular matrix and fibrogenic cytokines, such as IL-6 and IL-13, in the skin of Scl-cGVHD mice. In addition, VX-702 directly inhibited collagen production from fibroblasts in vitro. VX-702 was shown to be a promising candidate for use in treating patients with Scl-cGVHD and SSc.

      PubDate: 2017-02-09T14:14:35Z
      DOI: 10.1016/j.ajpath.2016.12.016
  • Thrombin Induces Inositol Trisphosphate–Mediated Spatially Extensive
           Responses in Lung Microvessels
    • Authors: Rachel Escue; Kathirvel Kandasamy; Kaushik Parthasarathi
      Abstract: Publication date: Available online 8 February 2017
      Source:The American Journal of Pathology
      Author(s): Rachel Escue, Kathirvel Kandasamy, Kaushik Parthasarathi
      Activation of plasma membrane receptors initiates compartmentalized second messenger signaling. Whether this compartmentalization facilitates the preferential intercellular diffusion of specific second messengers is unclear. Toward this, the receptor-mediated agonist, thrombin, was instilled into microvessels in a restricted region of isolated blood-perfused mouse lungs. Subsequently, the thrombin-induced increase in endothelial F-actin was determined using confocal fluorescence microscopy. Increased F-actin was evident in microvessels directly treated with thrombin and in those located in adjoining thrombin-free regions. This increase was abrogated by inhibiting inositol trisphosphate–mediated calcium release with Xestospongin C (XeC). XeC also inhibited the thrombin-induced increase in the amplitude of endothelial cytosolic Ca2+ oscillations. Instillation of thrombin and XeC into adjacent restricted regions increased F-actin in microvessels in the thrombin-treated and adjacent regions but not in those in the XeC-treated region. Thus, inositol trisphosphate, and not calcium, diffused interendothelially to the spatially remote thrombin-free microvessels. Thus, activation of plasma membrane receptors increased the ambit of inflammatory responses via a second messenger different from that used by stimuli that induce cell-wide increases in second messengers. Thrombin however failed to induce the spatially extensive response in microvessels of mice lacking endothelial connexin43, suggesting a role for connexin43 gap junctions. Compartmental second messenger signaling and interendothelial communication define the specific second messenger involved in exacerbating proinflammatory responses to receptor-mediated agonists.

      PubDate: 2017-02-09T14:14:35Z
      DOI: 10.1016/j.ajpath.2016.12.014
  • Growth Factor Midkine Promotes Nuclear Factor of Activated T
           Cells–Regulated T-Cell–Activation and Th1 Cell Differentiation in
           Lupus Nephritis
    • Authors: Tomohiro Masuda; Kayaho Maeda; Waichi Sato; Tomoki Kosugi; Yuka Sato; Hiroshi Kojima; Noritoshi Kato; Takuji Ishimoto; Naotake Tsuboi; Kenji Uchimura; Yukio Yuzawa; Shoichi Maruyama; Kenji Kadomatsu
      Abstract: Publication date: Available online 7 February 2017
      Source:The American Journal of Pathology
      Author(s): Tomohiro Masuda, Kayaho Maeda, Waichi Sato, Tomoki Kosugi, Yuka Sato, Hiroshi Kojima, Noritoshi Kato, Takuji Ishimoto, Naotake Tsuboi, Kenji Uchimura, Yukio Yuzawa, Shoichi Maruyama, Kenji Kadomatsu
      Activated T cells play crucial roles in the pathogenesis of autoimmune diseases, including lupus nephritis (LN). The activation of calcineurin/nuclear factor of activated T cells (NFAT) and STAT4 signaling is essential for T cells to perform various effector functions. Here, we identified the growth factor midkine (MK; gene name, Mdk) as a novel regulator in the pathogenesis of 2,6,10,14-tetramethylpentadecane-induced LN via activation of NFAT and IL-12/STAT4 signaling. Wild-type (Mdk +/+) mice showed more severe glomerular injury than MK-deficient (Mdk −/−) mice, as demonstrated by mesangial hypercellularity and matrix expansion, and glomerular capillary loops with immune-complex deposition. Compared with Mdk −/− mice, the frequency of splenic CD69+ T cells and T helper (Th) 1 cells, but not of regulatory T cells, was augmented in Mdk +/+ mice in proportion to LN disease activity, and was accompanied by skewed cytokine production. MK expression was also enhanced in activated CD4+ T cells in vivo and in vitro. MK induced activated CD4+ T cells expressing CD69 through nuclear activation of NFAT transcription and selectively increased in vitro differentiation of naive CD4+ T cells into Th1 cells by promoting IL-12/STAT4 signaling. These results suggest that MK serves an indispensable role in the NFAT-regulated activation of CD4+ T cells and Th1 cell differentiation, eventually leading to the exacerbation of LN.

      PubDate: 2017-02-09T14:14:35Z
      DOI: 10.1016/j.ajpath.2016.12.006
  • Cardiomyocyte Hypertrophy in Arrhythmogenic Cardiomyopathy
    • Authors: Mustafa Gerçek; Muhammed Gerçek; Sebastian Kant; Sakine Simsekyilmaz; Astrid Kassner; Hendrik Milting; Elisa A. Liehn; Rudolf E. Leube; Claudia A. Krusche
      Abstract: Publication date: Available online 7 February 2017
      Source:The American Journal of Pathology
      Author(s): Mustafa Gerçek, Muhammed Gerçek, Sebastian Kant, Sakine Simsekyilmaz, Astrid Kassner, Hendrik Milting, Elisa A. Liehn, Rudolf E. Leube, Claudia A. Krusche
      Arrhythmogenic cardiomyopathy (AC) is a hereditary disease leading to sudden cardiac death or heart failure. AC pathology is characterized by cardiomyocyte loss and replacement fibrosis. Our goal was to determine whether cardiomyocytes respond to AC progression by pathological hypertrophy. To this end, we examined tissue samples from AC patients with end-stage heart failure and tissue samples that were collected at different disease stages from desmoglein 2-mutant mice, a well characterized AC model. We find that cardiomyocyte diameters are significantly increased in right ventricles of AC patients. Increased mRNA expression of the cardiac stress marker natriuretic peptide B is also observed in the right ventricle of AC patients. Elevated myosin heavy chain 7 mRNA expression is detected in left ventricles. In desmoglein 2-mutant mice, cardiomyocyte diameters are normal during the concealed disease phase but increase significantly after acute disease onset on cardiomyocyte death and fibrotic myocardial remodeling. Hypertrophy progresses further during the chronic disease stage. In parallel, mRNA expression of myosin heavy chain 7 and natriuretic peptide B is up-regulated in both ventricles with right ventricular preference. Calcineurin/Nfat signaling, which is linked to pathological hypertrophy, is observed during AC progression, as evidenced by Nfatc2 and Nfatc3 mRNA in cardiomyocytes and increased mRNA of the Nfat target regulator of calcineurin 1. Taken together, we demonstrate that pathological hypertrophy occurs in AC and is secondary to cardiomyocyte loss and cardiac remodeling.

      PubDate: 2017-02-09T14:14:35Z
      DOI: 10.1016/j.ajpath.2016.12.018
  • Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and
           Vascular Endothelial Growth Factor Inhibition
    • Authors: Evandro M. Neto-Neves; Mary Beth Brown; Maria V. Zaretskaia; Samin Rezania; Adam G. Goodwill; Brian P. McCarthy; Scott A. Persohn; Paul R. Territo; Jeffrey A. Kline
      Abstract: Publication date: Available online 7 February 2017
      Source:The American Journal of Pathology
      Author(s): Evandro M. Neto-Neves, Mary Beth Brown, Maria V. Zaretskaia, Samin Rezania, Adam G. Goodwill, Brian P. McCarthy, Scott A. Persohn, Paul R. Territo, Jeffrey A. Kline
      Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo. More important, PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. Moreover, at 3 and 6 weeks, PE + SU rats showed a 40% and 32% decrement in peak rate of oxygen consumption during aerobic exercise, respectively. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor–dependent vascular remodeling. This model may enable experiments that reveal a better pathophysiological understanding of how PE transitions to CTEPH in humans and provide an animal model to test new treatments.

      PubDate: 2017-02-09T14:14:35Z
      DOI: 10.1016/j.ajpath.2016.12.004
  • TNFΔARE Mice Display Abnormal Lymphatics and Develop Tertiary
           Lymphoid Organs in the Mesentery
    • Authors: Sonia Rehal; Pierre-Yves von der Weid
      Abstract: Publication date: Available online 6 February 2017
      Source:The American Journal of Pathology
      Author(s): Sonia Rehal, Pierre-Yves von der Weid
      Chronic inflammatory diseases are associated with a persistent and enhanced response to environmental antigens. As an adaptive response to this exaggerated immune state, affected tissue typically develops tertiary lymphoid organs. Studies of Crohn disease (CD), a chronic inflammatory disease of the intestinal tract, report tertiary lymphoid organs present within the mucosal wall, along with other lymphatic diseases, such as lymphangiogenesis and obstructed lymphatic vessels. These observations suggest that downstream mesenteric lymphatic vessels and lymph drainage into mesenteric lymph nodes may be compromised. However, information is lacking on the morphologic features and functional status of mesenteric lymphatics in CD. Using confocal imaging, PCR, flow cytometry, and functional strategies, we addressed these questions in the established TNFΔARE mouse model of CD and found that this mouse model had many lymphatic abnormalities reminiscent of human CD. These abnormalities include intestinal lymphangiectasia, mesenteric lymph node lymphadenopathy, and lymphangiogenesis in both the mesentery and mucosa. Critically, TNFΔARE mice also present mesenteric tertiary lymphoid organs and have altered lymphatic transport of dendritic cells to mesenteric lymph nodes, two features likely to actively modulate immunity. Our findings provide key insights into lymphatic remodeling in the TNFΔARE mouse model. They shed light on the involvement of these lymphatic changes in immune dysfunctions observed in CD and suggest the lymphatic system as new target for therapeutic options.

      PubDate: 2017-02-09T14:14:35Z
      DOI: 10.1016/j.ajpath.2016.12.007
  • Dexamethasone-Induced Ocular Hypertension in Mice
    • Authors: Gaurang Patel; Tien Phan Prabhavathi Maddineni Ramesh Kasetti Cameron Millar
      Abstract: Publication date: Available online 4 February 2017
      Source:The American Journal of Pathology
      Author(s): Gaurang C. Patel, Tien N. Phan, Prabhavathi Maddineni, Ramesh B. Kasetti, J. Cameron Millar, Abbot F. Clark, Gulab S. Zode
      Glucocorticoid (GC)-induced ocular hypertension (OHT) is a serious adverse effect of prolonged GC therapy that can lead to iatrogenic glaucoma and permanent vision loss. An appropriate mouse model can help us understand precise molecular mechanisms and etiology of GC-induced OHT. We therefore developed a novel, simple, and reproducible mouse model of GC-induced OHT. GC-induced myocilin expression in the trabecular meshwork (TM) has been suggested to play an important role in GC-induced OHT. We further determined whether myocilin contributes to GC-OHT. C57BL/6J mice received weekly periocular conjunctival fornix injections of a dexamethasone-21-acetate (DEX-Ac) formulation. Intraocular pressure (IOP) elevation was relatively rapid and significant, and correlated with reduced conventional outflow facility. Nighttime IOPs were higher in ocular hypertensive eyes compared to daytime IOPs. DEX-Ac treatment led to increased expression of fibronectin, collagen I, and α-smooth muscle actin in the TM in mouse eyes. No changes in body weight indicated no systemic toxicity associated with DEX-Ac treatment. Wild-type mice showed increased myocilin expression in the TM on DEX-Ac treatment. Both wild-type and Myoc−/− mice had equivalent and significantly elevated IOP with DEX-Ac treatment every week. In conclusion, our mouse model mimics many aspects of GC-induced OHT in humans, and we further demonstrate that myocilin does not play a major role in DEX-induced OHT in mice.

      PubDate: 2017-02-04T09:31:17Z
  • Hypoxia Directs Human Extravillous Trophoblast Differentiation in a
           Hypoxia-Inducible Factor–Dependent Manner
    • Authors: Anna Wakeland; Francesca Soncin Matteo Moretto-Zita Ching-Wen Chang Mariko Horii
      Abstract: Publication date: Available online 4 February 2017
      Source:The American Journal of Pathology
      Author(s): Anna K. Wakeland, Francesca Soncin, Matteo Moretto-Zita, Ching-Wen Chang, Mariko Horii, Don Pizzo, Katharine K. Nelson, Louise C. Laurent, Mana M. Parast
      Villous cytotrophoblasts are epithelial stem cells of the early human placenta, able to differentiate either into syncytiotrophoblasts in floating chorionic villi or extravillous trophoblasts (EVTs) at the anchoring villi. The signaling pathways regulating differentiation into these two lineages are incompletely understood. The bulk of placental growth and development in the first trimester occurs under low oxygen tension. One major mechanism by which oxygen regulates cellular function is through the hypoxia-inducible factor (HIF), a transcription factor complex stabilized under low oxygen tension to mediate cellular responses, including cell fate decisions. HIF is known to play a role in trophoblast differentiation in rodents; however, its role in human trophoblast differentiation is poorly understood. Using RNA profiling of sorted populations of primary first-trimester trophoblasts, we evaluated the first stage of EVT differentiation, the transition from epidermal growth factor receptor+ villous cytotrophoblasts into human leukocyte antigen-G+ proximal column EVT (pcEVT) and identified hypoxia as a major pcEVT-associated pathway. Using primary cytotrophoblasts, we determined that culture in low oxygen directs differentiation preferentially toward human leukocyte antigen-G+ pcEVT, and that an intact HIF complex is required for this process. Finally, using global RNA profiling, we identified integrin-linked kinase and associated cytoskeletal remodeling and adhesion to be among HIF-dependent pcEVT-associated signaling pathways. Taken together, we propose that oxygen regulates EVT differentiation through HIF-dependent modulation of various cell adhesion and morphology-related pathways.

      PubDate: 2017-02-04T09:31:17Z
  • This Month in AJP
    • Abstract: Publication date: Available online 17 January 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: 2017-02-04T09:31:17Z
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